General Considerations for Clinical Trials E8 (R1) Flashcards
Important principles of ethical conduct of clinical studies and the protection of participants, including special populations, have their origins in what?
The Declaration of Helsinki
Clinical studies should be designed, planned, conducted, analyzed, and reported according to what in order to achieve their objectives?
Sound scientific principles
What is the purpose of a clinical study?
To generate reliable information to answer the research questions and support decision making while protecting study participants
What is the cardinal logic behind serially conducted studies?
That the results of prior studies should inform the plan of later studies
Consulting with patients and/or patient organizations during drug development can help to ensure that patients’ perspectives are captured. Patients provide their perspective of living with a condition, which may contribute to:
The determination of endpoints that are meaningful to patients, selection of appropriate population and duration of the study, and use of acceptable comparators.
The quality of design approach to clinical research involves focusing on critical to quality factors to ensure what?
- The protection of the rights, safety, and wellbeing of study participants
- The generation of reliable and meaningful results
- The management of risks to those factors using a risk-proportionate approach
What is the primary consideration in design, planning, conduct, analysis, and reporting of clinical studies and a necessary component of clinical development programs?
Quality
The likelihood that a clinical study will answer the research questions while preventing important errors can be dramatically improved through prospective attention to the design of all components of the:
- Study protocol
- Study procedures
- Associated operational plans and training
True/False:
Activities such as document and data review and monitoring, where conducted retrospectively, are an important part of a quality assurance process and when combined with audits, are sufficient to ensure quality of a clinical study.
False.
Activities such as document and data review and monitoring, where conducted retrospectively, are an important part of a quality assurance process; but, even when combined with audits, they are NOT SUFFICIENT to ensure quality of a clinical trial.
Quality must be built into the design of a study.
Good planning and implementation of a clinical study are derived from attention to design elements of clinical studies such as:
- The need for clear pre-defined study objectives that address the primary scientific question(s)
- Selection of appropriate participants that have the disease, condition, or molecular/genetic profile that is being studied
- Use of approaches to minimize bias, such as randomization, blinding or masking, and/or control of confounding
- Endpoints that are well-defined, measurable, clinically meaningful, and relevant to patients
Operational criteria that are also important to study quality are:
- Ensuring a clear understanding of feasibility of the study
- Selection of suitable investigator sites
- Quality of specialized analytical and testing facilities and procedures
- Processes that ensure data integrity
Critical to quality factors are attributes of a study whose integrity is fundamental to:
- The protection of study participants
- The reliability and interpretability of the study results
- The decisions made based on the study results
The design of a clinical study should reflect:
- The state of knowledge and experience with the drug
- The condition to be treated, diagnosed or prevented
- The underlying biological mechanism (of both the condition and the treatment)
- The population for which the drug is intended
Who should identify the critical to quality factors of a clinical study?
The sponsor and other parties designed quality into a clinical study
A key aspect of a quality approach to study design is to ask whether the objectives being addressed by the study are clearly articulated:
- Whether the study is designed to meet the research question it sets out to address
- Whether these questions are meaningful to patients
- Whether the study hypotheses are specific and scientifically valid
Identification of critical to quality factors will be enhanced by approaches that include the following elements:
- Establishing a culture that supports open dialogue
- Focusing on activities essential to the study
- Engaging stakeholders in study design
- Reviewing critical to quality factors
- Critical to quality factors in operational practice
True/False:
Inflexible, “one size fits all” approaches should be encouraged. Standardized operating procedures are necessary and beneficial for conducting good quality studies.
False.
Inflexible, “one size fits all” approaches should be DISCOURAGED. Standardized operating procedures are necessary and beneficial for conducting good quality studies, BUT study specific strategies and actions are also needed to effectively and efficiently support quality in a study.
A feasibility assessment involves consideration of:
- Study design
- Implementation elements that could impact the successful completion of clinical development from an operational perspective
- Regional differences in medical practice and patient populations
- The availability of qualified investigators/site personnel with experience in conducting a clinical study
- Availability of equipment and facilities required to successfully conduct the study
- Availability of the targeted patient population and the ability to enroll a sufficient number of participants to meet the study objectives
- The retention and follow up of study participants to meet the study objectives
Focus should be given to activities that are essential to the study. Consideration should be given to eliminating nonessential activities and data collection from the study to increase quality by:
- Simplifying conduct
- Improving study efficiency
- Targeting resources to critical areas
Study resources should be deployed to identify and prevent or control what?
Errors that matter
What studies need specific attention during proactive planning and ongoing review of critical to quality factors and risk management?
Studies with adaptive features and/or interim decision points
True/False:
Drug development planning encompasses quality of medicinal product, but does not include chemistry, manufacturing and controls (CMC), and non-clinical and clinical studies (pre and post-approval).
False.
Drug development encompasses quality of medicinal products, INCLUDING chemistry, manufacturing and controls (CMC), and non-clinical and clinical studies (pre and post-approval).
During drug development, age-appropriate formulation development may be a consideration when clinical studies are planned in what population?
Pediatric
During drug development, more extensive characterization of physicochemical properties may be required for what kind of products?
Complex or biological products
Changes in a product during development should be supported by comparability data to ensure what?
To ensure the ability to interpret study results across the development program
The non-clinical assessment usually includes:
- Toxicology
- Carcinogenicity
- Immunogenicity
- Pharmacology
- Pharmacokinetics
- Other evaluations to support clinical studies
The scope of non-clinical studies, and their timing with respect to clinical studies, depend on a variety of factors that inform further development, such as:
- The drug’s chemical or molecular properties
- Pharmacological basis of principal effects
- Route of administration
- Absorption, distribution, metabolism, and excretion (ADME)
- Physiological effects on organ systems
- Dose/concentration-response relationships
- Metabolites
- Duration of action and use
ADME
Absorption, distribution, metabolism, and excretion
The structure of the drug development program will be shaped by many considerations and comprised of studies with different what?
Different objectives, designs, and dependencies
True/False:
Clinical drug development is often described as consisting of four temporal phases, it is important to appreciate that the phase concept is a requirement, but the phases of drug development may overlap or be combined.
False.
Although clinical drug development is often described as consisting of four temporal phases, it is important to appreciate that the phase concept is a description and NOT a requirement, and that the phases of drug development may overlap or be combined.
Why are initial clinical studies typically more limited in size and duration?
To provide an early evaluation of short-term safety and tolerability as well as proof of concept of efficacy
Initial clinical studies may provide what type of information needed to inform further clinical studies?
- Pharmacodynamic
- Pharmacokinetic
- Other information needed to choose a suitable dosage range and/or administration schedule
As more information is known about a drug, clinical studies may expand in size and duration, and may include what?
- More diverse study populations
- More secondary endpoints in addition to the primary measures of efficacy
The use of biomarkers has the potential to:
- Facilitate the availability of safer and more effective drugs
- Guide dose selection
- Enhance a drug’s benefit-risk profile
What should always be the first priority when designing early clinical studies, especially for the initial administration of an investigational product to humans?
The protection of study participants
The initial and subsequent administration of a drug to humans is usually intended to determine what?
- The tolerability of the dose range expected to be evaluated in later clinical studies
- The nature of adverse reactions that can be expected
Pharmacokinetic studies are particularly important to assess:
- The clearance of the drug
- To anticipate possible accumulation of parent drug or metabolites
- Interactions with metabolic enzymes and transporters
- Potential drug-drug interactions
What sub-populations should be considered when obtaining pharmacokinetic information on sub-populations with potentially different metabolism or excretion?
- Patients with renal or hepatic impairment
- Geriatric patients
- Children
- Ethnic subgroups
True/False:
Pharmacodynamic studies and studies relating drug levels to response (PK/PD studies) should only be conducted in healthy volunteer participants.
False.
Depending on the drug and the endpoint of interest, pharmacodynamic studies and studies relating drug levels to response (PK/PD studies) may be conducted in healthy volunteer participants OR in patient with the condition or disease.
Which phase study is considered an exploratory study?
Phase 2
Which phase study is considered a confirmatory study?
Phase 3
What are exploratory (Phase 2) studies designed to do?
- Investigate safety and efficacy in a selected population of patients for whom the drug is intended
- Refine the effective dose(s) and regimen
- Refine the definition of the targeted population
- Provide a more robust safety profile for the drug
- Evaluate the potential study endpoints for subsequent studies
What are confirmatory (Phase 3) studies designed to do?
- Confirm the preliminary evidence accumulated in earlier clinical studies that a drug is safe and effective for use for the intended indication and recipient population
- Provide an adequate basis for marketing approval
- Support adequate instructions for use of the drug and official product information
- Evaluate the drug in participants with or at risk of the condition or disease who represent those who will receive the drug once approved
Irrespective of the intended duration of drug administration, the duration of effect of the drug will also inform what?
The duration of follow-up
Study endpoints for confirmatory studies should:
Be clinically relevant and reflect disease burden or be of adequate surrogacy for predicting disease burden or sequelae
Why do special populations require additional investigation during drug development?
Special populations have unique risk/benefit considerations and/or because they can be anticipated to need modification of the dose or schedule of a drug
Particular attention should be paid to the ethical considerations related to what in vulnerable populations?
Informed consent
True/False:
Studies in special populations may be conducted during any phase of development to understand the drug effects in these populations.
True
Where pregnant women volunteer to be enrolled in a clinical study, or a participant becomes pregnant while participating in a clinical study, what is necessary?
Follow-up evaluation of the pregnancy and its outcome and the reporting of outcomes
Excretion of the drug or its metabolites into human milk should be examined where applicable and feasible. When nursing mothers are enrolled in clinical studies who else is monitored?
Their babies are monitored for the effects of the drug
What phase study is considered a post-approval study?
Phase 4
True/False:
Phase 4 studies are considered necessary for approval.
False.
Phase 4 studies are NOT considered necessary for approval but are often important for optimizing the drug’s use.
True/False:
Post-approval studies may be conducted to address a regulatory requirement.
True.
Commonly conducted post-approval studies include:
- Additional drug-drug interaction
- Dose-response
- Safety studies
- Studies designed to support use under the approved indication
Post-approval studies may explore use of the drug in the real-world setting of clinical practice and may also inform:
Health economics and health technology assessments
True/False:
After initial approval, drug development may continue with studies of new or modified indications in new patient populations, new dosage regimens, or new routes of administration. If a new dose, formulation, or combination is studied though, additional non-clinical and/or human pharmacology studies are not needed.
False.
After initial approval, drug development may continue with studies of new or modified indications in new patient populations, new dosage regimens, or new routes of administration. If a new dose, formulation, or combination is studied, additional non-clinical and/or human pharmacology studies MAY BE INDICATED.
What is an estimand?
A quantity that is to be estimated in a statistical analysis.
Estimands provide:
A precise description of the treatment effects reflecting the clinical questions posed by the study objectives.
What does the estimand summarize at the population level?
What outcomes would be in the same patients under the different treatment conditions being compared
Is a study where the allocation of individuals to the study drug(s) is controlled by study procedures, an interventional study or an observational study?
Interventional
Is a study where allocation to the drug is not controlled but exposer to the drug(s) is observed in the study, an interventional study or an observational study?
Observational
Adaptive design studies allow for:
Prospectively planned modifications to the study, such as changes in the population studies or changes in doses of the drug studied over the course of the study, based on accumulating data.
Master protocol studies allow for:
The investigation of multiple drugs or multiple conditions under a shared framework.
Platform studies allow for:
Multiple drugs to be investigated in a continuous manner, with different drugs entering the study at different times and leaving the study based on pre-specified decision rules.
Adaptive, master protocol, and platform studies are all examples of?
Randomized studies
The population to be studied should be chosen to support what?
The study objectives
How is the study population defined?
Through the inclusion and exclusion criteria for the study
In general, studies conducted early in a development program, when little is known about the safety of the drug, are more what in study population definitions?
Homogenous
Studies conducted in the later phases of drug development or post-approval are often more what in study population definitions?
Heterogeneous
Why might a study population be narrowly defined?
To reduce risk to study participants or to maximize the sensitivity of the study for detecting a certain effect.
Why might a study population be broadly defined?
To more closely represent the diverse populations for which the drug is intended.
The number of participants (sample size) in a study is usually determined by the primary objective of the study. If the sample size is determined on some other basis, then this should be made clear and justified. For example, a sample size determined to address safety questions or meet important secondary objectives may need?
A larger number of participants than needed for addressing the primary efficacy question.
The major purpose of a control group is to:
Separate the effect of the treatment(s) from the effects of other factors such as natural course of the disease, other medical care received, or observer of patient expectations.
What is the intent of using an internal control group?
To help ensure that the only differences between treatment groups are due to the treatment they receive and not due to differences in the selection of participants, the time and measurement of study outcomes, or other differences.
How does an external control group differ from an internal control group?
With an external control group, individuals are selected from an external source, and the individuals may have been treated at an earlier time (historical control group) or during the same time but in another setting than participants in the study.
True/False:
The use of external controls generally mitigates the potential for bias better than internal controls.
False.
The use of INTERNAL controls generally mitigates the potential for bias better than EXTERNAL controls, particularly in conjunction with randomization, the suitability.
Response Variable
A response variable is an attribute of interest that may be affected by the drug.
What might the response variable relate to?
- Pharmacokinetics
- Pharmacodynamics
- Efficacy
- Safety of the drug
- The use of the drug
Study endpoints are the response variables that are chosen to assess what?
Drug effects
What should the primary endpoint be capable of?
Providing clinically relevant and convincing evidence related to the primary objective of the study.
Secondary Endpoints
Either supportive measurements related to the primary objective or measurements of effects related to the secondary objectives.
Exploratory Endpoints
Used to further explain or to support study findings or to explore new hypotheses for later research.
The definition of each study endpoint should be specific and include:
How and at what time points in a participant’s treatment course of the drug and follow-up it is ascertained
In studies with internal control groups, randomization is used to ensure what?
Comparability of treatment groups, thereby minimizing the possibility of bias in treatment assignment.
Careful consideration of the potential for intercurrent events to occur during the study and their impact will help with identification of critical to quality factors, such as:
- Reducing study discontinuation
- Continuing data collection following treatment discontinuation
- Retrieving data after study discontinuation, if appropriate
Why does randomization done at the start of the study?
To address differences between the groups at the time of randomization
True/False:
Randomization at the start of the study prevents bias due to differences arising during the study.
False.
Randomization at the start of the study addresses differences between the groups a the time of randomization but does NOT prevent bias due to differences arising during the study.
How does concealing the treatment assignments (blinding) affect bias?
Concealing the treatment assignments (blinding) limits the occurrence of conscious or unconscious bias in the conduct and interpretation of a clinical study that may affect the course of treatment, monitoring, endpoint ascertainment, and participants’ responses.
In an open-label study, the consequences of the lack of blinding may be reduced by:
The use of pre-specified decision rules for aspects of study conduct, such as recruitment, treatment assignment, participation management, safety reporting, and response variable ascertainment.
Why are specific considerations related to information flow and confidentiality necessary regarding interim results?
Knowledge of interim results (whether individual or treatment group level) has the potential to introduce bias or influence the conduct of the study and interpretation of study results.
When should the principal features of the statistical analysis of a study be planned and where should they be outlined?
- During the design of the study
- They should be clearly specified in a protocol written before the study begins
Full details of the planned statistical analysis should be specified and documented before when?
Before knowledge of the study results that may reveal the drug effects.
This may be accomplished using a separate statistical analysis plan.
What should the statistical analysis include to assess the impact of the assumptions made for the primary and important secondary analyses on the results of the study?
Pre-specified sensitivity analyses
For double-blind studies, when should the statistical analysis be finalized?
Before treatment assignments are revealed
Ideally, when would details pertaining to the primary and secondary analyses be finalized for open-label and single-blind studies?
Before the first participant is randomized or allocated to study intervention
For what studies is pre-specification of the analysis approach particularly important?
Studies that make use of existing data sources rather than primary data collection
The statistical analysis should be carried out in accordance with the prospectively defined analysis plan, and all deviations from the plan should be indicated where?
In the study report
Study Data
All information generated, collected, or used in the context of the study ranging from existing source data to study-specific assessments.
The study data should contain the necessary information to:
- Conduct the statistical analysis specified in the protocol and statistical analysis plan
- Monitor for participant safety, protocol adherence, and data integrity
Study data can be broadly classified into two types:
- Data generated specifically for the present study (primary data collection)
- Data obtained from sources external to the present study (secondary data use)
Primary Data Collection
Data generated specifically for the present study.
Secondary Data Use
Data obtained from sources external to the present study.
Data generated for the study may be collected via:
- Case report forms
- Laboratory measurements
- electronic patient reported outcomes
- Mobile health tools
Examples of external sources of data include:
- Historical clinical studies
- National death databases
- Disease and drug registries
- Claims data
- Medical and administrative records from routine medical practice
Data quality attributes include:
- Consistency (uniformity of ascertainment over time)
- Accuracy (correctness of collection, transmission, and processing)
- Completeness (lack of missing information)
The use of standards for data recording and coding (or recoding) is important to:
- Support data reliability
- Facilitate correct analysis and interpretation of results
- Promote data sharing
With primary data collections what provides an opportunity to prospectively ensure the quality of the data?
The methods and standards established for use at the point of capture and subsequent processing
With secondary data use, what should be clearly described in the study protocol?
The relevance of the available data should be considered and clearly described in the study protocol
Successful application of the quality by design principles may minimize the need for what?
Modifications to the protocol
Individuals involved in study conduct should receive training commensurate with their role in the study. When should this training occur?
Prior to their becoming involved in the study
Why might updated training or retraining of individuals involved in study conduct be needed?
To address issues related to critical to quality factors observed during the course of the study, and/or implement protocol modifications
The manner and timelines in which study data are collected and managed are critical what?
Contributors to overall study data quality.
What can identify important data quality issues for corrective action?
- Operational checks
- Centralized data monitoring
- Statistical surveillance
What could inappropriate access to data during the conduct of the study compromise?
Study integrity
What are the goals of safety monitoring?
To protect study participants and to characterize the safety profile of the drug.
Clear criteria for stopping treatment or study procedures for a study participant while remaining in the study are necessary to ensure the protection of the participants but should also minimize what?
Loss of critical data
What group monitors accumulating data while the study is being conducted to make recommendations on whether to continue, modify, or terminate a study?
The Data Monitoring Committee
Clinical studies and their results should be adequately reported using formats appropriate for:
- The type of study (interventional or observational studies)
- The information being reported
The reporting of study results should be:
- Comprehensive
- Accurate
- Timely
Who should be provided with a factual summary of the overall study results in an objective, balanced and nonpromotional manner, including relevant safety information and any limitations of the study?
Study participants
When should participants be informed about the information they will receive and when they will receive it?
At the time of providing informed consent
The transparency of clinical research in drug development includes:
The registration of clinical studies, before they start, on publicly accessible and recognized databases, and the public posting of clinical study results.
Making objective and unbiased information publicly available can benefit:
Public health in general, as well as the indicated patient populations, through enhancing clinical research, reducing unnecessary clinical studies, and informing decisions in clinical practice.
In designing a study, the following aspects should be considered, where applicable, to support the identification of critical to quality factors:
- Engagement of all relevant stakeholders, including patients, is considered during
study planning and design. - The prerequisite non-clinical studies, and where applicable, clinical studies, are
complete and adequate to support the study being designed. - The study objectives address relevant scientific questions appropriate for a given
study’s role in the development program, taking into account the accumulated
knowledge about the product. - The clinical study design supports a meaningful comparison of the effects of the
drug when compared to the chosen control group. - Adequate measures are used to protect participants’ rights, safety, and welfare
(informed consent process, Institutional Review Board/Ethics Committee review,
investigator and clinical study site training, pseudonymization). - Information provided to the study participants should be clear and understandable.
- Competencies and training required for the study by sponsor and investigator staff,
relevant to their role, should be identified. - The feasibility of the study should be assessed to ensure the study is operationally
viable. - The number of participants included, the duration of the study, and the frequency
of study visits are sufficient to support the study objective. - The eligibility criteria should be reflective of the study objectives and be well
documented in the clinical study protocol. - The protocol specifies the collection of data needed to meet the study objectives,
understand the benefit/risk of the drug, and monitor participant safety. - The choice of response variables and the methods to assess them are well-defined
and support evaluation of the effects of the drug. - Clinical study procedures include adequate measures to minimize bias (e.g.,
randomization, blinding). - The statistical analysis plan is pre-specified and defines the analysis methods
appropriate for the endpoints and the populations of interest. - Systems and processes are in place that support the study conduct to ensure the
integrity of critical study data. - The extent and nature of study monitoring are tailored to the specific study design
and objectives and the need to ensure participants’ safety. - The need for and appropriate role of a data monitoring committee is assessed.
- The reporting of the study results is planned, comprehensive, accurate, timely, and
publicly accessible
What are the objectives of a human pharmacology study?
- Assess tolerance and safety
- Define/describe clinical PK and PD
- Explore drug metabolism and drug interactions
- Evaluate activity, assess immunogenicity
- Assess renal/hepatic tolerance
- Assess cardiac toxicity
What are the objectives of an exploratory study?
- Explore use for the intended indication
- Estimate dose/dosing regimen for subsequent studies
- Explore dose-response/exposure-response relationship
- Provide basis for confirmatory study design
What are the objectives of a confirmatory study?
- Demonstrate/confirm efficacy
- Establish safety profile in larger, more representative patient populations
- Provide an adequate basis for assessing the benefit/risk relationship to support licensing
- Establish dose-response/exposure-response relationship
- Establish a safety profile and confirm efficacy in specific populations
What are the objectives of a post-approval study?
- Extend understanding of benefit/risk relationship in general or special populations and/or environments
- Identify less common adverse reactions
- Refine dosing recommendations
PK
Pharmacokinetic
PD
Pharmacodynamic
BA Studies
Bioavailability
