The Fundamentals of Clinical Research - P. Michael Dubinsky

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for forbidden concomitant foods, drinks, medications, and/or procedures that are practical and easy for subjects to comply

       Considerations for study blinding procedures that are easy for subjects and research staff to comply

      See chapters on protocol and data collection design considerations and study operational considerations for more strategies and details (Chapter 18 The Clinical Trial Protocol and Amendments; Chapter 14 Trial Management; Start‐up, On‐Study, and Close‐Out)

      A trial subject is volunteering to be administered an investigational product in a clinical trial. Those involved in the conduct of the trial must protect the rights, safety, well‐being, and confidentiality of the trial subject. Although there are no formal GCP or regulatory stipulations for research subjects to follow, the trial subject can also help to facilitate these protections, as well as the integrity of trial data and the overall compliance for the conduct of a clinical trial if the subject complies with study protocol and operational procedures. Trial subjects are therefore asked to comply with protocol and operational procedures but cannot be penalized for not following or coerced into following those procedures.

      There a several voluntary responsibilities for a subject to help facilitate the protection of their rights, safety, well‐being, data integrity, and general trial compliance. Additionally the trial protocol, data collection methods, and study operations may be designed in a manner that also facilitates the protection of their rights, safety, well‐being, data integrity, and trial compliance.

      Knowledge Check Questions

      1 Who is a trial subject?

      2 Why are the responsibilities of a trial subject voluntary?

      3 What are some of the voluntary responsibilities for a subject to help facilitate the protection of their rights, safety, well‐being?

      4 What are some of the voluntary responsibilities for a subject to help facilitate data integrity?

      5 What are some of the voluntary responsibilities for a subject to help facilitate general trial compliance?

      6 What are some quality‐by‐design principles that apply to protocol design that help to facilitate subject voluntary compliance?

      7 What are some quality‐by‐design principles that apply to data collection methods that help facilitate subject voluntary compliance?

      8 What are some quality‐by‐design principles that apply to study treatment(s) design that help to facilitate subject voluntary compliance?

      9 Overheard:They ask a lot of questions just for curiosity and I don't know all that is in the consent form anyway.Investigator delegate who instructed a college student who volunteered as a healthy research subject to swallow the study medication (capsules) per the appointed clock time just as the subject was about to ask a question about the study. Beds for study subjects for the phase 1 first‐in human study were lined up side by side in the research facility. A clock above each bed was used to record the time of the study procedure. A nurse took the subject's vital signs, followed by another who drew blood, and the subinvestigator physician followed with the cup of water and study dose to research subject.Comment and discuss:Were any of the subject's rights violated in this scenario?Are there any issues with investigator delegation of responsibility at this site?

      1 1 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), Integrated Addendum to ICH E6(R1):Guideline for Good Clinical Practice, E6(R2) (2016). Current Step 4 version dated 9 November 2016. https://www.ich.org/page/efficacy‐guidelines

       P. Michael Dubinsky

      GCP Key Point

       Regulatory Authorities are part of the ICH team that draft ICH Guidance documents. They work to ensure that the guidance reflects the current regulatory expectations. Understanding their role is important.

      Among the players in the clinical trial endeavor, the regulatory authority has a unique and highly visible role. Understanding the roles of the regulatory authority whether it is as a gatekeeper approving a trial application or an inspector following up on a complaint, the regulatory authority is in a unique position of control and influence. Placing the roles and responsibilities of the regulatory authority in perspective is therefore meaningful.

      In this chapter, you will be introduced to the primary roles and responsibilities of the Regulatory Authority (or Competent Authority) in terms of those functions which are highlighted in the GCP framework. The primary roles, i.e. functions, of the regulator are:

       Reviewing and making decisions on clinical trial applications.

       Oversight and inspection of the other players involved in the clinical trial endeavor to ensure conformance with GCP, investigational plans, and applicable regulations.

      In addition, you will gain insight into why the regulator has responsibility for these functions and is therefore accountable for implementing them.

      When one reviews the ICH E6(R2), the number of references to the regulatory authorities (regulators) is limited and there is no specific section devoted to delineating roles or responsibilities for this important player in the clinical trial process. Regulatory authorities are of course mentioned several times in the body of the ICH E6(R2) guideline. Examples include Section 5.10 Notification/Submission to Regulatory Authority (ies) and Section 5.20.2 – Noncompliance – which speaks to the need for regulatory authorities to be notified if an investigator is terminated from participation in a trial. Therefore, one needs to look elsewhere to fully frame out and define the roles and responsibilities of the regulatory authority from a GCP standpoint.

      The ICH E6(R2) guideline does, however, include a definition of a regulatory authority and it is useful to reflect on it because it sets the stage for how these entities fit, from a GCP standpoint into the clinical trial arena. The definition reads in part: Regulatory Authorities: Bodies having the power to regulate. In the ICH E6(R2) guidance, the expression “Regulatory Authorities” includes the authorities that review submitted clinical data and those that conduct inspections (see Section 1.29). These bodies are sometimes referred to as competent authorities. Note: The terms Regulatory Authority, regulator, and competent authority all are used in this topic write up interchangeably.

      The roles of regulatory authorities in the oversight of clinical trials have been an evolutionary process often driven by tragic events. As noted in Chapter 1 History, the topic the birth defects caused by the product Thalidomide in many newborns was instrumental in moving legislative bodies worldwide to require substantial evidence of safety and effectiveness before allowing a new drug product on the market. Such events and the failure of industry or professional groups to self‐regulate in an effective manner

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