Experts Urge More Research on Growing Use of Humans in Clinical Research

From left, Christine Grady and Ivor Pritchard

Amid a rapid increase in the number of recruits for clinical trials and calls for stronger regulatory protections of research subjects, several specialists told a 2 May briefing hosted by AAAS and The Hastings Center that there is insufficient data to say whether the protections system is seriously broken or not.

Despite gaps in the system and a perception that it is not working as well as it could, "we don't have a lot of data to say exactly what's wrong," said Christine Grady, head of the section on human subjects research in the Department of Bioethics at the National Institutes of Health Clinical Center. Without better data on who is being protected and what harm may be occurring in clinical trials, Grady said, "we cannot judge the quality of the protections."

Karen Maschke

Karen Maschke, associate for ethics and science policy at The Hastings Center—a bioethics think tank in Garrison, N.Y.—made a similar plea for more information. She said there is little aggregate data on who participates in clinical trials and what happens to them. How many adults and children are in clinical trials? Where are the trials being conducted? What diseases or agents are being studied? What adverse events have been reported and why?

Ivor Pritchard, acting director of the Office of Human Research Protection (OHRP) for the U.S. Department of Health and Human Services, also agreed on the need for more systematic analysis of clinical trial outcomes. "To predict the risk of harm, we need to know how many studies produce good effects, how many produce bad effects, and how many produce no difference," he said.

There is little question that the landscape of clinical trials has been changing dramatically, spurring calls for reform and updating of participant protection rules that were written in the 1970s. By one estimate, the number of clinical trials in the United States jumped from 40,000 to 59,000 between the years 2000 and 2006. The number of participants needed to fill industry-sponsored clinical trials reportedly grew from 2.8 million in 1999 to 19.8 million in 2005.

That growth has been marked by significant changes in the financing and location of clinical trials. Where once most trials took place in academic medical centers and were funded by the federal government or philanthropic organizations, now many are being outsourced to private companies and physicians' offices or are being conducted abroad, particularly in Eastern Europe and Asia.

Experts have questioned whether the current system of research protections is adequate for the new clinical trials environment. As the industry role in sponsorship of clinical trials has grown, so have concerns about potential conflicts of interest between industry sponsors and researchers. Rare but highly publicized cases of participant deaths during clinical trials also have raised questions about the adequacy of federal oversight. Experts also note that the current research rules do not explicitly address new technological frontiers such as stem cell research or the potential for inducing heritable genetic changes in humans.

The federal protection system was adopted in the 1970s after revelations about the Tuskegee Syphilis Study, in which a group of African-American men with syphilis were followed for many years but not offered effective treatment even when it became available. In response to the public outcry over the Tuskegee study and other cases of unethical research, Congress authorized new rules on the conduct of experiments involving humans. Research subjects were required to give informed consent after being told fully about the potential risks and benefits of a study. An Institutional Review Board, or IRB, must ensure that the consent procedures are adequate and that the research is undertaken in an ethical manner.

The regulations were aimed at research studies funded by the federal Department of Health and Human Services (HHS), primarily through its National Institutes of Health (NIH). Pritchard's OHRP administers the rules for HHS. Privately funded clinical trials do not fall under the rules but many institutions apply them to all of their studies, whether federally funded or not. The federal Food and Drug Administration administers its own version of the research rules for clinical trials on drugs, biological agents, or devices that are subject to FDA approval. Nonetheless, there remain significant gaps in coverage. Many clinical trials do not fall under either the OHRP or the FDA umbrella, but there are no accurate data that reveal how many, according to Maschke.

Even when clinical trials are covered by the current system, there have been nagging performance issues. The Institutional Review Boards have had to deal with increasingly complex research projects that may require patient recruitment at as many as 1,000 different sites. Partly, that is driven by the NIH and industry's effort to broaden the participation in clinical trials by enlisting community clinics and physicians' offices in addition to the academic medical centers. For drugs aimed at rare cancers, for example, such broad recruitment can be mandatory in order to find enough participants for a valid study. "We've gone out far and wide into the country," Pritchard said.

But the increasing number of research sites means more IRBs are involved with each study as well. The federal rules do allow cooperative review, Pritchard said, in which all parties to a clinical trial agree to assign the ethics and informed consent review to a single IRB. In practice, he said, institutions are often reluctant to cede authority to an IRB at another institution. The result can be multiple IRB reviews and multiple revisions to the research protocol before the clinical trial can begin.

The same issue arises when parts of a clinical trial are outsourced to institutions or contractors in one or more nations abroad. The study must adhere to ethical and procedural rules in those nations as well in the United States. Although HHS can deem another nation's patient protection rules to be equivalent to its own, Pritchard said that has not happened so far. As more clinical trials are moved abroad, experts say, it will become even more important for there to be uniform standards of protection for research subjects at all levels of income and literacy. In 2007, 38% of the clinical trials registered on the NIH's ClinicalTrials.gov Web site were conducted abroad, up from 16% in 2001.

As private sponsorship of clinical trials has mushroomed both here and abroad, so have questions about potential conflicts of interest between corporate sponsors and researchers. While NIH and FDA require researchers to disclose some types of financial relationships to the agencies, there is no universal requirement for disclosure to the participants in the research studies. The American College of Physicians has been encouraging physician-researchers to improve communication with patients they recruit into trials. An ACP brochure has a list of questions for patients to ask, including: Who is paying for the study? Who will make money from the results? As both a researcher and a doctor, how will your research goals affect your decisions about my regular care?

Maschke also urged more transparency for the public in the IRB process. There is no requirement that IRBs disclose their deliberations and decision-making on ethical questions. Maschke suggested establishment of a publicly accessible database of written IRB opinions so that researchers and the public can compare notes on how any disagreements were addressed and resolved.

While the reassessment of human subjects protections is ongoing, there have been some encouraging steps in recent years, Grady said. She mentioned the voluntary accreditation of IRBs to help bring some uniformity to the process of interpreting and following the federal regulations. OHRP and FDA also have been discussing cooperation on a program that would require registration of IRBs as a step toward getting a better handle on the number of such boards and their performance.

The NIH has had success with its voluntary information registry, ClinicalTrials.gov. The site provides a searchable list of federally and privately supported clinical trials conducted in the United States and abroad. It gives patients, family members and the public information about a trial's purpose, who may participate, locations, and phone numbers for more details.

There also is increasing emphasis on the need for ethics education and training for all who conduct clinical trials. Pritchard said his office strongly recommends that researchers and their assistants receive adequate instruction on ethics and human protections. He said OHRP is preparing to circulate a request for public comments on whether OHRP should issue a new rule that would make education on research protections mandatory.

Grady said it also makes sense to develop a more centralized system for dealing with the problem of multiple reviews of a pending clinical trial. "To have one hundred institutions reviewing the same study doesn't always make sense," she said. One possibility is a regional research organization that would be responsible for reviewing and monitoring all clinical trials within a particular geographic area.

There also have been suggestions for an independent national board or a public-private partnership to provide a single oversight structure for human research studies. Maschke noted that one proposal before Congress in the 1970s was for such a national entity, comparable to the Securities and Exchange Commission in the financial world. This type of entity could have enforcement and monitoring authority to ensure that clinical trials are conducted properly and that research personnel are adequately trained.

Earl Lane

8 May 2008