The Fundamentals of Clinical Research. P. Michael Dubinsky

associated with the prescribing of drugs by physicians and other health care professionals via their professional licensing programs. The Federal Food Drug and Cosmetic Act contains language which translates into FDA keeping its distance from the practice of medicine or regulating professional practices.

GCP is therefore only a part of the GXP regulatory scheme which is embedded in the drug development continuum. It represents a still evolving portion of the culture of quality that has been evolving in the clinical development arena for some time. It of course only applies to the authorized human biomedical clinical trials which are conducted to generate data of safety and efficacy but those are the trials where data integrity and subject protections are most important. Interestingly the FDA has not adopted the ICH E6(R2) as a formal regulatory requirement as have a number of foreign regulatory authorities. However, the FDA played a leading role in the development of the ICH E6 (R2) standard and references ICH GCP (R2) in several key spots of the governing investigational drug regulations. So the FDA certainly agrees with GCP and its use in guiding human trials. FDA refers to its regulations governing investigational drug studies as being GCP. Admittedly much of what is contained in ICH E6 (R2) was drawn from the FDA’s existing regulations.

      3.2.4 Manufacturing the Investigational Drug Product

      Returning to Plate 1 we see the reference to current Good Manufacturing Practice (cGMP) regulations as it applies to the investigational drug product. The manufacturing of the investigational drug product must meet the cGMP regulations but on a graduating scale. FDA in 2008 published a guidance document describing its policy regarding the application of the cGMP requirements for Phase I investigational drugs. In summary, FDA provides some leeway for a manufacturer’s compliance with the full range of 21 CFR 211 requirements in the earliest stages of clinical testing but that leeway starts to evaporate once Phase II begins and by Phase III of clinical testing of a new drug the manufacture of the investigational drug product is expected to be in full compliance with 21 CFR 211. Whether that is always the case may be up for debate since the FDA from a programmatic standpoint does not routinely or programmatically inspect the manufacture of new drugs being used in clinical trials. That said if the FDA were to find that an investigational drug product was not being manufactured in conformance with applicable cGMP or was adulterated or misbranded they can and will act to contain its use if the responsible firm does not do so.

      3.2.5 Common Properties of GXPs

      So what is it that ties the three GXP disciplines together? It is the culture of quality and building quality into all aspects and processes that are employed. If you turn to Chapter 30 and the diagram depicting the quality management system you can visualize that whether the investigational product is being manufactured, undergoing preliminary testing to assess its toxicity, or being administered to humans as part of a clinical trial the same set of quality characteristics are brought to bear.

Qualification of people, places, and things must be performed against a standard or set of criteria. Training must occur not only in the general aspects of the discipline but also in the details which apply, for example a clinical trial protocol. Written procedures must be in place, trained against and followed. Keeping written procedures current is one of the most demanding, but necessary aspects of this quality characteristic. Maintaining records and documentation which is accurate and complete cannot be overemphasized. Documenting data and events whether by hand or electronically is essential; however, it remains one of the quality activities that is the most difficult to convince people is critical. Keeping records is not viewed as fun by many people. Ensuring that all involved parties and systems are engaged when making changes is a management step that demands inclusiveness. Operating under a management system that has identified the risks associated with the trial and which represent a critical to quality categorization along with any planned mitigation is a characteristic which evolved from the medical device manufacturing arena but has become an accepted and necessary practice throughout GXP. Learning and making changes based on implementing a corrective and preventive action program is also a process which was born in the medical device regulatory scheme but adds value to the clinical trial endeavor because it forces systematic change not just one off corrections. From the Quality Assurance standpoint auditing programs either internally or by external parties highlights not just the issues but also the successes in a program. Lastly having the involvement of management that is empowered to make changes and is committed to doing so when needed is key to completing the GXP scheme in general and GCP is particular.

3.3 Summary

      Once a firm has decided to pursue a drug development process it enters a regulated environment which includes GLP, GCP, and cGMP. The plans, actions, and decisions associated with the firm’s drug development initiative must be in tune with and guided by these regulatory requirements. GCP is a part of the regulatory scheme not the entire regulatory scheme.

      Knowledge Check Questions

      1 GXP refers to what three regulatory concepts?

      2 Repurposing of a drug is one approach to drug development. True or False

      3 A drug being used in a Phase I study must meet all cGMP requirements according to FDA. True or False

      4 Post approval prescribing of drug products is governed by state and local officials. True or False

      5 ICH E6(R2) Is a regulatory requirement in the United States. True or False

Reference

      1 1 Repurposing existing drugs for new indications. 1 January (2017). https://www.the‐scientist.com/features/repurposing‐existing‐drugs‐for‐new‐indications‐32285?archived_content=9BmGYHLCH6vLGNdd9YzYFAqV8S3Xw3L5 (accessed 27 January 2020)

4 The Intersection of GCP and Regulation

       P. Michael Dubinsky

      GCP Key Point

       GCP expectation intersects the entire functional scheme of clinical development for pharmaceutical medicinal products. Understanding the intersections is useful and enlightening.

      The emergence of the ICH closely parallels with the emergence of current GCP because the ICH served as a catalyst for development of Standards such as the ICH E6(R2). The ICH‐GCP (R1) was one of the first standards developed by the ICH. It was recognized that such a standard was needed. Regulatory Authorities had worked on building the GCP expectations into their regulatory schemes by detailing them in codes or regulations then interpreting the codes using mechanisms such as inspections and industry meeting presentations. The World Health Organization (WHO) had pursued developing principles of good clinical research practice as early as the late 1960s however the WHO was not a regulatory or standard setting organization so their guidance did not represent requirements nor was it mandated under any laws. The regulatory authorities were not working collaboratively to further their GCP thinking and as a result the requirements across countries and regions were evolving differently. It took an industry‐regulatory authority initiative – The ICH – to open the door to establishing a pathway for harmonization of GCP as well as other drug development requirements. That initiative has flourished and expanded.

4.1 Introduction

      In Chapter 1 – History of GCP outlines key aspects of the birth of the ICH organization and its growth from 1990