California Pacific Currents 2002
Clinical Research Grows Up: New Rules Will Protect Patients
Responding to widely publicized problems at top-notch research facilities, many U.S. medical centers — including the California Pacific — have recently tightened their policies protecting patients enrolled in clinical trials. While the overall quality of research involving human subjects is still considered extremely high, the biotechnology boom has rapidly increased the number of trials for experimental treatments. It has also injected the possibility of new financial incentives into the research equation.
This mix of plentiful clinical trials and monetary incentives has accelerated the development and availability of life-saving therapies. But the mix has also been volatile, increasing the chances for hasty decisions, missed details, misunderstandings, lapses in judgment, and the potential for outright conflicts of interests.
Questions of Integrity
Here are just a few examples of what’s gone wrong between the good intention and the complex reality of clinical trials at major medical research centers in the U.S.:
- In a Baltimore-based clinical trial intended to reveal what triggers asthma attacks, faulty review of a research protocol and misleading informed consent forms led to healthy individuals being exposed to a dangerous irritant, hexamethonium. One patient, a healthy volunteer who actually worked at the research center, died of respiratory failure.
- In an Oklahoma trial of an experimental vaccine to prevent malignant melanoma, an overly optimistic oncologist gave the vaccine to the wrong types of patients (including a pregnant patient) and failed to make clear all the potential side effects. Eventually, an inspection found 20 research protocol violations.
- In innovative trials involving immune therapy and bone marrow transplantation to combat cancer, several researchers at a cancer research center in the Northwest gave patients monoclonal antibodies from a company in which they held a financial interest. The rates of death in treated patients were much higher than expected, raising questions about how the investigators’ personal financial stakes may have clouded their recruitment and management of patients.
While there have been federal safeguards for patients in clinical trials since the mid 1970s, the mistakes listed here and other similarly vivid cases — made at some of the world’s most prestigious research institutions — have prompted the general public to question the integrity of medical researchers. That arousal of public concern is now motivating researchers to tighten the rules.
“When it gets into Time magazine,” says Martha Anderson, PhD, director, Research Program Development, at the Research Institute, “doctors start paying attention.” But Anderson is quick to mention the balance that is required to protect patients while making sure that promising new therapies aren’t stifled. And she says it’s not only researchers who resist overly tight reins on research.
“Patients like to go to hospitals where research is done,” she says. “In oncology today, much treatment takes place in the context of research. And access to research is probably one reason that California Pacific is on the AARP (American Association of Retired Persons) top-50 hospital list.”
Can patient protections be beefed up while innovation in therapy is maintained? That’s the balancing act that will challenge all research centers as they evaluate policies in key areas such as informed consent, confidentiality, and conflict of interest.
The Institutional Review Board
The Food and Drug Administration (FDA), the National Institutes of Health (NIH), and the Office of Human Research Protection (OHRP), all part of the Department of Health and Human Services, have generated volumes of regulations aimed at protecting the rights and welfare of patients involved in clinical research. Obviously, these regulatory groups can’t monitor the tens of thousands of clinical trials going on every day around the country, so each research center sanctions local Institutional Review Boards (IRBs) to interpret the chapter and verse of those federal regulations — and to approve and review all trials involving humans.
“Our primary intent is protection of our human subjects,” says David Busch, MD, chair of the Medical Center’s 18-member IRB and an active member of California Pacific's medical staff. “We do everything possible to keep them informed and safe.” This oversight committee meets twice each month to review new research proposals and progress reports. Over 170 clinical research studies are underway at the Medical Center. Dr. Busch says IRB members represent a broad spectrum of medical specialties at California Pacific (including, for example, behavioral science, immunology, transplantation, critical care, rheumatology, ophthalmology, neurology, nursing, and pharmacy) — plus several members from the community, but he acknowledges that they can’t provide expertise in every area of medicine. This is why Madeliene Carlos, the Research Institute’s non-voting IRB regulatory specialist, sends proposals for scientific merit review to other California Pacific medical experts.
“One thing is certain in this job,” says Carlos after listing the responsibilities and resources of the IRB, “and that’s change. The regulatory agencies have been coming out with sweeping new guidelines, and it’s a challenge to stay on top of them.” The stiffened IRB rules have resulted, not surprisingly, in added layers of complexity for researchers. The checklist alone of IRB instructions and applications now runs several pages. “The complexity and hassle factor is real,” admits Dr. Busch. “Participation in clinical research now takes a real commitment,” he says. “But these rules are critical to patient safety and our IRB here actually has a good record of facilitating this process.”
Robert Miller, MD, chairman of Neuroscience at the Medical Center, is one researcher who recognizes these tradeoffs. “The increasing regulation is a sad but necessary reality,” he says. “We’ve all seen the temporary closure of research at top institutions like Johns Hopkins, Duke, and the University of Pennsylvania because of noncompliance, so our team views the increasing regulations as a necessary step to ensure that we maintain the highest standards of excellence.”
One special issue that all IRBs now confront is patient confidentiality. “We need to guarantee,” stresses Dr. Busch, “that identifiable patient information, tissues, and blood samples will be used for research with the consent of individuals and only for the purposes intended.” Thus, while California Pacific will be subject to the new federal privacy standards related to patient information (for example, the Health Insurance Portability and Accountability Act that is expected to become effective in April 2003), researchers must take added precautions to guarantee confidentiality. NIH regulations require, for example, that even laboratory scientists taking blood or tissue samples from human subjects must pass a certification exam involving IRB and confidentiality issues. The chair of the IRB is required to pass a certification exam, and efforts to increase the formal training of all clinicians performing human research are also underway.
Recruitment of patients for clinical trials is another specific issue that attracts IRB oversight. For example, while the IRB sometimes allows researchers to advertise for healthy volunteers or patients, the approved enrollment criteria are always strictly applied. “We try to recruit patients only with their doctor’s knowledge,” says Anderson. And while the study sponsor may reimburse patients for expenses, the money is never allowed to reach a level where it creates an incentive to enroll.
Another key issue for IRBs is informed consent, the policy requiring human subjects to understand the full risks of participation. All subjects are required to sign a form acknowledging they have read and understood the risks — and the IRB must first review the content and language of that consent form. In recent years, the length of a typical consent form has increased in direct proportion to concerns over patient safety.
“Our consent forms are very proactive,” says Lynne Day, director of Clinical Research at the Research Institute. She says this crucial document must not only detail all potential risks and side effects in patient-friendly language, it must also include information on alternative treatments, what to do in case of injury, costs, confidentiality, and conflict of interest. It must also make clear that participation is voluntary and that the potential for a real clinical benefit may be very low.
“In many trials, especially in oncology,” Day says, “the potential for therapeutic benefit is unknown or minimal, but the patient may be inclined to participate based solely on a doctor’s recommendation.” In these situations, Day says it’s best if someone other than the physician-researcher explains the consent form to the patient. “Patients consented by their treating physician tend to think they’re getting a standard-of-care treatment rather than an experimental medicine,” she explains.
A 14-page informed consent form, of course, shifts much of the burden for decision-making to the patient. In an age of patients researching their own illness on the Internet and then demanding the latest tests or treatments, such a shift away from the “doctor-knows-best” syndrome may seem appropriate. But as pointed out by Busch, many patients struggle to comprehend all the information. “Despite our best efforts to present consent forms in simple language,” he says “many of these long forms are still overwhelming for patients.” Thus, once again, creating a balance becomes the challenge for the IRB.
Conflict of Interest
The other hot-button that demands the attention of both the IRB and the Research Institute today is financial conflict of interest. While many researchers are paid for their research efforts, it’s understood that they should not financially benefit from a positive or negative result of their clinical trial, or, in fact, any research project. Such a vested interest in the outcome of the study could unduly influence practically all aspects of the trial, from study design, through patient recruitment, informed consent, monitoring, safety reporting, results interpretation, and publication.
To avoid conflicts of interest, FDA and NIH policies now require disclosure of financial interests (eg, stock, options, board membership, speaking fees, and equipment grants) above certain thresholds in companies related to specific research projects. At California Pacific, researchers are asked to report any level of relevant holdings, including those of a spouse or dependent child. The goal is to avoid even the appearance of conflict of interest. Retirement accounts or mutual funds where the researcher does not control the individual stock choice need not be disclosed.
All researchers fill out a disclosure form once each year (more often if their portfolio changes) and this form is reviewed in conjunction with proposals submitted either to the IRB or to an extramural funding agency. Heightened sensitivity to conflict of interest issues — and the need for ongoing in-house expertise in these complex and touchy financial issues — recently led the Research Institute to establish a permanent Conflict of Interest Committee separate from the IRB. Chaired by Warren Browner, MD, MPH, the Institute’s scientific director, the committee’s goal is to identify, manage, and reduce potential research-related conflicts of interest.
“We obtain information from all of our investigators about any potential conflicts of interest, review their reports, and look into any of those that raise concerns,” says Dr. Browner. “So far, everyone has been extremely cooperative.”
Any potential conflict noted by the COI Committee is discussed one-on-one with the investigator. If an agreement can't be reached between the COI Committee and the investigator, this could lead to establishment of an impartial data monitoring committee or other measures, up to denial of the proposed research application.
If human subjects are involved in a study, conflicts of interest are disclosed to the patient in the consent form. Funding sources for studies and conflicts of interest are also revealed in research publications in scientific journals.
Browner says procedures to avoid conflicts of interest are just one more example of ongoing Research Institute efforts to improve patient protection. “We need to ensure,” he adds “that patient safety and well-being are paramount concerns in the design, execution, and analysis of all clinical research at California Pacific.”
Growing Up, Getting Better
Based on recent findings of significant flaws in U.S. medical research, the clinical trial process is maturing rapidly. The painful growth spurts of the past few years are forcing the adolescent clinical trial “industry” to grow up. One indicator of this new maturity is the dawning realization among most of the country’s 600,000+ doctors that doing a clinical trial is not a skill that “any competent physician” is qualified to perform. Skills in handling informed consent, confidentiality, and conflict of interest require as much dexterity and thoughtful attention as those for taking a physical or inserting a catheter. With IRBs throughout the U.S. acting as the local hubs for researcher education on these critical research skills, the quality of clinical trials will improve, and all patients — current and future — will benefit.