P. Michael Dubinsky - The Fundamentals of Clinical Research

Before a trial may be initiated, the Sponsor must communicate its intention to the governing regulatory authority or authorities who will provide feedback as to whether or not the trial may be conducted. The Sponsor reports the progress and the final outcome of the trial to the authority(ies) who review, ask questions, or request additional information as needed form the Sponsor. The Sponsor also engages the Investigator and provides them with the investigational product for the trial and all information they need to execute the trial at the trial site.

Prior to the Investigator initiating the clinical trial, the Investigator must obtain an approval from a duly constituted IRB/IEC to conduct the trial. The Investigator will communicate the progress and outcome of the trial to the IRB/IEC as well as the Sponsor. The Investigator, of course, will recruit the Trial Subject, who is asked to volunteer for the trial and to commit to following the trial procedures. The Trial Subject has the right to contact the IRB/IEC at any time if they have questions or concerns regarding the conduct of the clinical trial.

Lastly, the Regulatory Authority oversees all the players who have GCP responsibilities. We note that the Investigator and IRB/IEC do not typically communicate directly with the Regulatory Authority for routine trial conduct, but may certainly do so if the need arises.

In this overview, we answered the questions: Who are the main players involved in the conduct of clinical research? and, How do the main players interact with each other in the clinical research arena? The activities of the Sponsor, Investigator, IRB/IEC, and Regulatory Authority are regulated; and the Regulatory Authority has complete oversight of the Sponsor, Investigator, and IRB. We note that they all are responsible in some way to ensure the protection of the rights, safety, and well‐being of the research subject, for whom there are no regulatory “responsibilities” because their participation in a trial is completely voluntary, with the option to discontinue at any time. The GCP responsibilities of each of the players are be addressed in greater detail in separate chapters.

1 Who are the main players involved in the conduct of clinical research?

2 What is the role of the IRB/IEC?

3 What is the role of the Sponsor?

4 What is the role of the Investigator?

5 What is the role of the Trial Subject?

6 What is the role of the Regulatory Authority?

7 How do the various players interact?

1 1 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), Integrated Addendum to ICH E6(R2):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

The absence or failure of researchers to follow or have in place ethical standards and safeguards resulted in several key policy documents, e.g. Declaration of Helsinki being developed. The IRB/IEC functionally implements ethical expectations contained in those documents.

In other chapters the authors touch on some details about historical events which resulted in the development and issuance of policy documents which define the ethical expectations associated with the conduct of clinical trials. The Nuremburg Code, Declaration of Helsinki and Belmont Report were all developed and put in place in reaction to ethical abuses by researchers. Institutional Review Boards (IRBs) were the operating or functional demonstration of ethical oversight beginning in the US circa the 1960s. The US FDA put regulations in place circa 1971 and in 1974 the National Research Act formalized the requirements for having IRBs review planned clinical research. Regulations governing both the IRBs and requiring informed consent of trial subjects were in place circa 1981. The US IRB system was initially developed and implemented by academic medical institutions. In Europe the system of ethical oversight was largely developed by governments and became known as independent ethics committees (IECs). Since the ICH E6 (R2) was a work product of the both the US FDA and the EU EMA along with the Japanese health authority both titles were included in the ICH Glossary.

The roles and responsibilities of the IRB/IEC as spelled out in section 3 of the guideline involve a range of activities from making the decision as to whether a proposed trial is approved for implementation to what constitutes required record keeping for the IRB/IEC. The IRB/IEC roles and responsibilities section are fittingly at the very beginning of the guideline since without their approval the trial cannot begin.

The objectives of this chapter are to review the requirements/expectations for IRB/IEC as found in the ICH E6 (R2) Guideline at section 3. The GCP expectations speak to:

1 Responsibilities of the IRB/IEC

2 Composition, functions, and operations of the IRB/IEC

3 Procedures for the IRB/IEC

4 Records that the IRB/IEC is expected to maintain

In addition, the chapter will highlight some of the areas where IRB/IECs have not adhered to these expectations. Such information should be useful as the risk assessment for a trial is prepared.

The IRB/IEC first and foremost is responsible for safeguarding the rights, safety, and well‐being of the human subjects participating in the trial. If a trial involves a population that is considered vulnerable, e.g. children, then the IRB/IEC must apply an even more rigorous approach to their review and assessment of documents, people, processes, and places.

All the critical and essential documents which define the clinical trial are provided to the IRB/IEC for assessment and approval. That includes the Protocol, Informed Consent Form, Investigator’s Brochure, subject recruitment materials such as advertisements, and the investigator’s qualifications. Their conclusions about the acceptability of the investigational plan and the supporting materials are determinative when it comes to starting the trial. Absent their approval the trial cannot proceed. The IRB/IEC must provide their approval/favorable opinion. The IRB/IEC can require modifications to any of the essential documents as well as disapproving a study. In addition, their review must be ongoing which usually means annually but can differ if the IRB/IEC so decides. Vulnerable populations such as children call for the IRB/IEC to be even more attentive to details such as the circumstances under which the subject’s consent is obtained and who may give consent on behalf of the subject. Compensation for participation in a trial is permitted in some form by most regulatory authorities. However, the method and monetary value of compensation associated with payment often calls for close review to ensure that subjects are not coerced or enticed in a manner which violates ethical standards. And it is not just the amount of a payment that could be problematic but also any claims related to the effect that the investigational product may have on the disease or injury being treated.

Membership or makeup of the IRB/IEC as described in the guideline focuses on two aspects. A minimum number of members is set at five with one having a nonscientific background and one being independent of the institution or trial site. The investigator and sponsor must not have a voting representative on the IRB/IEC but can provide information about the trial as part of the IRB/IEC evaluation process. Outside experts can be invited to participate in the information gathering process if needed. The exact number of members and their credentials may be controlled by regulation or law for the country or region where the trial is to be conducted and those requirements must be followed.