CRA Exam Questions, Terms, & ICH GCP Guidelines


1.Accessible populationgeographically and temporally defined subset of the target population that is available for the study.2.Accuracythe accuracy of a variable is the degree to which it actually represents what it is intended to represent. This has important influence on the validity of the study.3.Accuratefree of systematic error4.Advantages of multiple unrelated hypothesesincreases the efficiency of the study, making it possible to answer more questions with a single research effort and to discover more of the true associations that exist in the population.5.Alphathe probability of committing a type I error (level of statistical significance).6.Alternative hypothesisthe proposition that there is an association.7.Background/significancesets the proposed study in context and gives its rationale (What is known about the topic at hand? Why is the research question important? What kind of answers will the study provide?)8.Bench-to-bedsidea thorough understanding of the underlying basic science.9.Betathe probability of making a type II error. 1-Beta=power10.Bonferronitype of approach to multiple hypothesis testing is usually too stringent.11.Case-control designinvestigator compares a group of people who have a disease or condition with another group who do not.12.Chi-squared testcan be used to compare the proportion of subjects in each of two groups who have a dichotomous outcome.13.Clinical trialestablish the effects of an intervention.14.Clustered samplessubjects are sampled by groups.15.Cluster samplerandom sample of natural groupings of individuals in the population (useful when population is widely diverse).

16.Cohort studiesamong observational studies in which observations are made in a group of subjects that is followed over time.17.Complex hypothesiscontains more than one predictor or outcome variable.18.Confidence intervalsa range of values about the sample mean or proportion. A confidence interval is a measure of the precision of a sample estimate. An interval with a greater confidence level is wider, and therefore more likely to include the true population value, than an interval with a lower confidence level.19.Consecutive sampleconsecutively selecting every accessible person who meets the entry criteria. Especially desirable when it amounts to taking the entire accessible population over a long enough period to include seasonal variations or other temporal changes that are important to the research question.20.Construct validityrefers to how well a measurement conforms to theoretical constructs.21.Content validityexamines how well the assessment represents all aspects of the phenomena under study.22.Continuous variableswhen the variable of interest is continuous, a confidence interval around the mean of that variable is often reported. To estimate the sample size for that confidence level (1) estimate the standard deviation (2) specify the desired precision of the CI (3) select the confidence level for the interval.23.Continuous variablesquantified on an infinite scale. The number of possible values of body weight, for example, is limited only by the sensitivity of the machine that is used to measure it.24.Convenience samplethe study sample is often made up of people who meet the entry criteria and are easily accessible to the investigator.25.Correlation coefficient(r) is not used frequently in sample size calculations, it can be useful when the predictor and outcome variables are both continuous. The correlation coefficient is a measure of the strength of the linear association between the two variables, it varies between -1 and +1. Negative variables indicate that as one variable increases, the other decreases. The closer the absolute value of r is to 1, the stronger the association; the closer to 0, the weaker the association.

26.Cox proportional hazards analysiscan adjust both for confounders and for differences in length of follow-up.27.Creativitymajor role in the process of conceiving research questions, imagining new methods to address old questions and having fun with ideas.28.Criterion-relateddegree to which a new measurement correlates with well-accepted existing measures.29.Cross-sectional studiesobservations are made on a single occasion.30.Descriptiveexplore the lay of the land - i.e. describing distribution of diseases and health-related characteristics in the population.31.DesignObservational study- passive role in observing the events taking place in the study subjects. Clinical trial- apply an intervention and examine its effects on these events.32.Dichotomizeanother strategy when there is insufficient information. When the mean and the standard deviation of a continuous or categorical variable are in doubt. Categories can be lumped into two groups, and continuous variables can be split at their mean or median. The chi-squared test can be used to make a reasonable estimate of sample size.33.Dichotomouscategorical variables with two possible values.34.Dichotomous variablesresults can be expressed as a confidence interval around the estimated proportion of subjects with one of the values. This includes studies of the sensitivity or specificity of a diagnostic test, which appear at first glance to be continuous variables but are actually dichotomous—proportions expressed as percentages. To estimate the sample size (1) estimate expected proportion with the variable of interest in the population (2) specify the desired precision of the CI (3) select the confidence level for the interval.35.Discretea scale whose units are limited to integers.36.Effect sizecan often be estimated from previous studies in the literature and consultation with experts.

37.Estimate sample size with insufficient information(1) extensive search for previous and related findings on the topic and similar research questions (2) small pilot study or obtaining a data set for secondary analysis to obtain the missing ingredients before embarking on the main study (3) recognize that for continuous variables that have a roughly bell-shaped distribution the standard deviation can be estimated as ¼ of the difference b/w the high and low ends of the range of values that occur commonly, ignoring extreme values.38.Ethicalif the study poses unacceptable physical risks or invasion of privacy, the investigator must seek other ways to answer the question.39.Exclusion criteriafrugile (include as many as possible, exclude the smallest), specifying subsets of the population that will not be studied because of (a high likelihood of being lost to follow-up, an inability to provide good data, being at high risk of possible adverse effects). A good general rule that keeps things simple and preserves the number of potential study subjects is to have as few exclusion criteria as possible.40.External validitythe degree to which these conclusions can be appropriately applied to people and events outside the study.41.Feasiblenumber of subjects, technical expertise, cost in time and money, scope.42.Fixed sample sizethe investigator must work backward.43.Generalizabilityrarely a simple yes-or-no matter; it is a complex qualitative judgment that is highly dependent on the investigator's choice of population and of sampling design.44.The goal of sample sizeplanning is to estimate an appropriate number of subjects for a given study design.45."gold standard"a reference technique that is considered accurate.46.Hypothesisinvestigator must develop plans for estimating sample size and for managing and analyzing the study data.47.The hypothesisis a version of the research question that provides the basis for testing the statistical significance of the findings. The hypothesis allows the investigator to calculate the sample size.48.The hypothesisshould be stated in writing at the outset of the study.49.Hypothesis generationa process of unanticipated associations that appear during the collection and analysis of a study's result.

50.Inclusion and exclusion criteriadefine the target population- the kinds of patients best suited to the research question.51.Inclusion criteriaincluded in the study. Specifying populations relevant to the research question and efficient for study; demographic characteristics, clinical characteristics, geographic characteristics, temporal characteristics.52.InferencesThe classic Framingham study was an early approach to designing a study that would allow inferences from findings observed in a sample to be applied to a population.53.Instrument bias (systematic)can result from faulty function of a mechanical instrument.54.Instrument variability (source of random error)variability in the measurement due to changing environmental factors such as temperature, aging mechanical components, different reagent lots, and so on.55.Interestingconfirming that you are not the only one who finds the question interesting.56.Internal validitythe degree to which the investigator draws the correct conclusions about what actually happened in the study.57.Interventionthe effects of which are studied by clinical trials.58.Measurement errorthreatening the inferences from the study measurements to the phenomena of interest.59.Measurements should besensitive, specific, appropriate, provide adequate distribution of responses, and be objective.60.Mentora new investigator apprentices with an experienced mentor—who has the time and interest to work with them regularly.61.Minimizing sample size and maximizing poweruse continuous variables, use paired measurements, use more precise variables, use unequal group sizes, and use a more common outcome.62.New technologiesgenerates new insights and questions about familiar clinical problems.63.New toolssingle nucleotide polymorphisms, gene expression arrays, imaging and proteomics.64.Nominalvariables have categories that are not ordered; type O blood, for example is neither more nor less than type B; nominal variables tend to have a qualitative and absolute character that makes them straightforward to measure.

65.Non-responsethe proportion of eligible subjects who agree to enter the study influences the validity of inferring that the sample represents the population. People who are difficult to reach and those who refuse to participate once they are contacted tend to be different from people who enroll. The level of nonresponse that will compromise the gneralizability of the study depends on the research question and on the reasons for not responding.66.Novelcontributes new information.67.Null hypothesisstates that there is no association between the predictor and outcome variables in the population.68.Observer bias (systematic)a distortion, conscious or unconscious, in the perception or reporting of the measurement by the observer.69.Observer variability (source of random error)variability in measurement that is due to the observer and includes such things as choice of words in an interview and skill in using a mechanical instrument.70.One-sidedhypothesis specifies the direction of the association between the predictor and outcome variable.71.One-sided Z testthe chi-squared test is always two-sided, this is an equivalent test for one-sided hypotheses.72.Operations manualcollection of specific procedural instructions, questionnaires, and other materials designed to ensure a uniform and standardized approach to carrying out the study with good quality control. Research question: the uncertainty about something in the population that the investigator wants to resolve by making measurements on her study subjects.73.Ordinalvariables have categories that do have order, such as sever, moderate, and mild pain.74.Outcome variables"dependent"75.Outlinestandardized checklist to remind the investigator to include all the components.76.Populationa good choice of study subjects serves the vital purpose of ensuring that the findings in the study accurately represent what is going on in the population of interest.77.Powerreasonable probability.78.Precisefree of random error79.Precisionthe degree to which the observed prevalence approximates 20% each time a sample is drawn.

80.Precisionthe degree to which it is reproducible, with nearly the same value each time it is measured. Precision is also a function of random error (the greater the error, the less precise the measurement).81.Predictor variablefar more likely to be on biological grounds to be causal.82.Primary hypothesiscan be tested statistically without argument about whether to adjust for multiple hypothesis testing. This is the hypothesis in which the study has been designed around.83.Prior probabilitythe issue of significance level depends on prior probability.84.Prospective studies (cohort)being in the present and follow the subjects into the future.85.P valuethe probability of seeing an effect as big as or bigger than that in the study by chance if the null hypothesis actually were true.86.Random errora wrong result due to chance—sources of variation that are equally likely to distort estimates from the study in either direction.87.Randomizationis used to control for the influence of confounding variables (other predictors of the outcomes such as intake of red meat or income level that could be related to dietary fish and confuse the interpretation of the findings).88.Randomized blinded trialamong clinical trial options this is usually the best design.89.Related hypothesesif the findings are consistent, the study conclusions are made stronger.90.Relevantare the outcomes likely and how will they advance scientific knowledge, influence practice guidelines and health policy, or guide further research.91.Reproducibilityprecision is assessed as the reproducibility of repeated measurements, either comparing measurements made by the same person or different people.92.Research questionthe objective of the study, the uncertainty the investigator wants to resolve.93.Retrospective studies (cohort)examine information and specimens that have been collected in the past.94.Samplethe protocol must specify a sample of subjects that can be studied at an acceptable cost in time and money, yet one that is large enough to control random error and representative enough to allow generalizing the study finding to populations of interest.

95.Samplethe group of subjects specified to the protocol (a sample of the population of interest).96.Sampling errorthreatens inferences from the study subjects to the population.97.Scholarshippublished literature in an area of study, necessary to good research.98.Simple hypothesiscontains one predictor and one outcome variable99.Simple random sampledrawn by enumerating the units of the population and selecting a subset at random. Most common use of this approach in clinical research is when the investigator whishes to select a representative subset from a population that is larger than she needs.100.Skeptical attitudeabout prevailing beliefs can stimulate good research questions.101.Specifica specific hypothesis leaves no ambiguity about the subjects and variables or about how the test of statistical significance will be applied.102.Standard effect sizea unitless quantity that makes it possible to estimate a sample size when an investigator cannot obtain information about the variability of the outcome variable; it also simplifies comparisons between the effect sizes of different variables.103.Stratified random sampledividing the population into subgroups according to characteristics such as sex or race and taking a random sample from each of these "strata."104.Studyingthe association between a predictor and an outcome variable in order to draw casual inference.105.Study planfinding an important research question that is transformed into a feasible and valid study plan.106.Study protocolexpansion of the outline, used to plan the study and to apply for grant support.107.Study samplesubset of the accessible population that participates in the study.108.Subject bias (systematic)distortion of the measurement by the study subject, for example, in reporting an event (respondent or recall bias).109.Subject variability (source of random error)refers to intrinsic biologic variability in the study subjects due to such things as fluctuations in mood and time since last medication.110.Systematic errorthe greater the error, the less accurate the variable.

111.Systematic sampleresembles a srs in first enumerating the population but differs in that the sample is selected by a preordained periodic process (i.e. Framingham).112.Target populationclinical and demographic characteristics define the target population, the large set of people throughout the world to which the results will be generalized.113.Teachingideas for studies often occur while preparing presentations or during discussions with inquisitive students.114.Tenacityreturning to a troublesome problem repeatedly until a resolution is reached that feels comfortable.115.Translational researchstudies of how to translate findings from the ivory tower into the "real world."116.T testused to determine whether the mean value of a continuous outcome variable in one group differs significantly from that in another group. The t test assumes that the distribution of the variable in each of the two groups approximates a normal curve.117.Two-sidedhypothesis states only that an association exists; it does not specify the direction.118.Type I errorfalse positive119.Type II errorfalse negative120.Validatingthe general approach to validating an abstract measure is to begin by searching the literature and consulting with experts in an effort to find a suitable instrument that has already been validated.121.Validityhow well the measurement represents the phenomenon of interest.122.Variableswill represent the phenomena of interest. The variables are usually proxies for the phenomena.123.Within-subject standard deviationthe reproducibility of continuous variables.


1.21 CFR 11 (Electronic Records; Electronic Signatures 2014), often referred to as Part 11, was published on 20 May 1997, and was intended toenable the use of electronic documents in the regulatory process for drugs and devices2.A 27-year-old female subject with an opportunistic infection was entered into a clinical trial for a novel treatment.The study drug was administered from May 15th to June 30th.On June 2nd, the subject complained of reduced hearing in both ears. An audiogram performed on June 4th revealed the subject had severe hearing loss. The Investigator considered this hearing loss a disability for the subject.Anytime an Investigator identifies an adverse event, the next steps will be to make sure it is properly documented in the patient's medical files, and to ensure that it gets entered into the Case Report Form (or CRF) as an adverse event. If the event qualifies as a Serious Adverse Event, an SAE form also needs to be completed immediately and submitted to the Sponsor.3.According to ICH (2016) E6 Section 4.9.3, any changes to source data should be?1. Traceable
2. Not obscure the original entry
3. Should be explained if necessary (for example, via an audit trail)4.According to ICH (2016) E6 Section 5.18, the purposes of trial monitoring are to verify that1. The rights and well-being of human subjects are protected.
2. The reported trial data are accurate, complete, and verifiable from source documents.
3. The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with applicable regulatory requirements.5.According to the Declaration of Helsinki, physicians may use an unproven intervention.True6.ADMINISTRATIVE OVERHEADClinical sites may require as much as 30% administrative overhead in addition to per patient grant amount. This cost covers management and legal resources needed to provide clinical research oversight and legal review of clinical contracts respectively.7.Adolescents12 to 16-18 years (dependent on region)8.Advances against subject payment (enrollment-based):If no subjects are enrolled the money will have to be refunded to the sponsor.9.Adverse Drug Reaction (ADR)The phrase "responses to a medicinal products" means that a 
causal
relationship between a medicinal product and an 
adverse
event is at least a 
reasonable
possibility, i.e., the relationship cannot be ruled out.10.An Adverse Event is defined in the ICH E2A guideline as follows"Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment."
There is also the clarification that an AE is therefore:"Any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease, whether or not considered related to the medicinal product."11.Adverse Events Seriousness is based on...the patient/event outcome." Usually involves events that "pose a threat to a patient's life or functioning."12.After a SAE has occurred, how should a subject identification occur on the immediate and follow-up reports?By their subject identification number.

13.Alternative methods of disposition of study product, such as destruction of the product by the site or shipment of the product to another site are not allowed.False, Alternative methods of disposition, such as destruction of the product by the site or shipment of the product to another site, must be explicitly authorized in writing by the sponsor. Methods of destruction also must conform to local procedures and Occupational Safety and Health Administration (OSHA) requirements. It is common for a sponsor representative (the study monitor) to observe the destruction of the study product.14.Any deviation should be ______________________________ (ICH [2016] E6 Section 4.5).explained in writing15.Any time the randomization procedure is not followed or the code is broken, it raises a red flag during an audit or inspection. T/F?True16.Bayesian ApproachesApproaches to data analysis that provide a posterior probability distribution for some
parameter (e.g. treatment effect), derived from the observed data and a prior
probability distribution for the parameter. The posterior distribution is then used as
the basis for statistical inference.17.Before an investigational product can be shipped to an investigator, the research sponsor must file a?1. Form FDA 1571 (also known as the Investigational New Drug [IND] application). 
2. IRB Approval18.Bias (Statistical & Operational)The systematic tendency of any factors associated with the design, conduct, analysis
and evaluation of the results of a clinical trial to make the estimate of a treatment
effect deviate from its true value. Bias introduced through deviations in conduct is
referred to as 'operational' bias. The other sources of bias listed above are referred to
as 'statistical'.19.Biological Product (or Biologic)is "any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment or cure of diseases or injuries" (21 CFR 600.3 [Biological Products: General 2014]).20.Blind ReviewThe checking and assessment of data during the period of time between trial
completion (the last observation on the last subject) and the breaking of the blind, for
the purpose of finalising the planned analysis.21.Blister packages (where each drug is placed in an individual plastic dome on a card) enhance compliance in three ways:1. They are easy to use.
2. They package one dose under each dome (so subjects receive the correct dose amount).
3. They can carry specific written instructions on the card so that subjects know exactly when to take their study drug(s).22.CATEGORIZE THE BUDGET COMPONENTS INTO 3 CATEGORIES.1. DIRECT COSTS
2. INDIRECT COSTS
3. INVOICE ITEMS23.The chief difficulty with crossover designs concerns 
carryover
, that is, the 
residual
influence of treatments in subsequent treatment periods. Carryover effects are most unlikely to occur if the 
washout
time between the two periods is sufficiently 
long.
...24.Children2 to 11 years

25.Classifying Clinical Studies According to Objective: Human PharmacologyObjective of Study 
• Assess tolerance
• Define/describe PK1 and PD2
• Explore drug metabolism
and drug interactions
• Estimate activity 
Study Examples
• Dose-tolerance studies
• Single and multiple dose
PK and/or PD studies
• Drug interaction studies26.Classifying Clinical Studies According to Objective: Therapeutic
Confirmatory
Objective of Study 
• Demonstrate/confirm
efficacy
• Establish safety profile
• Provide an adequate basis
for assessing the benefit/risk
relationship to support
licensing
• Establish dose-response
relationship 
Study Examples 
• Adequate, and well
controlled studies to
establish efficacy
• Randomised parallel doseresponse
studies
• Clinical safety studies
• Studies of mortality/
morbidity outcomes
• Large simple trials
• Comparative studies27.Classifying Clinical Studies According to Objective: Therapeutic
Exploratory
Objective of Study
• Explore use for the targeted
indication
• Estimate dosage for
subsequent studies
• Provide basis for
confirmatory study design,
endpoints, methodologies 
Study Examples 
• Earliest trials of
relatively short duration
in well- defined narrow
patient populations, using
surrogate or
pharmacological endpoints
or clinical measures
• Dose-response exploration
studies

28.Classifying Clinical Studies According to Objective: Therapeutic UseObjective of Study
Refine understanding of
benefit/risk relationship in
general or special
populations and/or
environments
• Identify less common
adverse reactions
• Refine dosing
recommendation 
Study Examples 
• Comparative effectiveness
studies
• Studies of
mortality/morbidity
outcomes
• Studies of additional
endpoints
• Large simple trials
• Pharmaco29.CLINICAL SAFETY DATA MANAGEMENT:
DEFINITIONS AND STANDARDS FOR
EXPEDITED REPORTING
ICH E2A30.CLOSE-OUT FEESClose-out fees include time spent by site staff to reconcile clinical trial data, finances and regulatory documents during study closure. Not all sites require this payment but has started to become a more common practice in recent years.31.The consent process should be conducted in the language spoken by the subject, and the consent form should be translated into that language. T/F?True32.The content for an IND for studies of marketed products is the same as the content for studies of new drugs, with what exception?A copy of the approved labeling (including the package insert) can be provided in lieu of the Investigator's Brochure (IB).33.Content ValidityThe extent to which a variable (e.g. a rating scale) measures what it is supposed to
measure.34.Contrary to popular belief, it is not always necessary or advisable to break the code in a medical emergency. The code should be broken only when the identity of the investigational product that the subject received will determine the treatment to be given to that subject for the emergency. T/F?True35.The data reported on the CRF must beconsistent with the source documents, and any discrepancies between the CRF and source document should be explained.36.Dispensing/administration information should be recorded inThe case report form (CRF) and the subject's medical record, so there is a record of experimental product exposure.37.double-blindedneither the investigator nor the subject knows which treatment the subject is to receive

38.Double-DummyA technique for retaining the blind when administering supplies in a clinical trial,
when the two treatments cannot be made identical. Supplies are prepared for
Treatment A (active and indistinguishable placebo) and for Treatment B (active and
indistinguishable placebo). Subjects then take two sets of treatment; either A (active)
and B (placebo), or A (placebo) and B (active).39.Drug usage is reconciled by reviewing the paper trail, includingShipping records showing receipt of the investigational product
Dispensing/administration records showing usage of the product
Reconciliation records for unaccounted-for product
Final disposition records documenting disposal of investigational product40.DSMBData and Safety Monitoring Board: The DSMB is made of people external to the study investigative group. They are generally independent of the sponsor of the study and of the manufacturer of any product that is being evaluated or of direct competitor manufactures. They ensure the safety and welfare of subjects by monitoring data for safety concerns, etc.41.DSMBData AND Safety Monitoring Board: The DSMB is made of people external to the study investigative group. They are generally independent of the sponsor of the study and of the manufacturer of any product that is being evaluated or of direct competitor manufactures. They ensure the safety and welfare of subjects by monitoring data for safety concerns, etc.42.During Phase _______ studies, researchers test a new drug in normal volunteers (healthy people). In most cases, 20 to 80 healthy volunteers or people with the disease/condition participate.143.Electronic or paper forms to track investigational products should indicate?the product's name, strength, and formulation44.Equivalence TrialA trial with the primary objective of showing that the response to two or more
treatments differs by an amount which is clinically unimportant. This is usually
demonstrated by showing that the true treatment difference is likely to lie between a
lower and an upper equivalence margin of clinically acceptable differences.45.Examples of budget Invoice
Items
1. Subject travel, lodging, meals, parking
reimbursement
2. Record archiving
3. Subcontractor payments46.EXAMPLES OF Direct
Costs
• Study personnel (e.g., labor)
• Tests/procedures (i.e., services that generate
bills, regardless of the payer source)
• Operating expenses (e.g., phones, faxes,
copying)47.EXAMPLES OF Indirect
Costs
• Institutonal expenses (e.g., support services,
space, IT, HR)
• Driven by Institutonal policy
• Infrastructure within the unit (i.e., study team
make-up, management)48.EXAMPLES OF LABOR COSTSA. CLINICAL RESEARCH ASSISTANTS OR ASSOCIATES (CRAS)
B. PROJECT MANAGER (ALSO KNOWN AS CLINICAL TRIAL MANAGER OR STUDY MANAGER)
C. DATA MANAGER
D. SCIENTIST
E. BIOSTATISTICIAN
F. QUALITY

49.Failure to comply with GCP guidelines may ultimately result in the inability to continue conducting clinical trials. T/F?True50.Failure to maintain the product as required or a lack of written evidence that storage conditions were met may result in ________________. Therefore, it is imperative to maintain records of appropriate storage conditions during clinical trials.FDA disqualification of data that could have supported a new drug application (NDA)51.The FDA also requires information about the ______________________ of each investigator and subinvestigator who will use the investigational product as part of the clinical trial.credentials52.The FDA has indicated in guidance that it is acceptable to conduct the consent discussion by phone and satisfy the requirement for a signed consent document by having the signed and dated consent form returned by facsimile (fax). T/F?True53.The FDA regulations do not require the IRB to ensure that assent from children is obtained. T/F?False: The FDA regulations do not include a similar requirement for obtaining assent from adults; however, the FDA regulations require the IRB to ensure that assent from children is obtained, unless the requirement for assent is waived.54.The FDA regulations require the label for investigational drugs to contain specific information. Labels on investigational drugs may differ in design but all such labels should contain the following minimum primary information:1. Name of the study
2. Name of the study drug (even the placebo is labeled with the study drug code)
3. Subject study number
4. How supplied (for example, the number of tablets per container)
Dose per unit (mg per tablet, mg/mL, etc.)
5. Lot number
6. Batch number
7. A federal statement limiting use to experimental studies: "Caution: New Drug - Limited by Federal Law to Investigational Use" (Investigational New Drug Application 2014)55.The following information is subbmitted to the FDA to obtain an IND. 1-101. Cover letter
2. Form FDA 1571 [IND]
3. Form FDA 1572 (Statement of Investigator)
4. Introductory statement and general investigational plan
5. Investigator's Brochure
6. Protocol(s)
7. Chemistry, manufacturing, and controls information
8. Pharmacology and toxicology information
9. Previous human experience with drug
10. Additional information
Relevant information56.Form FDA 1571 is aContractual agreement between the sponsor and FDA.57.FORM FDA 1572STATEMENT OF INVESTIGATOR58.Form FDA 1572 (Statement of Investigator). By signing this form, the investigator enters into a legally binding contract withthe FDA59.Frequentist MethodsStatistical methods, such as significance tests and confidence intervals, which can be
interpreted in terms of the frequency of certain outcomes occurring in hypothetical
repeated realisations of the same experimental situation.

60.Full Analysis SetThe set of subjects that is as close as possible to the ideal implied by the intention-totreat
principle. It is derived from the set of all randomised subjects by minimal and
justified elimination of subjects.61.GENERAL CONSIDERATIONS FOR CLINICAL TRIALSICH E862.Generalisability, GeneralisationThe extent to which the findings of a clinical trial can be reliably extrapolated from
the subjects who participated in the trial to a broader patient population and a
broader range of clinical settings.63.Generally, the sponsor will enter into a _________________________with the investigator and site. This agreement is a contract that defines both the terms of study conduct and the financial agreements. There are also several other documents that must be completed before the investigator can begin to conduct in the trial.a clinical trial agreement (CTA)64.General Principles OF CLINICAL INVESTIGATION OF MEDICINAL PRODUCTS
IN THE PEDIATRIC POPULATION ICH GUIDANCE
Pediatric patients should be given medicines that have been appropriately evaluated
for their use.65.GENERAL PRINCIPLES : Protection of clinical trial subjectsThe principles and practices concerning protection of trial subjects are stated in the
ICH Guideline on Good Clinical Practice (ICH E6). These principles have their origins
in The Declaration of Helsinki and should be observed in the conduct of all human
drug investigations.66.Global Assessment VariableA single variable, usually a scale of ordered categorical ratings, which integrates
objective variables and the investigator's overall impression about the state or change
in state of a subject.

67.How to Report expedited adverse
events
The CIOMS-I form has been a widely accepted standard for expedited adverse
event reporting. However, no matter what the form or format used, it is
important that certain basic information/data elements, when available, be
included with any expedited report, whether in a tabular or narrative
presentation.68.The ICH (2016) E6 guidance document provides detailed information regarding the following:Principles of ICH GCP
IRB
Investigator
Sponsor
Clinical trial protocol and protocol amendments
Investigator's Brochure
Essential documents for the conduct of a clinical trial69.ICH [2016] E6 Section 4.8.8The person obtaining consent should also sign and date the consent form70.ICH (2016) E6 Section 4.12 notes the following:4.12.1 - If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator should inform the institution where applicable, and the investigator/institution should promptly inform the sponsor and the IRB, and should provide the sponsor and the IRB a detailed written explanation of the termination or suspension.71.ICH E2A was developed to...provide standard definitions and terminology for key aspects of clinical safety reporting;create a mechanism for handling expedited reporting during the investigational phase.72.ICH E6 is?as a standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.73.ICH E6 notes that if the clinical trial is prematurely terminated or suspended, regardless of the reason, that the investigator or the organization should promptly notify?1. The subjects in the study. 
2. The investigator /organization should be certain that appropriate therapy and follow-up are provided for the subjects. 
3. Where required by regulations, the investigator/organization may also need to inform the regulatory authorities of the premature termination or suspension of the trial.74.ICH HARMONISED TRIPARTITE GUIDELINE E11CLINICAL INVESTIGATION OF MEDICINAL PRODUCTS
IN THE PEDIATRIC POPULATION75.If a deviation was needed to eliminate a hazard, the deviation must bedocumented and rationale submitted to the sponsor, IRB, and regulatory authorities.76.If an investigator plans to deviate from the protocol for a purpose other than to eliminate an immediate hazard, the investigator mustobtain prior approval from the sponsor and the IRB77.If a pharmacist is unavailable, an ______________________________ individual should ensure that the product is appropriately stored.appropriately qualified and delegated78.If a research pharmacy is not available, investigational products can be stored in other areas as long as the following requirements are metSponsor-directed storage requirements are followed.
Area is monitored, with written evidence of appropriate storage conditions (temperature monitoring logs for the room, refrigerator, etc.).
Access is limited at all times (key or other entry device required).
Product is supplied only to subjects in the trial.
Accountability records are maintained.
Space is adequate.

79.If for some reason the Investigator did not provide a causality assessment, the Sponsor
would
assume the event is considered related, because the Sponsor is not allowed
to downgrade the assessment of relatedness. If the Sponsor instead assumed the event to
be unrelated and the Investigator later reported on the causality and indicated at least a
possible relationship, the Sponsor would technically have downgraded the event.80.If the investigator deviates from the protocol without IRB approval to eliminate an immediate hazard to subjects, the investigator should report the deviation ___________________to the sponsor and the IRB per their reporting requirements (ICH [2016] E6 Section 4.5.4).as soon as possible81.In addition, if relevant to the research, legally effective informed consent will also include the following elements:A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant), which are currently unforeseeable.
Anticipated circumstances under which the subject's participation may be terminated by the investigator without regard to the subject's consent.
Any additional costs to the subject that may result from participation in the research.
The consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject.
A statement that significant new findings developed during the course of the research which may relate to the subject's willingness to continue participation will be provided to the subject.
The approximate number of subjects involved in the study.82.In cases where an Investigator would make an assessment of an event being related and
the Sponsor would not agree, assessing the event as being unrelated,
the Sponsor is not
allowed to downgrade the relatedness from 'yes' to 'no'. As soon as the Investigator says
anything from "possibly related" to "related", the Sponsor has to mark the event as needing
expedited reporting and act accordingly.83.The IND application outlinesthe general investigational plan for the development of the drug. Amendments to the IND are made (for example, new protocols or new side effect information) as the product moves through the clinical development process.84.Independent Data Monitoring Committee (IDMC) (Data and Safety
Monitoring Board, Monitoring Committee, Data Monitoring Committee)
An independent data-monitoring committee that may be established by the sponsor to
assess at intervals the progress of a clinical trial, the safety data, and the critical
efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or
stop a trial.85.Indirect Cost Rate (IDC)All procedural and non-procedural line items. Exemptions: subject stipends /reimbursements.86.In early-phase clinical trials, _________ quantities of drug are neededsmaller87.Infants and toddlers28 days to 23 months

88.The informed consent process does not need to be documented in the medical record or source file. T/F?False: The informed consent process should be documented in the medical record or source file (as well as documentation regarding communication of new information).89.In limited circumstances, the FDA allows an investigator to obtain consent verbally without obtaining a signature on the consent form. T/F?In limited circumstances, the FDA allows an investigator to obtain consent verbally without obtaining a signature on the consent form (21 CFR 56.109[c][1] [Institutional Review Boards 2014]).90.In Phase _______ studies, researchers administer the drug to a group of patients with the disease or condition for which the drug is being developed. Typically involving a few hundred patients, these studies aren't large enough to show whether the drug will be beneficial.291.Intention to treat analysisStatistical analysis of data from subjects according to the group to which they were assigned despite noncompliance with the study protocol92.Intention-To-Treat PrincipleThe principle that asserts that the effect of a treatment policy can be best assessed by
evaluating on the basis of the intention to treat a subject (i.e. the planned treatment
regimen) rather than the actual treatment given. It has the consequence that subjects
allocated to a treatment group should be followed up, assessed and analysed as
members of that group irrespective of their compliance to the planned course of
treatment.93.Interaction (Qualitative & Quantitative)The situation in which a treatment contrast (e.g. difference between investigational
product and control) is dependent on another factor (e.g. centre). A quantitative
interaction refers to the case where the magnitude of the contrast differs at the
different levels of the factor, whereas for a qualitative interaction the direction of the
contrast differs for at least one level of the factor.94.Interim AnalysisAny analysis intended to compare treatment arms with respect to efficacy or safety at
any time prior to the formal completion of a trial.95.Inter-Rater ReliabilityThe property of yielding equivalent results when used by different raters on different
occasions.96.In the FDA Information Sheets, the FDA recommends that informed consent must be obtained before the subject participates in any procedures that are done solely for research purposes, including determining eligibility for the study and withdrawing medication (wash-out). T/F?True97.In the guidance, the FDA noted that there are two instances when it is necessary for an investigator to complete and sign a new Form FDA 1572:When an investigator is participating in a new protocol that has been added to the IND
When a new investigator is added to the study

98.Investigational Drugis "a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use" (ICH [2016] GCP E6 Section 1.33).99.Investigational New Drug (IND)is "a new drug, antibiotic drug, or biological drug that is used in a clinical investigation. The term also includes a biological product that is used in vitro for diagnostic purposes" (21 CFR 312.3 [Investigational New Drug Application 2014]).100.Investigational Productany unapproved drug or biological product undergoing clinical trials to provide evidence to regulatory authorities that the product is safe and efficacious.101.Investigational Product is defined by ICH (2016) asas "a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.102.The investigational product shipment will usually include apackaging list or shipping invoice103.Investigational products must be stored according toprotocol specifications and the manufacturer's directions104.The Investigator determines that the event is unrelated to study drug, and that the subject's severe hearing loss is a serious, unexpected adverse event.The Sponsor accepts the Investigator's causality assessment. What are the Sponsor's expedited reporting obligations to regulatory authorities at this time, per the ICH-E2a guidelines, for this event?There are no expedited reporting obligations at this time.105.The investigator does not have to maintain records to document that the subjects were provided the doses specified in the protocol. T/F?False106.An Investigator instructs the site team at a trial team meeting to send SAE reports to the Sponsor as per the required timelines only if the timelines are feasible to adhere to in view of the needs of the overall medical practice. If not, the Investigator requires the site trial team to send the safety information reports at any convenient time to ensure continuation of the medical practice's daily tasks. In view of what you learned so far, is the Investigator instructing the site team properly?The Investigator is not instructing the site team properly. Not respecting SAE reporting timelines could delay the discovery of new, important safety information related to the IP by the Sponsor. As a result, there are delays in informing all participating site Investigators of a potential safety issue for their trial subjects and in updating the IB. The Investigator and the site staff play an important role in safeguarding patient safety not just for the subjects enrolled in the trial at their own site, but for all trial subjects at every participating site.107.The investigator is required to make the study records available to?the monitor, auditors, the IRB, the FDA, and other regulatory authorities.108.The investigator must maintain study records forat least two (2) years after the drug has been granted marketing approval in the U.S. for the indication tested in the study or, if no application will be filed or if the application is not approved for the indication, for at least two (2) years after the investigation is terminated and the FDA is notified.109.Investigators agreeing to participate in pharmaceutical company-sponsored clinical investigations have commitments to1. Sponsor
2. IRB
3. Subjects
4. FDA

110.Investigators also must provide periodic updates to the IRB in accordance with its policies. This typically occurs ___________________________ but may be required more often by the individual IRB (ICH [2016] E6 Section 4.9.7).at least once per year111.Investigators are required to report serious adverse events (SAEs) ________________ to the sponsor organizationpromptly112.Investigators can delegate the responsibility of product accountability (control) to qualified personnel, such as the pharmacist or study coordinator? T/F?True113.Investigator's commitments to the FDA are?Allow inspections of the facilities and records.
Retain study records.
Comply with GCP standards.114.In what situations, where an individual has a life-threatening condition and the following requirements are met and documented, can you use a test article without consent. (21 CFR 50.23)1. The investigator, with the concurrence of another physician, believes the situation necessitates the use of a test article. 
2. The subject and/or LAR is unable to communicate consent;
3. There is insufficient time to obtain consent;
4. No alternative exists that will provide an equal or better chance of saving the subject's life; and
5. The IRB is informed of the use of the investigational product without informed consent within five (5) working days of the event.115.The IRB can waive the requirement for assent if it determinesThe children are incapable of understanding the research;

There is a prospect of direct benefit to the children that is not available outside of the research; or

If the requirements for a waiver of consent (21 CFR 50.55[c] [Protection of Human Subjects 2014]) are met.116.Items requiring an invoice (not included in the per subject payment)1. Non-procedural fees (subject travel, dry ice)
2. Procedural assessments that do not pertain to every subject enrolled or may be considered optional per the study.117.It is important for investigators to have proper equipment available to satisfy storage requirements and also to have ________________ in place to ensure that storage requirements are continuously satisfied.procedures118.It is the sponsor-investigator's responsibility to comply with GCP when conducting a study. T/F?True119.It may sometimes be 
desirable
to use more than one primary variable, each of which (or a subset of which) could be 
sufficient
to cover the range of 
effects
of the 
therapies. t/f?
True

120.KEY DATA ELEMENTS FOR INCLUSION IN EXPEDITED
REPORTS OF SERIOUS ADVERSE DRUG REACTIONS 1. Patient Details
Initials
Other relevant identifier (clinical investigation number, for example)
Gender
Age and/or date of birth
Weight
Height121.(LAR)Legally Authorized Representative- means an individual, judicial, or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedure(s) involved in the research.122.LARLegally Authorized Representative - A legally authorized person who can consent on behalf of a subject123.List of examples of vulnerable subjects"children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons" (21 CFR 56 [Institutional Review Boards 2014]).124.A longitudinal study in which subjects receive a sequence of different treatments (or exposures) is what type of study?Crossover design study.125.Managing Blinded Therapy CasesWhen the sponsor and investigator are blinded to individual patient treatment
(as in a double-blind study), the occurrence of a serious event requires a decision
on whether to open (break) the code for the specific patient. If the investigator
breaks the blind, then it is assumed the sponsor will also know the assigned
treatment for that patient.126.Meta-AnalysisThe formal evaluation of the quantitative evidence from two or more trials bearing on
the same question. This most commonly involves the statistical combination of
summary statistics from the various trials, but the term is sometimes also used to
refer to the combination of the raw data.127.Minimum number of members on an IRB5128.The most important design techniques for avoiding bias in clinical trialsare 
blinding
and 
randomization
, and these should be 
normal
features of most controlled clinical trials intended to be included in a 
marketing
application.129.Multicentre trials are carried out for two main reasons?1. a multicentre trial is
an accepted way of evaluating a new medication more efficiently; under some
circumstances, it may present the only practical means of accruing sufficient subjects
to satisfy the trial objective within a reasonable time-frame. 
2. a trial may be designed as a multicentre (and multi-investigator) trial
primarily to provide a better basis for the subsequent generalisation of its findings.130.Non-Inferiority TrialA trial with the primary objective of showing that the response to the investigational
product is not clinically inferior to a comparative agent (active or placebo control).131.Non-refundable startup fees1. Clinical Study Evaluation Committee (CSEC)
IND Safety Reporting.
2. PI eCRF Training
3. Monitoring space
4. Recruitment
5. Record Retention 
6. Radiology start-up
7. Pharmacy (start-up and close-out)

132.Non-refundable start-up fees:There are some sponsors that include stipulations such as receipt of all regulatory documents, IRB approval and/or site initiation visit.133.OBJECTIVES OF THE CLINICAL INVESTIGATION OF MEDICINAL PRODUCTS
IN THE PEDIATRIC POPULATION GUIDANCE?
to encourage and facilitate timely pediatric medicinal
product development internationally. The guidance provides an outline of critical
issues in pediatric drug development and approaches to the safe, efficient, and ethical
study of medicinal products in the pediatric population.134.Often phase I trials do not involve drug packaging for individual subjects because only one or two doses are given to any subject. Therefore, phase I drug products may be supplied in?bulk containers, such as bottles of 100 tablets135.On 24 July 2017, the FDA issued guidance that they will not object if an IRB approves a waiver or alteration of consent for a no more than minimal risk clinical investigation if the IRB determines that (FDA 2017): T/F?True136.Once an IND application becomes effective, a sponsor-investigat is required to submit the following reports/updates to the FDA.1. PROTOCOL 2. AMENDMENTS
3. INFORMATION 4. AMENDMENTS
5. ADVERSE EVENTS 
6. IND SAFETY REPORTS
7. ANNUAL REPORTS
8. FINAL REPORTS
9. FINANCIAL DISCLOSURE 10. REPORTS137.Once IRB approval is obtained and other organizational prerequisites have been satisfied, the study can begin at the investigator's site. The sponsor organization will "initiate" a site through a site visit or other mechanism. At this initiation stage, the ________________ will be reviewed. Once a site is initiated, study product may be shipped to the site and subject recruitment may begin.protocol, data-collection instructions, and regulatory obligations138.Once the study has been terminated, the investigator is required to _____________ and provide .notify the IRB
a summary (final) report139.OTHER FACTORS THAT CAN INCREASE THE BUDGET?A. PROTOCOL AMENDMENTS
B. INFLATION, VALUE ADDED TAX (VAT) AND FOREIGN EXCHANGE 
C. TRIAL ENROLLMENT DELAYS140.Patient grant costs are broken down intoscreening, baseline and follow-up visits and medical imaging costs141.Periodically during the trial, the sponsor organization will contact or visit the site and monitor the study's progress. During site visits, the sponsor representative willreview and retrieve data, address data discrepancies, inventory drug and study supplies, and review the study records.142.per protocol analysisAnalysis of all subjects in a study who completed the study as per the protocol .143.Per subject payment withholdingIndustry sponsors typically withhold a percentage of study payments until the study is completed. The percent withheld is usually 10% or greater.

144.Phases of Clinical Development1. Phase I (Most typical kind of study: Human Pharmacology) 
2. Phase II (Most typical kind of study: Therapeutic Exploratory) 
3. Phase III (Most typical kind of study: Therapeutic Confirmatory) 
4. Phase IV (Variety of Studies: - Therapeutic Use)145.Phase _____ studies are closely monitored and gather information about how a drug interacts with the human body. Researchers adjust dosing schemes based on animal data to find out how much of a drug the body can tolerate and what its acute side effects are.1146.Phase _____ trials are carried out once the drug or device has been approved by FDA during the Post-Market Safety Monitoring4147.Price cappingPrice capping is not desirable. Price caps on devices expose the institution to substantial financial risk and should be negotiated out of the budget.148.Primary purpose of a phase 1 study?Safety and Dosage (Determine the metabolic and pharmacologic action of the drug in humans).149.Procedures that are to be performed as part of the subject's medical care, and which would be done whether or not the participation in the trial were being considered, may not be completed prior to signing the Informed Consent. T/F?False: Procedures that are to be performed as part of the subject's medical care, and which would be done whether or not the participation in the trial were being considered, may be completed, and the information used for determining eligibility, without first obtaining informed consent from the subject.150.Products with More than one Presentation or UseTo avoid ambiguities and uncertainties, an ADR that qualifies for expedited
reporting with one presentation of a product (e.g., a dosage form, formulation,
delivery system) or product use (e.g., for an indication or population), should be
reported or referenced to regulatory filings across other product presentations
and uses.151.Providing a unified standard for Europe, US and Japan to facilitate the acceptance of clinical trials is the.....Mission statement of the ICH152.Purpose of phase 2 clinical trials?Efficacy and side effects, Up to several hundred people with the disease/condition.153.Reactions Associated with Active Comparator or Placebo TreatmentIt is the sponsor's responsibility to decide whether active comparator drug
reactions should be reported to the other manufacturer and/or directly to
appropriate regulatory agencies. Sponsors must report such events to either the
manufacturer of the active control or to appropriate regulatory agencies. Events
associated with placebo will usually not satisfy the criteria for an ADR and,
therefore, for expedited reporting.154.The records should reflect ___________________ of all investigational products received by the investigator. In other words, investigators are responsible for every individual unit of product received, and for all other study medication (non-investigational).reconciliation

155.Regulations and ICH E6 guideline require investigators to maintain records of all investigational products received, dispensed, or disposed of for _______________________________.at least two (2) years after the study has been completed or the investigational product has been approved for marketing.156.Reporting Time Frames- All Other Serious, Unexpected ADRsSerious, unexpected reactions (ADRs) that are not fatal or life-threatening must
be filed as soon as possible but no later than 15 calendar days after first
knowledge by the sponsor that the case meets the minimum criteria for expedited
reporting.157.Reporting Time Frames- Fatal or Life-Threatening Unexpected ADRsRegulatory agencies should be notified (e.g., by telephone, facsimile
transmission, or in writing) as soon as possible but no later than 7 calendar days
after first knowledge by the sponsor that a case qualifies, followed by as complete
a report as possible within 8 additional calendar days.158.The representative will also assess the suitability of including the _________________ in the study, according to the qualifications outlined in 21 CFR 312.53(a) (Selecting Investigators and Monitors).investigator159.Serious Adverse Event (SAE)Any untoward medical occurrence that at any dose. results in death, is life-threatening. requires inpatient hospitalization or causes prolongation of existing hospitalization.160.Single Cases of Serious, Unexpected ADRsAll adverse drug reactions (ADRs) that are both serious and unexpected are
subject to expedited reporting.161.SITE COSTSA. START-UP FEES
B. EC/IRB FEES
C. CLOSE-OUT FEES
D. STORAGE FEES
E. ADMINISTRATIVE OVERHEAD
F. SITE MANAGEMENT ORGANIZATION (SMO)162.SITE MANAGEMENT ORGANIZATION (SMO)In certain countries such as Japan, data entry and collection tasks are outsourced to SMOs. For post approval studies, sites do not provide research coordinator support. Thus sponsors are expected to hire SMOs to support the site or pay the sites to hire their preferred SMOs.163.Source Datameans all information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies).164.Source data should beAttributable
Legible, Contemporaneous, Original
Accurate, and Complete.165.Source Documentis the initial documentation of data in a clinical study and includes recorded observations, laboratory reports, medical records, etc.166.SponsorThe sponsor can be any legal entity, including a company, an academic organization, or an individual.167.Sponsor-InvestigatorAn individual who both initiates and conducts the clinical investigation and under whose immediate direction the investigational drug is being administered, used, or dispensed.168.Sponsor-investigators must develop monitoring plans based on the human subject protection and data integrity risks of the clinical trial. T/F?True

169.The sponsor is required to obtain financial disclosures before an investigator can participate in the trial and is required to receive updated information forone (1) year following completion of the trial. Investigators are required to promptly update this information if any relevant changes occur during the course of the trial and for one (1) year following completion of the trial (or all trials of the same product) at a particular site.170.The sponsor organization will generally assess the site first by means ofa pre-study site visit At this assessment visit, the sponsor representative will review the study requirements and answer any questions that the investigator or staff might have about the execution of the study.171.START-UP FEESClinical sites spend significant time to initiate a new clinical trial. Sites are responsible for site specific informed consent development, Ethics Committee (EC)/ Investigational Review Board (IRB) submissions, staff training including participation in investigator/ site coordinator meetings and site initiation visits and execute a clinical trial contract. It is typical for sponsor to pay anywhere between $2000 - $5000+ in site start-up fees.172.STORAGE FEESGovernment regulations require that clinical trial data be stored after study close-out. The duration for storage can range from 2-years to permanent storage. Thus it's not uncommon for sites to have boxes of regulatory paperwork that need to be stored once a clinical trial ends. The storage fees vary by country and site. 

Some sponsors make arrangements for site to send trial documents to an offsite storage location. Due to country specific regulations, a site might be unable to move documents outside their country.173.A SUADR which is serious due to the required hospitalization needs to be reported by the Sponsor to the regulatory authorities within what timeline?15 calendar days174.The subject can generally keep all unused drug. T/F?False: The subject must return all unused drug to the site, which then either returns it to the sponsor or destroys it, as the sponsor directs. The number of returned drugs must be counted to assess compliance with the protocol regimen. The protocol may specify how to measure subject compliance.175.Subjects who cannot write their name can "make their mark" on the informed consent form, as long as it is consistent with applicable state laws. T/F?True176.Superiority TrialA trial with the primary objective of showing that the response to the investigational
product is superior to a comparative agent (active or placebo control).177.Supplies should be ordered well before they actually will be needed, allowing enough time for packaging, processing, and shipping the order, typically ______ weeks.2-4 weeks178.Surrogate VariableA variable that provides an indirect measurement of effect in situations where direct
measurement of clinical effect is not feasible or practical.179.SUSARSuspected Unexpected Serious Adverse Reaction180.Term newborn infants(0 to 27 days)181.Therapeutic use, begins after drug approval is Phase_____?4

182.There are situations in addition to single case reports of "serious" adverse events
or reactions that may necessitate rapid communication to regulatory authorities;
appropriate medical and scientific judgement should be applied for each
situation.
Examples include:
a. For an "expected," serious ADR, an increase in the rate of occurrence which is
judged to be clinically important.
b. A significant hazard to the patient population, such as lack of efficacy with a
medicinal product used in treating life-threatening disease.
c. A major safety finding from a newly completed animal study (such as
carcinogenicity).183.This phase is most commonly done in healthy subjects and typically investigate human pharmacology. This phase is the initial administration of an investigational new drug into humans.Phase 1184.This phase of a drug study determines therapeutic benefit and is usually done in larger, specific populations.Phase 3185.Though investigators are ultimately responsible for the overall conduct of a clinical trial, study team members are often delegated responsibilities. For example, the investigator will delegate the consenting responsibility to the clinical research coordinator or delegate the drug dispensation to the pharmacist. The investigator must ensure the all study team members are qualified and knowledgeable about the study and their role. T/F?True186.Three categories of severity1. Mild — subject is aware of event, but it does not hinder normal daily activities
2. Moderate — subject is aware of event, and it hinders, but does not prevent, normal daily activities 
3. Severe — an event that prevents subject from performing normal daily activities187.Throughout the study, subjects do not need to be provided with new information that may affect their willingness to continue participation in the clinical trial. T/F?False188.To thoroughly assess their suitability for participation in the study, investigators mustreview the full protocol and IB189.Treatment EffectAn effect attributed to a treatment in a clinical trial. In most clinical trials the
treatment effect of interest is a comparison (or contrast) of two or more treatments.

190.Treatment EmergentAn event that emerges during treatment having been absent pre-treatment, or
worsens relative to the pre-treatment state.191.TRIAL DESIGN CONSIDERATIONS1 Parallel Group Design
2 Crossover Design
3 Factorial Designs
4 Group Sequential Designs192.Trial StatisticianA statistician who has a combination of education/training and experience sufficient
to implement the principles in this guidance and who is responsible for the statistical
aspects of the trial.193.The type of clinical study where two groups of treatments, A and B, are given so that one group receives only A while another group receives only B.Parallel Design194.The type of clinical trial design that evaluates a medical device or treatment by observing participant outcomes (and possibly other measures, such as side-effects) on a prescribed schedule, and modifying parameters of the trial protocol in accord with those observations.Adaptive Design195.Type of Trial Comparisons?1 Trials to Show Superiority 
2 Trials to Show Equivalence or Non-inferiority 
3 Trials to Show Dose-response Relationship196.Typically, drug manufacturers will package the investigational drug according toindividual clinical trial needs197.Unexpected Adverse Drug ReactionAn adverse reaction, the nature or 
severity
of which is not 
consistent
with the applicable 
product
information (e.g., Investigator's Brochure for an 
unapproved
investigational medicinal product)198.Upon receipt of the supplies, the investigator shouldverify the shipment and product information. For example, if white tablets were received but yellow capsules were expected, the investigator should contact the sponsor. The shipment also should be examined for evidence of damage during shipment, and the sponsor should be notified if damage has occurred.199.Vulnerable Subjectsindividuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. (ICH [2016] E6 Section 1.61)200.WHAT ARE NON-STANDARD OF CARE TESTSMedical device trials may require non-standard of care tests such as medical imaging scans. Insurance companies or medical care agencies generally do not reimburse non-standard of care costs. Therefore you should include them in your clinical trial budget.

201.WHAT ARE PROCEDURE COSTS?Medical payor such as Medicare or private insurance may reimburse clinical trial procedure costs. If procedure reimbursement is available, you don't need to budget for the procedure cost. In case a brand new procedure where no reimbursement available, budget for the procedure costs.202.WHAT ARE SOME OF THE MISCELLANEOUS COSTS FOUND IN THE BUDGET?A. INVESTIGATOR MEETINGS
B. TRAVEL
C. DOCUMENT TRANSLATIONS
D. TECHNOLOGY SOLUTIONS
E. REGULATORY FILING FEES203.WHAT ARE SOME OF THE SITE MANAGEMENT COSTSA. PRE-STUDY VISITS
B. SITE INITIATION VISITS (SIV)
C. MONITORING
D. CLOSE-OUT204.What if the Sponsor Did Not Agree
with the Investigator's Causality Assessment?
If the Sponsor would at this point not agree with the Investigator on the assessment that the
event is unlikely to be related, the Sponsor is allowed to upgrade the relatedness from 'no' to
'yes'. The Sponsor would then report the Investigator's opinion alongside its own
assessment, which would differ. In this case, expedited reporting would be required for the
event.205.What is an Investigator's Brochure (IB)is a compilation of the clinical and nonclinical data on the investigational product and serves as a resource for investigators and IRBs during the conduct of a clinical trial.206.What is the purpose of the Data and Safety Monitoring Board?To assess the progress of a clinical trial, the safety data and the critical efficacy endpoints.207.What resources do I need to develop a budget?1. Schedule of Assessments
2. Institutional Fees
3. Evaluation and Procedure Charges
4. Staff Allocation with Hourly Rates208.When a drug is dispensed or administered to a subject, the dispenser/administrator must record information on the drug accountability form such asIdentification of the product administered
Dosage
Date and time
Subject's identification code209.When adverse events are reported to the Sponsor post-study, the Sponsor should do which of the following things?1. Assess Causality
2. Determine Unexpectedness
3. File Report210.When completing the SAE form, what are the four minimum data points to complete for the Sponsor to be able to process the SAE?1. What product it concerns, 
2. Which site is doing the reporting, 3. Which patient on that site the SAE concerns, 
4. What the actual event was that was deemed serious.211.When is verbal consent prior to participation in a clinical research study permitted?When the patient is illiterate.212.When responsibilities are delegated, _________________________ remains ultimately responsible for compliance with the protocol, regulations, and IRB requirements.the investigator213.Who conducts clinical research Quality Control (QC) activities?Monitor214.Who determines the severity of an adverse event?The Investigator

215.Who is ultimately responsible for the accountability and disposition of all investigational products provided by the sponsor for the study.The Investigator216.Who may have direct access to the subjects' medical records?Subject and Investigator217.Who submits the completed, signed Form FDA 1572 to the FDA?The sponsor218.With this study design, subjects are randomly assigned to treatments.Randomized Design219.World Medical Association (WMA) Ethical PrincipalsDeclaration of Helsinki

.21 CFR 11 (Electronic Records; Electronic Signatures 2014), often referred to as Part 11, was published on 20 May 1997, and was intended toenable the use of electronic documents in the regulatory process for drugs and devices2.According to ICH (2016) E6 Section 4.3.3if the subject agrees, the investigator should inform the subject's primary physician about the subject's participation in the trial. ICH (2016) E6 Section 4.3.4 also notes that "although a subject is not obliged to give his/her reason(s) for withdrawing prematurely from a trial, the investigator should make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights."3.According to ICH (2016) E6 Section 4.6.3, product accountability includes:Records of receipt of the product at the site (that is, shipping records)
Supplying of the product to subjects (that is, dispensing logs)
Monitoring usage by subjects according to the protocol ("pill counts")
Return or destruction of the product at the end of the trial4.According to ICH (2016) E6 Section 4.9.3, such changes to source data should betraceable, should not obscure the original entry and should be explained if necessary (for example, via an audit trail) (ICH 2016).5.According to ICH (2016) E6 Section 5.18, the purposes of trial monitoring are to verify that1. The rights and well-being of human subjects are protected.
2. The reported trial data are accurate, complete, and verifiable from source documents.
3. The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with applicable regulatory requirements.6.ADMINISTRATIVE OVERHEADClinical sites may require as much as 30% administrative overhead in addition to per patient grant amount. This cost covers management and legal resources needed to provide clinical research oversight and legal review of clinical contracts respectively.7.Adolescents12 to 16-18 years (dependent on region)8.Advances against subject payment (enrollment-based):If no subjects are enrolled the money will have to be refunded to the sponsor.9.Alternative methods of disposition of study product, such as destruction of the product by the site or shipment of the product to another site are not allowed.Alternative methods of disposition, such as destruction of the product by the site or shipment of the product to another site, must be explicitly authorized in writing by the sponsor. Methods of destruction also must conform to local procedures and Occupational Safety and Health Administration (OSHA) requirements. It is common for a sponsor representative (the study monitor) to observe the destruction of the study product.10.Any deviation should be ______________________________ (ICH [2016] E6 Section 4.5).explained in writing11.Any time the randomization procedure is not followed or the code is broken, it raises a red flag during an audit or inspection. T/F?True12.Bayesian ApproachesApproaches to data analysis that provide a posterior probability distribution for some
parameter (e.g. treatment effect), derived from the observed data and a prior
probability distribution for the parameter. The posterior distribution is then used as
the basis for statistical inference.13.Before an investigational product can be shipped to an investigator, the research sponsor must file a?Form FDA 1571 (also known as the Investigational New Drug [IND] application). In addition, ICH (2016) E6 states "the sponsor should not supply an investigator/institution with the investigational product(s) until the sponsor obtains all required documentation (e.g., approval/favorable opinion from IRB/IEC and regulatory authority(ies))."

14.Bias (Statistical & Operational)The systematic tendency of any factors associated with the design, conduct, analysis
and evaluation of the results of a clinical trial to make the estimate of a treatment
effect deviate from its true value. Bias introduced through deviations in conduct is
referred to as 'operational' bias. The other sources of bias listed above are referred to
as 'statistical'.15.Biological Product (or Biologic)is "any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment or cure of diseases or injuries" (21 CFR 600.3 [Biological Products: General 2014]).16.Blind ReviewThe checking and assessment of data during the period of time between trial
completion (the last observation on the last subject) and the breaking of the blind, for
the purpose of finalising the planned analysis.17.Blister packages (where each drug is placed in an individual plastic dome on a card) enhance compliance in three ways:They are easy to use.
They package one dose under each dome (so subjects receive the correct dose amount).
They can carry specific written instructions on the card so that subjects know exactly when to take their study drug(s).18.Budget developmentThe process of identifying all of the expenses associated with participating in a clinical trial.19.Budget negotiationThe process of engaging the sponsor in a dialogue that results in a final budget that covers the costs of participating in a clinical trial.20.BY signing the FDA1572, the investigator agrees specifically to:Personally conduct or supervise the study in accordance with the protocol and GCP guidelines.
Protect the health and welfare of research subjects in accordance with 21 CFR 50 (Protection of Human Subjects 2014), by ensuring subjects that the product is investigational, ensuring that study procedures are explained adequately and performed appropriately, and by promptly identifying and reporting safety information, among other responsibilities.
Report to the sponsor adverse events (AEs) that occur.
Ensure that all personnel assisting in the conduct of the trial understand their obligations and commitments.
Maintain adequate and accurate records, and make these records available for inspection.
Ensure that an IRB that complies with the requirements in 21 CFR 56, and provides initial and ongoing review and approval of the investigation.
Comply with the requirements in 21 CFR 312 (Investigational New Drug Application 2014).21.Case Report Form (CRF)The tool used to record data collected during a clinical trial. The researcher submits the CRF to the sponsor.22.CATEGORIZE THE BUDGET COMPONENTS INTO 3 CATEGORIES.1. DIRECT COSTS
2. INDIRECT COSTS
3. INVOICE ITEMS23.Children2 to 11 years24.Classifying Clinical Studies According to Objective: Human PharmacologyObjective of Study 
• Assess tolerance
• Define/describe PK1 and PD2
• Explore drug metabolism
and drug interactions
• Estimate activity 
Study Examples
• Dose-tolerance studies
• Single and multiple dose
PK and/or PD studies
• Drug interaction studies

25.Classifying Clinical Studies According to Objective: Therapeutic
Confirmatory
Objective of Study 
• Demonstrate/confirm
efficacy
• Establish safety profile
• Provide an adequate basis
for assessing the benefit/risk
relationship to support
licensing
• Establish dose-response
relationship 
Study Examples 
• Adequate, and well
controlled studies to
establish efficacy
• Randomised parallel doseresponse
studies
• Clinical safety studies
• Studies of mortality/
morbidity outcomes
• Large simple trials
• Comparative studies26.Classifying Clinical Studies According to Objective: Therapeutic
Exploratory
Objective of Study
• Explore use for the targeted
indication
• Estimate dosage for
subsequent studies
• Provide basis for
confirmatory study design,
endpoints, methodologies 
Study Examples 
• Earliest trials of
relatively short duration
in well- defined narrow
patient populations, using
surrogate or
pharmacological endpoints
or clinical measures
• Dose-response exploration
studies

27.Classifying Clinical Studies According to Objective: Therapeutic UseObjective of Study
Refine understanding of
benefit/risk relationship in
general or special
populations and/or
environments
• Identify less common
adverse reactions
• Refine dosing
recommendation 
Study Examples 
• Comparative effectiveness
studies
• Studies of
mortality/morbidity
outcomes
• Studies of additional
endpoints
• Large simple trials
• Pharmaco28.CLINICAL SAFETY DATA MANAGEMENT:
DEFINITIONS AND STANDARDS FOR
EXPEDITED REPORTING
ICH E2A29.CLOSE-OUT FEESClose-out fees include time spent by site staff to reconcile clinical trial data, finances and regulatory documents during study closure. Not all sites require this payment but has started to become a more common practice in recent years.30.The concept of subject vulnerability is important to research ethics and to regulatory compliance. FDA at 21 CFR 56.111(b) (Institutional Review Boards 2014) requires that"when some or all of the subjects are likely to be vulnerable to coercion or undue influence, additional safeguards have been included in the study to protect the rights and welfare of these subjects.31.Consent and AssentAs a rule, a pediatric subject is legally unable to provide informed consent. Therefore
pediatric study participants are dependent on their parent(s)/legal guardian to
assume responsibility for their participation in clinical studies. Fully informed
consent should be obtained from the legal guardian in accordance with regional laws
or regulations. All participants should be informed to the fullest extent possible about
the study in language and terms they are able to understand. Where appropriate,
participants should assent to enroll in a study (age of assent to be determined by
IRB's/IEC's or be consistent with local legal requirements).32.The consent process should be conducted in the language spoken by the subject, and the consent form should be translated into that language. T/F?True33.Considerations for Individual Clinical Trials1 Objectives
2 Design
3 Conduct
4 Analysis
5 Reporting

34.CONSIDERATIONS FOR OVERALL CLINICAL DEVELOPMENT : Trial Context1 Development Plan 
a. Confirmatory Trial 
b. Exploratory Trial
2 Scope of Trials
a. Population
b. Primary and Secondary Variables 
c. Composite Variables 
d. Global Assessment Variables 
e. Multiple Primary Variables 
f. Surrogate Variables 
g. Categorised Variables
3 Design Techniques to Avoid Bias 
a. Blinding 
b. Randomisation35.Considerations for the Development Plan : Non-Clinical StudiesImportant considerations for determining the nature of non-clinical studies and their
timing with respect to clinical trials include:
a) duration and total exposure proposed in individual patients
b) characteristics of the drug (e.g. long half life, biotechnology products)
c) disease or condition targeted for treatment
d) use in special populations (e.g. women of childbearing potential)
e) route of administration
The need for non-clinical information including toxicology, pharmacology and
pharmacokinetics to support clinical trials is addressed in the ICH M3 and S6
documents.36.Considerations for the Development Plan : Pharmacological and Pharmacokinetic StudiesThe basis and direction of the clinical exploration and development rests on the nonclinical
pharmacokinetic and pharmacology profile, which includes information such
as:
a) Pharmacological basis of principal effects (mechanism of action).
b) Dose-response or concentration-response relationships and duration of action
c) Study of the potential clinical routes of administration
d) Systemic general pharmacology, including pharmacological effects on major organ
systems and physiological responses
e) Studies of absorption, distribution, metabolism and excretion37.Considerations for the Development Plan : Safety StudiesFor the first studies in humans, the dose that is administered should be determined
by careful examination of the prerequisite non-clinical pharmacokinetic,
pharmacological and toxicological evaluations (see ICH M3). Early non-clinical
studies should provide sufficient information to support selection of the initial human
dose and safe duration of exposure, and to provide information about physiological
and toxicological effects of a new drug.

38.The content for an IND for studies of marketed products is the same as the content for studies of new drugs, with what exception?A copy of the approved labeling (including the package insert) can be provided in lieu of the Investigator's Brochure (IB).39.Content ValidityThe extent to which a variable (e.g. a rating scale) measures what it is supposed to
measure.40.Contrary to popular belief, it is not always necessary or advisable to break the code in a medical emergency. The code should be broken only when the identity of the investigational product that the subject received will determine the treatment to be given to that subject for the emergency. T/F?True41.DATA ANALYSIS CONSIDERATIONS1 Prespecification of the Analysis
2 Analysis Sets
3 Missing Values and Outliers
4 Data Transformation 
5 Estimation, Confidence Intervals and Hypothesis Testing 
6 Adjustment of Significance and Confidence Levels 
7 Subgroups, Interactions and Covariates
8 Integrity of Data and Computer Software Validity42.The data reported on the CRF must beconsistent with the source documents, and any discrepancies between the CRF and source document should be explained.43.Dispensing/administration information should be recorded inThe case report form (CRF) and the subject's medical record, so there is a record of experimental product exposure.44.double-blindedneither the investigator nor the subject knows which treatment the subject is to receive45.Double-DummyA technique for retaining the blind when administering supplies in a clinical trial,
when the two treatments cannot be made identical. Supplies are prepared for
Treatment A (active and indistinguishable placebo) and for Treatment B (active and
indistinguishable placebo). Subjects then take two sets of treatment; either A (active)
and B (placebo), or A (placebo) and B (active).

46.DropoutA subject in a clinical trial who for any reason fails to continue in the trial until the
last visit required of him/her by the study protocol.47.Drug Supplier/Manufacturermeans in addition to producing the drug, the company also supplies the investigator with the drug for use in the study.48.Drug usage is reconciled by reviewing the paper trail, includingShipping records showing receipt of the investigational product
Dispensing/administration records showing usage of the product
Reconciliation records for unaccounted-for product
Final disposition records documenting disposal of investigational product49.During the initial visit, the sponsor organization typically provides a study document storage unit. Site personnel must maintain the study records in this storage unit throughout the study.

Examples of the records that must be maintained include
Protocol and any amendments
IB
Sample and all approved versions of ICFs
Data-collection instructions
IRB submissions, correspondence, and approvals
Copy of Form FDA 1572
Copies of financial disclosure forms
Subject recruitment and retention records
Investigational agent accountability records
Correspondence (between sponsor, investigator, IRB, and regulatory authorities)50.EC/IRB FEESEC/IRB fees are in addition to site start-up fees. These fees cover the time spent by EC/IRB to plan and conduct review of the clinical trial protocol and other associated materials. Many EC/IRBs update and publish their rates annually.51.Electronic or paper forms to track investigational products should indicate?the product's name, strength, and formulation52.ELEMENTS OF REPORTING1 Evaluation and Reporting 
2 Summarising the Clinical Database53.ELEMENTS OF Summarising the Clinical Database1 Efficacy Data
2 Safety Data54.ELEMENTS OF THE EVALUATION OF SAFETY AND TOLERABILITY1 Scope of Evaluation 
2 Choice of Variables and Data Collection 
3 Set of Subjects to be Evaluated and Presentation of Data
4 Statistical Evaluation
5 Integrated Summary55.Equivalence TrialA trial with the primary objective of showing that the response to two or more
treatments differs by an amount which is clinically unimportant. This is usually
demonstrated by showing that the true treatment difference is likely to lie between a
lower and an upper equivalence margin of clinically acceptable differences.56.Essential DocumentsAre defined by ICH (2016) E6 (Section 1.23) as the documents which individually and collectively permit evaluation of the conduct of a study and the quality of the data produced.57.EthicalConforming to an established set of principles or accepted professional standards of conduct.

58.Ethical Issues in Pediatric StudiesThe pediatric population represents a vulnerable subgroup. Therefore, special
measures are needed to protect the rights of pediatric study participants and to shield
them from undue risk.59.Examples of budget Invoice
Items
1. Subject travel, lodging, meals, parking
reimbursement
2. Record archiving
3. Subcontractor payments60.EXAMPLES OF Direct
Costs
• Study personnel (e.g., labor)
• Tests/procedures (i.e., services that generate
bills, regardless of the payer source)
• Operating expenses (e.g., phones, faxes,
copying)61.EXAMPLES OF Indirect
Costs
• Institutonal expenses (e.g., support services,
space, IT, HR)
• Driven by Institutonal policy
• Infrastructure within the unit (i.e., study team
make-up, management)62.EXAMPLES OF LABOR COSTSA. CLINICAL RESEARCH ASSISTANTS OR ASSOCIATES (CRAS)
B. PROJECT MANAGER (ALSO KNOWN AS CLINICAL TRIAL MANAGER OR STUDY MANAGER)
C. DATA MANAGER
D. SCIENTIST
E. BIOSTATISTICIAN
F. QUALITY63.EXEMPTIONS FROM THE REQUIREMENT FOR AN INDAccording to 21 CFR 312.2(b) (Investigational New Drug Application 2014), investigations using a marketed drug or biologic do not require submission of an IND if all six conditions below are met:

1. It is not intended to be reported to FDA in support of a new indication for use or to support any other significant change in the labeling for the drug.
2. It is not intended to support a significant change in the advertising for the product.
3. It does not involve a route of administration or dosage level, use in a subject population, or other factor that significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the drug.
4. It is conducted in compliance with the requirements for Institutional Review Board (IRB) review and informed consent.
5. It is conducted in compliance with the requirements concerning the promotion and sale of drugs.
6. It does not intend to invoke 21 CFR 50.24 (exception from informed consent for emergency research).64.EXPLAIN CLINICAL EVALUATION COMMITTEE (CEC) COSTSAdverse event and endpoint data is adjudicated by a non-biased, independent CEC. CEC is generally composed 3 or more physicians. CEC members review adverse events and trial endpoints in a team setting or independently.

A sponsor can hire physicians to serve as the CEC and reimburse them at fair market value rates. It is more cost effective for sponsor to contract with physicians directly. But the sponsor has to assign its own resources to manage the CEC.

The other option is for the sponsor to outsource management and conduct of CEC activities. However this option is more expensive because you are hiring professionals to manage the CEC.

CEC is a very important component of medical device clinical trial. Adjudicated adverse event data is highly regarded by regulatory agencies and the physician community. In many cases, it is a requirement to have adjudicated adverse event data in order to get the product on market.

65.EXPLAIN DATA SAFETY MONITORING BOARD (DSMB) COSTSDSMB is sometimes known as the the Data Monitoring Committee (DMC). According to IMARC research, the purpose of the DMC is to advise the sponsor on continuing safety of the trial subjects and those yet to be recruited and provide continuing validity and scientific merit of the study.

For budgeting purposes, it is important to know that DSMB is required during trial enrollment phase. In some cases DSMB meetings occur till all patients have reached their primary endpoint. The decision of whether or not to conduct DSMB meetings after the primary endpoint is reached, is up to the sponsor.66.EXPLAIN INDEPENDENT CORELAB ANALYSIS COSTSMany medical device trials collect imaging data such as angiograms, CT scans and X-Rays. Since this data comes from multiple sites, variability is expected. An independent corelab standardizes the collection and analysis of imaging data.

Corelab costs can add up quickly. Costs depend upon the number of images analyzed per patient, the time it takes for the corelab to analyze the data, and the duration of the trial.

Corelabs usually hire analysts to collect and calibrate data from different sites. The final analysis is usually done by a physician. Given the complexity of imaging data collection and analysis combined with the importance of corelab data to regulatory agencies, it is important that adequate and accurate budget is allocated for independent corelab analysis.67.EXPLAIN MEDICAL DEVICE COSTSOnce you are ready to enroll patients in the clinical trial, you'll need to ship medical devices to the sites. Most sites will expect to receive these devices for free. The only exception is when conducting post approval trials for commercially available devices.

Medical device manufacturers conduct trials for indication expansion. For example, a stent company may conduct a trial to get their heart stent approved for use in a different anatomy. For such expansion trials, sponsors may need to provide commercially available devices to sites at no cost. 

Whether or not you want to provide devices at no cost is a business decision. When investigational medical devices are provided at no cost, sites enroll faster and have a much stronger, collaborative relationship with the sponsor.68.EXPLAIN PHYSICIAN CONSULTING COSTSPhysicians are consulted during all phases of a clinical trial. Physician guidance is needed to develop clinical trial strategy, enrollment plan, final data analysis and publication plans.

Physician consulting costs can be anywhere between $150 - $600+ per hour. The billable rate varies based on physician's medical expertise and geographical location. If a clinical trial is interesting to the physician, he or she may be willing to provide consulting services at little or no cost.69.Failure to comply with GCP guidelines may ultimately result in the inability to continue conducting clinical trials. T/F?True70.Failure to maintain the product as required or a lack of written evidence that storage conditions were met may result in ________________. Therefore, it is imperative to maintain records of appropriate storage conditions during clinical trials.FDA disqualification of data that could have supported a new drug application (NDA)

71.The FDA also requires information about the ______________________ of each investigator and subinvestigator who will use the investigational product as part of the clinical trial.credentials72.The FDA and HHS issued joint guidance for IRBs, investigators, and sponsors on the use of electronic systems to obtain informed consent. T/F?True: The FDA and HHS issued joint guidance for IRBs, investigators, and sponsors on the use of electronic systems to obtain informed consent. The guidance (FDA and HHS 2016) focuses on the procedures to be followed when using eIC. The FDA and HHS (2016) guidance also makes it clear that the responsibility for obtaining the subject's consent ultimately lies with the investigator, and cannot be delegated to an electronic system.73.The FDA has indicated in guidance that it is acceptable to conduct the consent discussion by phone and satisfy the requirement for a signed consent document by having the signed and dated consent form returned by facsimile (fax). T/F?True74.The FDA regulations no not require the IRB to ensure that assent from children is obtained. T/F?False: The FDA regulations do not include a similar requirement for obtaining assent from adults; however, the FDA regulations require the IRB to ensure that assent from children is obtained, unless the requirement for assent is waived.75.The FDA regulations require the label for investigational drugs to contain specific information. Labels on investigational drugs may differ in design but all such labels should contain the following minimum primary information:Name of the study
Name of the study drug (even the placebo is labeled with the study drug code)
Subject study number
How supplied (for example, the number of tablets per container)
Dose per unit (mg per tablet, mg/mL, etc.)
Lot number
Batch number
A federal statement limiting use to experimental studies: "Caution: New Drug - Limited by Federal Law to Investigational Use" (Investigational New Drug Application 2014)76.The following information is subbmitted to the FDA to obtain an IND. 1-101. Cover letter
2. Form FDA 1571 [IND]
3. Form FDA 1572 (Statement of Investigator)
4. Introductory statement and general investigational plan
5. Investigator's Brochure
6. Protocol(s)
7. Chemistry, manufacturing, and controls information
8. Pharmacology and toxicology information
9. Previous human experience with drug
10. Additional information
Relevant information77.The following information must be reported by investigators to the company that submits the new drug application (NDA) (21 CFR 54 [Financial Disclosure by Clinical Investigators 2014]):Compensation made to the investigator in which the value of compensation could be affected by study outcome
A proprietary interest in the tested product, including, but not limited to, a patent, trademark, copyright, or licensing agreement
Any equity interest in the sponsor of a covered study (that is, any ownership interest, stock options, or other financial interest whose value cannot be readily determined through reference to public prices)
Any equity interest in a publicly held company that exceeds $50,000 in value78.Form FDA 1571 is aContractual agreement between the sponsor and FDA.79.FORM FDA 1572STATEMENT OF INVESTIGATOR80.Form FDA 1572 (Statement of Investigator). By signing this form, the investigator enters into a legally binding contract withthe FDA

81.For purposes of financial disclosures, the term "clinical investigator" includes anyone who is directly involved in the treatment or evaluation of research subjects. The term also includeshe spouse and each dependent child of the investigator (21 CFR 54 [Financial Disclosures by Clinical Investigators 2014]).82.Frequentist MethodsStatistical methods, such as significance tests and confidence intervals, which can be
interpreted in terms of the frequency of certain outcomes occurring in hypothetical
repeated realisations of the same experimental situation.83.Full Analysis SetThe set of subjects that is as close as possible to the ideal implied by the intention-totreat
principle. It is derived from the set of all randomised subjects by minimal and
justified elimination of subjects.84.GENERAL CONSIDERATIONS FOR CLINICAL TRIALSICH E885.Generalisability, GeneralisationThe extent to which the findings of a clinical trial can be reliably extrapolated from
the subjects who participated in the trial to a broader patient population and a
broader range of clinical settings.86.Generally, the sponsor will enter into a _________________________with the investigator and site. This agreement is a contract that defines both the terms of study conduct and the financial agreements. There are also several other documents that must be completed before the investigator can begin to conduct in the trial.a clinical trial agreement (CTA)87.General Principles OF CLINICAL INVESTIGATION OF MEDICINAL PRODUCTS
IN THE PEDIATRIC POPULATION ICH GUIDANCE
Pediatric patients should be given medicines that have been appropriately evaluated
for their use.88.GENERAL PRINCIPLES : Protection of clinical trial subjectsThe principles and practices concerning protection of trial subjects are stated in the
ICH Guideline on Good Clinical Practice (ICH E6). These principles have their origins
in The Declaration of Helsinki and should be observed in the conduct of all human
drug investigations.

89.GENERAL PRINCIPLES : Scientific approach in design and analysisClinical trials should be designed, conducted and analysed according to sound
scientific principles to achieve their objectives; and should be reported appropriately.
The essence of rational drug development is to ask important questions and answer
them with appropriate studies. The primary objectives of any study should be clear
and explicitly stated.90.Global Assessment VariableA single variable, usually a scale of ordered categorical ratings, which integrates
objective variables and the investigator's overall impression about the state or change
in state of a subject.91.HOW DO i CALCULATE BASELINE/INDEX PROCEDURE AND FOLLOW-UP VISITS REIMBURSEMENTSDepending on the clinical trial design, data is collected at baseline or index procedures and follow-up visits. The site coordinator is generally responsible for entering the data in the case report form. Sites are reimbursed for the time spent to collect clinical trial data.

Based on number and type data fields you are collecting, you'll want to estimate the site coordinator time needed to collect and input trial data. Then multiply the estimated coordinator time by the hourly bill rate to obtain the fair market value for each patient visit.

In some cases, sponsors may choose to reimburse patients. Reimbursement for patients can include paying for their participation, reimbursement for travel, meals or overnight hotel stays.92.How do I determine screen failure reimbursments?During the budgeting process, map out the complete patient screening workflow. Speak with a few clinical sites to understand how many patients they would have to see in order to find one qualified patient. For example, a site may need to screen four patients to find one qualified patient. Understand how many hours the site is spending on screening activities and reimburse accordingly. Therefore it's not unusual to reimburse sites anywhere between $50 to $250+ per screen failure.93.How to Report expedited adverse
events
The CIOMS-I form has been a widely accepted standard for expedited adverse
event reporting. However, no matter what the form or format used, it is
important that certain basic information/data elements, when available, be
included with any expedited report, whether in a tabular or narrative
presentation.94.The ICH (2016) E6 guidance document provides detailed information regarding the following:Principles of ICH GCP
IRB
Investigator
Sponsor
Clinical trial protocol and protocol amendments
Investigator's Brochure
Essential documents for the conduct of a clinical trial95.ICH (2016) E6 Section 4.1 notes a number of investigator obligations:The investigator(s) should be qualified by education, training, and experience to assume responsibility for the proper conduct of the trial, should meet all the qualifications specified by the applicable regulatory requirement(s), and should provide evidence of such qualifications through an up-to-date curriculum vitae (CV) and/or other relevant documentation requested by the sponsor, the IRB, and/or the regulatory authority(ies).
The investigator should be thoroughly familiar with the appropriate use of the investigational product(s), as described in the protocol, in the current Investigator's Brochure (IB), in the product information and in other information sources provided by the sponsor.
The investigator should be aware of, and should comply with, good clinical practice (GCP) and the applicable regulatory requirements.
The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authority(ies).
The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties.96.ICH (2016) E6 Section 4.3 describesthe investigator's responsibilities with respect to medical care of subjects. According to the guidance, investigators should make certain that adequate medical care is provided to the subjects for adverse events (AEs) and abnormal laboratory values that are related to the trial. If the investigator becomes aware that medical care is needed, the investigator should inform the subject. A qualified physician (or dentist, when appropriate) should be responsible as either an investigator or sub-investigator for all trial-related medical (or dental) decisions.

97.ICH (2016) E6 Section 4.6 also outlines the requirements of investigators. The investigator is responsible forproduct accountability at the study site and maintenance of the clinical and research records.98.ICH [2016] E6 Section 4.8.8The person obtaining consent should also sign and date the consent form99.ICH (2016) E6 Section 4.8.15 requires the protocol to describe the process for conducting research in emergency situations without first obtaining consent and requires IRB approval of the process. T/F?True100.ICH (2016) E6 Section 4.12 notes the following:4.12.1 - If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator should inform the institution where applicable, and the investigator/institution should promptly inform the sponsor and the IRB, and should provide the sponsor and the IRB a detailed written explanation of the termination or suspension.101.ICH E6 is?as a standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.102.ICH E6 notes that if the clinical trial is prematurely terminated or suspended, regardless of the reason, that the investigator or the organization should promptly notify?1. The subjects in the study. 
2. The investigator /organization should be certain that appropriate therapy and follow-up are provided for the subjects. 
3. Where required by regulations, the investigator/organization may also need to inform the regulatory authorities of the premature termination or suspension of the trial.103.ICH HARMONISED TRIPARTITE GUIDELINE E11CLINICAL INVESTIGATION OF MEDICINAL PRODUCTS
IN THE PEDIATRIC POPULATION104.If a deviation was needed to eliminate a hazard, the deviation must bedocumented and rationale submitted to the sponsor, IRB, and regulatory authorities. In some instances, an investigator inadvertently deviates from the protocol. When such unplanned deviations are discovered, the investigator should explain the deviation in writing. In addition, the investigator should take appropriate corrective actions and follow the steps necessary to ensure that similar deviations do not occur in the future.105.If an investigator plans to deviate from the protocol for a purpose other than to eliminate an immediate hazard, the investigator mustobtain prior approval from the sponsor and the IRB106.If a pharmacist is unavailable, an ______________________________ individual should ensure that the product is appropriately stored.appropriately qualified and delegated107.If a research pharmacy is not available, investigational products can be stored in other areas as long as the following requirements are metSponsor-directed storage requirements are followed.
Area is monitored, with written evidence of appropriate storage conditions (temperature monitoring logs for the room, refrigerator, etc.).
Access is limited at all times (key or other entry device required).
Product is supplied only to subjects in the trial.
Accountability records are maintained.
Space is adequate.108.If the investigator deviates from the protocol without IRB approval to eliminate an immediate hazard to subjects, the investigator should report the deviation ___________________to the sponsor and the IRB per their reporting requirements (ICH [2016] E6 Section 4.5.4).as soon as possible

109.If the IRB does not approve the study, requires additional information, or requires changes to the consent form or protocol, the investigator shouldnotify the sponsor who will assist the investigator in responding to the IRB queries110.If there are other changes to information contained on a signed and dated Form FDA 1572 (for example, an IRB address change or the addition of a clinical research lab), the investigator shoulddocument the changes in the clinical study records and inform the sponsor of the changes, so that the sponsor can appropriately update the IND. The guidance explains that for such changes, the Form FDA 1572 does not need to be revised and a new Form FDA 1572 does not need to be completed and signed by the investigator.111.In addition, if relevant to the research, legally effective informed consent will also include the following elements:A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant), which are currently unforeseeable.
Anticipated circumstances under which the subject's participation may be terminated by the investigator without regard to the subject's consent.
Any additional costs to the subject that may result from participation in the research.
The consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject.
A statement that significant new findings developed during the course of the research which may relate to the subject's willingness to continue participation will be provided to the subject.
The approximate number of subjects involved in the study.112.In addition to the above requirements, investigators should comply with the following guidelines during the consent process:The language used to obtain consent is nontechnical and scientific terms or concepts are explained.
The subject has an opportunity to ask questions and those questions have been answered to the subject's satisfaction.
The consent form or consent discussion does not include any exculpatory language through which the subject is made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, the sponsor, the organization, or its agents from liability for negligence.
Inform subjects that they can withdraw from the study at any time.113.The IND application outlinesthe general investigational plan for the development of the drug. Amendments to the IND are made (for example, new protocols or new side effect information) as the product moves through the clinical development process.114.Independent Data Monitoring Committee (IDMC) (Data and Safety
Monitoring Board, Monitoring Committee, Data Monitoring Committee)
An independent data-monitoring committee that may be established by the sponsor to
assess at intervals the progress of a clinical trial, the safety data, and the critical
efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or
stop a trial.115.Indirect Cost Rate (IDC)All procedural and non-procedural line items. Exemptions: subject stipends /reimbursements.116.In early-phase clinical trials, _________ quantities of drug are neededsmaller117.Infants and toddlers28 days to 23 months118.Informed Consent Form (also called Informed Consent Document)The document that includes the information needed for potential subjects to have sufficient information to provide informed consent to participate in a clinical trial.119.The informed consent process does not need to be documented in the medical record or source file. T/F?False: The informed consent process should be documented in the medical record or source file (as well as documentation regarding communication of new information).

120.The informed consent process includes:Recruiting subjects, including advertising for research subjects and discussions that occur during the screening process
Providing specific information about the study in a way that is understandable to potential subjects while giving them adequate time to consider participation
Answering the potential subjects' questions
Obtaining the voluntary agreement of subjects to take part in the study
Verifying the subjects' continued consent to participate as the study progresses121.Initial Investigational Pharmacy FeeThis is a one-time fee that includes study initiation and closing costs. The fee reimburses the investigational pharmacy for the time that is required of the pharmacist (PharmD) and/or pharmacy technician (PT) to perform non-dispensing related tasks122.In limited circumstances, the FDA allows an investigator to obtain consent verbally without obtaining a signature on the consent form. T/F?In limited circumstances, the FDA allows an investigator to obtain consent verbally without obtaining a signature on the consent form (21 CFR 56.109[c][1] [Institutional Review Boards 2014]).123.In October 2009, FDA issued the Guidance for Industry: Investigator Responsibilities - Protecting the Rights, Safety, and Welfare of Study Subjects. This guidance (FDA 2009b) clarifiesthe general responsibilities of the investigator applicable to clinical trials of drugs, biologics, and devices. It also emphasizes an investigator's obligation to protect the rights, safety, and welfare of study subjects and the investigator's responsibility to supervise the conduct of the clinical trial.124.In some instances, investigators are required to disclose the financial interests they have in the sponsoring organization and in the outcome of the investigation. Disclosures are required for "covered clinical studies," which areclinical trials of drugs or devices from which the data will be submitted to the FDA to support a marketing application or relied upon by the FDA to establish effectiveness (21 CFR 54 [Financial Disclosure by Clinical Investigators 2014]).125.Intention-To-Treat PrincipleThe principle that asserts that the effect of a treatment policy can be best assessed by
evaluating on the basis of the intention to treat a subject (i.e. the planned treatment
regimen) rather than the actual treatment given. It has the consequence that subjects
allocated to a treatment group should be followed up, assessed and analysed as
members of that group irrespective of their compliance to the planned course of
treatment.126.Interaction (Qualitative & Quantitative)The situation in which a treatment contrast (e.g. difference between investigational
product and control) is dependent on another factor (e.g. centre). A quantitative
interaction refers to the case where the magnitude of the contrast differs at the
different levels of the factor, whereas for a qualitative interaction the direction of the
contrast differs for at least one level of the factor.127.Interim AnalysisAny analysis intended to compare treatment arms with respect to efficacy or safety at
any time prior to the formal completion of a trial.128.Inter-Rater ReliabilityThe property of yielding equivalent results when used by different raters on different
occasions.

129.In the FDA Information Sheets, the FDA recommends that informed consent must be obtained before the subject participates in any procedures that are done solely for research purposes, including determining eligibility for the study and withdrawing medication (wash-out). T/F?True130.In the guidance, the FDA noted that there are two instances when it is necessary for an investigator to complete and sign a new Form FDA 1572:When an investigator is participating in a new protocol that has been added to the IND
When a new investigator is added to the study131.Intra-Rater ReliabilityThe property of yielding equivalent results when used by the same rater on different
occasions.132.In treatment situations where an individual has a life-threatening condition and the following requirements are met and documented (21 CFR 50.23)The investigator, with the concurrence of another physician, believes the situation necessitates the use of a test article (in other words, an investigational drug, device, or biologic);
The subject and/or LAR is unable to communicate consent;
There is insufficient time to obtain consent;
No alternative exists that will provide an equal or better chance of saving the subject's life; and
The IRB is informed of the use of the investigational product without informed consent within five (5) working days of the event.133.Investigational Drugis "a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use" (ICH [2016] GCP E6 Section 1.33).134.Investigational New Drug (IND)is "a new drug, antibiotic drug, or biological drug that is used in a clinical investigation. The term also includes a biological product that is used in vitro for diagnostic purposes" (21 CFR 312.3 [Investigational New Drug Application 2014]).135.Investigational Productany unapproved drug or biological product undergoing clinical trials to provide evidence to regulatory authorities that the product is safe and efficacious.136.Investigational Product is defined by ICH (2016) asas "a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.137.The investigational product shipment will usually include apackaging list or shipping invoice138.Investigational products must be stored according toprotocol specifications and the manufacturer's directions139.The investigator does not have to maintain records to document that the subjects were provided the doses specified in the protocol. T/F?False140.The investigator is also required to provide evidence that he or she is qualified to properly conduct the trial through submission ofan up-to-date curriculum vitae (CV) (ICH [2016] E6 Section 4.1.1.).141.The investigator is required to make the study records available to?the monitor, auditors, the IRB, the FDA, and other regulatory authorities.

142.The investigator is required to submit all investigational materials to the IRB for approval. These documents includethe protocol, informed consent form (ICF), Investigator's Brochure (IB), subject recruitment procedures and material, and any written information to be provided to the subjects (ICH [2016] E6 Section 4.4). Each IRB may have additional requirements based on the type of investigation being conducted. Once IRB approval is obtained, the investigator notifies the sponsor organization.143.The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data in the CRFs and in all required reports(ICH [2016] E6 Section 4.9.1).144.The investigator must maintain study records forat least two (2) years after the drug has been granted marketing approval in the U.S. for the indication tested in the study or, if no application will be filed or if the application is not approved for the indication, for at least two (2) years after the investigation is terminated and the FDA is notified.145.Investigators agreeing to participate in pharmaceutical company-sponsored clinical investigations have commitments tothe sponsor, IRB, subjects, and FDA146.Investigators also must provide periodic updates to the IRB in accordance with its policies. This typically occurs ___________________________ but may be required more often by the individual IRB (ICH [2016] E6 Section 4.9.7).at least once per year147.Investigators cannot delegate the responsibility of product accountability (control) to qualified personnel, such as the pharmacist or study coordinator? T/F?False: Investigators can delegate the responsibility of product accountability (control) to qualified personnel, such as the pharmacist or study coordinator148.Investigator's commitments to the FDA are?Allow inspections of the facilities and records.
Retain study records.
Comply with GCP standards.149.Investigator's commitments to the IRB are?Submit study documents for initial and ongoing approval.
Notify IRB of SAEs (per IRB requirements).
Notify IRB of unanticipated problems involving risks to subjects or others.
Provide periodic updates (as required by IRB).
Provide notice of study completion/termination and summary of the study.150.Investigator's commitments to the RESEARCH SUBJECTS are?Ensure that informed consent is obtained before starting study procedures.
Ensure that study procedures are explained adequately and performed appropriately.
Ensure that the rights and welfare of study subjects are protected.
Ensure the medical safety of the subject to the extent possible.151.Investigator's commitments to the sponsor areRecruit subjects within the agreed timeframe.
Perform study procedures according to the protocol.
Complete and submit required regulatory documents (Form FDA 1572, financial disclosure forms).
Notify the sponsor of any facility changes or changes that call for a revised Form FDA 1572.
Maintain study site records (Form FDA 1572, disclosure forms, study team training logs).
Maintain subject source documents and study records.
Notify sponsor of serious AEs.152.An investigator shall administer the drug only to subjects under the investigator's personal supervision or under the supervision of a subinvestigator responsible to the investigator. The investigator shall not supply the investigational drug to any person not authorized under this part to receive it(21 CFR 312.61 [Investigational New Drug Application 2014]).

153.Investigators may delegate responsibilities to appropriately qualified persons. This must be documented in writing, usually with a _________________ 
that contains the names of study staff members and the responsibilities assigned to them, with their signature and date as well as the PI's initials and date. The investigator is still ultimately responsible for the conduct of the study, and is responsible for supervising and/or training any individual to whom he/she delegates tasks (ICH [2016] 4.2.5).
a delegation of authority log154.The IRB can waive the requirement for assent if it determinesThe children are incapable of understanding the research;

There is a prospect of direct benefit to the children that is not available outside of the research; or

If the requirements for a waiver of consent (21 CFR 50.55[c] [Protection of Human Subjects 2014]) are met.155.IRB fees:Pay attention to terms that limit the number of IRB amendments and renewals that can be invoiced. These limits should be negotiated out of the budget.156.IRB Fee TypesInitial Review, Annual Renewal, Amendment157.Items requiring an invoice (not included in the per subject payment)1. Non-procedural fees (subject travel, dry ice)
2. Procedural assessments that do not pertain to every subject enrolled or may be considered optional per the study.158.It is important for investigators to have proper equipment available to satisfy storage requirements and also to have ________________ in place to ensure that storage requirements are continuously satisfied.procedures159.It is the sponsor-investigator's responsibility to comply with GCP when conducting a study. T/F?True160.KEY DATA ELEMENTS FOR INCLUSION IN EXPEDITED
REPORTS OF SERIOUS ADVERSE DRUG REACTIONS 1. Patient Details
Initials
Other relevant identifier (clinical investigation number, for example)
Gender
Age and/or date of birth
Weight
Height

161.KEY DATA ELEMENTS FOR INCLUSION IN EXPEDITED
REPORTS OF SERIOUS ADVERSE DRUG REACTIONS 2. Suspected Medicinal Product(s)
Brand name as reported
International Non-Proprietary Name (INN)
Batch number
Indication(s) for which suspect medicinal product was prescribed or tested
Dosage form and strength
Daily dose and regimen (specify units - e.g., mg, ml, mg/kg)
Route of administration
Starting date and time of day
Stopping date and time, or duration of treatment162.KEY DATA ELEMENTS FOR INCLUSION IN EXPEDITED
REPORTS OF SERIOUS ADVERSE DRUG REACTIONS 3. Other Treatment(s)
For concomitant medicinal products (including non-prescription/OTC medicinal
products) and non-medicinal product therapies, provide the same information as
for the suspected product.163.KEY DATA ELEMENTS FOR INCLUSION IN EXPEDITED
REPORTS OF SERIOUS ADVERSE DRUG REACTIONS 4. Details of Suspected Adverse Drug Reaction(s)
Start date (and time) of onset of reaction
Stop date (and time) or duration of reaction
Dechallenge and rechallenge information
Setting (e.g., hospital, out-patient clinic, home, nursing home) 
Outcome164.KEY DATA ELEMENTS FOR INCLUSION IN EXPEDITED
REPORTS OF SERIOUS ADVERSE DRUG REACTIONS 5. Details on Reporter of Event (Suspected ADR)
Name
Address
Telephone number
Profession (speciality)165.KEY DATA ELEMENTS FOR INCLUSION IN EXPEDITED
REPORTS OF SERIOUS ADVERSE DRUG REACTIONS 6. Administrative and Sponsor/Company Details
Source of report: was it spontaneous, from a clinical investigation (provide
details), from the literature (provide copy), other?
Date event report was first received by sponsor/manufacturer
Country in which event occurred
Type of report filed to authorities: initial or follow-up (first, second, etc.)
Name and address of sponsor/manufacturer/company
Name, address, telephone number, and FAX number of contact person in
reporting company or institution
Identifying regulatory code or number for marketing authorisation dossier or
clinical investigation process for the suspected product (for example IND or CTX
number, NDA number)
Sponsor/manufacturer's identification number for the case (this number must be
the same for the initial and follow-up reports on the same case).166.Legally Authorized Representative (LAR)means an individual, judicial, or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedure(s) involved in the research.167.List of examples of vulnerable subjects"children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons" (21 CFR 56 [Institutional Review Boards 2014]).168.Managing Blinded Therapy CasesWhen the sponsor and investigator are blinded to individual patient treatment
(as in a double-blind study), the occurrence of a serious event requires a decision
on whether to open (break) the code for the specific patient. If the investigator
breaks the blind, then it is assumed the sponsor will also know the assigned
treatment for that patient.169.Meta-AnalysisThe formal evaluation of the quantitative evidence from two or more trials bearing on
the same question. This most commonly involves the statistical combination of
summary statistics from the various trials, but the term is sometimes also used to
refer to the combination of the raw data.

170.Minimum criteria for reportingInformation for final description and evaluation of a case report may not be
available within the required time frames for reporting outlined above.
Nevertheless, for regulatory purposes, initial reports should be submitted within
the prescribed time as long as the following minimum criteria are met: an
identifiable patient; a suspect medicinal product; an identifiable reporting source;
and an event or outcome that can be identified as serious and unexpected, and for
which, in clinical investigation cases, there is a reasonable suspected causal
relationship. Follow-up information should be actively sought and submitted as
it becomes available.171.Multicentre TrialA clinical trial conducted according to a single protocol but at more than one site, and
therefore, carried out by more than one investigator.172.Multicentre trials are carried out for two main reasons?1. a multicentre trial is
an accepted way of evaluating a new medication more efficiently; under some
circumstances, it may present the only practical means of accruing sufficient subjects
to satisfy the trial objective within a reasonable time-frame. 
2. a trial may be designed as a multicentre (and multi-investigator) trial
primarily to provide a better basis for the subsequent generalisation of its findings.173.NAME SOME EXAMPLES OF NON-PATIENT COSTSA. CLINICAL EVALUATION COMMITTEE (CEC)
B. DATA SAFETY MONITORING BOARD (DSMB)
C. PHYSICIAN CONSULTING
D. INDEPENDENT CORELAB ANALYSIS
E. MEDICAL DEVICE COST174.Non-Inferiority TrialA trial with the primary objective of showing that the response to the investigational
product is not clinically inferior to a comparative agent (active or placebo control).175.Non-refundable startup fees1. Clinical Study Evaluation Committee (CSEC)
IND Safety Reporting.
2. PI eCRF Training
3. Monitoring space
4. Recruitment
5. Record Retention 
6. Radiology start-up
7. Pharmacy (start-up and close-out)176.Non-refundable start-up fees:There are some sponsors that include stipulations such as receipt of all regulatory documents, IRB approval and/or site initiation visit.177.OBJECTIVES OF THE CLINICAL INVESTIGATION OF MEDICINAL PRODUCTS
IN THE PEDIATRIC POPULATION GUIDANCE?
to encourage and facilitate timely pediatric medicinal
product development internationally. The guidance provides an outline of critical
issues in pediatric drug development and approaches to the safe, efficient, and ethical
study of medicinal products in the pediatric population.

178.The obligations of a sponsor-investigator include?1. Implement a system to manage quality throughout the design, conduct, recording, evaluation, reporting, and archiving of clinical trials (ICH 2016).
2. Implement research as approved.
3. Report all changes to the IND to FDA including:
Protocol changes
Technical changes to CMC or preclinical section
4. Annual reports
5. Adverse Events (AEs) requiring expedited reporting
6. Monitor conduct and progress of clinical trial (this can be done through a risk-based approach) including documentation of monitoring plan and monitoring results.
7. Maintain records of receipt, shipment, and other disposition of the drug if the drug is considered investigational.
8. Review and evaluate information relevant to safety of the drug.
9. Provide oversight to subcontractors (for example, contract research organizations [CROs]).
10. Follow-up of non-compliance through root cause analysis and corrective and preventative actions.
11. Maintain record of location of essential documents for clinical trial.179.Obtaining informed consent from the subject involves?Providing information to the subject
Answering questions the subject may have to improve his or her comprehension
Obtaining the voluntary agreement of the subject to participate in the study only after the subject has had adequate time to process the information, discuss it with family, friends, and/or other health professionals, and make a true informed decision. While a specific timeframe for this process is not given in the regulations, it normally ranges from one day to several.180.Often phase I trials do not involve drug packaging for individual subjects because only one or two doses are given to any subject. Therefore, phase I drug products may be supplied in?bulk containers, such as bottles of 100 tablets181.On 24 July 2017, the FDA issued guidance that they will not object if an IRB approves a waiver or alteration of consent for a no more than minimal risk clinical investigation if the IRB determines that (FDA 2017):The clinical investigation involves no more than minimal risk (as defined in 21 CFR 50.3[k] or 56.102[i]) to subjects;
The waiver or alteration will not adversely affect the rights and welfare of the subjects;
The research could not practicably be carried out without the waiver or alteration; and
Whenever appropriate, the subjects will be provided with additional pertinent information after participation.
It is important to note that ICH E6 does not include provisions for waiving or altering consent for no more than minimal risk research.182.Once an IND application becomes effective, a sponsor-investigat is required to submit the following reports/updates to the FDA.1. PROTOCOL 2. AMENDMENTS
3. INFORMATION 4. AMENDMENTS
5. ADVERSE EVENTS 
6. IND SAFETY REPORTS
7. ANNUAL REPORTS
8. FINAL REPORTS
9. FINANCIAL DISCLOSURE 10. REPORTS

183.Once IRB approval is obtained and other organizational prerequisites have been satisfied, the study can begin at the investigator's site. The sponsor organization will "initiate" a site through a site visit or other mechanism. At this initiation stage, the ________________ will be reviewed. Once a site is initiated, study product may be shipped to the site and subject recruitment may begin.protocol, data-collection instructions, and regulatory obligations184.Once the study has been terminated, the investigator is required to _____________ and provide .notify the IRB
a summary (final) report185.Other examples of populations that may require additional considerations include:Subjects in emergency situations
Subjects who are marginalized in society
Members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, and members of the armed forces
Subjects with fatal or incurable diseases
The elderly
Persons in nursing homes
Unemployed or impoverished persons
Ethnic minority groups
Homeless persons, nomads, refugees186.OTHER FACTORS THAT CAN INCREASE THE BUDGET?A. PROTOCOL AMENDMENTS
B. INFLATION, VALUE ADDED TAX (VAT) AND FOREIGN EXCHANGE 
C. TRIAL ENROLLMENT DELAYS187.Other ICH documents with relevant information impacting on pediatric studies
include:
E2: Clinical Safety Data Management
E3: Structure and Content of Clinical Study Reports
E4: Dose-Response Information to Support Drug Registration
E5: Ethnic Factors in the Acceptability of Foreign Clinical Data
E6: Good Clinical Practice: Consolidated Guideline
E8: General Considerations for Clinical Trials
E9: Statistical Principles for Clinical Trials
E10: Choice of Control Group in Clinical Trials
M3: Nonclinical Safety Studies for the Conduct of Human Clinical Trials for
Pharmaceuticals
Q1: Stability Testing
Q2: Validation of Analytical Procedures
Q3: Impurity Testing

188.Part 11 specifies processes that must be in place to ensure that electronic documents and signatures are equivalent to paper documents and handwritten signatures. For systems to comply with Part 11, a number of requirements about computer systems and procedures (for example, record retention) must be met (21 CFR 56 [Institutional Review Boards 2014]; 21 CFR 312 [Investigational New Drug Application 2014]; 21 CFR 812 [Investigational Device Exemptions 2014]).Computer systems utilizing electronic records and signatures must ensure accuracy, reliability, and consistent performance. Standard operating procedures (SOPs), audits, testing, and training are required.
Computer systems must use and maintain secure, computer-generated, time-stamped audit trails independently recording the date and time of entries and actions that create, modify, or delete electronic records.
Computer systems must use system checks to ensure that only those individuals authorized to use the system are allowed access to the system (and access to only those parts of the system they have authorization to use), alter records, and perform operations.
Procedures must be established to ensure that records are retained for a duration of time, in an appropriate format, and that minimally they meet FDA requirements.189.Patient grant costs are broken down intoscreening, baseline and follow-up visits and medical imaging costs190.Payment frequency, payments may be based on:1. CRF completion /monitoring. 2. A milestone number of subjects enrolled; completed study visits. (A higher frequency of payments is desirable).191.Periodically during the trial, the sponsor organization will contact or visit the site and monitor the study's progress. During site visits, the sponsor representative willreview and retrieve data, address data discrepancies, inventory drug and study supplies, and review the study records.192.Per subject payments include what type of costs?Per subject payments include costs associated with each subject on each visit and they are often generated by the submission of CRFs to the sponsor.193.Per subject payment withholdingIndustry sponsors typically withhold a percentage of study payments until the study is completed. The percent withheld is usually 10% or greater.194.Phases of Clinical DevelopmentPhase I (Most typical kind of study: Human Pharmacology) 
Phase II (Most typical kind of study: Therapeutic Exploratory) 
Phase III (Most typical kind of study: Therapeutic Confirmatory) 
Phase IV (Variety of Studies: - Therapeutic Use) 
Development of an application unrelated to original approved use

195.Post-study EventsAlthough such information is not routinely sought or collected by the sponsor,
serious adverse events that occurred after the patient had completed a clinical
study (including any protocol-required post-treatment follow-up) will possibly be
reported by an investigator to the sponsor. Such cases should be regarded for
expedited reporting purposes as though they were study reports. Therefore, a
causality assessment and determination of expectedness are needed for a decision
on whether or not expedited reporting is required.196.Preferred and Included TermsThe set of data generated by the subset of subjects who complied with the protocol
sufficiently to ensure that these data would be likely to exhibit the effects of
treatment, according to the underlying scientific model. Compliance covers such
considerations as exposure to treatment, availability of measurements and absence of
major protocol violations.197.Preterm Newborn InfantsThe study of medicinal products in preterm newborn infants presents special
challenges because of the unique pathophysiology and responses to therapy in this
population. The complexity of and ethical considerations involved in studying
preterm newborn infants suggest the need for careful protocol development with
expert input from neonatologists and neonatal pharmacologists. Only rarely will it be
possible to extrapolate efficacy from studies in adults or even in older pediatric
patients to the preterm newborn infant.198.Price cappingPrice capping is not desirable. Price caps on devices expose the institution to substantial financial risk and should be negotiated out of the budget.199.Procedures that are to be performed as part of the subject's medical care, and which would be done whether or not the participation in the trial were being considered, may not be completed prior to signing the Informed Consent. T/F?False: Procedures that are to be performed as part of the subject's medical care, and which would be done whether or not the participation in the trial were being considered, may be completed, and the information used for determining eligibility, without first obtaining informed consent from the subject.200.Products with More than one Presentation or UseTo avoid ambiguities and uncertainties, an ADR that qualifies for expedited
reporting with one presentation of a product (e.g., a dosage form, formulation,
delivery system) or product use (e.g., for an indication or population), should be
reported or referenced to regulatory filings across other product presentations
and uses.

201.Quality of Investigational Medicinal ProductsFormulations used in clinical trials should be well characterised, including
information on bioavailability wherever feasible. The formulation should be
appropriate for the stage of drug development. Ideally, the supply of a formulation
will be adequate to allow testing in a series of studies that examine a range of doses.
During drug development different formulations of a drug may be tested. Links
between formulations, established by bioequivalence studies or other means are
important in interpreting clinical study results across the development program.202.Reactions Associated with Active Comparator or Placebo TreatmentIt is the sponsor's responsibility to decide whether active comparator drug
reactions should be reported to the other manufacturer and/or directly to
appropriate regulatory agencies. Sponsors must report such events to either the
manufacturer of the active control or to appropriate regulatory agencies. Events
associated with placebo will usually not satisfy the criteria for an ADR and,
therefore, for expedited reporting.203.The records should reflect ___________________ of all investigational products received by the investigator. In other words, investigators are responsible for every individual unit of product received, and for all other study medication (non-investigational).reconciliation

204.The regulations and guidance require that potential subjects (or their LARs) be given specific information before consent can be obtained. These requirements are found in FDA regulations (21 CFR 50.25 [Protection of Human Subjects 2014]) and in the ICH (2016) E6 Section 4.8. What information must be given to the subject (or the subject's LAR):Information that the study involves research, including:
An explanation of the purposes of the research
The expected duration of the subject's participation
A description of the procedures to be followed
Identification of any procedures that are experimental
Whether or not the study involves assignment and the probability of random assignment to each group
A description of the reasonably foreseeable risks, inconveniences, or discomforts to the subject.
A description of the potential benefits to the subject or to others, including a statement that there is no intended benefit to the subject, when appropriate.
A description of any alternative procedures or treatments that may be available to the subject. In addition, ICH (2016) E6 Section 4.8 requires including a description of the "important potential benefits and risks" associated with the available alternatives (alternatives could include choosing not to participate, or choosing supportive care or comfort care).
An explanation of how the confidentiality of records will be maintained, including a statement that records identifying the subject will be kept confidential and, to the extent permitted by applicable laws and/or regulations, will not be made publicly available. The subject should be provided with a list of entities that will have access to the records. For example, the FDA regulations require this description to state that the FDA may inspect the records. In addition, ICH (2016) E6 Section 4.8.10(n) requires the consent form to advise subjects that monitors, auditors, regulatory authorities, and the IRB will be granted direct access to the subject's original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations and that, by signing a written informed consent form (ICF), the subject (or subject's LAR) is authorizing such access. Subjects should also be told that their individual identity will remain confidential if the results of the trial are published.
For research involving more than minimal risk, an explanation should describe:
Whether there will be any compensation if injury occurs;
Whether there will be any medical treatment offered and who will bear the financial responsibility for treatment if injury occurs, and, if so, how and to what extent; or
Where the subject may obtain further information.
The specific office, name, and telephone number(s) of whom to contact for further information regarding the research subject's rights, the research study, and for a research-related injury.
A statement that participation is voluntary, that refusal to participate involves no penalty or loss of benefits to which the person is otherwise entitled, and that the subject may discontinue at any time without penalty or loss of benefits to which the subject is otherwise entitled.
The responsibilities the subject will have as a research subject.
If subjects will be paid for participation, information about payment and how the payment will be pro-rated should be included.
For research that must be posted on www.ClinicalTrials.gov (applicable clinical trials), the consent form must include the following statement: "A description of this clinical trial will be available on ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time" (21 CFR 50.25[c] [Protection of Human Subjects 2014]).205.Regulations and ICH E6 guideline require investigators to maintain records of all investigational products received, dispensed, or disposed of for _______________________________.Investigational product records must be maintained for the same duration as other study records, which is at least two (2) years after the study has been completed or the investigational product has been approved for marketing.

206.The regulations require that the consent process be understandable. Guidelines for improving understanding include:Providing consent in a language that is understandable to subjects or their representative
Providing non-English speaking subjects a translated ICF
Having a translator available to assist in the consent discussion, including communicating the subject's questions and the answers to those questions
Giving the individual sufficient time to think about the research before consenting to research study participation207.Reporting Time Frames- All Other Serious, Unexpected ADRsSerious, unexpected reactions (ADRs) that are not fatal or life-threatening must
be filed as soon as possible but no later than 15 calendar days after first
knowledge by the sponsor that the case meets the minimum criteria for expedited
reporting.208.Reporting Time Frames- Fatal or Life-Threatening Unexpected ADRsRegulatory agencies should be notified (e.g., by telephone, facsimile
transmission, or in writing) as soon as possible but no later than 7 calendar days
after first knowledge by the sponsor that a case qualifies, followed by as complete
a report as possible within 8 additional calendar days.209.The representative will also assess the suitability of including the _________________ in the study, according to the qualifications outlined in 21 CFR 312.53(a) (Selecting Investigators and Monitors).investigator210.ResearchThe systematic study of materials and sources in order to establish facts and reach new conclusions.211.Safety & TolerabilityThe safety of a medical product concerns the medical risk to the subject, usually
assessed in a clinical trial by laboratory tests (including clinical chemistry and
haematology), vital signs, clinical adverse events (diseases, signs and symptoms), and
34 
Statistical Principles for Clinical Trials
other special safety tests (e.g. ECGs, ophthalmology). The tolerability of the medical
product represents the degree to which overt adverse effects can be tolerated by the
subject.212.Screen failuresSponsors prefer to pay a flat fee for screen failures rather than paying for actual costs incurred. Compensation for actual costs incurred is preferable.213.Single Cases of Serious, Unexpected ADRsAll adverse drug reactions (ADRs) that are both serious and unexpected are
subject to expedited reporting.214.SITE COSTSA. START-UP FEES
B. EC/IRB FEES
C. CLOSE-OUT FEES
D. STORAGE FEES
E. ADMINISTRATIVE OVERHEAD
F. SITE MANAGEMENT ORGANIZATION (SMO)215.SITE MANAGEMENT ORGANIZATION (SMO)In certain countries such as Japan, data entry and collection tasks are outsourced to SMOs. For post approval studies, sites do not research coordinator support. Thus sponsors are expected to hire SMOs to support the site or pay the sites to hire their preferred SMOs.216.Source Datameans all information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies).

217.Source data should beattributable, legible, contemporaneous, original, accurate, and complete. If the investigator or research staff needs to make changes to a CRF, the sponsor's requirements for making such changes should be followed.218.Source Documentis the initial documentation of data in a clinical study and includes recorded observations, laboratory reports, medical records, etc.219.Special ConsiderationsStudies of Drug Metabolites
Drug-Drug Interactions
Special Populations 
Investigations in pregnant women
Investigations in nursing women 
Investigations in children220.Specific clinical study issues addressed IN THE CLINICAL INVESTIGATION OF MEDICINAL PRODUCTS
IN THE PEDIATRIC POPULATION GUIDANCE include?
(1) considerations when initiating a
pediatric program for a medicinal product; (2) timing of initiation of pediatric studies
during medicinal product development; (3) types of studies (pharmacokinetic,
pharmacokinetic/pharmacodynamic (PK/PD), efficacy, safety); (4) age categories; and
(5) ethics of pediatric clinical investigation. This guidance is not intended to be
comprehensive; other ICH guidances, as well as documents from regional regulatory
authorities and pediatric societies, provide additional detail.221.SponsorThe sponsor can be any legal entity, including a company, an academic organization, or an individual.222.Sponsor-InvestigatorAn individual who both initiates and conducts the clinical investigation and under whose immediate direction the investigational drug is being administered, used, or dispensed.223.Sponsor-investigators must develop monitoring plans based on the human subject protection and data integrity risks of the clinical trial. T/F?True224.The sponsor is required to obtain financial disclosures before an investigator can participate in the trial and is required to receive updated information forone (1) year following completion of the trial. Investigators are required to promptly update this information if any relevant changes occur during the course of the trial and for one (1) year following completion of the trial (or all trials of the same product) at a particular site.225.The sponsor organization will generally assess the site first by means ofa pre-study site visit At this assessment visit, the sponsor representative will review the study requirements and answer any questions that the investigator or staff might have about the execution of the study.226.The sponsor will determine if the investigator has adequate resources as outlined in ICH (2016) E6 Section 4.2:A potential for recruiting the required number of eligible subjects within the agreed recruitment period
Sufficient time to properly conduct and complete the trial within the agreed trial period
Adequate staff and facilities to conduct the trial properly and safely for the foreseen duration
That all persons assisting with the trial are adequately informed on the protocol, the investigational product, and their trial-related duties and functions227.Standard of Care vs. research onlyIt must be determined which services are standard of care (billable to the subject's insurance) and which services are billable to the study so that they can be appropriately incorporated in the budget and billing compliance plan.228.START-UP FEESClinical sites spend significant time to initiate a new clinical trial. Sites are responsible for site specific informed consent development, Ethics Committee (EC)/ Investigational Review Board (IRB) submissions, staff training including participation in investigator/ site coordinator meetings and site initiation visits and execute a clinical trial contract. It is typical for sponsor to pay anywhere between $2000 - $5000+ in site start-up fees.

229.Statistical Analysis PlanA statistical analysis plan is a document that contains a more technical and detailed
elaboration of the principal features of the analysis described in the protocol, and
includes detailed procedures for executing the statistical analysis of the primary and
secondary variables and other data.230.STATISTICAL PRINCIPLES FOR CLINICAL TRIALS
E9
This guidance is intended to give direction to sponsors in the design, conduct,
analysis, and evaluation of clinical trials of an investigational product in the context
of its overall clinical development.
The document will also assist scientific experts
charged with preparing application summaries or assessing evidence of efficacy and
safety, principally from clinical trials in later phases of development.231.STORAGE FEESGovernment regulations require that clinical trial data be stored after study close-out. The duration for storage can range from 2-years to permanent storage. Thus it's not uncommon for sites to have boxes of regulatory paperwork that need to be stored once a clinical trial ends. The storage fees vary by country and site. 

Some sponsors make arrangements for site to send trial documents to an offsite storage location. Due to country specific regulations, a site might be unable to move documents outside their country.232.The subject can generally keep all unused drug. T/F?False: The subject must return all unused drug to the site, which then either returns it to the sponsor or destroys it, as the sponsor directs. The number of returned drugs must be counted to assess compliance with the protocol regimen. The protocol may specify how to measure subject compliance.233.Subjects who cannot write their name can "make their mark" on the informed consent form, as long as it is consistent with applicable state laws. T/F?True234.Superiority TrialA trial with the primary objective of showing that the response to the investigational
product is superior to a comparative agent (active or placebo control).235.Supplies should be ordered well before they actually will be needed, allowing enough time for packaging, processing, and shipping the order, typically ______ weeks.2-4 weeks236.Surrogate VariableA variable that provides an indirect measurement of effect in situations where direct
measurement of clinical effect is not feasible or practical.237.Term newborn infants(0 to 27 days)238.There are situations in addition to single case reports of "serious" adverse events
or reactions that may necessitate rapid communication to regulatory authorities;
appropriate medical and scientific judgement should be applied for each
situation.
Examples include:
a. For an "expected," serious ADR, an increase in the rate of occurrence which is
judged to be clinically important.
b. A significant hazard to the patient population, such as lack of efficacy with a
medicinal product used in treating life-threatening disease.
c. A major safety finding from a newly completed animal study (such as
carcinogenicity).

239.Though investigators are ultimately responsible for the overall conduct of a clinical trial, study team members are often delegated responsibilities. For example, the investigator will delegate the consenting responsibility to the clinical research coordinator or delegate the drug dispensation to the pharmacist. The investigator must ensure the all study team members are qualified and knowledgeable about the study and their role. T/F?True240.Throughout the study, investigators are required to report serious adverse events (SAEs) ________________ to the sponsor organizationpromptly241.Throughout the study, subjects do not need to be provided with new information that may affect their willingness to continue participation in the clinical trial. T/F?False242.To thoroughly assess their suitability for participation in the study, investigators mustreview the full protocol and IB243.Treatment EffectAn effect attributed to a treatment in a clinical trial. In most clinical trials the
treatment effect of interest is a comparison (or contrast) of two or more treatments.244.Treatment EmergentAn event that emerges during treatment having been absent pre-treatment, or
worsens relative to the pre-treatment state.245.TRIAL CONDUCT CONSIDERATIONS1 Trial Monitoring and Interim Analysis
2 Changes in Inclusion and Exclusion Criteria 
3 Accrual Rates
4 Sample Size Adjustment
5 Interim Analysis and Early Stopping 
6 Role of Independent Data Monitoring Committee (IDMC)
(see Sections 1.25 and 5.52 of ICH E6)246.TRIAL DESIGN CONSIDERATIONS1 Parallel Group Design
2 Crossover Design
3 Factorial Designs
4 Group Sequential Designs

247.Trial StatisticianA statistician who has a combination of education/training and experience sufficient
to implement the principles in this guidance and who is responsible for the statistical
aspects of the trial.248.Two categories of studies involving sponsor-investigators?1. STUDIES INVOLVING INVESTIGATIONAL DRUGS DEVELOPED BY THE INVESTIGATOR
2. STUDIES INVOLVING A MANUFACTURER'S INVESTIGATIONAL OR APPROVED DRUG249.Type of Trial Comparisons?1 Trials to Show Superiority 
2 Trials to Show Equivalence or Non-inferiority 
3 Trials to Show Dose-response Relationship250.Typically, drug manufacturers will package the investigational drug according toindividual clinical trial needs251.Upon receipt of the supplies, the investigator shouldverify the shipment and product information. For example, if white tablets were received but yellow capsules were expected, the investigator should contact the sponsor. The shipment also should be examined for evidence of damage during shipment, and the sponsor should be notified if damage has occurred.252.Validation of Computer Systems isdefined by ICH (2016) E6 (Section 1.65) as a process of establishing and documenting that the specified requirements of a computerized system can be consistently fulfilled from design until decommissioning of the system or transition to a new system. The approach to validation should be based on a risk assessment that takes into consideration the intended use of the system and the potential of the system to affect human subject protection and reliability of trial results.253.Vulnerable Subjectsindividuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. (ICH [2016] E6 Section 1.61)254.WHAT ARE NON-STANDARD OF CARE TESTSMedical device trials may require non-standard of care tests such as medical imaging scans. Insurance companies or medical care agencies generally do not reimburse non-standard of care costs. Therefore you should include them in your clinical trial budget.255.WHAT ARE PROCEDURE COSTS?Medical payor such as Medicare or private insurance may reimburse clinical trial procedure costs. If procedure reimbursement is available, you don't need to budget for the procedure cost. In case a brand new procedure where no reimbursement available, budget for the procedure costs.256.WHAT ARE SOME OF THE MISCELLANEOUS COSTS FOUND IN THE BUDGET?A. INVESTIGATOR MEETINGS
B. TRAVEL
C. DOCUMENT TRANSLATIONS
D. TECHNOLOGY SOLUTIONS
E. REGULATORY FILING FEES257.WHAT ARE SOME OF THE SITE MANAGEMENT COSTSA. PRE-STUDY VISITS
B. SITE INITIATION VISITS (SIV)
C. MONITORING
D. CLOSE-OUT258.What is an Institutional Review Board (IRB)Defined by FDA at 21 CFR 56.102(g) (Institutional Review Boards 2014) as "any board, committee, or other group formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of, biomedical research involving human subjects.259.What is an Investigator's Brochure (IB)is a compilation of the clinical and nonclinical data on the investigational product and serves as a resource for investigators and IRBs during the conduct of a clinical trial.260.What is the Investigational Maintenance FeeThis fee is assessed monthly starting when inventory has been received until study close-out and study drug(s) are destroyed or returned to sponsor. This fee may also be paid on an annual basis

261.What resources do I need to develop a budget?1. Schedule of Assessments
2. Institutional Fees
3. Evaluation and Procedure Charges
4. Staff Allocation with Hourly Rates262.When a clinical trial includes subjects who can only be enrolled in the trial with the consent of the subject's LAR (for example, minors or subjects with severe dementia), the subject should be informed about the trial to the extent compatible with the subject's understanding and, if capable, the subject should assent, or agree, by signing and personally dating the written informed consent. T/F?True: (ICH [2016] E6 Section 4.8.12).263.When a drug is dispensed or administered to a subject, the dispenser/administrator must record information on the drug accountability form such asIdentification of the product administered
Dosage
Date and time
Subject's identification code264.When obtaining consent from subjects for participation in clinical trials, the investigator must ensure that the following requirements are satisfied:Consent must be legally effective.
The language used to obtain consent must be understandable to the subject (or the subject's LAR).
Consent must be obtained under circumstances that allow the subject (or the subject's LAR) sufficient time to decide whether or not to participate.
Consent must be obtained without undue influence or coercion.265.When responsibilities are delegated, _________________________ remains ultimately responsible for compliance with the protocol, regulations, and IRB requirements.the investigator266.Who is ultimately responsible for the accountability and disposition of all investigational products provided by the sponsor for the study.The Investigator267.Who submits the completed, signed Form FDA 1572 to the FDA?The sponsor


1.Adverse Drug Reaction (ADR)All noxious and unintended responses to a medicinal product related to any dose2.Adverse Event (AE)Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment--any unfavorable and unintended sign , symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product3.Applicable Regulatory RequirementsAny law(s) and regulation(s) addressing the conduct of clinical trials of investigational products4.AuditA systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analyzed and accurately reported according to the protocol, sponsor's standard operating procedures, (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s)5.Audit CertificateA declaration of confirmation by the auditor that an audit has taken place6.Audit ReportA written evaluation by the sponsor's auditor of the results of the audit7.Audit TrailDocumentation that allows reconstruction of the course of events8.Blinding/MaskingA procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s).9.Case Report Form (CRF)A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject.10.Clinical Trial/StudyAny investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy11.Clinical Trial/Study ReportA written description of a trial/study of any therapeutic, prophylactic, or diagnostic agent conducted in human subjects, in which the clinical and statistical description, presentations, and analyses are fully integrated into a single report12.Comparator (Product)An investigational or marketed product, or placebo, used as a reference in a clinical trial.13.Compliance to TrialsAdherence to all the trial-related requirements, Good Clinical Practice (GCP) requirements, and the applicable regulatory requirements14.ConfidentialityPrevention of disclosure, to other than authorized individuals, of a sponsor's proprietary information or of a subject's identity.15.ContractA written, dated, and signed agreement between two or more involved parties that sets out any arrangements on delegation and distribution of tasks and obligations and, if appropriate, on financial matters.16.Contract Research Organization (CRO)A person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or more of a sponsor's trial-related duties and functions.17.Coordinating CommitteeA committee that a sponsor may organize to coordinate the conduct of a multicenter trial.18.Coordinating IvestigatorAn investigator assigned the responsibility for the coordination of investigators at different centers participating in a multicenter trial19.Direct AccessPermission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial20.DocumentationAll records, in any form that describe or record the methods, conduct, and/or results of a trial, the factors affecting a trial, and the actions taken21.E2ADefinitions and Standards for Expedited Reporting

22.E2A Attachment 1 -- Key Data Elements for Inclusion in Expedited Reports of Serious Adverse Drug Reactions1. Patient Details Initials
2. Suspected Medicinal Products
3. Other Treatments
4. Details of Suspected Adverse Drug Reactions
5. Details on Reporter of Event (Suspected ADR)
6. Administrative and Sponsor/Company Details23.E2A IIntroduction24.E2A IIDefinitions and Terminology Associated with Clinical Safety Experience25.E2A II.ABasic Terms26.E2A II.A.1Adverse Event (or Adverse Experience)27.E2A II.A.2Adverse Drug Reaction (ADR)28.E2A II.A.3Unexpected Adverse Drug Reaction29.E2A II.BSerious Adverse Event or Adverse Drug Reaction30.E2A II.CExpectedness of an Adverse Drug Reaction31.E2A IIIStandards for Expedited Reporting32.E2A III.AWhat Should be Reported?33.E2A III.A.1Single Cases of Serious, Unexpected ADRs --All adverse drug reactions (ADRs) that are both serious and unexpected are subject to expedited reporting--source should always be specified, causality assessment required34.E2A III.A.2Other Observations --
a) for an "expected," serious ADR, an increase in the rate of occurrence which is judged to be clinically important
b) a significant hazard to the patient population, such as lack of efficacy with a medicinal product used in treating life-threatening disease
c) a major safety finding from a newly comleted animal study35.E2A III.BReporting Time Frames36.E2A III.B.1Fatal or Life-Threatening Unexpected ADRs
- Fatal or life-threatening, unexpected ADRs
occurring in clinical investigations qualify for very rapid reporting. Regulatory agencies should be notified (e.g., by telephone, facsimile transmission, or in writing) as soon as possible but no later than 7 calendar days after first knowledge by the sponsor that a case qualifies, followed by as complete a report as possible within 8
additional calendar days. 
- This report must include an assessment of the importance and implication of the findings, including relevant previous experience with the same or similar medicinal products.37.E2A III.B.2All Other Serious, Unexpected ADRs
-Serious, unexpected reactions (ADRs) that are not fatal or life threatening must be filed as soon as possible but no later than 15 calendar days after first knowledge by the sponsor that the case meets the minimum criteria for expedited reporting

38.E2A III.B.3Minimum Criteria for Reporting
-Information for final description and evaluation of a case report may not be available within the required time frames for reporting outlined
above. 
- for regulatory purposes, initial reports should be submitted within the prescribed time as long as the following minimum criteria are met: 
a) an identifiable patient; 
b) suspect medicinal product; 
c) identifiable reporting source; 
d) event or outcome that can be identified as serious and unexpected, and for which, in clinical investigation cases, there is a reasonable suspected causal relationship. 
-Follow-up information should be actively sought and
submitted as it becomes available.39.E2A III.CHow to Report40.E2A III.DManaging Blinded Therapy Cases41.E2A III.EMiscellaneous Issues42.E2A III.E.1Reactions Associated with Active Comparator or Placebo Treatment
-Sponsor's responsibility to decide whether reaction to be reported to manufacturer or to appropriate regulatory agenicies43.E2A III.E.2Products with More than one Presentation or Use44.E2A III.E.3Post-study events
-serious adverse events that occurred after the patient had completed a clinical study will possibly be reported by an investigator to the sponsor45.E2A III.FInforming Investigators and Ethics Committees/Institutional Review Boards of New Safety Information46.E6(R1) 1Glossary of terms47.E6(R1) 2The Principles of ICH GCP48.E6(R1) 2.1Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s)49.E6(R1) 2.2Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks.50.E6(R1) 2.3The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.51.E6(R1) 2.4The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.52.E6(R1) 2.5Clinical trials should be scientifically sound, and described in a clear detailed protocol.53.E6(R1) 2.6A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB) approval/favorable opinion.54.E6(R1) 2.7The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.55.E6(R1) 2.8Each individual involved in conducting a trial should be qualified by eduction, training, and experience to perform his or her respective task(s).

56.E6(R1) 2.9Freely given informed consent should be obtained from every subject prior to clinical trial participation57.E6(R1) 2.10All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting interpretation and verification.58.E6(R1) 2.11The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).59.E6(R1) 2.12Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol.60.E6(R1) 2.13Systems with procedures that assure the quality of every aspect of the trial should be implemented.61.E6(R1) 3.1Institutional Review Board/Independent Ethics Committee (IRB/IEC)--Responsibilities62.E6(R1) 3.1.1An IRB/IEC should safeguard the rights, safety, and well-being of all trial subjects. Special attention should be paid to trials that may include vulnerable subjects63.E6(R1) 3.1.2The IRB/IEC should obtain the following documents: trial protocols/amendments, written informed consent forms and consent form updates that the investigator proposes for use in the trial, subject recruitment procedures, written information to be provided to subjects, Investigator's Brochure, available safety information, information about payments, and compensation available to subjects, the investigator's current curriculum vitae and/or other documentation evidencing qualifications, and any other documents that the IRB/IEC may need to fulfill its responsibilities.64.E6(R1) 3.1.3The IRB/IEC should consider the qualifications of the investigator for the proposed trial, as documented by a current curriculum vitae and/or by any other relevant documentation the IRB/IEC requests65.E6(R1) 3.1.4The IRB/IEC should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to human subjects, but at least once per year66.E6(R1) 3.1.5The IRB/IEC may request more information than is outlined in paragraph 4.8.10 be given to subjects when, in the judgement of the IRB/IEC, the additional information would add meaningfully to the protection of the rights, safety and/or well-being of the subjects.67.E6(R1) 3.1.6When a non-therapeutic trial is to be carried out with the consent of the subject's legally acceptable representative, the IRB/IEC should determine that the proposed protocol and/or other documents adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials68.E6(R1) 3.1.7Where the protocol indicates that prior consent of the trial subject or the subject's legally acceptable representative is not possible, the IRB/IEC should determine that the proposed protocol and/or other documents adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials69.E6(R1) 3.1.8The IRB/IEC should review both the amount and method of payment to subjects to assure that neither presents problems of coercion or undue influence on the trial subjects. Payments to a subject should be prorated and not wholly contingent on completion of the trial by the subject.70.E6(R1) 3.1.9The IRB/IEC should ensure that information regarding payment to subjects, including the methods, amounts, and schedule of payment to trial subjects, is set forth in the written informed consent form and any other written information to be provided to subjects. The way payment will be prorated should be specified.71.E6(R1) 3.2Institutional Review Board/Independent Ethics Committee (IRB/IEC)--Composition, Functions and Operations72.E6(R1) 3.2.1The IRB/IEC should consist of a reasonable number of members, who collectively have the qualifications and experience to review and evaluate the science, medical aspects, and ethics of the proposed trial. It is recommended that the IRB/IEC should include:
a) at least five members
b) at least one member whose primary area of interest is in a nonscientific area
c) at least one member who is independent of the institution/trial site. Only those IRB/IEC members who are independent of the investigator and the sponsor of the trial should vote/provide opinion on a trial-related matter. A list of IRB/IEC members and their qualifications should be maintained.73.E6(R1) 3.2.2The IRB/IEC should perform its functions according to written operating procedures, should maintain written records of its activities and minutes of its meetings, and should comply with GCP and with the applicable regulatory requirements

74.E6(R1) 3.2.3An IRB/IEC should make its decisions at announced meetings at which at least a quorum, as stipulated in its written operating procedures, is present75.E6(R1) 3.2.4Only members who participate in the IRB/IEC review and discussion should vote/provide their opinion and/or advise76.E6(R1) 3.2.5The investigator may provide information on any aspect of the trial, but should not participate in the deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC77.E6(R1) 3.2.6An IRB/IEC may invite nonmembers with expertise in special areas for assistance78.E6(R1) 3.3Institutional Review Board/Independent Ethics Committee (IRB/IEC)--Procedures
-The IRB/IEC should establish, document in writing, and follow its procedures79.E6(R1) 3.3.1Determining its composition(names and qualifications of the members) and the authority under which it is established80.E6(R1) 3.3.2Scheduling, notifying its members of, and conducting its meetings.81.E6(R1) 3.3.3Conducting initial and continuing review of trials.82.E6(R1) 3.3.4Determining the frequency of continuing review, as appropriate.83.E6(R1) 3.3.5Providing, according to the applicable regulatory requirements, expedited review and approval/favorable opinion of minor changes in ongoing trials that have the approval/favorable opinion of the IRB/IEC.84.E6(R1) 3.3.6Specifying that no subject should be admitted to a trial before the IRB/IEC issues its written approval/favorable opinion of the trial85.E6(R1) 3.3.7Specifying that no deviations from, or changes of, the protocol should be initiated without prior written IRB/IEC approval/favorable opinion of an appropriate amendment, except when necessary eliminate immediate hazards to the subjects or when the changes involves only logistical or administrative aspects to the trial.86.E6(R1) 3.3.8Specifying that the investigator should promptly repot to the IRB/IEC
a) deviations from, or changes of, the protocol to eliminate immediate hazards to the trial subjects
b) changes increasing the risk to subjects and/or affecting significantly the conduct of the trail
c) all adverse drug reactions (ADRs) that are both serious ad unexpected
d) new information that may affect adversely the safety of the subjects or the conduct of the trial.87.E6(R1) 3.3.9Ensuring that the IRB/IEC promptly notify in writing the investigator/institution concerning:
a) its trial-related decisions/opinions
b) the reasons for its decisions/opinions
c) Procedures for appeal of its decisions/opinions.88.E6(R1) 3.4Institutional Review Board/Independent Ethics Committee (IRB/IEC)--Records
-The IRB/IEC should retain all relevant records for a period of at least 3 years after completion of the trial and make them available upon request from the regulatory authorities89.E6(R1) 4Investigator90.E6(R1) 4.1Investigator's Qualifications and Agreements91.E6(R1) 4.1.1The investigator(s) should be qualified by education, training, and experience to assume responsibility of the proper conduct of the trial, should meet all the qualifications specified by the applicable regulatory requirement(s), and should provide evidence of such qualifications through up-to-date curriculum vitae and/or other relevant documentation requested by the sponsor, the IRB/IEC, and/or the regulatory authorities92.E6(R1) 4.1.2The investigator should be thoroughly familiar with the appropriate use of the investigational products, as described int he protocol, in the current Investigator's Brochure, in the product information and in other information sources provided by the sponsor.

93.E6(R1) 4.1.3The investigator should be aware of, and should comply with, GCP and the applicable regulatory requirements.94.E6(R1) 4.1.4The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authorities95.E6(R1) 4.1.5The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties96.E6(R1) 4.2Investigator-Adequate Resources97.E6(R1) 4.2.1The investigator should be able to demonstrate a potential for recruiting the required number of suitable subjects within the agreed recruitment period.98.E6(R1) 4.2.2The investigator should have sufficient time to properly conduct and complete the trial within the agreed trial period.99.E6(R1) 4.2.3The investigator should have available an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely.100.E6(R1) 4.2.4The investigator should ensure that all persons assisting with the trial are adequately informed about the protocol, the investigational products, and their trial-related duties and functions.101.E6(R1) 4.3Investigator-Medical Care of Trial Subjects102.E6(R1) 4.3.1A qualified physician (or dentist when appropriate), who is an investigator or a sub-investigator for the trial, should be responsible for all trial-related medical (or dental) decisions.103.E6(R1) 4.3.2During and following a subject's participation in a trial, the investigator/institution should ensure that adequate medical care is provided to a subject for any adverse events, including clinically significant laboratory values, related to the trial. The investigator/institution should inform a subject when medical care is needed for intercurrent illness(es) of which the investigator becomes aware104.E6(R1) 4.3.3It is recommended that the investigator inform the subject's primary physician about the subjects participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician being informed.105.E6(R1) 4.3.4Although a subject is not obliged to give his/her reason(s) for withdrawing prematurely from a trial, the investigator should make a reasonable effort to ascertain the reasons, while fully respecting the subject's rights.106.E6(R1) 4.4Investigator--Communication with IRB/IEC107.E6(R1) 4.4.1Before initiating a trial, the investigator/institution should have written and dated approval/favorable opinion from the IRB/IEC for the trial protocol, written informed consent form, consent form updates, subject recruitment procedures, and any other written information to be provided to subjects108.E6(R1) 4.4.2As part of the investigator's/institution's written application to the IRB/IEC, the investigator/institution should provide the IRB/IEC with a current copy of the Investigator's Brochure. If the Investigator's Brochure is updated during the trial, the investigator/institutions should supply a copy of the updated Investigator's Brochure to the IRB/IEC.109.E6(R1) 4.4.3During the trial the investigator/institution should provide to the IRB/IEC all documents subject to review.110.E6(R1) 4.5Investigator--Compliance with Protocol111.E6(R1) 4.5.1The investigator/institution should conduct the trial in compliance with the protocol agreed to by the sponsor and, if required, by th regulatory authorities and which was given approval/favorable opinion by the IRB/IEC. The investigator/institution and the sponsor should sign the protocol, or an alternative contract, to confirm agreement112.E6(R1) 4.5.2The investigator should not implement any deviation from, or changes of the protocol without agreement by the sponsor and prior review and documented approval/favorable opinion from eh IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the changes involves only logistical or administrative aspects of the trial.

113.E6(R1) 4.5.3The investigator, or person designated by the investigator, should document and explain any deviation froth approved protocol.114.E6(R1) 4.5.4The investigator may implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to trial subjects without prior IRB/IEC approval/favorable opinion. As soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be submitted (a) to the IRB/IEC for review and approval/favorable opinion, (b) to the sponsor for agreement and, if required, (c) to the regulatory authority(ies)115.E6(R1) 4.6Investigational Product(s)116.E6(R1) 4.6.1Responsibility for investigational product(s) accountability at the trial site(s) rests with the investigator/institution117.E6(R1) 4.6.2Where allowed/required, the investigator/institution may/should assign some or all of the investigator's/institution's duties for investigational product(s) accountability at the trial site(s) to an appropriate pharmacist or another appropriate individual who is under the supervision of the investigator/institution118.E6(R1) 4.6.3The investigator/institution and/or a pharmacist or other appropriate individual, who is designated by the investigator/institution, should maintain records of the product's delivery to the trial site, the inventory at the site, the use by each subject, and the return to the sponsor or alternative disposition of unused product(s). These records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the investigational product(s) and trial subjects. Investigators should maintain records that document adequately that the subjects were provided the doses specified by the protocol and reconcile all investigational product(s) received from the sponsor119.E6(R1) 4.6.4The investigational product(s) should be stored as specified by the sponsor and in accordance with applicable regulatory requirement(s)120.E6(R1) 4.6.5The investigator should ensure that the investigational product(s) are used only in accordance with the approved protocol121.E6(R1) 4.6.6The investigator, or a person designated by the investigator/institution, should explain the correct use of the investigational product(s) to each subject and should check, at intervals appropriate for the trial, that each subject is following the instructions properly122.E6(R1) 4.7Randomization Procedures and Unblinding123.E6(R1) 4.8Informed Consent of Trial Subjects124.E6(R1) 4.8.1In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement(s), and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. Prior to the beginning of the trial, the investigator should have the IRB/IEC's written approval/favorable opinion of the written informed consent form and any other written information to be provided to subjects.125.E6(R1) 4.8.2The written informed consent form and any other written information to be provided to subjects should be revised whenever important new information becomes available that may be relevant to the subject's consent. Any revised written informed consent form, and written information should receive the IRB/IEC's approval/favorable opinion in advance of use. The subject or the subject's legally acceptable representative should be informed in a timely manner if new information becomes available that may be relevant to the subject's willingness to continue participation in the trial. The communication of this information should be documented126.E6(R1) 4.8.3Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or to continue to participate in a trial127.E6(R1) 4.8.4None of the oral and written information concerning the trial, including the written informed consent form, should contain any language that causes the subject or the subject's legally acceptable representative to waive or to appear to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor, or their agents from liability for negligence128.E6(R1) 4.8.5The investigator, or a person designated by the investigator, should fully inform the subject or, if the subject is unable to provide informed consent, the subject's legally acceptable representative, of all pertinent aspects of the trial including the written information and the approval/favorable opinion by the IRB/IEC

129.E6(R1) 4.8.6The language used in the oral and written information about the trial, including the written informed consent form, should be as non-technical as practical adn should be understandable to the subject or the subject's legally acceptable representative adn the impartial witness, where applicable.130.E6(R1) 4.8.7Before informed consent may be obtained, the investigator, or a person designated by the investigator, should provide the subject or the subject's legally acceptable representative ample time and opportunity to inquire about details of the trial and to decide whether or not to participate in the trial. All questions about the trial should be answered to the satisfaction of the subject or the subject's legally acceptable representative131.E6(R1) 4.8.8Prior to a subject's participation in the trial, the written informed consent form should be signed and personally dated by the subject or by the subject's legally acceptable representative, and by the person who conducted the informed consent discussion.132.E6(R1) 4.8.9If a subject is unable to read or if a legally acceptable representative is unable to read, an impartial witness should be present during the entire informed consent discussion. After the written informed consent form and any other written information to be provided to subjects, is read and explained to the subject or the subject's legally acceptable representative, and after the subject or the subject's legally acceptable representative has orally consented to the subject's participation in th etrial and, if capapble of doing so, has signed adn personally dated the informed cosnent form, the witness should sign adn personally date the consent form. By signing the consent form, the witness attests that the information in th e consent form and any other written information was accurately explained to, and apparently understood by, the subject or the subject's legally acceptablerepresentative, and that informed consent was freely given by the subject or the subject's legally acceptable representative133.E6(R1) 4.8.10 Both the informed consent discussion and the written informed consent form and any other written information to be provided to subjects should include explanations of. . .Part 1a) That the trial involves research
b) The purpose of the trial
c) The trial treatment(s) and the probability for random assignment to each treatment
d) The trial procedures to be followed, including all invasive procedures
e) The subject's responsibilities
f) Those aspects of the trial that are experimental
g) The reasonably foreseeable risks or inconveniences to the subject and, when applicable to an embryo, fetus, or nursing infant
h) the reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be made aware of this134.E6(R1) 4.8.10 Both the informed consent discussion and the written informed consent form and any other written information to be provided to subjects should include explanations of. . .Part 2i) The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important potential benefits and risks
j) The compensation and/or treatment available to the subject in the event of trial-related injury
k) The anticipated prorated payment, if any, to the subject for participating in the trial
l) The anticipated expenses, if any, to the subject for participating in the trial
m) That the subject's participation in the trial is voluntary and that the subject may refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise entitled
n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be granted direct access to the subject's original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality fo the subject, to the extent permitted by applicable laws and regulations and that, by signing a written informed consent form, the subject or the subject's legally acceptable representative is authorizing such access

135.E6(R1) 4.8.10 Both the informed consent discussion and the written informed consent form and any other written information to be provided to subjects should include explanations of. . .Part 3o) That records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available. If the results of the trial are published, the subject's identity will remain confidential
p) That the subject or the subject's legally acceptable representative will be informed in a timely manner if information becomes available that may be relevant to the subject's willingness to continue participation in the trial
q) The person(s) to contact for further information regarding the trial and the rights of trial subjects, and whom to contact in the event of trial-related injury
r) The foreseeable circumstances and/or reasons under which the subject's participation in the trial may be terminated.
s) The expected duration of the subject's participation in the trial
t) The approximate number of subjects involved in the trial136.E6(R1) 4.8.11Prior to participation i the trial, the subject or the subject's legally acceptable representative should receive a copy of the signed and dated written informed consent form and any other written information provided to the subjects. During a subject's participation in the trial the subject or the subject's legally acceptable representative should receive a copy of the signed and dated consent form updates and a copy of any amendments to the written information provided to subjects.137.E6(R1) 4.8.12When a clinical trial (therapeutic or non-therapeutic) includes subjects who can only be enrolled in the trial with the consent of the subject's legally acceptable representative, the subject should be informed about the trial to the extent compatible with the subject's understanding and, if capable, the subject should sign and personally date the written informed consent138.E6(R1) 4.8.13Except as described in 4.8.14, a non-therapeutic trial, should be conducted in subjects who personally give consent and who sign and date the written informed consent.139.E6(R1) 4.8.14--Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable representative provided the following conditions are fulfilled. . .Part 1a) The objectives of the trial can not be met by means of a trial in subjects who can give informed consent personally
b) The foreseeable risks to the subjects are low
c) The negative impact on the subject's well-being is minimized and low
d) The trial is not prohibited by law
e) The approval/favorable opinion of the IRB/IEC is expressly sought on the inclusion of such subjects, and the written approval/favorable opinion covers this aspect140.E6(R1) 4.8.14--Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable representative provided the following conditions are fulfilled. . .Part 2Such trials, unless an exception is justified, should be conducted in patients having a disease or condition for which the investigational product is intended. Subjects in these trials should be particularly closely monitored and should be withdrawn if they appear to be unduly distressed.141.E6(R1) 4.8.15In emergency situations, when prior consent of the subject is not possible, the consent of the subject's legally acceptable representative, if present, should be requested. When prior consent of the subject is not possible, and the subject's legally acceptable representative is not available, enrollment of the subject should require measures described in the protocol and/or elsewhere, with documented approval/favorable opinion by the IRB/IEC, to protect the rights, safety and well-being of the subject and to ensure compliance with applicable regulatory requirements. The subject or the subject's legally acceptable representative should be informed about the trial as soon as possible and consent to continue and other consent as appropriate should be requested142.E6(R1) 4.9Records and Reports143.E6(R1) 4.9.1The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the CRF's and infall required reports.144.E6(R1) 4.9.2Data reported on the CRF, that are derived from source documents, should be consistent with the source documents or the discrepancies should be explained

145.E6(R1) 4.9.3Any change or correction to a CRF should be dated, initialed, and explained (if necessary) and should not obscure the original entry; this applies to both written and electronic changes or corrections. Sponsors should provide guidance to investigators and/or the investigators' designated representatives on making such corrections. Sponsors should have written procedures to assure that changes or corrections in CRFs made by sponsor's designated representatives are documented, are necessary, and are endorsed by the investigator. The investigator should retain records of the changes and corrections.146.E6(R1) 4.9.4The investigator/institution should maintain the trial documents as specified in Essential Documents for the Conduct of a Clinical Trial and as required by the applicable regulatory requirement(s). The investigator/institution should take measures to prevent accidental or premature destruction of these documents.147.E6(R1) 4.9.5Essential documents should be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period however if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to when these documents no longer need to be retained.148.E6(R1) 4.9.6The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution.149.E6(R1) 4.9.7Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the investigator/institution should make available for direct access all requested trial-related records150.E6(R1) 4.10Progress Report151.E6(R1) 4.10.1The investigator should submit written summaries of the trial status to the IRB/IEC annually, or more frequently, if requested by the IRB/IEC.152.E6(R1) 4.10.2The investigator should promptly provide written reports to the sponsor, the IRB/IEC and, where applicable, the institution on any changes significantly affecting the conduct of the trial, and/or increasing the risk to subjects153.E6(R1) 4.11Safety Reporting154.E6(R1) 4.11.1All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the protocol or other document identifies as not needing immediate reporting. The immediate reports should be followed promptly by detailed, written reports. The immediate and follow-up reports should identify subjects by unique code numbers assigned to the trial subjects rather than by the subjects' names personal identification numbers, and/or addresses. The investigator should also comply with the applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to the regulatory authority(its) an the IRB/IEC155.E6(R1) 4.11.2Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be reported to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in the protocol156.E6(R1) 4.11.3For reported deaths, the investigator should supply the sponsor and the IRB/IEC with any additional requested information157.E6(R1) 4.12.1If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator should inform the institution where applicable, and the investigator/institution should promptly inform the sponsor and the IRB/IEC, and should provide the sponsor and the IRB/IEC a detailed written explanation of the termination or suspension158.E6(R1) 4.12.2If the sponsor terminates or suspends a trial, the investigator should promptly inform the institutions where applicable and the investigator/institution should promptly inform the IRB/IEC and provide the IRB/IEC a detailed written explanation of the termination or suspension159.E6(R1) 4.12.3If the IRB/IEC terminates or suspends its approval/favorable opinion of a trial, the investigator should inform the institution where applicable and the investigator/institution should promptly notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension.160.E6(R1) 4.12--Premature Termination or Suspension of a TrialIf the trial is prematurely terminated or suspended for any reason, the investigator/institution should promptly inform the trial subjects, should assure appropriate therapy and follow-up for the subjects, and where required by the applicable regulatory requirement(s), should inform the regulatory authority(ies)

161.E6(R1) 4.13 -- Final Report(s) by InvestigatorUpon completion of the trial, the investigator, where applicable, should inform the institution; the investigator/institution should provide the IRB/IEC with a summary of the trial's outcome, and the regulatory authority(its) with any reports required162.E6(R1) 5Sponsor163.E6(R1) 5.1Quality Assurance and Quality Control164.E6(R1) 5.1.1The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s)165.E6(R1) 5.1.2The sponsor is responsible for securing agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by domestic and foreign regulatory authorities166.E6(R1) 5.1.3Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly.167.E6(R1) 5.1.4Agreements, made by the sponsor with the investigator/institution and any other parties involved with the clinical trial, should be in writing, as part of the protocol or in a separate agreement168.E6(R1) 5.2Contact Research Organization (CRO)169.E6(R1) 5.2.1A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor The CRO should implement quality assurance and quality control170.E6(R1) 5.2.2Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in writing171.E6(R1) 5.2.3Any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor.172.E6(R1) 5.2.4All references to a sponsor in this guideline also apply to a CRO to the extent that a CRO has assumed the trial related duties and functions of a sponsor173.E6(R1) 5.3 -- Medical ExpertiseThe sponsor should designate appropriately qualified medical personnel who will be readily available to advise on trial related medical questions or problems. If necessary, outside consultant(s) may be appointed for this purpose.174.E6(R1) 5.4Trial Design175.E6(R1) 5.4.1The sponsor should utilize qualified individuals as appropriate, throughout all stages of the trial process, from designing the protocol and CRFs and planning the analyses to analyzing and preparing interim and final clinical trial reports176.E6(R1) 5.4.2For further guidance: Clinical Trial Protocol and Protocol Amendment(s), the ICH Guideline for Structure and Content of Clinical Study Reports, and other appropriate ICH guidance on trial design, protocol and conduct177.E6(R1) 5.5Trial Management, Data Handling, and Record Keeping178.E6(R1) 5.5.1The sponsor should utilize appropriately qualified individuals to supervise the overall conduct of the trial, to handle the stat, to verify the data, to conduct the statistical analysis, and to prepare the trial reports179.E6(R1) 5.5.2The sponsor may consider establishing an independent data-monitoring committee (IDMC) to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial. The IDMC should have written operating procedures and maintain written records of all its meetings

180.E6(R1) 5.5.3 When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should:a) Ensure and document that the electronic data processing system(s) conforms to the sponsor's established requirements for completeness, accuracy, reliability, and consistent intended performance
b) Maintains SOPs for using these systems
c) Ensure that the systems are designed to permit data changes in such a way that the data changes are documented and that there is no deletion of entered data
d) Maintain a security system that prevents unauthorized access to the data
e) Maintain a list of the individuals who are authorized to make data changes
f) Maintain adequate backup of the data
g) Safeguard the blinding, if any181.E6(R1) 5.5.4If data are transformed during processing, it should always be possible to compare the original data and observations with the processed data182.E6(R1) 5.5.5The sponsor should use an unambiguous subject identification code that allows identification of all the data reported for each subject183.E6(R1) 5.5.6The sponsor, or other owners of the data, should retain all of the sponsor-specific essential documents pertaining to the trial184.E6(R1) 5.5.7The sponsor should retain all sponsor-specific essential documents in conformance with the applicable regulatory requirement(s) of the country(ies) where the product is approved, and/or where the sponsor intends to apply for approval(s)185.E6(R1) 5.5.8If the sponsor discontinues the clinical development of an investigational product, the sponsor should maintain all sponsor-specific essential documents for at least 2 years after formal discontinuation or in conformance with the applicable regulatory requirement(s)186.E6(R1) 5.5.9If the sponsor discontinues the clinical development of an investigational product, the sponsor should notify all the trial investigators/institutions and all the regulatory authorities187.E6(R1) 5.5.10Any transfer of ownership of the data should be reported to the appropriate authority(ies), as required by the applicable regulatory requirement(s)188.E6(R1) 5.5.11The sponsor specific essential documents should be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period however if required by the applicable regulatory requirement(s) or if needed by the sponsor189.E6(R1) 5.5.12The sponsor should inform the investigator(s)/institution(s) in writing of the need for record attention and should notify the investigator(s)/institution(s) in writing when the trial related records are no longer needed190.E6(R1) 5.6Investigator Selection191.E6(R1) 5.6.1The sponsor is responsible for selecting the investigator(s)/institution(s). Each investigator should be qualified by training and experience and should have adequate resources to properly conduct the trial for which the investigator is selected. If organization of a coordinating committee and/or selection of coordinating investigator(s) are to be utilized in multi center trials, their organization and/or selection are the sponsor's responsibility192.E6(R1) 5.6.2Before entering an agreement with an investigator/institution to conduct a trial, the sponsor should provide the investigator(s)/institution(s) with the protocol and an up-to-date Investigator's Brochure, and should provide sufficient time for the investigator/institution to review the protocol and the information provided193.E6(R1) 5.6.3 Part 2The sponsor and the investigator/institution should sign the protocol, or an alternative document, to confirm this agreement194.E6(R1) 5.6.3 -- The sponsor should obtain the investigator's/institution's agreement. . .a) to conduct the trial in compliance with GCP, with th applicable regulatory requirement(s), and with the protocol agreed to by the sponsor and given approval/favorable opinion by the IRB/IEC
b) to comply with procedures for data recording/reporting
c) to permit monitoring, auditing and inspection 
d) to retain the trial related essential documents until the sponsor informs the investigator/institution these documents are no longer needed

195.E6(R1) 5.7--Allocation of ResponsibilitiesPrior to initiating a trial, the sponsor should define, establish, and allocate all trial-related duties and functions.196.E6(R1) 5.8Compensation to Subjects and Investigators197.E6(R1) 5.8.1If required by the applicable regulatory requirement(s), the sponsor should provide insurance or should indemnify the investigator/ the institution against claims arising fro the trial, except for claims that arise from malpractice and/or negligence198.E6(R1) 5.8.2The sponsor's policies and procedures should address the costs of treatment of trial subjects in the event of trial-related injuries in accordance with the applicable regulatory requirements199.E6(R1) 5.8.3The trial subjects receive compensation, the method and manner of compensation should comply with applicable regulatory requirement(s)200.E6(R1) 5.9 -- FinancingThe financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution201.E6(R1) 5.10 -- Notification/Submission to Regulatory Authority(ies)Before initiating the clinical trial(s), the sponsor (or the sponsor and the investigator, if required by the applicable regulatory requirement(s)) should submit any required application(s) to the appropriate authority(ies) for review, acceptance, and/or permission (as required by the applicable regulatory requirement(s)) to begin the trial(s). Any notification/submission should be dated and contain sufficient information to identify the protocol202.E6(R1) 5.11Confirmation of Review by IRB/IEC203.E6(R1) 5.11.1--The sponsor should obtain from the investigator/institutiona) The name and address of the investigator's/institution's IRB/IEC
b) A statement obtained from the IRB/IEC that it is organized and operates according to GCP and the applicable laws and regulations.
c) Documented IRB/IEC approval/favorable opinion and, if requested by the sponsor, a current copy of protocol, written informed consent form and any other written information to be provided to subjects, subject recruiting procedures, and documents related to payments and compensation available to the subjects, and any other documents that the IRB/IEC may have requested204.E6(R1) 5.11.2If the IRB/IEC conditions its approval/favorable opinion upon change(s) in any aspect of the trial, such as modification(s) of the protocol, written informed consent form and any other written information to be provided to subjects, and/or other procedures, the sponsor should obtain from the investigator/institution a copy of the modification(s) made and the date approval/favorable opinion was given bytes IRB/IEC205.E6(R1) 5.11.3The sponsor should obtain from the investigator/institution documentation and dates of any IRB/IEC re-approvals/re-evaluations with favorable opinion, and of any withdrawals or suspensions of approval/favorable opinion206.E6(R1) 5.12Information on Investigational Product(s)207.E6(R1) 5.12.1When planning trials, the sponsor should ensure that sufficient safety and efficacy data from nonclinical studies an/or clinical trials are available to support human exposure by the route, at the dosages, for the duration, and in the trial population to be studied208.E6(R1) 5.12.2The sponsor should update the Investigator's Brochure as significant new information becomes available.209.E6(R1) 5.13Manufacturing, Packaging, Labelling, and Coding Investigational Product(s)210.E6(R1) 5.13.1The sponsor should ensure that the investigational product(s) is characterized as appropriate to the stage of development of the product(s), is manufactured in accordance with any applicable GMP, and is coded and labelled in a manner that protects the blinding, if applicable. In addition, the labelling should comply with applicable regulatory requirement(s)211.E6(R1) 5.13.2The sponsor should determine, for the investigational product(s), acceptable storage temperatures, storage conditions, storage times, reconstitution fluids and procedures, and devices for product infusion, if any. The sponsor should inform all involved parties of these determinations.212.E6(R1) 5.13.3The investigational product(s) should be packaged to prevent contamination and unacceptable deterioration during transport and storage

213.E6(R1) 5.13.4In blinded trials, the coding system for the investigational product(s) should include a mechanism that permits rapid identification of the product(s) should include a mechanism that permits rapid identification of the product(s) in case of a medical emergency, but does not permit undetectable breaks of the blinding214.E6(R1) 5.13.5If significant formulation changes are made in the investigational or comparator product(s) during the course of clinical development, the results of any additional studies of the formulated product(s) needed to assess whether these changes would significantly alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in clinical trials215.E6(R1) 5.14Supplying and Handling Investigational Product(s)216.E6(R1) 5.14.1The sponsor is responsible for supplying the investigator(s)/institution(s) with the investigational product(s)217.E6(R1) 5.14.2The sponsor should not supply an investigator/institution with the investigational product(s) until the sponsor obtains all required documentation218.E6(R1) 5.14.3The sponsor should ensure that written procedures include instructions that the investigator/institution should follow for the handling and storage of investigational product(s) for the trial and documentation thereof. The dispensing, retrieval of unused product from subjects, and return of unused investigational product(s) to the sponsor (or alternative disposition if authorized by the sponsor and in compliance with the applicable regulatory requirement(s))219.E6(R1) 5.14.4 -- The sponsor should . . .a) Ensure timely delivery of investigational product(s) to the investigator(s)
b) Maintain records that document shipment, receipt, disposition, return, and destruction of the investigational product(s).
c) Maintain a system for retrieving investigational products and documenting this retrieval
d) Maintain a system for the disposition of unused investigational product(s) and for the documentation of this disposition220.E6(R1) 5.14.5 -- Th sponsor shoulda) Take steps to ensure that the investigational product(s) are stable over the period of use
b) maintain sufficient quantities of the investigational product(s) used in the trials to reconfirm specifications, should this become necessary, and maintain records of batch sample analysis and characteristics. To the extent stability permits, samples should be retained either until the analyses of the trial data are complete or as required but he applicable regulatory requirement(s), whichever represents the longer retention period.221.E6(R1) 5.15Record Access222.E6(R1) 5.15.1The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) provide direct access to source data/documents for trial-related monitoring, audits, IRB/IEC review, and regulatory inspection223.E6(R1) 5.15.2The sponsor should verify that each subject has consented, in writing, to direct access to his/her original medical records for trial-related monitoring, audit, IRB/IEC review, and regulatory inspection224.E6(R1) 5.16Safety Information225.E6(R1) 5.16.1The sponsor is responsible for the ongoing safety evaluation of the investigational product(s)226.E6(R1) 5.16.2The sponsor should promptly notify all concerned investigator(s)/institution(s) and the regulatory authority(ies) of findings that could affect adversely the safety of subjects, impact the conduct of the trial, or alter the IRB/IEC's approval/favorable opinions to continue the trial227.E6(R1) 5.17Adverse Drug Reaction Reporting228.E6(R1) 5.17.1The sponsor should expedite the reporting to all concerned investigator(s)/institution(s), to the IRB(s)/IEC(s), where required, and to the regulatory authority(ies) of all adverse drug reactions (ADRs) that are both serious and unexpected229.E6(R1) 5.17.2Such expedited reports should comply with the applicable regulatory requirement(s) and with the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting230.E6(R1) 5.17.3The sponsor should submit to the regulatory authority(ies) all safety updates and periodic reports, as required by applicable regulatory requirement(s).

231.E6(R1) 5.18Monitoring232.E6(R1) 5.18.1 -- Purpose--The purposes of trial monitoring are to verify thata) the rights and well-being of human subjects are protected
b) the reported trial data are accurate, complete, and verifiable from source documents
c) the conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s)233.E6(R1) 5.18.2 -- Selection and Qualifications of Monitorsa) monitors should be appointed by the sponsor
b) Monitors should be appropriately trained, and should have the scientific and/or clinical knowledge needed dod monitor the trial adequately. A monitor's qualifications should be documented
c) monitors should be thoroughly familiar with the investigational product(s) the protocol, written informed consent form and any other written information to be provided to subjects, the sponsor's SOPs, GCP, and the applicable regulatory requirement(s)234.E6(R1) 5.18.3 -- Extent and Nature of MonitoringThe sponsor should ensure that the trials are adequately monitored. The sponsor should determine the appropriate extent and nature of monitoring. The determination of the extent and nature of monitoring should be based on consideration such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. In general there is a need for on-site monitoring, before, during, and after the trial; however in exceptional conjunction with procedures such as investigators' training and meetings, and excessive written guidance can assure appropriate conduct of the trial in accordance with GCP. Statistically controlled sampling may be an acceptable method for selecting the data to be verified235.E6(R1) 5.18.4 -- Monitor's Responsibilities -- The monitor(s) in accordance with the sponsor's requirements should ensure that the trial is conducted and documented properly by carrying out the following activities when relevant and necessary to the trial and the trial site: 

c) verifying ,for the investigational product(s): (Part 2)
i) That storage times and conditions are acceptable, and that supplies are sufficient throughout the trial
ii) that the investigational product(s) are supplied only to subjects who are eligible to receive it and at the protocol specified dose(s)
iii) that subjects are provided with necessary instruction on properly using, handling, storing, and returning the investigational product(s)
iv) that the receipt, use, and return of the investigational product(s) at the trial sites are controlled and documented adequately
v) that the disposition of unused investigational requirement(s) and is in accordance with the sponsor236.E6(R1) 5.18.4 -- Monitor's Responsibilities -- The monitor(s) in accordance with the sponsor's requirements should ensure that the trial is conducted and documented properly by carrying out the following activities when relevant and necessary to the trial and the trial site: 

m) Checking the accuracy and completeness of the CRF entries, source documents and other trial-related records against each other. The monitor specifically should verify that: (Part 5)
i) the data required by the protocol are reported accurately on the CRFs and are consistent with the source documents
ii) any dose and/or therapy modifications are well documented for each of the trial subjects
iii) aderse events, concomitant medications and intercurrent illnesses are reported in accordance with the protocol on the CRF's
iv) visits that the subjects fail to make, tests that are not conducted, and examinations that are reported as such on the CRFs
v) All withdrawals and dropouts of enrolled subjects from the trial are reported and explained on the CRFs

237.E6(R1) 5.18.4 -- Monitor's Responsibilities -- The monitor(s) in accordance with the sponsor's requirements should ensure that the trial is conducted and documented properly by carrying out the following activities when relevant and necessary to the trial and the trial site: (Part 1)a) Acting as the main line of communication between the sponsor and the investigator
b) Verifying that the investigator has adequate qualifications and resources and remain adequate throughout the trial period, that facilities, including laboratories, equipment, and staff, are adequate too sales and properly conduct the trial and remain adequate throughout the trial period.238.E6(R1) 5.18.4 -- Monitor's Responsibilities -- The monitor(s) in accordance with the sponsor's requirements should ensure that the trial is conducted and documented properly by carrying out the following activities when relevant and necessary to the trial and the trial site: (Part 3)d) Verifying that the investigator follows the approved protocol and all approved amendment(s), if any
e) Verifying that written informed consent as obtained before each subject's participation in the trial
f) Ensuring that the investigator receives the current Investigator's Brochure, all documents, and all trial supplies needed to conduct the trial properly and to comply with the applicable regulatory requirement(s)
g) Ensuring that the investigator and the investigator's trial staff are adequately informed about the trial239.E6(R1) 5.18.4 -- Monitor's Responsibilities -- The monitor(s) in accordance with the sponsor's requirements should ensure that the trial is conducted and documented properly by carrying out the following activities when relevant and necessary to the trial and the trial site: (Part 4)h) Verifying that the investigator and the investigator's trial staff are performing the specified trial functions, in accordance with the protocol and any other written agreement between the sponsor and the investigator/institution, and have not delegated these functions to unauthorized individuals
i) verifying that the investigator is enrolling only eligible subjects
j) reporting the subject recruitment rate
k) Verifying that source documents and other trial records are accurate, complete, kept up-to-date and maintained
l) Verifying that the investigator provides all the required reports, notifications, applications, and submissions, and that these documents are accurate, complete, timely, legible, dated, and identify the trial240.E6(R1) 5.18.4 -- Monitor's Responsibilities -- The monitor(s) in accordance with the sponsor's requirements should ensure that the trial is conducted and documented properly by carrying out the following activities when relevant and necessary to the trial and the trial site: (Part 6)n) Informing the investigator of any CRF entry error, omission, or illegibility. The monitor should ensure that appropriate corrections, additions, or deletions are made, dated, explained (if necessary), and initialed by the investigator or by a member of the investigator's trial staff who is authorized to initial CRF changes for the investigator. This authorization should be documented
o) Determining whether all adverse events (AEs) are appropriately reported within the time periods required by GCP, the protocol, the IRB/IEC, the sponsor, and the applicable regulatory requirement(s)
p) determining whether the investigator is maintaining the essential documents
q) communicating deviations from the protocol, SOPs, GCP, and the applicable regulatory requirements to the investigator and taking appropriate action designed to prevent recurrence of the detected deviations241.E6(R1) 5.18.5 -- Monitoring ProcduresThe monitor(s) should follow the sponsor's established written SOPs as well as those procedures that are specified by the sponsor for monitoring a specific trial

242.E6(R1) 5.18.6 -- Monitoring Reporta) the monitor should submit a written report to the sponsor after each trial site visit or trial related communication
b) reports should include the date, site, name of the monitor, and name of the investigator or the other individual(s) contacted
c) reports should include a summary of what the monitor reviewed and the monitor's statements concerning the significant findings/facts, deviations and deficiencies, conclusions actions taken or to be taken and/or nations recommended to secure compliance
d) the review and follow-up of the monitoring report with the sponsor should be documented by the sponsor's designated representative243.E6(R1) 5.19Audit -- If or when sponsors perform audits, as part of implanting quality assurance, they should consider the following (5.19.1-5.19.3)244.E6(R1) 5.19.1 --PurposeThe purpose of a sponsor's audit, which is independent of and separate from routine monitoring or quality control functions, should be to evaluate trial conduct and compliance with the protocol, sops, GCP, and the applicable regulatory requirements245.E6(R1) 5.19.2 -- Selection and Qualification of Auditorsa) the sponsor should appoint individuals, who are independent of the clinical trials/systems, to conduct audits
b) The sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly. An auditor's qualifications should be documented246.E6(R1) 5.19.3 -- Auditing Proceduresa) the sponsor should ensure that the auditing of clinical trials/systems is conducted in accordance with the sponsor's written procedures on what to audit, how to audit, the frequency of audits, and the form and content of audit reports.
b) the sponsor's audit plan and procedures for a trial audit should be guided by the importance of the trial to submissions to regulatory authorities, the number of subjects in the trial, the type and complexity of the trial, the level of risks to the trial subjects, and any identified problem(s)
c) the observations and findings of the auditor(s) should be documented
d) to preserve the independence and value of the audit functions, the regulatory authorities should not routinely request the audit reports. Regulatory authorities may seek access to an audit report on a case by case basis when evidence of serious GCP non-compliance exists, or in the course of legal proceedings
e) when required by applicable law or regulation, the sponsor should provide an audit certificate247.E6(R1) 5.20Noncompliance248.E6(R1) 5.20.1Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirements by a investigator/institution, or by members of ht sponsor's staff should lead to prompt action by the sponsor to secure compliance249.E6(R1) 5.20.2If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should terminate the investigator's/instiution's participation in the trial. When an investigator's/institution's participation is terminated because of noncompliance, the sponsor should notify promptly the regulatory authorities250.E6(R1) 5.21 -- Premature Termination or Suspension of a TrialIf a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigators/institutions, and the regulatory authorities of the termination or suspension and the reasons for the termination or suspension. The IRB/IEC should also be informed promptly and provided the reasons for the determination or suspension by the sponsor or by the investigator/institution, as specified by the applicable regulatory requirements251.E6(R1) 5.22 -- Clinical Trial/Study ReportsWhether the trial is completed or prematurely terminated, the sponsor should ensure that the clinical trial reports are prepared and provided to the regulatory agencies as required by the applicable regulatory requirements. The sponsor should also ensure that the clinical trial reports in marketing applications meet the standards of the ICH Guidelines for Structure and Content of Clinical Study Report (NOTE: the ICH Guideline for Structure and Content of Clinical Study Reports specifies that abbreviated study reports may be acceptable in certain cases252.E6(R1) 5.23Multicenter Trials253.E6(R1) 5.23.1All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authorities, and given approval/favorable opinion by the IRB/IEC254.E6(R1) 5.23.2The CRFs are designed to capture the required data at all multi center trial sites. For those investigators who are collecting additional data, supplemental CRFs should also be provided that are designed to capture the additional data

255.E6(R1) 5.23.3The responsibilities of coordinating investigators and the other participating investigators are documented prior to the start of the trial256.E6(R1) 5.23.4All investigators are given instructions on following the protocol, on complying with a uniform set of standards for the assessment of clinical and laboratory findings, and on completing the CRFs257.E6(R1) 5.23.5Communication between investigators is facilitated258.E6(R1) 6Clinical Trial Protocol and Protocol Amendments259.E6(R1) 6.1General Information260.E6(R1) 6.1.1Protocol title, protocol identifying number, and date. Any amendments should also bear the amendment numbers and dates261.E6(R1) 6.1.2Name and address of the sponsor and monitor262.E6(R1) 6.1.3Name and title of the persons authorized to sign the protocol and the protocol amendments for the sponsor263.E6(R1) 6.1.4Name, title, address, and telephone numbers of the sponsor's medical expert/dentist for the trial264.E6(R1) 6.1.5Name and title of the investigators who are responsible for conducting the trial, and the address and telephone numbers of the trial sites265.E6(R1) 6.1.6Name, title, address, and telephone numbers of the qualified physician or dentist who is responsible for all trial-site related medical or dental decisions (if other than investigator)266.E6(R1) 6.1.7Names and addresses of the clinical laboratories and other medical and/or technical departments and/or institutions involved in the trial267.E6(R1) 6.2Background Information268.E6(R1) 6.2.1Name and description of the investigational products269.E6(R1) 6.2.2A summary of findings from nonclinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial270.E6(R1) 6.2.3summary of the known and potential risks and benefits, if any, to human subjects.271.E6(R1) 6.2.4Description of and justification for the route of administration, dosage, dosage regimen, and treatment periods272.E6(R1) 6.2.5A statement that the trial will be conducted in compliance with the protocol, GCP and the applicable regulatory requirements273.E6(R1) 6.2.6Description of the population to be studied274.E6(R1) 6.2.7References to literature and data that are relevant to the trial, and that provide background for the trial275.E6(R1) 6.3 -- Trial Objectives and PurposeA detailed description of the objectives and the purpose of the trial276.E6(R1) 6.4.1A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial277.E6(R1) 6.4.2A description of the type/design of trial to be conducted and a schematic diagram of trial design, procedures and stages278.E6(R1) 6.4.3A description of the measures taken to minimize/avoid bias, including
a) Randomization
b) Blinding279.E6(R1) 6.4.4A description of the trial treatments and the dosage and dosage regimen of the investigational products. Also include a description of the dosage form, packaging, and labelling of the investigational products280.E6(R1) 6.4.5The expected duration of subject participation, and a description of the sequence and duration of all trial periods, including follow-up if any281.E6(R1) 6.4.6A description of the "stopping rules" or "discontinuation criteria" for individual subjects, parts of trial and entire trial282.E6(R1) 6.4.7Accountability procedures for the investigational products, including the placebos and comparators, if any

283.E6(R1) 6.4.8Maintenance of trial treatment randomization codes and procedures for breaking codes284.E6(R1) 6.4.9The identification of any data to be recorded directly on the CRFs and to be considered to be source data285.E6(R1) 6.4 --Trial DesignThe scientific integrity of the trial and the credibility of the data from the trial depend substantially on the trial design286.E6(R1) 6.5Selection and Withdrawal of Subjects287.E6(R1) 6.5.1Subject inclusion criteria288.E6(R1) 6.5.2Subject exclusion criteria289.E6(R1) 6.5.3Subject withdrawal criteria and procedure specifying 
a) when and how to withdraw subjects from the trial/investigational product treatment
b) the type and timing of the data to be collected for withdrawn subjects
c) whether and how subjects are to be replaced
d) the follow-up for subjects withdrawn from investigational product treatment/trial treatment290.E6(R1) 6.6Treatment of Subjects291.E6(R1) 6.6.1the treatments to be administered, including the names of all the products, the doses, the dosing schedules, the route/modes of administration, and the treatment periods, including the follow-up periods for subjects for each investigational product treatment/trial treatment group/arm of the trial292.E6(R1) 6.6.2Medications/treatments permitted (including rescue medication) and not permitted before and/or during the trial293.E6(R1) 6.6.3Procedures for monitoring subject compliance294.E6(R1) 6.7Assessment of Efficacy295.E6(R1) 6.7.1Specifications of the efficacy parameters296.E6(R1) 6.7.2Methods and timing for assessing, recording, and analyzing of efficacy parameters297.E6(R1) 6.8Assessment of Safety298.E6(R1) 6.8.1Specification of safety parameters299.E6(R1) 6.8.2The methods and timing for assessing, recording, and analyzing safety parameters300.E6(R1) 6.8.3Procedures for eliciting reports of and for recording and reporting adverse event and intercurrent illnesses301.E6(R1) 6.8.4The type and duration of the follow-up of subjects after adverse events302.E6(R1) 6.9Statistics303.E6(R1) 6.9.1A description of the statistical methods to be employed, including timing of any planned interim analysis304.E6(R1) 6.9.2The number of subjects planned to be enrolled. In multimeter trials, the numbers of enrolled subjects projected for each trial site should be specified. Reason for choice of sample size, including reflections on (or calculations of) the power of the trial and clinical justification305.E6(R1) 6.9.3The level of significance to be used

306.E6(R1) 6.9.4Criteria for the termination of the trial307.E6(R1) 6.9.5Procedure for accounting for missing, unused, and spurious data308.E6(R1) 6.9.6Procedures for reporting any deviations from the original statistical plan (any deviations from the original statistical plan should be described and justified in protocol and/or in the final report as appropriate309.E6(R1) 6.10 -- Direct Access to Source Data/DocumentsThe sponsor should ensure that it is specified in the protocol or other written agreement that the investigators/institutions will permit trial-related monitoring, audits, IRB/IEC review, and regulatory inspections, providing direct access to source data/documents310.E6(R1) 6.11Quality Control and Quality Assurance311.E6(R1) 6.12Ethics --Description of ethical considerations relating to the trial312.E6(R1) 6.13Data Handling and Record Keeping313.E6(R1) 6.14Financing and Insurance -- if not addressed in a separate agreement314.E6(R1) 6.15Publication Policy -- if not addressed in a separate agreement315.E6(R1) 6.16Supplements316.E6(R1) 6 -- Clinical Trial Protocol and Protocol AmendmentsThe contents of a trip protocol should generally include the following topics. However site specific information may be provided on separate protocol pages, or addressed in a separate agreement, and some of the information listed below may be contained in other protocol referenced documents, such as an Investigator's Brochure317.E6(R1) 7Investigator Brochure318.E6(R1) 7.1 -- IntroductionThe Investigator's Brochure (IB) is a compilation of the clinical and nonclinical data on the investigational products that are relevant to the study of the products in human subjects. Its purpose is to proved the investigators and others involved in the trial with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods of administration: and safety monitoring procedures. The IB also provides insight to support the clinical management of the study subjects during the course of the clinical trial. The information should be presented in a concise, simple, objective, balanced, and non-promotional form that enables a clinician, or potential investigator, to understand it and make his/her own unbiased risk-benefit assessment of the appropriateness of the proposed trial. For this reason, a medically qualified person should generally participate int he editing of an IB, but the contents o the IB should be approved by the disciplines that generated the described data.319.E6(R1) 7.2General Considerations320.E6(R1) 7.2.1 -- Title PageThis should proved the sponsor's name, the identity of each investigational product (research number, chemical or approved generic name, the trade names where legally permissible and desired by the sponsor), and the release date. It is also suggested that an edition number, and a reference to the number and date of the edition it supersedes, be provided.321.E6(R1) 7.2.2 -- Confidentiality StatementThe sponsor may wish to include a statement instructing the investigator/recipients to treat the IB as a confidential document for the sole information and use of the investigator's team and the IRB/IEC322.E6(R1) 7.3Contents of the Investigator's Brochure323.E6(R1) 7.3.1Table of Contents324.E6(R1) 7.3.2Summary -- a brief summary should be given, highlighting the significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic, and clinical information available that is relevant to the stage of clinical development of the investigational product325.E6(R1) 7.3.3Introduction -- A brief introductory statement should be provided that contains the chemical name of the investigational products, all active ingredients, the investigational products pharmacological class and its expected position within their class, the rationale for performing research with the investigational products, and the anticipated prophylactic, therapeutic, or diagnostic indications. Finally, the introductory statement should provide the general approach to be followed in evaluating the investigational product

326.E6(R1) 7.3.4Physical, Chemical, and Pharmaceutical Properties and Formulation -- A description should be provided of the investigational product substances , and a brief summary should be given of the relevant physical, chemical, and pharmaceutical properties. To permit appropriate safety measures to be taken in the course of the trial, a description of the formulations to be used, including excipients, should be provided and justified if clinically relevant. Instructions for the storage and handling of the dosage forms should also be given. Any structural similarities to other known compounds should be mentioned327.E6(R1) 7.3.5 -- Nonclinical studies: IntroductionThe results of all relevant nonclinical pharmacology, toxicology, pharmacokinetic, and investigational product metabolism studies should be provided in summary form. This summary should address the methodology used, the results, and a discussion of the relevance of the findings to the investigated therapeutic and the possible unfavorable and unintended effects in humans.328.E6(R1) 7.3.5 -- Nonclinical studies: Introduction -- Nonclinical Pharmacologya summary of the pharmacological aspects of the investigational product and, where appropriate, its significant metabolites studied in animals, should be included. Such a summary should incorporate studies that assess potential therapeutic activity as well as those that assess safety329.E6(R1) 7.3.5 -- Nonclinical studies: Introduction -- Pharmacokinetics and Product Metabolism in AnimalsA summary of the pharmacokinetics and biological transformation and disposition of the investigational product in all species studied should be given. The discussion of the findings should address the absorption and the local and systemic bioavailability of the investigational product and its metabolites, and their relationship to the pharmacological and toxicological findings in animal species330.E6(R1) 7.3.5 -- Nonclinical studies: Introduction -- ToxicologyA summary of the toxicological effects found in relevant studies conducted in different animal species should be described under the following headings where appropriate: 
- Single dose
- Repeated dose
- Carcinogenicity
- Special studies
- Reproductive toxicity
- Genotoxicity (mutagenicity)331.E6(R1) 7.3.6 -- Effects in Humans: IntroductionA thorough discussion of the known effects of the investigational products in humans should be provided, including information on pharmacokinetics, metabolism, pharmacodynamics, dose response, safety, efficacy, and other pharmacological activities. Where possible, a summary of each completed clinical trial should be provided. Information should also be provided regarding results of any use o fate investigational products other than from in clinical trials, such as from experience during marketing332.E6(R1) 7.3.6 -- Effects in Humans: Introduction -- Marketing ExperienceThe IB should identify countries where the investigational product has been marketed or approved. Any significant information arising from eh marketed use should be summarized. The IB should also identify all the countries where the investigational product did not receive approval/registration for marketing or was withdrawn from marketing/registration333.E6(R1) 7.3.6 -- Effects in Humans: Introduction -- Pharmacokinetic and Product Metabolism in HumansA summary of information on the pharmacokinetics of the investigational products should be presented, including the following, if available:
- Pharmacokinetics
- Bioavailability of the investigational product
- Population subgroups
- Interactions
- Other pharmacokinetic data

334.E6(R1) 7.3.6 -- Effects in Humans: Introduction -- Safety and Efficacy (Part 1)A summary of information should be provided about the investigational products safety, pharmacodynamics, efficacy,a dn dose response that were obtained fro preceding trials in humans. The implications of this information should be discussed. IN cases where a number of clinical trials have been completed, the use of summaries of safety and efficacy across multiple trials by indications in subgroups may provide a clear presentation of the data. Tabular summaries of adverse drug reactions for all the clinical trials would be useful. Important differences in adverse drug reaction patterns/incidences across indications or subgroups should be discussed335.E6(R1) 7.3.6 -- Effects in Humans: Introduction -- Safety and Efficacy (Part 2)The IB should provide a description of the possible risks and adverse drug reactions to be anticipated on the basis of prior experiences with the product under investigation and with related products. A description should also be provided of the precautions or special monitoring to be done as part of the investigational use of the products336.E6(R1) 7.3.7 -- Summary of Data and Guidance for the InvestigatorThis section should provide an overall discussion of the nonclinical and clinical data, and should summarize the information from various sources on different aspects of the investigational products, wherever possible. In this way, the investigator can be provided with the most informative interpretation of the available data and with an assessment of the implications of the information for future clinical trials.
Where appropriate, the published reports on related products should be discussed. This could help the investigator to anticipate adverse drug reactions or other problems in clinical trials337.E6(R1) 8Essential Documents for the Conduct of a Clinical Trial338.E6(R1) 8.1 -- IntroductionEssential Documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standard of Good Clinical Practice and with all applicable regulatory requirements339.E6(R1) 8.2.Before the Clinical Phase of the Trial Commences340.E6(R1) 8.2.1 -- Investigator's BrochureTo document that relevant and current scientific information about the investigational product has been provided to the investigator
LOCATION: 
-Investigator/institution 
-Sponsor341.E6(R1) 8.2.2 -- Signed Protocol and Amendments if any, and Sample Case Report Form (CRF)To document investigator and sponsor agreement to the protocol/amendments and CRF
LOCATION:
-Investigator/institution
-Sponsor342.E6(R1) 8.2.3 -- Advertisement for Subject RecruitmentTo document that recruitment measures are appropriate and not coercive
LOCATION:
-Investigator/institution343.E6(R1) 8.2.3 -- Information Given to Trial Subject --Any Other Written InformationTo document the subjects will be given appropriate written information to support their ability to give fully informed consent 
LOCATION:
-Investigator/institution
-Sponsor344.E6(R1) 8.2.3 -- Information Given to Trial Subject --Informed Consent Formto document the informed consent
LOCATION:
-Investigator/institution
-Sponsor

345.E6(R1) 8.2.4 --Financial Aspects of the TrialTo document the financial agreement between the investigator/institution and the sponsor for the trial
LOCATION:
-Investigator/institution
-Sponsor346.E6(R1) 8.2.5 -- Insurance StatementTo document that compensation to subjects for trial-related injury will be available
LOCATION:
-Investigator/institution
-Sponsor347.E6(R1) 8.2.6 -- Signed Agreement Between Involved PartiesTo document agreements
LOCATION:
-Sponsor
-Investigator/Institution when involved348.E6(R1) 8.2.7 -- Dated, Documented Approval/Favorable Opinion of IRB/IECTo document that the trial has been subject to IRB/IEC review and given approval/favorable opinion. To identify the version number and date of documents
LOCATION:
-Investigator/institution
-Sponsor349.E6(R1) 8.2.8 -- IRB/IEC CompositionTo document that the IRB/IEC is constituted in agreement with GCP
LOCATION:
-Investigator/institution
-sponsor -where required350.E6(R1) 8.2.9 -- Regulatory Authorities Authorization/Approval/Notification of ProtocolTo document appropriate authorization/approval/notification by the regulatory authorities has been obtained prior to initiation of regulatory requirements
LOCATION:
-Investigator/Institution -where required
-Sponsor -where required351.E6(R1) 8.2.10 -- Curriculum Vitae and/or Other Relevant Documents Evidencing Qualifications of Investigators and Sub-InvestigatorsTo document qualifications and eligibility to conduct trial and/or provide medical supervision of subjects
LOCATION:
-Investigator/Institution
-Sponsor352.E6(R1) 8.2.11 -- Normal Values/Ranges for Medical/Laboratory/Technical Procedures and/or Tests Included in the ProtocolTo document normal values and/or ranges of tests
LOCATION:
-Investigator/Institution
-Sponsor353.E6(R1) 8.2.12 -- Medical/Laboratory/Technical Procedures/TestsTo document compétence of facility to perform required tests, and support reliability of results
LOCATION:
-Investigator/Institution -where required
-Sponsor354.E6(R1) 8.2.13 -- Sample of Labels Attached to Investigational Product ContainersTo document compliance with applicable labeling regulations and appropriateness of instructions provided to the subjects
LOCATION:
-Sponsor

355.E6(R1) 8.2.14 -- Instructions for Handling of Investigational Products and Trial-Related MaterialsTo document instructions needed to ensure proper storage, packaging, dispensing and disposition of investigational products and trial related materials
LOCATION:
-Investigator/Institution
-Sponsor356.E6(R1) 8.2.15 -- Shippng Records for Investigational Products and Trial-Related MaterialsTo document shipment dates, batch numbers and method of shipment of investigational products and trial-related materials. Allows tracking of product batch, review of shipping conditions, and accountability
LOCATION:
-Investigator/Institution
-Sponsor357.E6(R1) 8.2.16 -- Certificates of Analysis of Investigational Products ShippedTo document identity, purity, and strength of investigational products to be used in the trial
LOCATION:
-Sponsor358.E6(R1) 8.2.17 -- Decoding Procedures for Blinded TrialsTo document how, in case of an emergency, identity of blinded investigational product can be revealed without breaking the blind for the remaining subjects' treatment
LOCATION:
-Investigator/Institution
-Sponsor
-Third Party -if applicable359.E6(R1) 8.2.18 -- Master Randomization ListTo document method for randomization of trial population
LOCATION:
-Sponsor
-Third Party -if applicable360.E6(R1) 8.2.19 -- Pre-Trial Monitoring ReportTo document that the site is suitable for the trial
LOCATION:
-Sponsor361.E6(R1) 8.2.20 -- Trial Initiation Monitoring ReportTo document that trial procedures were reviewed with the investigator and the investigator's trial staff
LOCATION:
-Investigator/Institution
-Sponsor362.E6(R1) 8.3During the Clinical Conduct of the Trial -- all documents in 8.2 plus the following363.E6(R1) 8.3.1 -- Investigator's Brochure UpdatesTo document that investigator is informed in a timely manner of relevant information as it becomes available
LOCATION:
-Investigator/Institution
-Sponsor364.E6(R1) 8.3.2 -- Any Revision to Trial DocumentsTo document revisions of these trial related documents that take effect during trial 
LOCATION:
-Investigator/Institution
-Sponsor365.E6(R1) 8.3.3 -- Dated, Documented Approval/Favorable Opinion of IRB/IEC of Trial Related DocumentsTo document that the amendments and/or revisions have been subject to IRB/IEC review and were given approval/favorable opinion. To identify the version number and date of the documents
LOCATION: 
-Investigator/Institution
-Sponsor

366.E6(R1) 8.3.4 -- Regulatory Authorities Authorization/Approvals/Notifications Where Required for Protocol Amendments and Other DocumentsTo document compliance with applicable regulatory requirements
LOCATION:
-Investigator/Institution -where required
-Sponsor367.E6(R1) 8.3.5 -- Curriculum Vitae For New Investigators and/or Sub InvestigatorsTo document qualifications and eligibility to conduct trial and/or provide medical supervision of subjects
LOCATION:
-Investigator/Institution
-Sponsor368.E6(R1) 8.3.6 -- Updates to Normal Values/Ranges for Medical/Laboratory/Technical Procedures/Tests Included in the ProtocolTo document normal values and ranges that are revised during the trial
LOCATION:
-Investigator/Institution
-Sponsor369.E6(R1) 8.3.7 -- Updates of Medical/Laboratory/Technical Procedures/Tests Certification, Accreditation, Established QC and/or External QA, or Other ValidationTo document that test remain adequate throughout the trial period
LOCATION:
-Investigator/Institution -where required
-Sponsor370.E6(R1) 8.3.8 -- Documentation of Investigational Products and Trial-Related Materials ShipmentTo document shipment dates, batch numbers and method of shipment of investigational products and trial-related materials. Allows tracking of product batch, review of shipping conditions, and accountability
LOCATION:
-Investigator/Institution
-Sponsor371.E6(R1) 8.3.9 -- Certificates of Analysis for New Batches of Investigational ProductsTo document identity, purity, and strength of investigational products to be used in the trial
LOCATION:
-Sponsor372.E6(R1) 8.3.10 -- Monitoring Visit ReportsTo document site visits by, and findings of, the monitor
LOCATION:
-Sponsor373.E6(R1) 8.3.11 -- Relevant Communications Other than Site Visits: letters, meeting notes, notes of telephone callsTo document any agreements or significant discussions regarding trial administration, protocol violations, trial conduct, adverse event (AD) reporting
LOCATION:
-Investigator/Institution
-Sponsor374.E6(R1) 8.3.12 -- Signed Informed Consent FormsTo document that consent is obtained in accordance with GCP and protocol and dated prior to participation of each subject in trial. Also to document direct access permission
LOCATION:
-Investigator/Institution375.E6(R1) 8.3.13 -- Source DocumentsTo document the existence of the subject and substantiate integrity of trial data collected. To include original documents related to the trial, to medical treatment, and history of subject
LOCATION:
-Investigator/Institution376.E6(R1) 8.3.14 -- Signed, Dated and Completed Case Report Forms (CRF)To document that the investigator or authorized member of the investigator's staff confirms the observations recorded
LOCATION:
-Investigator/Institution -copy
-Sponsor -original

377.E6(R1) 8.3.15 -- Documentations of CRF CorrectionsTo document all changes/additions or corrections made to CRF after initial data were recorded
LOCATION:
-Investigator/Institution -copy
-Sponsor -original378.E6(R1) 8.3.16 -- Notification by Originating Investigator to Sponsor of Serious Adverse Events and Related ReportsNotification by originating investigator to sponsor of serious adverse events and related reports in accordance with 4.11
LOCATION:
-Investigator/Institution
-Sponsor379.E6(R1) 8.3.17 -- Notification by Sponsor and/or Investigator, Where Applicable, to Regulatory Authorities and IRB/IECs of Unexpected Serious Adverse Drug Reactions and of Other Safety InformationNotification by sponsor and/or investigator where applicable, to regulatory authorities and IRB/IECs of unexpected serious adverse drug reactions in accordance with 5.17 and 4.11.1 and of other safety information in accordance with 5.16.2 and 4.11.2
LOCATION:
-Investigator/Institution -where required
-Sponsor380.E6(R1) 8.3.18 -- Notification by Sponsor to Investigators of Safety InformationNotification by sponsor to investigators of safety information in accordance with 5.16.2
LOCATION:
-Investigator/Institution
-Sponsor381.E6(R1) 8.3.19 -- Interim or Annual Reports to IRB/IEC and AuthoritiesInterim or annual reports provided to IRB/IEC in accordance with 4.10 and to authorities in accordance with 5.17.3
LOCATION:
-Investigator/Institution
-Sponsor -where required382.E6(R1) 8.3.20 -- Subject Screening LogTo document identification of subjects who entered pre-trial screening
LOCATION:
-Investigator/Institution
-Sponsor -where required383.E6(R1) 8.3.21 -- Subject Identification Code ListTo document that investigator/institution keeps a confidential list of names of all subjects allocated to trial numbers on enrolling in the trial. Allows investigator/institution to reveal identity of any subject
LOCATION:
-Investigator/Institution384.E6(R1) 8.3.22 -- Subject Enrollment LogTo document chronological enrollment of subjects by trial number
LOCATION:
-Investigator/Institution385.E6(R1) 8.3.23 -- Investigational Products Accountability at the SiteTo document that investigational products have been used according to the protocol
LOCATION:
-Investigator/Institution
-Sponsor386.E6(R1) 8.3.24 -- Signature SheetTo document signatures and initials of all persons authorized to make entries and/or corrections on CRFs
LOCATION:
-Investigator/Institution
-Sponsor

387.E6(R1) 8.3.25 -- Record of Retained body Fluids/Tissue Samples (If Any)To document location and identification of retained samples if assays need to be repeated
LOCATION:
-Investigator/Institution
-Sponsor388.E6(R1) 8.4After Completion or Termination of the Trial --all documents in sections 8.2 and 8.3 plus these389.E6(R1) 8.4.1 -- Investigational Products Accountability at Siteto document that the investigational products have been used according to the protocol. To document the final accounting of investigational products received at the site, dispensed to subjects, returned by the subjects, and returned to sponsor
LOCATION:
-Investigator/Institution
-Sponsor390.E6(R1) 8.4.2 -- Documentation of Investigational Product DestructionTo document destruction of unused investigational products by sponsor or at site
LOCATION:
-Investigator/Institution -if destroyed at site
-Sponsor391.E6(R1) 8.4.3 -- Completed Subject Identification Code ListTo permit identification of all subjects enrolled in the trial in case follow-up is required. List should be kept in a confidential manner and for agreed upon time
LOCATION:
-Investigator/Institution392.E6(R1) 8.4.4 -- Audit Certificate (if available)To document that audit was performed 
LOCATION:
-Sponsor393.E6(R1) 8.4.5 -- Final Trial Close-Out Monitoring ReportTo document that all activities required for trial close-out are completed, and copies of essential documents are held in the appropriate files
LOCATION:
-Sponsor394.E6(R1) 8.4.6 -- Treatment Allocation and Decoding DocumentationsReturned to sponsor to document any decoding that may have occurred
LOCATION:
-Sponsor395.E6(R1) 8.4.7 -- Final Report by Investigator to IRB/IEC Where Required, and Where Applicable, to the Regulatory AuthoritiesTo document completion of the trial
LOCATION:
-Investigator/Institution396.E6(R1) 8.4.8 -- Clinical Study ReportTo document results and interpretations of trial
LOCATION:
-Investigator/Institution -if applicable
-Sponsor397.E8General Considerations for Clinical Trials398.E8 1Objectives of this document399.E8 1 -- Objecties of this Documenta) describe internationally accepted principles and practices in the conduct of both individual clinical trials and overall development strategy for new medicinal products
b) facilitate the evaluation and acceptance of foreign clinical trial data by promoting common understanding of general principles, general approaches and the definition of relevant terms
c) Present an overview of the ICH clinical safety and efficacy documents and facilitate the user's access to guidance pertinent to clinical trials within these documents
d) provide a separate glossary of terms used in the ICH clinical safety and efficacy related documents that pertain to clinical trials and indicate which documents contain them400.E8 2.General Principles

401.E8 2.1Protection of clinical trial subjects402.E8 2.2Scientific approach in design analysis403.E8 2.2 Type of Study: Human Pharmacology-assess tolerance 
-describe PK and PD
-Explore drug metabolism and drug interactions
-estimate activity404.E8 2.2 Type of Study: Therapeutic Confirmatory-demonstrate/confirm efficacy
-establish safety profile
provide an adequate basis for assessing the benefit/risk relationship to support licensing
-establish dose-response relationship405.E8 2.2 Type of Study: Therapeutic Exploratory-explore use for the targeted indication
-estimate dosage for subsequent studies
-provide basis for confirmatory study design, endpoints, methodologies406.E8 2.2 Type of Study: Therapeutic Use-refine understanding of benefit/risk relationship in general or special populations and/or environments
-identify less common adverse reactions
-refine dosing recommendation407.E8 3Development Methodology --covers issues and considerations related to the development plan and to its individual component studies408.E8 3.1Considerations for the Development Plan409.E8 3.1.1NonClinical Studies410.E8 3.1.1.1Safety Studies -- early non-clinical studies should provide sufficient information to support selection of the initial human dose and safe duration of exposure and to provide information about physiological and toxicological effects of a new drug411.E8 3.1.1.2Pharmacological and Pharmacokinetic Studies -- includes information such as:
a) pharmacological basis of principal effects
b) dose-response or concentration-response relationships and duration of action
c) study of the potential clinical routes of administration
d) systemic general pharmacology, including pharmacological effects on major organ systems and physiological responses
e) studies of absorption, distribution, metabolism and excretion412.E8 3.1.2Quality of Investigational medicinal Products -- formulations used in clinical trials should be well characterized, including information on bioavailability wherever feasible413.E8 3.1.3Phases of Clinical Development414.E8 3.1.3.1Phase I (Most typical kind of study: Human Pharmacology)415.E8 3.1.3.1.5development of an application unrelated to original approved use after initial approval
-new or modified indications
-new dosage regimens
-new routes of administration
-additional patient populations416.E8 3.1.3.1.a -- Estimation of initial safety and tolerabilityintended to determine the tolerability of the dose range expected to be needed for later clinical studies and to determine the nature of adverse reactions that can be expected--typically include both single and multiple dose administration417.E8 3.1.3.1.b --Pharmacokinetics-may be assessed via separate studies or as a part of efficacy, safety and tolerance studies
-important to assess the clearance of the drug and to anticipate possible accumulation of parent drug or metabolites and potential drug-drug interactions

418.E8 3.1.3.1.c -- Assessment of Pharmacodynamics-depending on the drug and the endpoint studied, pharmacodynamic studies and studies relating drug blood levels to response (PK/PD studies) may be conducted in healthy volunteer subjects or in patients with the target disease
-can provide early estimates of activity and potential efficacy and may guide the dosage and dose regimen in later studies419.E8 3.1.3.1.d -- Early Measurement of Drug Activity-preliminary studies of activity or potential therapeutic benefit may be conducted in Phase I as a secondary objective420.E8 3.1.3.2Phase II (Most typical kind of study: Therapeutic Exploratory)
-usually considered to start with the initiation of studies in which the primary objective is to explore therapeutic efficacy in patients
-goal is to determine the doses and regimen for Phase III trials
-evaluation of potential study endpoints, therapeutic regimens and target populations for further study421.E8 3.1.3.3Phase III (Most typical kind of study: Therapeutic Confirmatory)
-primary objective is to demonstrate, or confirm therapeutic benefit
-intended to provide an adequate basis for marketing approval
-further explore the dose-response relationship or explore the drug's use in wider populations, in different stages of disease, or in combination with another drug
-complete the information needed to support adequate instructions for use of the drug422.E8 3.1.3.4Phase IV (Variety of Studies: Therapeutic Use)
-begins after drug approval
-all studies performed after drug approval and related to the approved indication
-important for optimizing the drug's use423.E8 3.1.4Special Considerations424.E8 3.1.4.1Studies of Drug Metabolites425.E8 3.1.4.2Drug-Drug Interactions426.E8 3.1.4.3Special Populations
a) investigations in pregnant women
b) investigations in nursing women
c) investigations in children427.E8 3.2Considerations for Individual Clinical Trials428.E8 3.2.1Objectives
-should be clearly stated and may include exploratory or confirmatory characterization of safety and/or efficacy and/or assessment of pharmacokinetic parameters and pharmacological, physiological, biochemical effects429.E8 3.2.2Design
-should be chosen to provide the desired information
-appropriate comparators
-primary and secondary endpoints and plans for analysis
-methods of monitoring adverse events
-procedures for the follow-up of patients who stop treatment prematurely430.E8 3.2.2.1Selection of subjects
-stage of development and indication to be studied should be taken into account in selecting the subject population
- prior non-clinical and clinical knowledge
-stage of development and level of concern for safety431.E8 3.2.2.2Selection of Control Group
-comparison may be made with placebo, no treatment, active controls or of different doses of the drug under investigation432.E8 3.2.2.3Number of Subjects
-size of trial is influenced by the disease to be investigated, the object of the study and the study endpoints

433.E8 3.2.2.4Response Variables
-should be defined prospectively, giving descriptions of methods of observation and quantification
-study endpoints are the response variables that are chosen to assess drug effects that are related to pharmacokinetic parameters, pharmacodynamic measures, efficacy and safety434.E8 3.2.2.5Methods to Minimize or Assess Bias
-protocol should specify methods of allocation to treatment groups and blinding435.E8 3.2.2.5.aRandomization
-preferred means of assuring comparability of test groups and minimizing the possibility of selection bias436.E8 3.2.2.5.bBlinding
-an important means of reducing or minimizing the risk of biased study outcomes437.E8 3.2.2.5.cCompliance
-methods used to evaluate patient usage of the test drug should be specified in the protocol and the actual usage documented438.E8 3.2.3Conduct
-adherence to the study protocol is essential
-if modification of the protocol becomes necessary a clear description of the rationale for the modification should be provided in a protocol amendment439.E8 3.2.4Analysis
-protocol should have a specified analysis plan that is appropriate for the objectives and design of the study, taking into account the method of subject allocation, the measurement methods of response variables, specific hypotheses to be tested, and analytical approaches to common problems including early study withdrawal and protocol violations440.E8 3.2.5Reporting
-clinical study reports should be adequately documented following the approaches outlined in other ICH guidelines441.E9Statistical Principles for Clinical Trials442.E9 1Introduction443.E9 1.1Background and Purpose444.E9 1.2Scope and Direction
-For each clinical trial contributing to a marketing application, all-important details of its design and conduct and the principal features of its proposed statistical analysis should be clearly specified in a protocol written before the trial begins445.E9 2Considerations for Overall Clinical Development446.E9 2.1Trial Context447.E9 2.1.1Development Plan
-The broad aim of the process of clinical development of a new drug is to find out whether there is a dose range and schedule at which the drug can be shown to be simultaneously safe and effective, to the extent that the risk-benefit relationship is acceptable448.E9 2.1.2Confirmatory Trial
-and adequately controlled trial in which the hypotheses are stated in advance and evaluated
-necessary to provide firm evidence of efficacy or safety449.E9 2.1.3Exploratory Trial
-rationale and design nearly always rests on earlier work carried out in a series of exploratory studies
-should have clear and precise objectives
-objectives may not always lead to simple tests of pre-defined hypotheses450.E9 2.2Scope of Trials451.E9 2.2.1Population452.E9 2.2.2Primary and Secondary Variables
-the primary variable should be the variable capable of providing the most clinically relevant and convincing evidence directly related to the primary variable
-should be specified in the protocol, along with the rationale for its selection

453.E9 2.2.3Composite Variables
-if a single primary variable cannot be selected from multiple measurements associated with the primary objective, another useful strategy is to integrate or combine the multiple measurements into a single or 'composite' variable, using a pre-defined algorithm454.E9 2.2.4Global Assessment Variables
-developed to measure the overall safety, overall efficacy, and/or overall usefulness of a treatment
-integrates objective variables and the investigator's overall impression about the state or change in the state of the subject, and is usually a scale of ordered categorical ratings455.E9 2.2.5Multiple Primary Variables
-may be desirable to use more than one primary variable, each of which could be sufficient to cover the range of effects of the therapies456.E9 2.2.6Surrogate Variables
-used in a number of indications where they are believed to be reliable predictors of clinical benefit457.E9 2.2.7Categorized Variables
-dichotomization or other categorization of continuous or ordinal variables may sometimes be desirable458.E9 2.3Design Techniques to Avoid Bias
-the most important design techniques for avoiding bias in clinical trials are blinding and randomization, and thee should be normal features of most controlled clinical trials intended to be included in a marketing application459.E9 2.3.1Blinding
-blinding or making is intended to limit the occurrence of conscious and unconscious bias in the conduct and interpretation of a clinical trial arising from the influence which the knowledge of treatment may have on the recruitment and allocation of subjects, their subsequent care, the attitudes of subjects to the treatments, the assessment of end-points, the handling of withdrawals, the exclusion of data from analysis, and so on460.E9 2.3.2Randomization
-provides a sound statistical basis for the quantitative evaluation of the evidence relating to treatment effects461.E9 3Trial Design Considerations462.E9 3.1Design Configuration463.E9 3.1.1Parallel Group Design
-subjects are randomized to one of two or more arms, each arm being allocated a different treatment464.E9 3.1.2Crossover Design
-each subject is randomized to a sequence of two or more treatments, and hence acts as his own control for treatment comparisons465.E9 3.1.3Factorial Designs
-two or more treatments are evaluated simultaneously through the use of varying combinations of treatments466.E9 3.2Multicenter Trials467.E9 3.3Type of Comparison468.E9 3.3.1Trials to Show Superiority
-Efficacy is most convincingly established by demonstrating superiority to placebo in a placebo-controlled trial, by showing superiority to an active control treatment or by demonstrating a dose-response relationship469.E9 3.3.2Trials to Show Equivalence or Non-inferiority
-and investigational product is compared to a reference treatment without the objective of showing superiority
-divided by two major categories according to its objective; one is an 'equivalence' trial and the other is a 'non-inferiority' trial470.E9 3.3.3Trials to Show Dose-response Relationship
-how response is related to the dose of a new investigational product is a question to which answers may be obtained in all phases of development, and by a variety of approaches471.E9 3.4Group Sequential Designs
-used to facilitate the conduct of interim analysis

472.E9 3.5Sample Size
-the number of subjects in a clinical trial should always be large enough to provide a reliable answer to the questions addressed
-number is usually determined by the primary objective of the trial473.E9 3.6Data Capture and Processing
-collection of data and transfer of data from the investigator to the sponsor can take place through a variety of media, including paper case record forms, remote site monitoring systems, medical computer systems and electronic transfer474.E9 4Trial Conduct Considerations475.E9 4.1Trial Monitoring and Interim Analysis476.E9 4.2Changes in Inclusion and Exclusion Criteria
-should remain constant, as specified in the protocol, throughout the period of subject recruitment477.E9 4.3Accrual Rates478.E9 4.4Sample Size Adjustment479.E9 4.5Interim Analysis and Early Stopping
-an analysis intended to compare treatment arms with respect to efficacy or safety at any time prior to formal completion of a trial480.E9 4.6Role of Independent Data Monitoring Committee (IDMC) 
-may be established by the sponsor to assess at intervals the progress of a clinical trial, safety data, and critical efficacy variables and recommend to the sponsor whether to continue, modify or terminate a trial481.E9 5Data Analysis Considerations482.E9 5.1Pre specification of the Analysis483.E9 5.2Analysis Sets
-set of subjects whose data are to be included in the main analyses should be defined in the statistical section of the protocol
-documentation for all subjects for whom trial procedures were initiated may be useful484.E9 5.2.1Full Analysis Set
-the analysis set which is as complete as possible and as close as possible to the intention-to-treat ideal of including all randomized subjects485.E9 5.2.2Per Protocol Set
-valid cases
-efficacy sample
-evaluable subjects486.E9 5.2.3Roles of the Different Analysis Sets
-advantageous to demonstrate a lack of sensitivity of the principal trial results to alternative choices of the set of subjects analyzed487.E9 5.3Missing Values and Outliers488.E9 5.4Data Transformation489.E9 5.5Estimation, Confidence Intervals and Hypothesis Testing490.E9 5.6Adjustment of Significance and Confidence Levels491.E9 5.7Subgroups, Interactions and Covariates492.E9 5.8Integrity of Data and Computer Software Validity493.E9 6Evaluation of Safety and Tolerability

494.E9 6.1Scope of Evaluation495.E9 6.2Choice of Variables and Data Collection496.E9 6.3Set of Subjects to be Evaluated and Presentation of Data497.E9 6.4Statistical Evaluation498.E9 6.5Integrated Summary499.E9 7Reporting500.E9 7.1Evaluation and Reporting501.E9 7.2Summarizing the Clinical Database502.E9 7.2.1Efficacy Data503.E9 7.2.2Safety Data504.Essential DocumentsDocuments which individually and collectively permit evaluation of the conduct of a study and the quality of the data produced505.Good Clinical Practice (GCP)A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected506.IEC OpinionThe judgement and/or the advice provided by an Independent Ethics Committee (IEC)507.Impartial WitnessA person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who attends the informed consent process if the subject or the subject's legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject508.Independent Data-Monitoring Committee (IDMC) (Data and Safety Monitoring Board, Monitoring Committee, Data Monitoring Committee)An independent data-monitoring committee that may be established by the sponsor to assess at intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or stop a trial509.Independent Ethics Committee (IEC)An independent body constituted of medical professionals and non-medical members, whose responsibility it is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, reviewing and approving / providing favorable opinion on, the trial protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial subjects.510.Informed ConsentA process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject's decision to participate--documented by means of a written, signed and dated informed consent form511.InspectionThe act by a regulatory authority of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authorities to be related to the clinical trial and that may be located at the site of the trial, at the sponsor's and/or contract research organization's (CRO's) facilities, or at other establishments deemed appropriate by the regulatory authorities512.Institutional Review Board ApprovalThe affirmative decision of the IRB that the clinical trial has been reviewed and may be conducted at the institution site within the constraints set forth by the IRB, the institution, Good Clinical Practice (GCP), and the applicable regulatory requirements513.Institutional Review Board (IRB)An independent body constituted of medical, scientific, and non-scientific members, whose responsibility is to ensure the protection of the rights, safety, and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trial protocol and amendments and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects514.Institution (Medical)Any public or private entity or agency or medical or dental facility where clinical trials are conducted

515.Interim Clinical Trial/Study ReportA report of intermediate results and their evaluation based on analyses performed during the course of a trial516.Investigational ProductA pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.517.InvestigatorA person responsible for the conduct of the clinical trial at a trial site.518.Investigator's BrochureA compilation of the clinical and nonclinical data on the investigational product(s) which is relevant to the study of the investigational product(s) in human subjects.519.Legally Acceptable RepresentativeAn individual or juridical or other body authorized under applicable law to consent, on behalf of a prospective subject, to the subject's participation in the clinical trial.520.MonitoringThe act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).521.Monitoring ReportA written report from the monitor to the sponsor after each site visit and/or other trial-related communication according to the sponsor's SOPs.522.Multicenter TrialA clinical trial conducted according to a single protocol but at more than one site, and therefore, carried out by more than one investigator523.Nonclinical StudyBiomedical studies not performed on human subjects524.ProtocolA document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial.525.Protocol AmendmentA written description of a change to or formal clarification of a protocol.526.Quality Assurance (QA)All those planned and systematic actions that are established to ensure that the trial is performed ad the data are generated, documented, and reported in compliance with GCP and the applicable regulatory requirements527.Quality Control (QC)The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled528.RandomizationThe process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias.529.Randomization Procedures and UnblindingThe investigator should follow the trial's randomization procedures, if any, and should ensure that the code is broken only in accordance with the protocol. If the trial is blinded, the investigator should promptly document and explain to the sponsor any premature unblinding of the investigational product(s)530.Regulatory AuthoritiesBodies having the power to regulate.531.Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR)Any untoward medical occurrence that at any dose: 
-results in death
-is life-threatening
-requires inpatient hospitalization or prolongation of existing hospitalization
-results in persistent or significant disability/incapacity
-is a congenital anomaly/birth defect532.Source DataAll information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial533.Source DocumentsOriginal documents, data, and records.534.SponsorAn individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial535.Sponsor-InvestigatorAn individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to, or used by a subject.536.Standard Operating Procedures (SOPs)Detailed, written instructions to achieve uniformity of the performance of a specific function

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