Clinical research and regulatory oversight: A question of balance

In 1932, Charles Pollard was told he had “bad blood,” although he did not know what it meant at the time. He was one of more than 600 black men (412 with syphilis, 192 uninfected controls) who were enrolled in the Tuskegee Syphilis Study, sponsored by the U.S. Public Health Service (PHS).

The Tuskegee Syphilis Study ended in 1972 after Peter Buxton, a PHS venereal disease investigator in San Francisco, went to the Associated Press. During the 40 years of the study, the vast majority of the study participants went untreated, either with the mercury and arsenic compounds that would have been used in the early years of the study, or the much more effective penicillin after 1947. At the end of the study, 74 participants were alive, 28 had died of syphilis, 100 died of related complications, 40 of their wives had been infected and 19 of their children had congenital syphilis. In 1973, Mr. Pollard testified before a Senate subcommittee about his experiences as a study subject. In 1997, President Bill Clinton formally apologized to Tuskegee Study participants, including five of the eight remaining survivors who attended the White House ceremony.

Fast forward to 2009. On February 27, we submitted a NIH-sponsored multi-center protocol to our local Institutional Review Board (IRB) for review and approval to conduct the study at our research site. This was reviewed by the IRB on May 15, resulting in a letter of deferral on May 26, followed by our response on June 16, approved by the IRB on July 10, with delivery to us of stamped approved consent forms on July 20 and protocol registration by NIH on August 3 – five months and six days after our original submission.

The IRB’s four-page deferral letter contained 39 comments, six of which related to a substantive and appropriate request to clarify procedures related to safety and possible unblinding if a participant should become pregnant. The remaining 33 comments were relatively trivial administrative changes to the application forms, attachments and consent forms. Seventeen of these comments dealt with wording or structure of the consent form, which had been adapted from a protocol-specific template form provided and approved by the NIH. The 13-page consent form had a reading grade level score of 9.5 (sophomore in high school), which was unchanged by the IRB modifications. Our submission and resubmission were each comprised of 18 collated copies of a cover letter, the protocol, a lengthy protocol summary consisting of numerous attachments, consent forms, HIPAA forms and other materials weighing about 30 pounds.

The legacy of Tuskegee

The Tuskegee Syphilis Study arguably represents the most egregious example of unethical biomedical research in U.S. history. This tragedy led to the 1979 Belmont Report and the formation of the Office for Human Research Protections (OHRP). Clearly a better method for the protection of human subjects in research was needed. However, as demonstrated by our recent experience with local IRB review, regulatory oversight has evolved over the past four decades, perhaps to excess. My intent is not to be critical of our local IRB, per se. The undue delay in the process was related to an IRB that is overburdened and understaffed with a constant backlog of reviews, an administrative staff that spends a disproportionate amount of time moving documents to and from investigators and the reviewers, and review panels made up of committed professional colleagues and lay people (most of whom are volunteers) who are following often arduous instructions on study review and approval.

As featured in this issue of Infectious Disease News (click here to see, "IDSA identifies five areas which may obstruct translational research"), the Infectious Diseases Society of America’s policy statement “Grinding to a Halt: The Effects of the Increasing Regulatory Burden on Research and Quality Improvement Efforts,” written by William Burman and Robert Daum with the IDSA Research Committee, is an important contribution in the field of clinical research and its regulatory oversight.

Clinical research in medicine has expanded greatly in recent decades, leading to remarkable advances in the diagnosis and treatment of many diseases with improvements in survival and quality of life for affected patients. The protection of human subjects in the conduct of research is essential to ensure the safety of patients with new experimental therapies and that studies are carried out based on sound ethical principles. However, to provide those protections, a “regulatory-industrial complex” has evolved, imposing a considerable burden on clinical investigators, research staffs, IRBs, universities and clinical practices, pharmaceutical sponsors, the federal government and most importantly, patients with diseases in need of research.

The IDSA statement points out specific areas where the pendulum of regulatory oversight has swung too far and makes specific recommendations to undo or revise current processes. If implemented, these changes would lead to improvements, efficiencies, and cost-savings in the conduct of research.

The five areas in need of attention are:

• the Health Insurance Portability and Accountability Act (HIPAA),
• local review of multi-center studies,
• reporting of adverse events to local IRBs,
• pediatric research, and IRB reviews of quality improvement studies.

In the context of a complex arena, the recommendations are sound, practical and doable. Indeed, these remedies do not require new legislation. There are other areas where clinical research oversight can be improved, but these recommendations are a good start.

Burden of site monitoring

One additional area not discussed in the article is the burden of site monitoring during the conduct of studies. Monitoring visits are useful to ensure that study processes such as informed consent, selected data collection and source documentation have been properly carried out, and to provide constructive feedback to staff to improve site performance and reinforce good clinical practice. However, we should question the specific types and volume of information that are collected and reported, and whether or not this matters to the safety of the patients and science of the study.

Much of what occurs at site monitoring, the IRB example given above, and other aspects of regulatory oversight relate to a form of “referential existentialism,” where the monitor, sponsor, or IRB claim that something must be done a certain way because that is the law, regulation or guideline, when that is actually not the case if one looks at this information carefully. The IDSA statement calls for a new look and revisiting some of the rules, and to make changes within the rules or guidance and modify others when appropriate and reasonable.

What will it take to move forward to effect positive change? Other professional organizations should join forces with the IDSA to endorse these recommendations and advocate for change; all patients with different illnesses stand to benefit. Patients and patient advocacy groups need to be at the table; they can lead the way and provide crucial advice as to what is best for them.

Communication with different components of the research establishment, federal agencies, and IRB representatives need to occur, with proactive dialogue and broad input. Education and dissemination about these issues with providers, professional organizations, and patients will be necessary to get the word out, garner support, and encourage discussion. Finally, additional research in the field of regulatory oversight is needed, to better understand the best ways to ensure patient safety, achieve comprehensible but simpler informed consent, leading to more efficient and sensible processes to do research. As the IDSA statement eloquently concludes, it is time to restore balance.

David Cohn, MD, is associate director of Denver Public Health and professor of medicine in the division of infectious diseases at the University of Colorado Denver Health Sciences Center. He is also a member of the Infectious Disease News editorial board.