Stop False Reporting of Drug Benefits & Harms by Making FDA & NIH Work Together
Stop False Reporting of Drug Benefits & Harms by Making FDA & NIH Work Together
Your life may be in danger because the drug industry and medical device makers are allowed to make false claims about their products in medical journals—and the US Food and Drug Administration and National Institutes of Health aren’t doing anything about it.
Americans and their doctors depend on the Food and Drug Administration (FDA) and the National Institutes of Health (NIH) to make sure that scientific information about drugs and medical devices is accurate and openly available. Doctors look to the medical journals, where research about drugs and devices is published, so they can use those products in the safest and most effective way to improve the lives of their patients.
But there are major flaws in this system that threaten the health and safety of us all – flaws that can and must be fixed. All too often, information published in medical journals is misleading, exaggerated, or flat-out wrong because of a loophole in FDA and NIH regulation. This loophole allows drug and device makers to distort their published scientific results, which they do routinely in order to market their products to doctors. And patients are seriously harmed as a result.
This petition (below) calls on Congress to close that loophole, by requiring the FDA and the NIH to strengthen and coordinate their monitoring of the information that corporations submit about their products. This would allow medical journals for the first time to weed out deceptive analyses by drug and device makers. It would also allow others to check how well the medical journals did their job.
This petition asks Congress to require the U.S. Food and Drug Administration (FDA) and the National Institutes of Health (NIH) to coordinate so as to prevent misreporting of clinical trials.
It is by now no secret that medical journals often publish biased reports of clinical trials funded by industry. These biased reports exaggerate benefits and minimize harms of new medical products (drugs and medical devices). Corporations succeed in this practice by sending different information and statistical analyses to the NIH than what they sent to the FDA. Medical journals, which rely on NIH data, have no way to detect these discrepancies. Both the FDA and the NIH know that this happens, but they do nothing, so the misleading claims escape regulation. We aim to close this loophole.
SPECIFIC STEPS TO RECONCILE FDA DATA AND NIH DATA
Trials Registration: Our petition first asks Congress to require coordination between FDA and NIH in the registration of clinical trials. Already, these must be pre-registered with the FDA and with the NIH (through the NIH public site called ClinicalTrials.gov). The second of those steps is often ignored or delayed. We ask Congress to require posting of the study protocol and detailed plan of statistical analysis with ClinicalTrials.gov at the time of registration with the FDA (current rules for the NIH site allow a delay of 1-3 years beyond the date of final data collection). The key elements of trials registration are to declare the a priori study protocol and the a priori statistical analysis plan before the study actually begins. That includes specification in advance of the primary and secondary outcome measures by which efficacy and safety will be assessed. Any other outcome measures must be clearly labeled as exploratory or non-protocol. The FDA then shall post a notice on ClinicalTrials.gov confirming or disconfirming that the a priori protocols and plans of analysis registered at both sites are identical.
Reporting Results: We also ask Congress to require timely publication of trials results on the NIH site and certification by the FDA that the information placed on the public NIH site agrees with the results that the FDA itself reviewed. Congress shall require that the FDA shall (i) post the FDA's analyses on ClinicalTrials.gov as soon as the product is approved or disapproved for the requested indication; (ii) verify by notice whether corporate analyses reported on the NIH site are consistent with the a priori registered statistical analysis plan; (iii) verify by notice whether Results posted on ClinicalTrials.gov are concordant with Results determined by the FDA review; (iv) post on ClinicalTrials.gov a notice of any requested follow-up Phase 4 trial; (v) notify both the responsible party and ClinicalTrials.gov if the FDA determines that any corporate information placed on ClinicalTrials.gov conflicts with the data on file at the FDA; and (vi) notify both the responsible party and ClinicalTrials.gov if the FDA determines that any requested Phase 4 trial was not registered on ClinicalTrials.gov. Any publication or presentation or brochure or press release shall be required to display links to the trial’s registration on ClinicalTrials.gov and to any applicable FDA notices.
Expected Benefit: This petition requires both the FDA and NIH to meet their obligation to protect the public safety through genuine coordination of their joint oversight responsibilities. When FDA and NIH coordinate in these ways, then editors and reviewers at medical journals, and other stakeholders, can verify the fidelity of reported protocols and analyses. These provisions will allow stakeholders to determine whether any secondary analyses that use modified data sets or that address unplanned secondary questions have been properly identified.
These steps will prevent the widespread manipulation of in-house corporate statistical analyses that are the basis for misleading reports in the medical journals. Positive analyses based on the a priori protocol and statistical analysis plan may be clinically actionable, as determined by the FDA. However, positive in-house corporate statistical analyses based on modified outcome measures or protocol changes cannot be regarded as clinically actionable, even though that is implied in medical journal reports, e.g., for off-label us es and unapproved patient groups such as children. These changes will for the first time allow stakeholders to recognize such claims for what they are.
The complete text of this petition appears below, with full documentation of the statements made in this Executive Summary. You may sign the petition now or proceed to read the full petition. This petition is presented by the Science and Evidence Council of the Right Care Alliance. For information about the Right Care Alliance, go to www.rightcarealliance.org. Thank you for your interest!
PETITION TO CONGRESS: TRUTH IN RESEARCH LABELING
This petition builds upon the Final Rule issued September 16, 2016 by the U.S. Department of Health and Human Services (HHS) (1) and by NIH (2). The Final Rule aims to improve transparency by strengthening the compliance, surveillance, and enforcement of regulations for reporting clinical trials results. This petition addresses a serious remaining loophole – the lack of coordination between the FDA and NIH – which permits a lack of concordance or fidelity between information obtained by the two agencies. That loophole has permitted serious misrepresentations of clinical trials reporting in peer reviewed medical journals, to the detriment of public stakeholders.
The FDA regulates commercial claims made for new medical products but it does not regulate scientific claims made by sponsoring corporations in peer reviewed academic publications and elsewhere. NIH, meanwhile, is responsible for the public register of clinical trials named ClinicalTrials.gov (3). However, compliance with registration and reporting has been inconsistent, with no serious enforcement by NIH (4, 5), and the FDA does not monitor the information placed on ClinicalTrials.gov for fidelity to the FDA’s data base. This weak oversight by two Federal agencies, and their lack of coordination, has led over time to a high frequency of misleading scientific reports in medical journals (6-8). Both NIH and the FDA are aware of these problems but they take no action (4, 9).
This petition does not address the more general issue of bias and fraud in scientific publishing. The focus here is on the fidelity of commercially sponsored reporting and claims made primarily in medical journals for clinical trials that by law involve the FDA.
The unregulated and misleading corporate claims made in medical journals affect a wide range of stakeholders. These include:
· Editors and reviewers at medical journals: as explained below, editors and reviewers are currently unable to perform effective peer review of corporate clinical trials reports.
· Prescribing clinicians: physicians, nurse practitioners, physician assistants rely on these academic publications, directly and indirectly, for professional guidance. They require accurate and complete information on established efficacy for on-label uses or off-label uses, and on comparative effectiveness (how does an expensive new drug match up against a less costly older drug that they already have experience with, regarding efficacy, side effects, and tolerability?). The FDA does not monitor the quality of information published in medical journals on these essential questions.
· Professional organizations likewise rely on these publications when compiling clinical treatment guidelines for their members.
· Patients, in turn, rely on clinicians and the professional organizations for assurance that their treatment is consistent with best practice guidelines.
· Patients, in this information age, also rely increasingly on these academic publications for information in order to share decision making about treatment options with their clinicians.
· Patients exposed off-label to unapproved products for which the efficacy and safety evaluations are substandard, even though positive scientific claims were made in medical journals for off-label indications, are at above-normal risk of suffering adverse events.
· Pharmacy benefit managers and formulary managers give weight to the information and scientific claims made in these academic publications.
· Third-party payers, both Federal and private, likewise give weight to these academic publications for decisions on cost containment, budget planning, and setting premiums, which in turn affects patients and employers.
· Capital investors give serious weight to these publications when deciding on investment opportunities, initial public offerings, and start-up support for new enterprises.
· Financial advisors and financial journalists likewise rely on these publications when evaluating the prospects of medical product manufacturers.
· Basic biomedical scientists, especially those working in translational medicine, rely on the validity of these questionable publications in shaping new research programs for drug discovery.
In all these cases, bad information in the academic publications leads to bad decisions, bad outcomes, and misdirection of public and private financial resources.
Current Requirements are Flouted with Impunity
Beyond exploratory Phase 1 human studies, all clinical trials of drugs or medical devices in the U.S. must register in advance and must report results on ClinicalTrials.gov. Trials that aim to support a planned New Drug Application (NDA) or a Pre-Market Approval (PMA) for devices must be registered as well with the FDA. Registration is expected in advance of subject enrollment, and before any subjects have been assigned to the active drug group or to a comparison group (placebo or comparator drug).
Registration with the FDA includes advance or a priori specification of the protocol and of the plan of analysis. The plan of analysis specifies the primary and secondary end points in the trial by which efficacy and safety will be judged, as well as the planned statistical techniques. All modifications of the a priori protocol and plan of analysis after the trial begins must be reported for NDA and PMA trials, and those changes must be approved by the FDA. These a priori declarations are the consensus scientific standard by which clinical trials results are evaluated for approval or disapproval by the FDA. However, the new Final Rule permits delay of this a priori specification on ClinicalTrials.gov until the time results are reported (1). We believe that provision of the Final Rule should be rejected. It is through such delays that discrepancies can arise between the FDA and NIH data bases, allowing for corporate in-house analyses reported in medical journals to deviate from the consensus scientific standard of a priori specification. Those changes are usually unknown to journal editors, reviewers, and readers and they are not monitored by the FDA.
Compliance with registration and reporting requirements for ClinicalTrials.gov has been poor, but NIH has little record of effective enforcement (4, 5). Many trials are registered late and, by one account, about half of the trials between 2008 and 2012 were never registered (4). Serious discrepancies also are commonly found between what was reported on ClinicalTrials.gov versus the peer-reviewed journal articles reporting the same studies (4, 10). In addition, even when the FDA requests follow-up Phase 4 trials for safety, those trials often are never registered on ClinicalTrials.gov because they are never conducted by the corporations. By one report (11), corporate sponsors completed FDA-requested Phase 4 clinical trials necessary for upgrading to regular approval in only six of twenty-three fast-track approvals of cancer drugs. The new Final Rule (1) does address those compliance and reporting problems.
Medical Journals Lack Oversight Capacity
Medical product corporations exploit this gap in oversight. The result is a major disconnect between the commercial claims that are regulated by the FDA and the unregulated scientific claims that corporations promote through medical journals. Eric Topol, MD, who helped to expose the Vioxx scandal (12), recently summarized the ongoing corporate manipulation and corruption of clinical trials reporting (13). Topol noted in particular that “… the disparity between what appears in peer reviewed journals and what has been filed with regulatory agencies is long standing and unacceptable.”
Thus, what appears in medical journals very often differs from the information registered either with the FDA or on ClinicalTrials.gov, but neither of these Federal agencies monitors reports in the journals. Journal editors and reviewers are unable properly to evaluate the corporate in-house analyses made in submitted manuscripts because they don’t see the FDA registrations and, even if a registration does appear on ClinicalTrials.gov, there is no guarantee that it matches the FDA registration (4). The journals see only the data that the corporations allow them to see. These disconnects prevent medical journals from performing effective peer review of corporate clinical trials reports.
Gaming the System
There have been several recent, detailed exposés of this widespread manipulation, which sometimes amounts to frank corporate malfeasance (14-18). Details of the deceptive practices are well described in several of these case studies (e.g., 15, 16, 18). These practices include changing primary endpoints, and introducing unplanned endpoints following preliminary analyses, which is known as HARKING – hypothesizing after results are known. Other practices are ignoring protocol violations to improve the outcome of statistical analyses; suppressing negative secondary analyses that were in fact specified in advance; failure to report prespecified subgroup analyses so as to avoid negative marketing implications; and post hoc reclassification of adverse events as more benign than they were reported. Indeed, these manipulations are now considered business as usual rather than isolated aberrations (19). These intensive case studies of manipulated analyses are confirmed by pooled information derived from FDA data. Turner and colleagues (10) compared published scientific claims made for antidepressant drugs against the original FDA files for the clinical trials of those drugs. A graphic display of their findings is shown here. By hiding negative data and by biasing the corporate analyses, the drugs’ profiles were made to appear more positive.
Most corporate publications in medical journals address secondary questions that the original clinical trials were not designed to answer, using biased in-house statistical analyses that neither the FDA nor any other external agency ever reviewed or approved. These unregulated secondary publications (20) are driven by the overall corporate publishing plan (16), and they offer scientific conclusions about product benefit, especially for off-label uses, that should not be considered actionable for clinical use. They are also highly profitable, though at a cost of FDA-documented harms (18). Newly published internal corporate documents released through litigation give a clear picture of the conscious manipulation that occurs (15). However, the intentional and self-serving corporate deviations from the a priori protocols and plans of analysis are seldom disclosed to stakeholders.
A Specific Proposal
We now petition Congress to require the FDA and NIH to coordinate their monitoring and sharing of key information through ClinicalTrials.gov. Working together, the two agencies could enable stakeholders to verify whether purported scientific claims are faithful to the a priori protocols and plans of analysis originally registered with the FDA. Publication of analyses for which such fidelity cannot be verified shall be prohibited unless the deviations are positively identified (as in openly declared unplanned, secondary analyses). This prohibition shall include scientific claims for on-label or off-label uses made in medical journals, archival conference abstracts, continuing education materials, brochures distributed by sales representatives, direct-to-consumer advertising, and press releases issued by companies or their academic partners. It shall extend to FDA Phase 2, Phase 3, and Phase 4 clinical trials. By acting on this petition, Congress will create a mechanism for stakeholders independently to verify whether inferences about clinical use suggested by the unregulated corporate statistical analyses can be trusted.
Execution of this proposal will require coordination between the FDA and ClinicalTrials.gov. The first requirement will be for posting of the study protocol and detailed plan of statistical analysis with ClinicalTrials.gov at the time of registration (unlike the current provision in the Final Rule). The FDA will already have that information for NDA and PMA trials. The FDA then shall (i) post a notice on ClinicalTrials.gov confirming or disconfirming that the a priori protocols and plans of analysis registered at both sites are identical, with a cross reference to the NDA or PMA identifier. At later times the FDA shall (ii) post the FDA’s analyses on ClinicalTrials.gov as soon as the product is approved or disapproved for the requested indication, also with a cross reference to the NDA or PMA identifier; (iii) verify by notice whether Results posted on ClinicalTrials.gov are concordant with Results determined by the FDA review; (iv) post on ClinicalTrials.gov a notice of any requested Phase 4 trial, also with a cross reference to the NDA or PMA identifier; (v) notify both the responsible party and ClinicalTrials.gov if the FDA determines that any corporate information placed on ClinicalTrials.gov conflicts with the data on file at the FDA; and (vi) notify both the responsible party and ClinicalTrials.gov if the FDA determines that any requested Phase 4 trial was not registered on ClinicalTrials.gov. Any publication or presentation or brochure or press release shall be required to display links to the trial’s registration on ClinicalTrials.gov and to any applicable FDA notices. Editors and reviewers at medical journals, and other stakeholders, can then link to ClinicalTrials.gov for verification of the protocols and analyses described. The above requirements shall apply to both primary and secondary analyses of the clinical trials. These provisions will allow stakeholders to determine whether any secondary analyses that use modified data sets or that address unplanned secondary questions have been properly identified.
Manuscripts describing any clinical trials that were not registered with the FDA must be registered on ClinicalTrials.gov in advance of enrolling patients, with complete information on the a priori protocol and plan of analysis, as well as any changes in the course of the trial. Journal editors shall reject submitted manuscripts that do not meet these requirements.
Reporting of Results has been comprehensively addressed in the new Final Rule document (1). We urge an explicit provision that Results be posted on ClinicalTrials.gov at the time of any submission for publication, even where the Final Rule allows delay up to 3 years for unapproved products “if the sponsor certifies that it intends to continue development of the drug, biologic or device product for initial approval by the FDA…” (1).
Reliance on in-house corporate analyses to support published scientific claims is no longer acceptable because of the extensive evidence, reviewed above, that such analyses are manipulated. We cannot justify treating the production of scientific publications in medical journals any differently than we treat the production of medical devices and potent drugs. Our FDA continuously monitors drug and medical device production facilities for evidence of physical adulteration or quality defects. Nobody takes the corporation’s word for the integrity of the product, yet, because of lack of oversight by the FDA and NIH, adulterated in-house corporate analyses that appear in medical journals have wide currency with clinician prescribers and other stakeholders under the erroneously assumed guarantee of peer review.
Medical product manufacturers might claim relief from this proposal under the First Amendment. However, that constitutional provision does not permit scientific claims that the corporate officers or their academic consultants know or should know are invalid or deceptive. Likewise, the claim that those corporate analyses and reports in medical journals need not be regulated because they undergo peer review must be rejected: peer reviewers for medical journals don’t see all the real data – they see only the data the corporation wants them to see. Peer review is not certification, as the flood of contemporary retractions attests (21). Only the FDA has access to all the data to permit verification. Under this proposal, the key information needed for verification by stakeholders will become publicly accessible through ClinicalTrials.gov.
This proposal does not aim to stifle scientific creativity – secondary analyses of clinical trials are important for hypothesis generation that can lead to the next round of studies of a potentially promising product (19). Rather, this proposal aims to curb the misrepresentation of multiple unplanned or post hoc secondary analyses as clinically actionable. Nor does this proposal preempt the independent scientific functions of medical journals. Rather, by providing a means for external verification that submitted manuscripts are faithful to the a priori protocols and plans of analysis, this proposal frees the journals from an investigative duty for which they are not equipped and at which they regularly fail.
This petition complements other current initiatives for improving transparency in the reporting of clinical trials, notably the OpenTrialsFDA project organized by Erick Turner in the USA and Ben Goldacre in the U.K. (23). That project aims to extract past and future data from the FDA website so that Drug Approval Packages are more accessible. That development will dovetail well with our petition, which will ensure that, going forward, information placed on ClinicalTrials.gov is faithful to the FDA data base. The procedural changes we are requesting will increase the impact of the OpenTrialsFDA project.
This petition has two key elements: to mandate coordination between the FDA and NIH, and to ensure timely posting of protocols and statistical analysis plans on ClinicalTrials.gov.
The new HHS Final Rule on clinical trials reporting and transparency (1) addresses many significant deficiencies in the process, especially noncompliance with the rules for ClinicalTrials.gov. However, a serious loophole remains because of poor coordination between NIH and the FDA. That loophole has enabled a pervasive corruption of scientific reporting by commercial bias. A second critical component of this petition is the requirement for the trial sponsor to submit the a priori protocol and statistical analysis plan to ClinicalTrials.gov at the time of study registration, just as they do with the FDA. To delay that registration step until the time results are reported to ClinicalTrials.gov (as now sanctioned (1) in the Final Rule) is to invite a continuation of the misleading practices we have described.
External oversight is needed – the industry has demonstrated repeatedly that their own in-house analyses of clinical trials simply cannot be trusted (6-10, 13-20). The inherent conflict of interest is too great for Congress to ignore any longer, and the time for enforcement discretion is past. Allowing the FDA and NIH to continue the present neglect will only further compromise the science on which the many stakeholders depend. This kind of oversight is the basic reason we have an FDA and an NIH in the first place...
We are enclosing an addendum for possible use of the Congress with language for amending Section 801 of the Public Health Service Act (42 U.S.C. 282) to achieve the desired change.
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ADDENDUM TO PETITION, TRUTH IN RESEARCH LABELING
Needed Amendments to 2007 FDAAA Title VIII—Clinical Trial Databases
In general—Section 801 of the Public Health Service Act (42 U.S.C. 282) is amended by—
(1) Inserting after the period at the end of Sec. 801, subsection (j)(2)(A)(i) Expansion of Data Bank—
The Secretary shall also require the Director of NIH and Commissioner of the FDA to coordinate actions to certify that the clinical trial registry data bank, referred to in this subsection as the ‘registry data bank,’ contains the identical information, described under subsection (j)(2)(A)(ii) Content, as that which was submitted by the Responsible Party, as defined in subsection (j)(1)(A)(ix), to the FDA in support of the Responsible Party’s application for marketing approval of the new drug or device, subject to the provisions of subsection (j)(6) Limitation on Disclosure of Clinical Trial Information.
(2) Inserting after period at the end of Section 801, subsection (j)(3)(C)(iv) Certain Agreements—
(v) Discussion of the results of the trial at a scientific meeting or any other public or private forum, or publication in a scientific or academic journal or via brochure dissemination or via press release shall require disclosure by the author(s) to their respective audiences a) whether or not the reported results are based on a duly registered clinical trial and b) whether the reported results are based i) solely on the a priori or advance pre-specified primary analysis of Sec. 801(j)(A)(ii) Content, including primary and secondary outcomes, submitted in the Responsible Party’s application for marketing approval of the new drug or device, or ii) modification for post hoc exploratory analysis of this Content, or iii) some combination of b) i) and ii) together.
(3) Inserting after period at the end of Sec. 801, subsection (j)(7)(b)(1) Conforming Amendments, Prohibited Acts—
(4) Failure to submit to the clinical trials registry information identical to that which was submitted to the FDA in support of the Responsible Party’s application for marketing approval of the new drug or device, subject to the provisions of subsection (j)(6) Limitation on Disclosure of Clinical Trial Information, will be subject to delay by the FDA in processing the Responsible Party’s application for marketing approval of the new drug or device until the matter is resolved pursuant to the provisions of subsections (j)(5)(A)(i)-(iii) Coordination and Compliance, (j)(5)(B) Certification to accompany Drug, Biological Product, and Device Submissions, (j)(5)(D)(i)-(ii), Truthful Clinical Trial Information, and (j)(5)(E)(i)-(vi) Public Notices.
(5) Individual authors’ failure to disclose a) whether or not reported results are based on a duly registered clinical trial and b) whether the reported results are based i) solely on the a priori or advance statement of the pre-specified primary analysis of Sec. 801, subsection (j)(2)(A)(ii) Content, including primary and secondary outcomes, submitted in the Responsible Party’s application for marketing approval of the new drug or device, or ii) modification for post hoc exploratory analysis of this Content, or iii) some combination of b) i) and ii) together shall be subject to a civil monetary penalty of $10,000 per author violation with notification of the sponsor of the scientific meeting or any other public or private forum, or the editor of the scientific or academic journal that the violation had occurred and that the penalty was imposed.
(4) Inserting after the period at the end of Sec. 801(j)(1)(A) Definitions— (ix) The term “a priori or advance statement of pre-specified primary analysis of Sec. 801, subsection (j)(2)(A)(ii) Content, including primary and secondary outcomes,” means statement before blinding and before the study begins of pre-specified sample, measures and measurement end-points, and hypotheses relating to primary and secondary outcomes, and the statistical methods to be used in testing these hypotheses.
(x) The term “modification for post hoc exploratory analysis of the Sec. 801, subsection (j)(2)(A)(ii) Content, including primary and secondary outcomes,” means any deviation from any of the elements in the paragraph (ix) a priori or advance statement before blinding and before the study begins of pre-specified sample, measures, and measurement end-points, and hypotheses relating to primary and secondary outcomes, and the statistical methods to be used in testing these hypotheses.
Bernard J. Carroll, MBBS, PhD, FRCPsych. Professor and Chairman Emeritus, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC.
John H. Noble, Jr., Ph.D. Emeritus Professor, State University of New York at Buffalo.
John M. Nardo, MD. Assistant Professor, retired, Department of Psychiatry, Emory University, Atlanta, GA.