The Fundamentals of Clinical Research. P. Michael Dubinsky

2020)

      2 2 FDA (2000). Good Guidance Practices/Guidance documents FDA Regs at 21 CFR 10.115. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=10.115 (accessed 27 January 2020)

      3 3 EMA (2012). Reflection paper on laboratories that test clinical trial samples http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/05/WC500127124.pdf (accessed 27 January 2020)

      4 4 ISO (2011) ISO 14155:2011). Clinical Investigation of Medical Devices for Human Subjects — Good Clinical Practice. International Organization for Standardization https://www.iso.org/standard/45557.html (accessed 27 January 2020).

      5 5 Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on Clinical Trials on Medicinal Products for Human Use, and Repealing Directive 2001/20/EC https://ec.europa.eu/health//sites/health/files/files/eudralex/vol‐1/reg_2014_536/reg_2014_536_en.pdf (accessed 27 January 2020)

      6 6 Penn Medicine (2020). What is an Academic Medical Center. https://www.pennmedicine.org/about/benefits‐of‐an‐academic‐medical‐center (accessed 27 January 2020)

3 GCP in Context

       P. Michael Dubinsky

      GCP Key Point

       Good Clinical Practice is only one of the “good” cultures in the drug development scheme. A culture of good practices is essential for compliance with USA and international regulatory authority expectations, and aids in ensuring quality data, and protection of trial participants.

3.1 Introduction

      The drug development process depicted in Plate 1 is a lengthy and demanding endeavor. Good clinical practice is not an element in all of the steps, phases, and activities that makeup the full development process. However, keeping in perspective the fact that there are applicable regulatory requirements across the spectrum of the entire process and, at minimum best practices should be applied even when the step may not seem to involve regulatory oversight is a wise mindset to adopt. Applying the quality systems approach that is outlined in Chapter 30 as a guiding principle from the time a new drug concept is born to approval of a marketing application is a winning strategy.

3.2 Objectives

      The objectives of this chapter are:

      1 To put GCP into perspective with the other GXP. GXP is an acronym for Good Laboratory, manufacturing, and clinical practice requirements that are applicable during the drug development process.

      2 To emphasize that clinical development must apply the “good” practices culture which evolved from drug and device manufacturing regulations.

      3 To emphasize the importance of the cross connectivity of GXP requirements and the dependence of the overall drug development process on maintaining a compliance mindset while performing all steps, phases, and activities.…

      3.2.1 Discovery

      The first decision point in drug development is deciding to try and find a cure for or prevention of a disease. Medical researchers may pursue drug discovery based on learning about a disease process in a way that allows new approaches to slowing the disease down or possibly curing it. In the United States, there are government and nongovernmental organizations that pursue new cures and treatments for disease and injury for a variety of reasons. Profit‐based decisions are often seen as the driving force behind seeking new and/or innovative treatments or procedures but that is probably not the primary driving force in place at early stages of discovery. One approach that has been successful is called repurposing [1]. Commercial industry and research‐oriented academic institutions have been finding new applications for already approved or tested medicines. This approach to drug discovery has identified a number of innovative pathways. E.g. new uses for existing drugs, new uses for drugs whose development was cut short; and identifying side effects from tested drugs which may indicate useful new applications. Using scientific methods such as genetic testing also allows researchers to target a drug to a specific site in the human body thereby increasing drug efficacy. Repurposing existing drugs is also economically rewarding. One of the possible stumbling blocks encountered when pursuing this approach is when data and records from prior studies need to be resurrected for review and use in assessing the overall history of the drug’s use in trials. If that data was not collected in conformance with GCP and other Good Practices (GXP) its use may be limited and may stand in the path of pursuing a new application. My experience in this regard was when a firm wanted to use data from studies which were performed 14 years prior. Not only were the records questionable in terms of completeness but the ability to demonstrate that the data was collected in conformance with good clinical practices and/or the applicable regulatory requirements was not clear.

      3.2.2 1.4 Pre‐Clinical Studies

The next step in the drug development continuum is for researchers to begin assembling data on whether the drug is toxic, i.e., is there laboratory data showing it might cause harm. The initial tests will be done via in vivo animal testing and/or in vitro laboratory experiments. This nonclinical study activity places researchers directly into the regulatory environment in that conducting such testing must be done following the Good Laboratory Practice (GLP) regulations at 21 CFR 58 if the drug is intended for the US market. See Plate 1 Nonclinical Studies‐The ICH has developed safety guidelines addressing carcinogenicity, genotoxicity, and toxicity which form a basis for preclinical studies to be submitted to most global regulatory authorities including the FDA. These safety guidelines were one of the initial actions of the ICH when it was first founded and resulted in harmonizing many differing global approaches. The ICH safety guidelines are adopted by the US FDA as good guidance practices While there are provisions in the FDA’s Investigational New Drug (IND) Applications regulations at 21 CFR 312, allowing use of data from animal studies not performed in compliance with GLP, once a firm has decided to pursue a drug development scheme they ought to be following the GLP regulatory requirements. Since many of the GLP animal studies, intended to be submitted to the FDA, are performed at a relatively small number of GLP testing facilities which are regularly inspected by the FDA it is likely that the laboratory’s work will have been evaluated for conformance with the applicable regulations. If there are issues with the data gathered during the nonclinical phase of study it may stand in the way of moving to human administration of the investigational product.

      3.2.3 Clinical Studies

      Once sufficient data has been assembled to support administering the investigational drug product to humans an IND is filed and barring FDA placing it (the IND) on hold, human studies begin. It is at this time, the GCP expectations come to the fore and are the subject matter of this text.

      Once a firm has received approval of a new drug (or Biologic) they may decide to set aside most if not all clinical trials involving the product unless Phase IV trials have been ordered by the FDA. Of course in many cases, clinical trials are continued for a product and those trials whether ordered by FDA or not must be conducted in conformance with IND regulations and GCP expectations.

      Post approval use of the product by the medical professionals is not governed by the FDA or GCP, at least not in any formal manner. States