Clinical Trial Design Best Practices

In its most recent guidance, “E6 R# Good Clinical Practice (GCP)”, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and the FDA emphasized their current thinking on the principles of ICH GCP, underscoring the importance of participant safety, reliable results, and scientific soundness. The guidance also discusses the need for independent review, qualified personnel, and quality control. The guideline covers the responsibilities, composition, and procedures of the Institutional Review Board/Independent Ethics Committee (IRB/IEC) and the qualifications, responsibilities, and communication requirements for investigators. It also outlines the sponsor’s responsibilities, including trial design, resources, agreements, oversight, and safety reporting. The draft guidance also discusses data governance, computerized systems, and record-keeping, with a focus on data integrity, life cycle management, and security measures. It also covers the management of investigational products, quality management, and risk management.

In May 2023, the FDA released its guidance entitled “Decentralized Clinical Trials for Drugs, Biological Products and Devices” [https://www.regulations.gov/docket/FDA-2022-D-2870]. While that guidance discussed utilizing appropriate clinical protocols where trials occur in “non-traditional” locations (such as the participant’s homes), the principals were similar to those espoused in the recent GCP guidance – patient safety, ethical clinical design (regardless of the location of the trial) and the appropriate use of technology.

The ICH guidance emphasized the need to facilitate the mutual acceptance of trial data by regulatory authorities and highlighted the use of technology to ensure that participant safety is carefully protected. The ICH guidance also discussed the important role of appropriate informed consent from participants and full disclosure of financial relationships between sponsors and Clinical Research Organizations (CROs).

As summarized below, the guidance emphasized a “proportionate risk-based approach”:

• The guideline emphasizes the importance of protecting trial participants’ rights, safety, and well-being.
• The guideline encourages a quality culture and proactive design of quality in clinical trials.
• The guideline stresses the importance of identifying factors critical to quality and engaging stakeholders.
• The guideline applies to interventional clinical trials of investigational products.
• The guideline is structured into principles and annexes.
• The guideline should be read in conjunction with other ICH guidelines.
• The principles of GCP are flexible and applicable to a broad range of trials.
• Thoughtful consideration and planning are needed to address each trial’s specific aspects.
• The guideline encourages the use of innovative digital health technologies.
• The guideline is media neutral to allow for different technologies to be used.
• The guideline stresses the importance of including diverse patient populations.
• Stakeholder input is important for meaningful trial outcomes.
• Clinical trials should be designed to protect participants and ensure reliable results.
• Quality by design should be implemented to identify critical factors and risks.
• Trial processes should be proportionate to the importance of the data collected.
• The guideline outlines overarching principles for clinical trial conduct.
• The guideline stresses the importance of ethical principles and informed consent.
• Clinical trials should be reviewed by an independent ethics committee.
• Trials should be scientifically sound and based on current knowledge.
• Qualified individuals should be involved in the trial.
• Quality should be built into the design and conduct of the trial.
• Trial processes should be proportionate to the risks and importance of the data.
• The protocol should be clear and concise.
• Trials should generate reliable results.
• Roles and responsibilities should be clear and documented.
• Investigational products should be manufactured according to GMP standards.
• The guidance also discusses the importance of manufacturing, handling, and labeling investigational products in a manner that aligns with treatment assignment and maintains blinding.
• The IRB/IEC is responsible for the ethical review of the trial and should be familiar with local regulatory requirements.
• The IRB/IEC should safeguard trial participants’ rights, safety, and well-being.
• The IRB/IEC should review various information related to the trial, including the protocol, informed consent material, and investigator’s brochure.
• The IRB/IEC should document its reviews and decisions.
• The IRB/IEC should conduct continuing review of ongoing trials.
• The IRB/IEC may request additional information to protect participants.
• The IRB/IEC should review protocols for trials where prior consent is not possible.
• The IRB/IEC should review assent information for minors.
• The IRB/IEC should review compensation plans for participants.
• The IRB/IEC should be composed of a reasonable number of qualified members.
• The IRB/IEC should follow documented operating procedures.
• The IRB/IEC should make decisions at announced meetings.
• The investigator should be qualified by education, training, and experience.
• The investigator should be familiar with the appropriate use of the investigational product.
• The investigator should have sufficient resources to conduct the trial.
• The investigator may delegate trial-specific activities but retains ultimate responsibility.
• The investigator should permit monitoring and auditing by the sponsor and inspection by regulatory authorities.
• The investigator should communicate with the IRB/IEC and submit relevant information.
• The investigator should comply with the protocol and GCP.
• It also discusses the importance of documenting protocol deviations and implementing measures to prevent recurrence.
• The investigator should only deviate from the protocol to eliminate immediate hazards to participants.
• The investigator should inform the sponsor, IRB/IEC, and regulatory authorities if they terminate or suspend their involvement in a trial.
• The guidance discusses the importance of providing adequate medical care to participants for adverse events.
• The importance of obtaining and documenting informed consent.
• The informed consent process should include information on the trial, risks, benefits, and participant rights.
• The investigator should assess if re-consent is needed when new information becomes available.
• The investigator should not coerce or unduly influence participants.
• The investigator should conduct the informed consent process.
• The informed consent form should be signed and dated by the participant, witness, and investigator.
• In emergencies, the consent of the participant’s legally acceptable representative should be requested.
• The guidance discusses the importance of documenting the financial aspects of the trial in an agreement between the sponsor and the investigator/institution. It also emphasizes the importance of documenting agreements made by the sponsor with the investigator/institution, service providers, and any other parties involved with the clinical trial.

While the ICH/FDA guidance is extensive (the highlights above are by no means exhaustive), its principles are critically important for design sponsors, CRO(s), and manufacturers alike.

If you would like assistance with your clinical trial design, or have questions, please feel to reach out to TALG at any time.