fb tracking

Withholding Information on Unapproved Drug Marketing Applications: The Public Has a Right to Know

Health Letter, February 2018

By Sammy Almashat, M.D., M.P.H., and Michael Carome, M.D.

Note: This article was originally published, as it appears here, in the Journal of Law, Medicine & Ethics [J Law Med Ethics. 2017;45(2_suppl):46-49.]. View the abstract of the article on the publisher’s website (here).

The U.S. Food and Drug Administration (FDA) is a critical public health agency that regulates drugs, medical devices, food, cosmetics, and tobacco products, which together amount to one-fifth of all U.S. economic activity.[1] However, much of the information upon which the agency relies when making pivotal regulatory decisions with regard to such products is withheld from the public.

One prominent example of the FDA’s lack of transparency that has gained increasing attention in recent years concerns new drug applications (NDAs), including supplemental NDAs, that have been rejected by the agency or withdrawn by the company. The FDA’s long-standing policy is that it does not release its analyses of data submitted for such applications or disclose agency complete response letters (CRLs) notifying drug manufacturers of the non-approval decisions and the reasons for such actions, nor does the agency even notify the public that such rejections or withdrawals have occurred.[2] If a company abandons or withdraws a drug marketing application before the FDA takes action on it, the FDA is technically required by law to disclose the safety and efficacy information in the application “upon request,”[3] but the agency does not disclose the existence of such withdrawn or abandoned applications,[4] which effectively renders moot this legal obligation.

By contrast, the FDA routinely releases to the public its detailed analyses and findings related to data supporting the approval of a drug’s first NDA and, upon request by at least three individuals, of supplemental NDAs for new uses of already marketed drugs.[5]

Need for, and Benefits of, Increased Transparency on Unapproved Drug Marketing Applications

The recent report Blueprint for Transparency at the U.S. Food and Drug Administration (hereafter referred to as “Blueprint report”) highlights this issue, among other FDA transparency concerns.[6] This report builds on the work of the FDA’s 2010 Transparency Task Force, which made a number of recommendations to the agency, one of which was to release CRLs to shed light on why drug marketing applications were refused.[7]

The Blueprint report noted several potential benefits from releasing such information, including that “the clinical community can benefit from the insight, expertise, and analyses of FDA reviewers, and researchers can learn from the failures of previous medical products in subsequent research programs.”[8]

As detailed in the second focus area of the report, keeping the public in the dark about unapproved drug marketing applications prevents patients, researchers, and healthcare providers from gaining insight into why a drug’s application was not approved.[9] This lack of transparency is particularly troubling in cases where the FDA has found a currently marketed drug to be ineffective or unsafe for a newly proposed indication. Disclosure of the FDA’s findings in such cases would promote public health by encouraging healthcare providers to avoid prescribing drugs for unapproved (off-label) uses that the agency has deemed to be potentially dangerous or ineffective. This is especially important given the endemic practice within the pharmaceutical industry of illegally marketing drugs for off-label uses.[10]

Disclosure of CRLs is all the more important given the current permissive framework allowing the promotion of already marketed drugs for unapproved uses. Existing FDA guidance already permits drug and medical device manufacturers to market their products to physicians for unapproved uses through the dissemination of scientific or medical journal articles and reference publications.[11] The Medical Product Communications Act of 2017, which was introduced in the U.S. House of Representatives,[12] would further expand the scope of and permitted venues for off-label promotion while prohibiting the FDA from considering such off-label marketing activities as evidence of a manufacturer’s “intended uses” for a drug or medical device. Such erosions of restrictions on off-label marketing make it vital that healthcare professionals be informed of off-label uses that were deemed by the FDA to be too dangerous or ineffective for patients.

Failing to provide information on unapproved NDAs also gives companies free rein to craft their own self-serving narratives as to why their product applications were turned down. A 2015 study by FDA researchers compared 61 of the FDA’s CRLs issued to companies with the companies’ press releases announcing the failed marketing applications.[13] Unsurprisingly, the study found that in 11 (18%) of the 61 CRLs, com-panies did not issue a press release, and in 13 others (21%), the press release contained no information from the CRLs. Disturbingly, only 16% of the statements related to efficacy concerns and only 15% of the statements about safety concerns across all of the FDA CRLs were disclosed in the companies’ press releases. Disclosing all CRLs would allow the public, healthcare professionals, and other interested stakeholders access to an unbiased rendering of the reasons for the FDA’s rejection of a drug marketing application.

Finally, a new policy of transparency whereby the FDA discloses the existence of, and data related to, rejected applications for new drugs and new indications for already approved drugs also would be consistent with the Belmont Report’s basic ethical principle of beneficence governing human subjects research.[14] The beneficence principle establishes an ethical obligation to minimize possible harms and maximize potential benefits. In the event that a drug marketing application is rejected because the FDA determines that the drug’s harms outweigh its benefits for a particular use, both the drug company and the FDA have an ethical obligation to make this determination public in order to avoid future clinical trials of the drug (or, in some cases, a similar drug in the same class) that would unnecessarily expose human subjects to harm. Other drugmakers can avoid such clinical trials only if they are made aware of all previous clinical trial data in a timely manner. Unfortunately, the medical literature is not a comprehensive or accurate source of such data.[15]

Feasibility: The FDA Should Follow Europe’s and Canada’s Lead

A policy whereby the FDA releases CRLs and the underlying analyses leading to the agency’s decision not to approve a drugmaker’s application is certainly feasible. In 2004, the European Union (EU) required that the European Medicines Agency (EMA) make publicly accessible “information about all refusals [of human drug marketing applications] and the reasons for them.”[16] The same EU law also stipulated[17] that for all drug applications withdrawn by the sponsor before the EMA has issued a decision on the application, the agency must publish public assessment reports containing the agency’s analyses and conclusions related to the clinical data in the applications.[18] In the latter case, the law made clear that such disclosures can only occur after the EMA removes all “commercially confidential” information from the public assessment reports of the withdrawn marketing applications. One can now search the EMA’s website for all public assessment reports, with specific searches available for drugs that have been refused marketing authorization or that have been suspended or withdrawn after approval.[19]

Health Canada followed suit in 2015 when it announced that it would make available to the public all regulatory decision summaries, which contain the rationale for the agency’s decisions on drug marketing applications.[20] This decision notably included, for public release, “final negative decisions and cancellations” for all marketing applications for new drugs and new indications for existing drugs.[21] Similar to the European procedure, all regulatory decision summaries are now publicly searchable on Health Canada’s website.[22]

Thus, there exist one national and one multinational model of regulatory transparency to which the FDA can look for guidance should it choose to follow its sister agencies’ lead by allowing the American public to, for the first time, learn when the FDA rejects a drug’s marketing application and why it has done so.

Industry Argument Fails to Convince

To justify keeping the American public and healthcare providers in the dark about the FDA’s rejections of drug marketing applications, the pharmaceutical industry primarily has argued that disclosing such actions would reveal confidential commercial data and give other companies a competitive advantage. There are several reasons for rejecting this argument. First, a rejection by the FDA often occurs in parallel with a rejection by European or Canadian regulatory authorities, meaning that the failed marketing appli-cation and the reasons for the failure likely would become public knowledge anyway.

Second, although public disclosure of the FDA’s rejection of one company’s marketing application may allow competing companies to reap some monetary benefits by recalibrating similar research and development efforts, there is reason to believe that such disclosures would be economically advantageous to the industry in the aggregate. As the FDA’s Transparency Task Force pointed out in its 2010 report, disclosure of failed drug applications would allow other companies to more efficiently invest research monies into potentially more promising therapies.[23] Most companies eventually should benefit from such transparency.

Third, and most importantly, the current reality — in which companies remain unaware of a competitor’s rejected drug marketing application for a similar product or use and, as a result, continue to invest research dollars and to expose human research subjects to potential harm in clinical trials that are likely to be futile — is unacceptable from both a public health and an ethical perspective.

Right to Know

The FDA must join the EMA and Health Canada in allowing the public to know when a drug is deemed unsafe or ineffective for a certain use. Even not withstanding the public health benefits that disclosure of such information would reap, the public has a right to know when, how, and why the nation’s largest public health agency reaches major decisions on the products it regulates. What former FDA Commissioner Dr. Donald Kennedy noted in 1978 still holds true: “Governmental decisions, particularly regulatory decisions, should be based on publicly available information … This premise underlies the Freedom of Information Act, the Federal Advisory Committee Act, and the Government in the Sunshine Act. In enacting each of these statutes, the Congress implemented a basic principle of our political system: that people affected by governmental decisions have a right to know the basis on which they are made. Anyone who questions the wisdom of a regulatory decision should be able to examine the factual foundation of the decision.”[24]


[1] U.S. Food and Drug Administration, “Consumer Expenditure on FDA Regulated Products: 20 Cents of Every Dollar,” available at <https://blogs.fda.gov/fdavoice/index.php/2016/11/ consumer-expenditure-on-fda-regulated-products-20-cents-of-every-dollar/> (last visited November 9, 2017).

[2] 21 C.F.R. 314.430 (c) and (b).

[3] 21 U.S.C. §355(l)(1).

[4] FDA Transparency Working Group, Blueprint for Transparency at the U.S. Food and Drug Administration, March 13, 2017, available at <https://www.jhsph.edu/departments/health-policy-and-management/_pdf/FDA_Transparency.pdf> (last visited November 9, 2017). Also published in JLME 45, no. 4, Suppl. (2017) (hereinafter cited as Blueprint).

[5] 21 U.S.C. §355(l)(2).

[6] See Blueprint, supra note 4.

[7] U.S. Food and Drug Administration, Transparency Task Force, FDA Transparency Initiative: Draft Proposals for Public Comment Regarding Disclosure Policies of the U.S. Food and Drug Administration, May 2010, available at <https://wayback.archive-it.org/7993/20161022134022/http:/www.fda.gov/downloads/AboutFDA/Transparency/PublicDisclosure/GlossaryofAcronymsandAbbreviations/UCM212110.pdf> (last visited November 9, 2017).

[8] See Blueprint, supra note 4.

[9] Id.

[10] From 1991 through 2015, a total of 373 settlements were reached between the federal and state governments and pharmaceutical manufacturers, for a total of $35.7 billion. The unlawful promotion of drugs, mostly off-label marketing, was the single violation that resulted in the largest financial penalties. See: Public Citizen, “Twenty-Five Years of Pharmaceutical Industry Criminal and Civil Penalties: 1991 through 2015,” March 31, 2016, available at <https://www.citizen.org/our-work/health-and-safety/twenty-five-years-pharmaceutical-industry-criminal-and-civil-penalties-1991-through-2015> (last visited November 9, 2017).

[11] Food and Drug Administration, “Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices, January 2009, available at <https://www.fda.gov/RegulatoryInformation/Guidances/ucm125126.htm> (last visited November 9, 2017).

[12] H.R.1703 – Medical Product Communications Act of 2017. Introduced March 23, 2017, available at <https://www.congress.gov/bill/115th-congress/house-bill/1703/text> (last visited November 9, 2017).

[13] P. Lurie, H. S. Chahal, D. W. Sigelman, S. Stacy, J. Sclar, and B. Ddamulira, “Comparison of Content of FDA Letters Not Approving Applications for New Drugs and Associated Public Announcements from Sponsors: Cross Sectional Study,” BMJ 350 (2015): h2758.

[14] Department of Health Education and Welfare, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (April 18, 1979), available at <https://www.hhs.gov/ ohrp/regulations-and-policy/belmont-report/> (last visited November 9, 2017).

[15] E. H. Turner, A. M. Matthews, E. Linardatos, et al., “Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy,” New England Journal of Medicine 358, no. 3 (2008): 252-260; A. M. Roest, P. de Jonge, C. D. Williams, et al., “Reporting Bias in Clinical Trials Investigating the Efficacy of Second-Generation Antidepressants in the Treatment of Anxiety Disorders: A Report of 2 Meta-analyses,” JAMA Psychiatry 72, no. 5 (2015): 500-510.

[16] Official Journal of the European Union, Regulation (EC) No 726/2004 of the European Parliament and of the Council, at Article 12(3), available at <https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2004_726/reg_2004_726_en.pdf> (last visited November 9, 2017).

[17] Id., at Article 11.

[18] European Medicines Agency, European Public Assessment Reports: Background and Context, available at <http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/general/general_content_000433.jsp&mid=WC0b01ac058067fa25> (last visited November 9, 2017).

[19] European Medicines Agency, European Public Assessment Reports, available at <http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d125> (last visited November 9, 2017).

[20] Health Canada, Notice: Regulatory Decision Summaries and Submissions under Review, March 13, 2015, available at <http://www.hc-sc.gc.ca/dhp-mps/prodpharma/rds-sdr/drug-med/rds-sur-notice-phasei-avis-sdr-pce-eng.php> (last visited November 9, 2017).

[21] Id.

[22] Health Canada, “The Drug and Health Product Register,” available at <https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary.php> (last visited November 9, 2017).

[23] U.S. Food and Drug Administration, Transparency Task Force, FDA Transparency Initiative: Draft Proposals for Public Comment Regarding Disclosure Policies of the U.S. Food and Drug Administration (May 2010), available at <https://wayback.archive-it.org/7993/20161022134022/http:/www.fda.gov/downloads/AboutFDA/Transparency/PublicDisclosure/GlossaryofAcronymsandAbbreviations/UCM212110.pdf> (last visited November 9, 2017).

[24] Id.