The Fundamentals of Clinical Research. P. Michael Dubinsky

will not repeat that material but rather will outline how the ICH E6(R2) reflects the harmonized expectations of the industry‐regulatory authority collaboration which began working to draft the GCP Efficacy Guideline almost immediately after the establishment of the ICH as an organization.

4.2 Objectives

      The objectives of this chapter are to:

       Demonstrate how the ICH E6(R2) Guideline serves to underpin those practices which support subject safety and data integrity within the context of meeting regulatory authority requirements.

       Outline several ways the ICH guideline elements moved the conduct of clinical trials closer to meeting the expectation of regulatory compliance and best practices.

      Since this text is devoted to explaining fundamental precepts for good clinical practice this chapter will not address each topic area but rather select several examples of how the ICH E6(R2) moves clinical research several steps higher than the regulatory expectations which are generally acknowledged to be the minimum requirements for compliance with a statute, directive, or code.

4.3 The Principles of ICH E6(R2)

      The thirteen principles of ICH E6(R2) set a cultural tone which brings together ethical considerations, scientific requirements, and regulatory details in a succinct set of statements that are not always found in codes or regulations. In the United States, the FDA would have described such aspects in a preamble to a set of proposed regulations but would not have memorialized such principles in the regulations that are promulgated. However, having a set of principles to draw on gives the clinical trial players a set of cultural and ethical building blocks to use as they develop an investigational plan, prepare a protocol and train staff to conduct a clinical trial.

      The high‐level statements of principle that are found in this section of the ICH E6(R2) provide a reference point for just about every requirement that can be found in the lengthy and detailed requirements of the regulatory authorities. One could easily substitute the term policy for principles. The thirteen principles are the policies that will govern the entire scheme of a clinical trial activity from the time an application is submitted to a regulatory authority to the time the last subject is enrolled. See Chapter 6.

4.4 The Definition of GCP Embodies the Full Spectrum of Trial Activity – The Definition of GCP Reads

      4.4.1 Good Clinical Practice (GCP)

      A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.

      Taking several of the functional steps included in this definition one can quickly understand how the contents of the Guideline/Standard are structured.

      Design – The standard calls for the development of a scientifically sound protocol and investigator’s brochure. The Standard then proceeds to list the content expectations for each document. The Sponsor of a trial need only follow the Standard.

      Conduct – The Standard outlines expectations which inform the players how to conduct a trial. For example, obtaining approvals from the IRB as well as the appropriate regulatory authority prior to starting the trial; obtaining informed consent from subjects; maintaining data confidentiality and ensuring product accountability for the IMP. These are just a few examples.

      Records and Record Keeping – Ensuring the integrity of data is a must. The ICH E6(R2) includes details about the types of records that are necessary and how to manage those records. Examples are the Case Report Forms, product accountability and the entire Section 8 which outlines the essential document needs for the three phases of the trial.

      Reporting – There are a number of reporting requirements that are in place for a clinical trial to be in sync with the requirements of regulatory authorities. Reporting of adverse events, progress reports, final reports, reports of monitoring the trial sites and audit reports come to mind. The Standard references all these types of reporting expectations and others.

      This is just a brief listing of the manner in which the Standard, through well‐reasoned and thoughtful development, manages to encompass the full range of functional activities associated with clinical trial conduct.

4.5 Glossary

Suggesting that a list of definitions is important may seem trivial but having all the players on the same page calls for having everyone speak the same language, at least from the standpoint of meaning. Having a list of 65 terms that can be used by all and mean the same thing is a very important element. Clinical trials are complex undertakings requiring a broad range of specialists not all of whom are routinely involved in trials or who participate for certain parts and then leave to conduct their routine day‐to‐day business. Being certain that when terms are communicated, they mean the same to all parties in the conversation is important. The ICH E6(R2) Glossary accomplishes this objective.

4.6 Combining Key Elements

      The ICH E6(R2) brings together the key functional areas of the drug development process that call for the application of the principles. If you wanted to study the requirements governing subject safety and data integrity from the FDA regulations you would need to organize the requirements from several different sections of the Code of Federal regulations. The ICH E6(R2) contains the information necessary to put in perspective the responsibilities of the sponsor, investigator, and IRB/EC all in one document. The applicable requirements of the respective regulatory authority are always referenced for details but the pathway for compliance with expectations that underpin subject safety and data integrity are available in one place.

4.7 Being Linked to an Organization That Is Respected and Authoritative

      Standard setting organizations are generally seen as just that the “standard” setters. They have recognition as being thorough, authoritative, and quality oriented. The ICH is no exception and the ICH E6(R2) is hands down the final word when it comes to what constitutes good clinical practice. There are versions of the ICH E6(R2) good clinical practice guidelines published but for the most part they are renditions of the ICH E6(R2) which have been adapted to fit into the pharmaceutical regulatory scheme of a country, e.g. India. In addition organizations such as the World Health Organization (WHO) recognize the need for instructions such as that in ICH E6(R2) but are not standard setting entities themselves. The WHO has a handbook of GCP [1] but it is not advertised or promoted as a standard.

4.8 Standard Operating Procedures

The ICH E6(R2) lists the expectations for the development and use of Standard Operating Procedures (SOPs) in numerous sections. SOPs are generally viewed as a bedrock element in the requirements associated with the manufacturing and testing, labeling etc., for pharmaceutical medicinal products. However in the regulatory requirements promulgated by the US FDA defining the conduct of clinical trials at 21 CFR 312 – Investigational New Drug Applications the term procedures and/or standard operating procedures is not mentioned. Regulatory authorities such as the US FDA certainly expect sponsors and investigators to have written procedures for key processes and procedures in place but the requirements specifically stating that are just not there. The FDA’s regulations for IRBs and informed consent do speak to written procedures. However is clear on the need and expectation for written procedures. It is apparent in numerous sections e.g. 5.18.15 Monitoring Procedures and Auditing Procedures. A quick survey of the guideline shows numerous instances where the term procedures is used and it refers to SOPs. Regulators can, if needed cite the ICG E6(R2) as