P. Michael Dubinsky - The Fundamentals of Clinical Research

Meetings with regulatory authorities are encouraged for the Clinical Trial Sponsor at trial milestones. Those times are often just before submission of an application to conduct the trial and before embarking on each of the applicable phases. During such meetings topics such as complexities in the protocol, approach to compliance with elements of GCP can be on the agenda as well as the science of the IP and trial approach. After a trial a meeting may be scheduled to clarify outcomes prior to the submission of any marketing application. Regulatory authorities agree that meetings are useful. For example the US FDA includes specific references to meetings during the conduct of a clinical investigation in the controlling regulations.

In most situations the topics discussed are instrumental in the performance of clinical trial activities so documenting all outcomes, agreements, decisions, and follow‐up steps via a meeting record is important. ICH E6(R2) section 8.3.11 serves as a catch all in the TMF for the written record of such meeting minutes.

Face‐to‐face meetings are usually the most effective forum for ensuring that there is clarity between parties on all aspects of an endeavor such as a clinical trial. Conformance with one or more aspects of GCP can and is on the agenda of many meetings between sponsor and regulatory authority as well as between the parties performing steps in the trial. Therefore, the records of meetings and all forms of communications are vital. An often overlooked benefit of well‐documented communications is that they engender trust among the parties involved. Trust between parties goes a long way when issues arise and explanation must be made for decisions that impact a trial‐related matter.

This text is not meant to serve as specific training for the regulatory affairs personnel in terms of application preparation and submission. Many other reference texts describe the ins and outs of that task. It is however useful to reflect on the importance of GCP when noncompliance with it can have a significant impact on the review and processing of applications.

All of the regulatory authorities who receive and process applications have established internal instructions regarding the evaluation of noncompliance with regulatory requirements. Serious deficiencies are evaluated for their impact on the continued review and evaluation of an application as well as whether the trial should continue to be conducted at a site(s) or be placed on hold. Any decision to place a trial on hold would be based on a risk‐benefit evaluation to determine whether the risk factor may have changed due to the deficiencies. If, for example, adverse experience reports had not been made in a timely manner or at all, then the risk of the non‐reporting will be weighed by the competent authority. Many such deficiencies are identified during inspections of sponsors and/or sites. Regulatory authorities also receive reports from sponsors of situations, e.g. in the UK a serious breach of the requirements impacting the safety of subjects must be reported.

The clinical development pathway which is navigated by a sponsor’s regulatory affairs group is not a silo in terms of conformance with and adherence to GCP. The reach of GCP requirements runs throughout a sponsor’s organization if they are involved and participating in some aspect of a clinical trial activity. Interactions with regulatory authorities via any communication mechanism must be appropriately documented, shared to the extent necessary and available for review as part of the evidence that the overall trial was conducted in conformance with GCP.

1 Competent authorities prefer to have at least ten points of contact should there need to be communications between they and the sponsor about some aspect of a clinical trial. True or False?

2 The ICH E6(R2) Guideline calls for records of meeting and other relevant communications about a clinical trial to be maintained in section 5 6 8 9 (Circle the correct section)

3 Regulatory authorities support and encourage meetings to discuss issues which arise with clinical investigations. The US FDA reserves every Friday for such meetings. True or False?

4 Face‐to‐face meetings are a sound approach to discussing/communicating aspects of the conduct of a clinical trial with a regulatory authority. Such meetings also can build __?___ between the parties.

5 Nonconformance with GCP can be a rationale for placing a clinical trial or an investigational application on hold. True or False?

1 1 ICH. Website link for the international council for harmonization of technical requirements for pharmaceuticals for human use (ICH), https://www.ich.org/home.html(accessed 27 January 2020)

2 2 FDA (December 2017). Best practices for communication between IND sponsors and FDA during drug development. https://www.fda.gov/regulatory‐information/search‐fda‐guidance‐documents/best‐practices‐communication‐between‐ind‐sponsors‐and‐fda‐during‐drug‐development(accessed 27 January 2020)

3 3 Bargaje, C. (2011). Good documentation practice in clinical research. Perspectives in Clinical Research 2 (2): 59–63. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121265/?report=printable(accessed 27 January 2020).

Karen A. Henry

GCP and its principles are the foundational filters for performing any clinical trial activity or making any clinical trial‐related decision.

Experiments with and outright distribution and sale of products for the diagnosis, treatment, cure, or prevention of disease have resulted in a range of harmful effects to the safety and well‐being of humans. Individual countries established regulatory requirements for clinical research in the development of a product to prevent such harmful effects. However, due to the cost of redundancies in resources, time, and additional exposure of an unapproved product to human subjects, a single guideline was developed with consideration of the current good clinical practices (GCPs) of the European Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the World Health Organization (WHO). The objective of ICH E6 (R2) Guideline for GCP is to provide a unified standard for the European Union (EU), Japan, and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions. (ICH E6(R2) Introduction; Section on Good Clinical Practice History; Section on Drug Development in the Regulatory Environment).

The Guideline presents a set of international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects (ICH E6(R2) Introduction). The goal for anyone involved in the conception, planning, and execution of a trial is to conform with these standards that provide public assurance that the rights, safety, and well‐being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible. The Guideline starts with definitions and principles as the foundation for the responsibilities and operational standards that are presented in the Guideline.

In this chapter, we will define GCP and present a practical interpretation of the GCP principles.