The first major milestones in obtaining an informed consent were as follows:

Other medical and legal professional groups and organizations have created and approved various ethical standards for the conduct of clinical trials that also have had widespread impact. See the Additional Readings section for selected references.

Over the past few decades, the issues surrounding informed consent have mushroomed and are sometimes more contentious than ever before. A few of these are mentioned to indicate the types of issues that are being discussed.

The rule of thumb about when to obtain a subject’s informed consent to enter into a clinical trial and have him or her sign the document is prior to conducting any study-specific tests needed to evaluate subjects during the screening period. Routine laboratory tests or other tests that can be considered as part of routine care for that specific subject are able to be conducted (although definitely not required) prior to the formal informed consent process.

In some situations, it is desirable to have the patient sign the informed consent after one or more of the study-specific tests have been conducted. For example, in a highly complex open-label trial, where two groups are being compared with different procedures such as surgery, radiation, and other modalities (e.g., surgery and radiation versus drug therapy or standard of care), it would be confusing to the subject if one informed consent presented both types of treatments and this form was shown to the subject early on in the screening period and indicated to the subject that it is uncertain which treatment he would receive. This would be an opportunity to use two informed consents. Early in the screening period, one would provide a consent form only for the test(s) that are study specific and would determine eligibility for enrollment or determine which of the two treatments would be assigned to the patient. This would be a simple and short form that mentions the screening tests and indicates that a more extensive form will be given to the patient for his decision on enrolling after the results of the screening test(s) are obtained. Assuming the results of the screening tests allow the subject to enroll in the trial, the informed consent would indicate the specific treatment to be given to the subject and present the relevant information. Alternatively, a randomization process would occur, and then the subjects would be given one of two different forms to review and sign, again only discussing the treatment as it applies to them.

The advantages of this approach are to improve the subject’s understanding of the procedure and tests he will receive, minimize confusion, and (the author believes) simplify the informed consent process.

A Central IRB is one that reviews a clinical trial protocol, informed consent, and investigators’ brochure for more than a single site. They may review and approve a trial’s initiation for some or all sites in a multicenter trial.

Some of the reasons that Central IRBs were developed were because of the large workload of many local IRBs that dealt with single sites, many local IRBs took a great deal of time to review a protocol, and every change suggested to the investigator had to be incorporated or discussed with the sponsor and a response given to the IRB that re-reviewed the protocol. This cycle could be repeated several times. In addition, protocol changes required by one IRB had to be approved by all of the others; whereas if a Central IRB requested changes in a protocol, the changes would be for all sites in the trial (assuming the Central IRB was reviewing the protocol for all sites). Therefore, the Central IRB concept was an attempt to improve efficiency and reduce the time needed to initiate the trial.

Apart from members of Central IRBs, most IRBs are staffed by volunteer members, but the administration of a busy IRB is so costly that most academic nonprofit IRBs charge fees in the approximate range of $1,000 to $3,000 per protocol reviewed. The IRB members’ workload is huge, and a practice that many IRBs follow to make their workload more manageable is to assign two or three people the task of being a “lead” reviewer on a specific protocol. The lead reviewers read the protocol carefully and present their views to the entire group. This is an efficient mechanism but allows more issues to be unrecognized if others on the committee have not carefully read the protocol and informed consent.

Every IRB member should be trained to recognize content that requires input from additional reviewers. Some protocols require content area expertise that is not represented among IRB members. For example, a trial in children will require pediatricians to review the protocol, and if none are on an IRB, then it is generally a simple matter to enlist one or two to sit in the committee meetings for discussion of this protocol after the pediatrician(s) have read the protocol and related material. Expertise in regulatory affairs or toxicology or another function is often required to understand a protocol, and the IRB members may not be aware that someone with this expertise needs to be involved to assist with their review. For example, a clinical trial was conducted at Johns Hopkins University in which a ganglionic blockade agent was used in a new route of administration. The IRB‘s failure to fully appreciate this different route of administration led to the death of a healthy woman who volunteered for the clinical trial. The IRB can greatly reduce the chance that such tragedies occur by having a checklist that asks about special concerns in a protocol. An example of a checklist that an IRB can use to ensure it has considered relevant topics to review and has not overlooked items of importance was presented by Spilker (2002).