As discussed in previous articles in this series on human clinical research (see the September and October 2010 issues of the NMR Newsletter), a clinical trial is defined as an experiment performed in humans. The experiment is designed to determine the safety and efficacy of a product that is hypothesized to have a health benefit. Thus far, we have discussed the purpose and advantages to the sponsor of performing a clinical trial. We have also discussed some aspects of the general structure and design of a clinical trial. In this article, the importance of ethics in conducting a clinical trial will be discussed.

Medical ethics are ethics applied to the field of medicine and health. In the case of a human clinical trial, the concepts of medical ethics are applied to an experiment performed on human beings. Proper ethical conduct is critically important in a clinical trial. A clinical trial that is conducted in an unethical manner is not only morally wrong, but will lead to results that are not useful. The good news is, however, that it is not hard to conduct a clinical trial that is ethical. Fortunately, there is a wealth of well thought out information on ethics in clinical trials that has created a structure that can be followed by sponsors. This article, using a series of questions and answers, will attempt to introduce the reader to some key ethical concepts of a clinical trial. Please note that this article is an introduction and is not meant to be exhaustive. Remember that any ethical questions you have regarding a proposed clinical trial should be directed to a clinical research organization (CRO), IRB, hospital or clinical review board, appropriate government agency or any other group or body that plays an official role in overseeing good ethical practice of a clinical trial.

1) What is the difference between the sponsor of a clinical trial and the subjects enrolled in a clinical trial?

On the surface, the answer to this question is very easy. The sponsor is the entity sponsoring the clinical trial with regard to the study agent (i.e., the product, compound, or drug undergoing study) and/or funding. The subjects are the individual people enrolled in the clinical trial; the clinical trial experiment is being done on the subjects. However, there is a difference that forms the key concept that guides the ethics of a clinical trial. The sponsor stands to benefit from the results of a clinical trial whereas the subject does not necessarily stand to benefit. Although the subjects may have a health issue that may be solved by the product under study, that health benefit may only be hypothesized since it is not yet proven. Furthermore, if the clinical trial includes a placebo-controlled arm (see The Basic Structure and Design of a Clinical Trial, NMR Website, October, 2010), then there's a chance that the subject will not receive the product under study (see question #17). Additionally, in some clinical trials, there may be unresolved questions regarding the safety of the product that may adversely affect the subject's health.

2) What is an IRB?

IRB is an acronym that stands for Institutional Review Board. The IRB is a group of individuals with a variety of skills given the mission to protect human subjects enrolled in a clinical trial or in any other type of research that is performed on human beings. In the United States, the IRB derives its authority from the Federal Government through the Office for Human Research Protections (OHRP), which is a division of the Department of Health and Human Services (HHS) and the Food and Drug Administration (FDA). All functional IRBs should be registered with OHRP.

3) Who are the individuals that make up an IRB?

Generally, an IRB is composed of Ph.D. scientists and physicians. It is required that an IRB have at least one scientist who understands the medical area being explored by the clinical trial. In addition, it is required that the members of the IRB exhibit diversity. Diversity is defined as including a person who is not a scientist (or closely allied with a scientist such as a physician, nurse etc.) and who is able to understand the community from which subjects will be drawn. Non-scientific members of an IRB may be clergy, lawyers, patient advocates, or ethicists as well as others. An IRB may use outside consultants when necessary.

The minimum number of individuals on an IRB is five. However, many IRBs are much larger. The size of the IRB is often proportional to the number of proposals reviewed each year.

Only members of the IRB can vote on a proposed clinical trial. An IRB member must vote in person at the IRB meeting scheduled for this purpose. An IRB member who cannot attend the meeting may vote by video conference or conference call via telephone that is held while the IRB meeting is in progress. However, an IRB member may not vote by telephone, fax, email or postal mail, nor may an IRB member send a proxy. Outside consultants are not members of the IRB and may not vote.

4) What are the roles of the IRB?

The roles of the IRB include reviewing and monitoring clinical research projects involving human subjects. Following regulations set forth by the FDA and OHRP, the IRB reviews proposed clinical trials and either approves or disapproves of the trial. The IRB has the power to question members of clinical research groups and to request data and records. The IRB can request modifications to a clinical trial protocol and can stop a clinical trial in mid-course. The IRB is also empowered to make sure the subjects understand the nature of the clinical trial and that the protocol includes protection of the privacy of the subjects. In addition to federal law, the IRB must also abide by state and local laws and also be sensitive to the concerns and culture of the community that is encompassed by the clinical trial.

5) What does the IRB require from the sponsor to initiate a clinical trial?

Generally, the sponsor of a clinical trial names a person who is in charge of the trial. Often that person is called the Principle Investigator. In the case of a clinical trial with more than one study site, there may be a different Principle Investigator for each study site or sometimes there is one Principle Investigator for multiple study sites.

In order to gain approval for a proposed clinical trial, the IRB requires that the Principle Investigator submit a proposal. Basically, a proposal states the purpose of the clinical trial, provides a description of the study agent undergoing testing, and describes the methodology to be used on the subjects that will be used to carry out the clinical trial. (The IRB is not concerned about methodology related to the scientific quality of the clinical such as statistical analysis). A key component of the proposal is a copy of the informed consent document. The informed consent document, described further in question number 9, below, is one of the most important parts of the proposal presented to the IRB. The proposal includes a description of the proposed composition of the subject group, and the methods that will be used to protect the privacy of the subjects are described. In addition, all contact information for key personnel associated with the clinical trial must be included in the proposal. The IRB will begin the review process once the proposal is submitted.

Much of the information required by the IRB in the proposal is described in a document called the Investigator's Brochure. The Investigator's Brochure is prepared by the sponsor (or by a clinical research organization on behalf of the sponsor). Very often, the Investigator's Brochure, or parts of it, is included in the proposal submitted to the IRB.

6) How does the review process work?

Once the IRB has the proposal in hand, the review will commence. If the IRB is small, then all members of the IRB will read the entire proposal. If the IRB is large, usually two to four members of the IRB will be named primary reviewers of the proposal depending on their expertise; members who are not primary reviewers will read summaries of the proposal. The IRB will then discuss the proposals at a meeting. The Principle Investigator (and other key personnel or advisors) may attend the meeting in order to answer any questions the IRB may have. The IRB will then vote on the proposal. The vote can be an approval or disapproval. The IRB may also require modifications in the proposal before granting approval. Most IRBs will review modification requests quickly. It is not the purpose of the IRB to hold up a project; the IRB merely wants to protect human subjects while expediting the proposed clinical trial.

7) Might a sponsor be required to seek approval from more than one IRB?

Generally, sites that perform clinical trials have their own IRB. If a sponsor is performing a clinical trial at more than one site and each site has its own IRB, then the sponsor will have to seek approval from each IRB. This is generally not difficult since most IRBs are concerned with similar issues. However, it must be pointed out that securing approval to perform a clinical trial from one IRB does not guarantee approval from another IRB. Each IRB may have requirements that the Principle Investigator will have to address. In fact, in rare cases, clinical trials approved by the FDA are sometimes not immediately approved by a local IRB. When this happens, it may be due to the IRB's concerns about the community from which the subjects are being drawn. In such cases, the Principle Investigator can make appropriate modifications to the proposal designed to satisfy the concerns of the IRB.

8) What if a clinical trial site does not have its own IRB?

If a proposed clinical trial site does not have its own IRB, then an outside IRB can be used. There are many IRBs that provide oversight in such cases. A CRO will be able to locate an appropriate IRB for clinical trial sites that lack its own IRB.

9) What is the purpose of informed consent?

Each subject enrolled in a clinical trial must understand the purpose and any potential risks of the clinical trial. The subjects must also understand their rights. This information is communicated to the subject and the subject then agrees to participate in the clinical trial by providing informed consent. Informed consent generally consists of a written document that the subject can read and study. The subject can then agree to participate in a clinical trial by signing the document. The informed consent document is prepared by the sponsor, or a designee of the sponsor (including a CRO). The format of the informed consent is reviewed by the IRB.

It is critical to all IRBs that the informed consent be easily understood by potential subjects. For example, this may mean that the informed consent must be written at a sixth grade level. Any group with experience carrying out clinical trials, such as a CRO, will be able to prepare appropriate informed consent documents.

10) What kind of information does the IRB require from an ongoing clinical trial?

The IRB will require that certain kinds of information be formally communicated to the IRB while the clinical trial is being carried out. The most important types of information to be reported to the IRB are unanticipated or higher than expected numbers of adverse reactions and changes that must be made to the protocol while the clinical trial is underway. The need to report adverse reactions is obvious. The IRB must review and approve of any changes that must be made to the protocol, during an ongoing clinical trial.

11) How often does the IRB monitor an active clinical trial?

An IRB may monitor and actively audit the performance of the investigators as it feels is necessary. IRB monitoring includes requesting records, asking questions and even requiring a third party to witness various aspects of the clinical trial. The investigators must comply with monitoring requests made by the IRB.

12) Does the IRB benefit the sponsor in any way?

The key role of the IRB is to protect the subjects. However, although the powers of the IRB are designed to protect the subjects enrolled in the clinical trial, the IRB also helps the sponsor. The IRB helps the sponsor because the IRB has reviewed and approved the ethical considerations of the proposed trial. The sponsor knows that the IRB, which is completely independent of the sponsor and has no conflicts of interest with regard to the clinical trial, has examined and approved of the clinical trial and keeps a watchful eye on the progress of the trial. Therefore the sponsor knows that the clinical trial is being performed in an ethical and responsible manner.

13) The process of dealing with an IRB seems complex. Can a sponsor seek help in dealing with the requirements of an IRB?

Although the requirements of the IRB may seem complex, standard methods of designing clinical trial protocols include satisfying the ethical requirements of an IRB. People with clinical trial experience will be able to deal with all of the requirements and concerns of all IRBs; experienced people will be able to anticipate the concerns of most IRBs before submitting the proposals. For example, a reputable CRO will be able to provide all documentation required and answer all questions presented by the IRB.

14) A subject enrolled in a clinical trial wants to stop participating. Does that subject have the right to drop out of the clinical trial?

Yes. Each individual subject in a clinical trial is autonomous and has the right to stop participating in a clinical trial at any time regardless of how the sponsor feels about that.

15) Can the sponsor or any participants on the clinical trial team discuss any parameters relating to any specific individual subject in a clinical trial?

No. All subjects in a clinical trial have a right to privacy. The IRB will review that point as necessary and propose methods to protect a subject's privacy should that become a complicating issue for the sponsor. However, the right of a subject to privacy will not interfere with the sponsor's ability to gather the data required to complete the clinical trial.

16) How are subjects recruited?

Subjects recruited for a clinical trial must fit definitions for inclusion and exculsion according to the design of the clinical trial. Subjects fitting these definitions can then be recruited via clinicians or medical centers that deal with the specific health issues addressed by the clinical trial. Sponsors may also advertise for potential subjects in print, on the web, or on radio or TV. If the product undergoing study in a clinical trial is already on the market, the sponsor may recruit subjects from among the product's consumers.

17) If a clinical trial includes a placebo-control arm and the product undergoing testing in the clinical trial has promise of or shows a benefit, is it ethical to assign subjects to the placebo-control arm of the study?

Yes, as long as the informed consent has been properly carried out. The subjects must understand that if the clinical trial contains a placebo-control arm, that they may be receiving placebo and not the actual, active product. This approach is ethical according to most experts in ethics and to IRBs. However, it is also possible to design clinical trials that have a placebo-control arm in such a way that the subjects in the placebo arm can receive the actual, active product. For example, a crossover trial is a type of clinical trial that allows for subjects in the placebo-control arm to be moved to the treatment with active product. Design of a crossover trial often requires a longer study period over time in order to attain the proper statistical significance. Another approach is to offer subjects assigned to the placebo-control arm the active product after the trial has been completed.

Concluding Remarks

As shown by this brief question and answer session, the IRB sets up an effective method of both protecting subjects during a clinical trial and also helps to insure that the proposed clinical trial follows ethical guidelines. Complying with the expectations of the IRB is critical to the successful completion of a clinical trial. Although it may appear that compliance with an IRB is difficult, most experienced managers of clinical trials are able to set up a clinical trial that will meet the expectations of most IRBs. If a sponsor does not have their own experienced manager of clinical trials on staff, then a sponsor has the option of obtaining expert advice from a responsible clinical research organization. A responsible CRO will guide a sponsor in choosing sites that are appropriate for a specific clinical trial and will satisfy the requirements of each individual IRB.