Industry-sponsored studies may need more protections
Focus on your contracts
IRB approval of human-subject study protocols may be insufficient to truly protect research participants and the integrity of the investigators, particularly when an outside corporation sponsors the trial, a new study by researchers at Durham, NC-based Duke University claims.
In industry-sponsored research it is often the legal research contract with the institution, not the study protocol sent to the IRB, that has more weight in determining research conduct, says Kevin Schulman, MD, lead author of the study and professor of medicine at Duke University Medical Center.
"These contracts are important because the truth of the matter is research is governed by the contracts between the sponsors and institutions, not by the study protocols approved by the IRB," he says.
A survey of research agreements entered into by academic medical centers and sponsors between November 2001 and January 2002 indicated that few agreements meet the standards established by the International Committee of Medical Journal Editors (ICMJE).
The Duke researchers surveyed 108 member institutions of the Association of American Medical Colleges (AAMC) to determine the extent with which their contracts with clinical trial sponsors met the three main provisions of the ICMJE guidelines:
- whether authors of reports of multicenter trials had access to all trial data;
- whether the authors or an independent committee controlled editorial and publication;
- whether investigators were fully involved in the design and conduct of the trials.
The researchers found that the agreements rarely included such provisions. Only 1% required that authors of multicenter studies have independent access to all data from the trial, though institutions at coordinating centers for multicenter trials stipulated this level of access at a higher rate (50% of contracts).
The industry sponsors also typically control decisions regarding the publication of data from clinical studies. Provisions addressing the editorial content of the multicenter manuscripts appeared in 40% of contracts, while independent committees that would guarantee publication were specified in fewer than 1%. The agreements also did not ensure dissemination of findings from research on stored biological materials collected during clinical trials — these materials are collected by the industry sponsors for use in future research.
The research agreements are the only documents that legally bind the industry sponsor in terms of their conduct related to the research, Schulman explains. "Items like trial governance, and publication of results are contained in the study protocol, but rarely in the research agreement, and the sponsor is not legally bound to follow the study protocol."
In most cases, the research agreement is considered the legal document in the event of a disagreement between researchers and sponsors, he adds.
For example, a pharmaceutical company many initiate a multicenter trial of a new drug and sign research agreements with a number of different sites. These individual sites recruit participants into the trial and submit data to a central source. Study protocols are approved by each site’s IRB, says Schulman. But those protocols do not guarantee that data from all sites will be published, researchers writing up the study results for publication will have access to all data or that the sponsoring company will not simply just decide to pull funding if the initial results of the trial do not prove favorable.
"The agreements generally allow access to site-level data, but that is scientifically invalid in a multicenter trial," Schulman explains. "If I have 50 patients at Duke in a 10,000-person trial, what does it mean if I try to analyze the data on those 50 people? It doesn’t mean anything."
Investigators out of the loop
Site investigators and IRBs typically are not involved in the process of negotiating the terms of research agreements, he continues. The institution’s contract office and legal representatives of the sponsoring entity frequently work out the details of the research agreements without input from the IRB or researchers.
"Basically, if I am a site investigator at Duke, the research sponsor will give me a contract," he explains. "I will pass the contract on to the contracts office and they will negotiate with the sponsor."
At the same time, the proposed study protocol — governing how the trial is to be conducted at that site — will go before the IRB.
In the study, only 17 of the site respondents, and none of the centers serving as coordinating centers for multicenter trials, reported that their IRB routinely reviewed research agreements, Schulman says.
"In most cases, the IRB does not get involved in the contract at all," he notes.
The most troubling aspect of the survey’s findings was the lack of assurance that all study results would be reported, Schulman says.
A basic tenet of clinical research is humans participate in order to yield information that will help advance medical science and benefit society. A key facet is that results of the research will be made public — whether good or bad.
"If you cannot guarantee that results of a research trial will be published, then how can you ethically tell a person that what they are participating in is research?" Schulman asks. "If a company comes in and sponsors a study, the IRB signs off on the protocol, you recruit patients at that site and tell them they are participating in a research trial, but later the study doesn’t go the way the company hoped it to, and the results are never published? What are you recruiting people to at the site level?"
Conducting experiments involving humans, telling them it is a research study with no guarantee the results will ever be shared with others is not research, he emphasizes.
"If clinicians told participants up front that they were being asked to participate in a marketing study for a private company and that they would be exposed to a potentially toxic medication for the purpose of the manufacturer finding out whether the medication was effective and they could make money at their discretion, we would probably get a lot less participation," Schulman notes.
Not only do many research agreements not guarantee the objectivity of the research, but some investigators have been severely pressured to discard or not reveal study results that were not favorable to the sponsoring company, says David G. Nathan, MD, president emeritus of the Dana-Farber Cancer Institute in Boston.
In the same issue of the New England Journal of Medicine featuring the Duke study, Nathan co-wrote a report on the case of Nancy Oliveri, a Canadian clinical researcher at the Hospital for Sick Children in Toronto.
Oliveri was the lead researcher on a study of the iron chelator, deferiprone. The study was sponsored by Apotex, a Canadian generic drug manufacturer.
As part of the research contract, Oliveri and colleagues signed a confidentiality agreement that was consistent with the policy of the hospital at the time.
However, Oliveri then became concerned about the drug’s potential liver toxicity. She conducted a second study — without signing a confidentiality agreement — comparing hepatic iron levels in patients taking a similar drug and the test drug. Upon finding that certain patients did not do as well on deferiprone, she decided to submit the findings for publication and present the new data at a scientific meeting.
Apotex subsequently sued Oliveri for violation of the initial confidentiality agreement. The hospital administration referred her for research misconduct to the province’s medical licensing board. The board later found no basis for the misconduct allegations, and she was not disciplined.
Though the case is an egregious example of what can happen, it does illustrate the importance of protecting the independence and integrity of clinical researchers, Nathan says.
"This is a huge problem for the American Association of Medical Colleges," he tells IRB Advisor. "The deans of the schools must get in agreement."
It is not only the academic medical centers that must pay attention, however, adds Schulman.
Many multicenter studies are conducted with sites that are not teaching hospitals. Frequently, patients may be recruited at smaller hospitals and even in individual physician’s offices.
"There really needs to be one set of research ethics, regardless of where and how the participants were recruited," he notes.
Potential solutions
To ensure the integrity of industry-sponsored research, Schulman believes a standard research agreement should be used whenever an institution contracts with a company to participate in a research trial.
The contract would require publication of the study results, the establishment of an independent board to monitor the progress of the study and would require that the person or group writing the report have access to all site data.
An independent coordinating committee would also protect the study from undue influence from the company’s corporate objectives, he adds.
"In terms of trial governance issues, what if you’ve exposed all of these people to this medication — particularly in a Phase Four setting — and the sponsor realizes the results aren’t going their way and wants to pull the plug. If you had an independent committee, at least you’d have one check on that," he says. "If you decide a trial isn’t working because you can’t recruit enough people, that is one thing. We make mistakes sometimes in study design, and we can’t get the subjects we need. But, you would want someone who doesn’t have that outside interest to represent the patients."
Nathan agrees with Schulman’s proposals, but also feels that there also should be some standing authority in place to hear and resolve conflicts between industry sponsors and the institutions or researchers they contract with.
"We suggest in our article, that a standing committee of the National Academy of Sciences-Institute of Medicine might be established to consider such conflicts and make recommendations to resolve them," he notes.
For example, if a corporate sponsor an study author differ in their interpretation of results, an independent body should be available to resolve the dispute.
"It is most important to interpret the results independent," he says. "If the investigator and company do not agree on the interpretation, there must be away to adjudicate the problem." The center’s institutional review board should also bear some responsibility, he adds.
"IRBs are signing off on this research that is not research," he says. "There is still the question if you consent the person to participate in research, and that is not what in fact the project is, what have you done? Some courts have held that a consent agreement is a form of contract. If the contract says you are participating in research, when the institutions or investigators involved have no assurance that’s the case, then you have a hard time fulfilling your end of the contract."
IRB approval of human-subject study protocols may be insufficient to truly protect research participants and the integrity of the investigators, particularly when an outside corporation sponsors the trial, a new study by researchers at Durham, NC-based Duke University claims.
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