5
Implementation Issues

The various proposals for creating a clinical trial registry agree that such a registry is needed on the national or international level to benefit public health. They agree on most of the specific elements and that uniform standards for data disclosure should apply to all entities conducting human clinical trials, whether publicly or privately funded. In addition, a number of process issues need to be addressed, as follows:

  1. Process for Selection of Uniform Standards

  2. Balanced Process for Determining What Information Should Be Protected

  3. Mechanism to Ensure Compliance and Protect Against Promotion of Unauthorized Use of a Drug in Registry Postings

  4. Responsibility for Developing and Managing the Registry

PROCESS FOR SELECTION OF UNIFORM STANDARDS

Uniform standards are needed for the following:

  • Define what clinical trials would be posted at inception.

  • Define the required data fields to be posted when a clinical trial is initiated.

  • Define what clinical trial results information will be posted to a registry for completed clinical trials.



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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary 5 Implementation Issues The various proposals for creating a clinical trial registry agree that such a registry is needed on the national or international level to benefit public health. They agree on most of the specific elements and that uniform standards for data disclosure should apply to all entities conducting human clinical trials, whether publicly or privately funded. In addition, a number of process issues need to be addressed, as follows: Process for Selection of Uniform Standards Balanced Process for Determining What Information Should Be Protected Mechanism to Ensure Compliance and Protect Against Promotion of Unauthorized Use of a Drug in Registry Postings Responsibility for Developing and Managing the Registry PROCESS FOR SELECTION OF UNIFORM STANDARDS Uniform standards are needed for the following: Define what clinical trials would be posted at inception. Define the required data fields to be posted when a clinical trial is initiated. Define what clinical trial results information will be posted to a registry for completed clinical trials.

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary Such standards should apply to public and private funders of research and should provide a uniform template for presentation of results (e.g., the ICH E3 template—currently utilized globally to summarize results for global regulatory agencies). Much of Chapter 4 of this report documented discussions aimed toward reaching a common understanding of what those standards should be. BALANCED PROCESS FOR DETERMINING WHAT INFORMATION SHOULD BE PROTECTED A process to protect confidential and proprietary research, yet provide a mechanism for public disclosure as needed, already exists and is familiar to the U.S. Department of Health and Human Services in the area of public health information disclosures—the Freedom of Information Act (FOIA). FOIA exemptions for commercial information and trade secrets, and the consequent process for adjudication, potentially could be adapted for a clinical trial registry. Confidentiality protections are the cornerstone of the National Institutes of Health (NIH) grant submission process. Pending NIH grant applications and unfunded new and competing continuations and competing supplemental applications are withheld, as is “information which, if released, would adversely affect the competitive position of the person or organization.” These rules govern NIH basic and clinical research, including clinical trials. For reasons similar to those motivating the need to create broad clinical trial registries, FOIA was created in 1966 to give the public expansive access to the records and information in the possession and control of U.S. government agencies. There is a clear public interest in allowing the public access to this information, supported by many of the same reasons cited in support of mandatory clinical trial registries. However, Congress realized that the data in the government’s possession will, in a minority of cases, be very sensitive, and if forcibly made public, could create powerful disincentives for investigators or industry to innovate or share important information with the government. For this reason, Congress created some exemptions from forced disclosure of information in the government’s possession, but also created a process to guard against abuses. In most situations, the research entity will not be harmed by disclosing primary and secondary endpoints at the initiation of the clinical trial.

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary However, when there is no patent or no data package exclusivity or where a research entity is conducting research in a novel area subject to intense competition, then some of the research data of the innovator will need to be protected. This protection will need to be similar to the mechanism FOIA uses to regulate the protection of data included in New Drug Applications submitted to the Food and Drug Administration (FDA) or in grant proposals submitted to NIH. Some of the FOIA definitions and parts of the process might be applicable to the registry context, especially if a central registry is created and managed by a federal government entity such as the National Library of Medicine (NLM), which manages ClinicalTrials.gov. The utility and practicality of using FOIA in relation to the clinical trial registry needs further discussion. Comments on Balanced Process for Determining What Information Should Be Protected Jeanne Ireland, Director of Public Policy for the Elizabeth Glaser Pediatric AIDS Foundation, commented, “I’m no FOIA expert so I can’t comment too specifically, but I would say it does seem useful to build on an existing process so that there is clarity both on the part of the trial sponsors and on the part of the patients.” Dr. Deborah Zarin, Director of Clinical Trials.gov for NLM’s Lister Hill National Center for Biomedical Communications, stated that NLM did look into the FOIA issue. But rather than having the research sponsor enter the data in the fields, which would then have to be withheld from the public, NLM considered getting the protocol, keeping it in a non-public file, and having the fields filled in by the sponsor when they were ready. NLM would always have a way of saying “yes that’s consistent with the initial protocol” or “no it’s not.” But Dr. Zarin has not been able to get a clear reading as to whether those protocols could be obtained through FOIA until there is a test case. “There’s a fair amount of uncertainty about how that would work and what would actually happen.” Gail Cassell, Vice President of Scientific Affairs of Eli Lilly and a member of the Board on Health Sciences Policy (HSP), noted that in publicly funded research, it is common for proprietary information—not just intellectual property information—to be protected. The Freedom of Information Act system has been in place for nearly two decades and has

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary “worked effectively in favor of the public who funds that research,” she noted. MECHANISMS TO ENSURE COMPLIANCE AND PROTECT AGAINST PROMOTION OF UNAUTHORIZED USE OF A DRUG IN REGISTRY POSTINGS A purely voluntary system would not protect against the selective disclosures objected to in the past. Therefore it seems evident that a deterrent is needed to protect against failure to post required clinical trial information to a central registry and against promoting unauthorized uses of a drug in the registry. Mechanisms to ensure compliance are necessary to maintain the integrity and reliability of the clinical trial registry. Possible mechanisms include: Institutional Review Board (IRB) Checkpoint Posting to a central registry such as ClinicalTrials.gov could be made a condition of approval by the IRB. In such a case, the failure to post a clinical trial at inception would result in the inability of the study to begin because IRB approval is required for patient enrollment. Broader Role for FDA Audits To ensure that completed trial results are disclosed, the manager of the database could periodically audit the results data posted against the information that was posted when a clinical trial was initiated. Remedial Action: A Tiered Approach One approach that might provide an effective deterrent against real abuses but not penalize inadvertent missed disclosures would be to adopt a tiered approach to remedial action. In such a system, if noncompliance were found, the database manager for the registry could send a warning letter to the sponsor. This is the procedure that the FDA’s Division of Drug Marketing, Advertising, and Communications (DDMAC) currently follows for perceived violations of the agency’s rules on promotion of marketing and advertising of pharmaceuticals. As with DDMAC, the database manager would give the entity in noncompliance a

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary defined period of time to rectify the posting omission. If, for example, after 30 days the entity responsible for posting to the registry continues to be noncompliant, the warning letter could be turned into a public notice of noncompliance (i.e., a kind of “scarlet letter”) by posting it on the registry. If the entity responsible for posting the data still fails to do so, then the database manager could turn to the Department of Justice to negotiate a Consent decree, again like the process currently used by DDMAC. The New York Attorney General recently used the same mechanism in several high-profile cases involving the pharmaceutical and other industries. Of course, failure to register the clinical trial would also likely preclude publication of the data in a leading medical journal. The advantage of adopting this tiered approach to ensuring registry compliance is that it, like the FOIA application, builds on already existing and successful processes. Certainly the process used by the FDA to protect the public against violation of the agency’s promotional rules should be adequate to protect the integrity of a central clinical trial registry. Any remedial actions that would go beyond those used by DDMAC in its regulation of pharmaceutical advertising would likely be excessive. On the same note, a middle-tier step—between the notice of noncompliance and the costly and more severe move of turning to the Department of Justice—may be advisable. These suggestions are for compliance mechanisms in the United States. Assuring compliance for a global registry would pose a more daunting challenge. The FDA’s Role in Preventing Promotion of Unauthorized Use of a Drug No new processes need be created to guard against attempts to post registry information for purposes of promoting unauthorized uses of a drug by the drug’s manufacturer or marketer. Nor does the database manager for the registry need to be accountable for this oversight. The FDA’s DDMAC already is required by law to perform this duty. DDMAC authority extends to all attempts by drug sponsors to promote their products. Registry postings are legally no different from dissemination of marketing detail pieces in terms of whether DDMAC can regulate

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary them for off-label promotion. In fact, the FDA participants in these Institute of Medicine registry discussions confirmed that DDMAC has and will use this authority when registries are implemented. However, regulations outside the United States would need to be considered to ensure protection against commercialization on a global basis. Comments on Mechanisms to Ensure Compliance and Protect Against Promotion of Unauthorized Use of a Drug in Registry Postings Dr. Alan Breier, Vice President, Medical and Chief Medical Officer of Eli Lilly and Company, suggested two ways to ensure compliance while protecting proprietary information: (1) The study protocol and related amendments could be placed in a secure repository managed by an independent third party and the study summary could be matched to the protocol; or (2) in a slightly less complicated approach, study initiation templates could be used, such as an ICH E3 template, with confidential fields for proprietary information that become automatically available to the public when the drug is approved. “Let’s enter all of the important methodology at the initiation of the trial. We could then blind certain key proprietary fields, but the information is there. When the drug is then on the market and that important prescribing decision has to be made, it’s automatically unblinded. Then you’ve got all the methodology. You’ve then got the result piece that you amend to its methodology all on the same template,” Dr. Breier explained. Dr. Alfred Sandrock, Vice President, Medical Research-Neurology for Biogen Idec, added that the scientists in his company want to publish in the top journals in the world, a move that he believes is incentive enough to be as compliant as possible. In terms of making sure that all the fields are properly filled out, the National Library of Medicine has staff who check the ClinicalTrials.gov database to make sure all the fields are appropriately entered. Many companies have staff who have been trained to do this and to interface with the NLM staff. That model is workable. The strong incentive of wanting to publish in the top journals is enough incentive to register completely and honestly. Regarding an IRB checkpoint, Ms. Ireland stated that conditioning IRB approval on registration of a trial was a useful approach. She suggested that the IRBs not play an enforcement role. Rather, they would act

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary as a checkpoint, notifying whatever agency is playing the enforcement role, if a trial about to start is not registered. Dr. Marjorie Speers, Executive Director of the Association for the Accreditation of Human Research Protection Programs, noted that IRBs already feel overburdened and that she would be very cautious about having them assume this role. She also predicted redundancy in the case of multisite studies with multiple IRBs. John Schneider, Chair of the Council on Scientific Affairs of the American Medical Association, stated that using IRBs makes sense if their only job is to look for a unique identifier, indicating the trial has been registered. If it’s not there, the IRBs bounce it back. Dr. Breier echoed his statement. Suanna Bruinooge, representing the American Society of Clinical Oncology, suggested that planners contact some IRBs to further discuss feasibility. Dr. P.Pearl O’Rourke, Director of Human Research Affairs at Partners HealthCare System, Inc., stated that IRBs will need more clarity about what trials are included before signing on as a decision node. Several participants asked whether the FDA should be given a stronger role in a clinical trial registry. Ms. Ireland suggested that the FDA become part of the approval checkpoints. Could the FDA be given an auditing function to ensure veracity, if additional resources were provided? Dr. Speers added that registration should be a requirement to get an IND from the FDA. Sharon Terry, President and Chief Executive Officer of Genetic Alliance, noted that the FDA should have greater oversight. She was striving to show the benefit for industry. Perhaps by registering, industry would have an easier time with FDA processes. Sue Levi-Pearl, with the Tourette Syndrome Association, asked whether the FDA should play a critical role in the development of such a broad-based clinical database because the FDA has all the data, which are often proprietary. HSP Board Member Lynn Goldman of the Johns Hopkins Bloomberg School of Public Health noted that much of this information is submitted to the FDA. Much more goes to the FDA than would ever be on a registry. Could there be efficiency in having a component of what is submitted to the FDA transferred to a clinical trial registry? William Vaughan of Consumers Union submitted the following comment: “We believe that the FDA needs a number of additional au-

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary thorities and resources to give more emphasis to safety in the process of pre- and post-market approval of pharmaceuticals.” Regarding audits, Dr. Breier stated: “We’ve got to be able to audit posting commitments as well as accuracy, objectivity of summaries. Who will do it and how? And who will pay for it? It will be a very large task. What are the implications for compliance lapses? How are we going to put some teeth into the compliance checking?” Dr. Zarin described a pilot study going on at ClinicalTrials.gov in which staff are trying to reach IRB contacts and health authorities for non-U.S. trials to try to understand how much help they can provide in verifying that they, in fact, approve a trial in question, and whether they could actually verify more detailed information because the IRB has seen the protocol. She also noted that avoiding duplications is a big task, as is updating, for example, recruitment status. Ms. Ireland called for “reasonable financial penalties” for those who do not comply. Ms. Terry asked if there were a way to “incentivize” compliance. Lindsey Johnson from U.S. PIRG said that a “scarlet letter” for those who do not comply is not enough. “We need penalties that will resonate with the public, if we expect the public to trust the database.” RESPONSIBILITY FOR DEVELOPING AND MANAGING THE REGISTRY Different workshop participants suggested that a national registry might be managed by either a nonprofit organization or a trusted government agency. Expansion of the National Library of Medicine’s responsibility for ClinicalTrials.gov to include more trials and more information might be a logical way to build on existing programs. It was also noted that the FDA has some of the data that would be needed by a clinical trial registry.