Year : 2008 | Volume
: 56 | Issue : 4 | Page : 267--268
Finer nuances of clinical study agreements for research trials
Barun Kumar Nayak
P. D. Hinduja National Hospital and Medical Research Centre, Veer Savarkar Marg, Mahim, Mumbai - 400 016, India
Barun Kumar Nayak
P. D. Hinduja National Hospital and Medical Research Centre, Veer Savarkar Marg, Mahim, Mumbai - 400 016
|How to cite this article:|
Nayak BK. Finer nuances of clinical study agreements for research trials.Indian J Ophthalmol 2008;56:267-268
|How to cite this URL:|
Nayak BK. Finer nuances of clinical study agreements for research trials. Indian J Ophthalmol [serial online] 2008 [cited 2020 Aug 15 ];56:267-268
Available from: http://www.ijo.in/text.asp?2008/56/4/267/41409
Most of the doctors in India appear to be excited by the fact that clinical trials conducted in India are on the rise and our country may become a major hub for the same. The clinical trials may be institution-based or multi-centric and are increasingly being funded by pharmaceutical or biotechnical companies, research organizations or by the government, either partly or fully.  The conduct of these trials is handled by contract research organizations (CROs) and site management organizations (SMOs). All the parties involved have something at stake: the researchers/ institutions may have financial and non-financial gain,  the CROs and SMOs have priority to facilitate and complete the trials successfully in the shortest possible time, and the sponsors' stake is the highest as a positive outcome would lead to approval of their product by the Food and Drug Administration (FDA) or can lead to an increased sale of their FDA-approved products. The clinical study agreement (CSA) is a legal document which is sent by the company or CROs and SMOs to the participating researchers or institutions for execution. Researchers or institutions are by and large naοve in realizing the importance of CSAs. Every effort should be made to keep the conflict of interest out of the CSA,  , which usually runs in many pages and is drafted by the sponsors or CROs. This is considered as a legal document between the sponsors and institutions/researchers. In a famous case between Olivieri and Apotex, Apotex threatened Olivieri with legal action if she disclosed her genuine concerns about the safety of treatment to any third party without its consent.  Later, Aberman, the dean of the institution said: "If there's a contract between two parties, a third party doesn't have the right to step in and urge one of the parties not to abide by it".  Olivieri admitted that it was her mistake to sign the contract to keep the results confidential, without even showing the contract to a lawyer. Unfortunately, she was the sole signatory from the institution or the university. The main purpose of this editorial is to highlight some of the issues which should be looked into and addressed by the researchers before signing the CSAs.
Research in an institute is not only guided by the Institutional Review Board (IRB) but also by the legal agreement between sponsors and the institution. The institutions should ensure the proper conduct of trials at their end. Hence, the CSA should describe the party's roles in the design and conduct of trials, access to data, and publication commitment including publication rights and responsibility. The International Committee of Medical Journal Editors (ICMJE) revised its "Uniform requirements for manuscripts submitted to biomedical journals" to maintain the sanctity of research and publication.  The revisions made it mandatory for full disclosure of the sponsors' role as well as the assurance that researchers are not under the control of sponsors and have full independent control of study design, access to data, editorial and publication decisions.
Schulman et al. ,  conducted a national survey in the US and concluded, "academic institutions routinely engage in research that fails to adhere to ICMJE guidelines for trial design, access to data, and publication rights". These were the findings of the institutions in the US where the median number of site agreements executed in the previous year was 103 (inter-quartile range, 50 to 210).  The institutions in India should be careful as their exposure in this field is limited.
It is worthwhile noting certain findings of a survey conducted in the US of medical-school research administrators responsible for negotiating CSA with industry sponsors.  More than 85% respondents would not approve of the provision wherein industry sponsors get authority either to revise the manuscript or to take decision regarding publication of the research. Only 24% would agree to allow the sponsors to insert their own statistical analysis and 47% would disallow it. Fifty per cent would allow the sponsors to draft the manuscript while 40% would disallow it. Forty-one per cent would allow the provision of prohibiting the investigators from sharing data with third parties after the trial is over, 34% would disallow it and 24% were not sure about their stand. The data of this survey reflects the viewpoint of administrators who were experts in negotiating a large number of CSAs, as 51% of the respondents had handled more than 100 agreements in the previous year. Hence, while negotiating any contract one cannot ignore the outcome of this survey.
There is no guarantee that there will be no dispute after signing the contract. In the same survey mentioned earlier by Mello et al .  82% of institutions had at least one dispute with the industry sponsor in the previous five years, in spite of having a CSA. Seventy-five per cent institutions had payment-related disputes, 30% were related to intellectual property, 17% were related to access or control of data, 16% each were related to content of manuscripts and confidentiality of data. It is interesting to note that while 7% disputes went in litigation and arbitration, 37% were resolved quickly and 55% required extended negotiations. In case of dispute with sponsors resulting in litigation, the area of jurisdiction should be restricted to the area and country of the investigators to avoid unnecessary harassment.
The members of ICMJE pledged in 2001 not to review or publish articles where CSA prohibits researchers from the freedom of publication.  This implies that the CSA of sponsored trials will be reviewed prior to the initiation of processing of submitted manuscripts. Du Val  points out four major drawbacks in reviewing post-trial completion of the CSA and subsequent restriction of publication. First, after the completion of research, it will be unethical and a betrayal of the faith of subjects, not to publish, if scientifically significant findings are made. Second, this approach will not ensure review of CSAs if the findings are not submitted for publication such as in studies not intended for publication or studies with negative results. Third, it may not be possible for editors to undertake a comprehensive review of CSAs to judge the ethical standard of the same. Fourth, denying publication subverts the core issue of under-reporting. With these limitations in mind Du Val  has suggested thorough review of CSA by the IRB before signing the contract.
Let us look at the key issues that can arise and that should be addressed ethically in all CSAs. Publication issue must be looked into minutely. Blumenthal et al. ,  reported that 19.8% of a random sample of academic life scientists from major research institutions had their publication delayed by more than six months due to interference by sponsors. In a classic example, a group of researchers completed a study sponsored by Boots pharmaceuticals Inc. comparing the efficacy of sponsor's synthetic thyroid (synthyroid) with three other rival preparations. The researchers found it to be equally effective but the researchers and sponsors had anticipated synthyroid to be superior. Because of the restrictions posed in the agreement, Boots could block the publication of this significant finding for around seven years.  Another glaring example of sponsors' interference is the dispute between Olivieri and Apotex mentioned earlier. 
Disclosure to ensure patient safety is also an important aspect in professional standards of care. The CSA must give freedom to researchers to use discretion to determine what disclosures or warnings are to be made to subjects. Data analysis and reporting is another core issue; researchers should have complete freedom to analyze it independently. Any restrictions imposed by sponsors through CSA are not liked by the editors.  One should realize that statistics is the only science where different conclusions can be drawn using the same data. Confidentiality of information is also an important issue and CSA often seeks to protect the confidentiality of the sponsor's intellectual property. However, investigators should be permitted to disclose certain relevant information if required, in the best interest of science. Even certain information to the subjects should be permitted though the CSA. Financial costs and injury compensation to subjects should be clarified in the CSA. The cost of investigations, treatment and harm caused directly due to the research participation should be the responsibility of the sponsors. However, the sponsors can be absolved of this liability if the subject had grossly deviated from the protocol of the study. Provision for proper identification of harms and losses should be incorporated in the CSA to protect the independence and integrity of the institution and researchers. Certain reasonable exceptions to this may be if the harm has occurred due to acts of negligence or omission by the researcher or institution or if the investigator admits wrongdoing without the consent of the sponsors. The clause of premature termination of agreement and research should be clearly mentioned in the CSA. The valid ground for termination could be either ineffective treatment (to protect subjects from receiving the experimental drug) or clearly effective treatment (to give benefit of effective treatment to control group). The other reasons for termination could be safety concerns if the side-effects of the treatment are found to be unacceptable. Sometimes, the study might have to be terminated if the continuation of study is not found to be feasible. Sponsors should not be allowed to terminate the study due to lack of commercial viability or because the study proves to be negative for the sponsor. 
In the excitement of getting an opportunity to participate in sponsored trials and the associated benefits thereof, one should not ignore the importance of CSA and every effort should be made to modify it to safeguard the interest of investigators, institutions and subjects. Scientific harassment by pharmaceutical companies does occur.  The review of CSA by IRB as suggested by DuVal  is very helpful for the same besides maintaining the ethical standard of a clinical study.
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