The U.S. Food and Drug Administration (FDA) traditionally has kept confidential significant amounts of information relevant to the approval or non-approval of specific drugs, devices, and biologics and about the regulatory status of such medical products in FDA’s pipeline.
Objective
To develop practical recommendations for FDA to improve its transparency to the public that FDA could implement by rulemaking or other regulatory processes without further congressional authorization. These recommendations would build on the work of FDA’s Transparency Task Force in 2010.
Methods
In 2016-2017, we convened a team of academic faculty from Harvard Medical School, Brigham and Women’s Hospital, Yale Medical School, Yale Law School, and Johns Hopkins Bloomberg School of Public Health to develop recommendations through an iterative process of reviewing FDA’s practices, considering the legal and policy constraints on FDA in expanding transparency, and obtaining insights from independent observers of FDA.
Results
The team developed 18 specific recommendations for improving FDA’s transparency to the public. FDA could adopt all these recommendations without further congressional action.
Funding
The development of the Blueprint for Transparency at the U.S. Food and Drug Administration was funded by the Laura and John Arnold Foundation.
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References
1.
U.S. Food and Drug Administration, FDA Transparency Initiative: Draft Proposals for Public Comment Regarding Disclosure Policies of the U.S. Food and Drug Administration (May2010) (hereinafter “FDA TTFR”).
For example, in a case involving a request for clinical trial and related data for FDA approvals of sofosbuvir (Sovaldi®, Gilead) and sofosbuvir/ledipasvir (Harvoni®, Gilead) under the Freedom of Information Act, the FDA has produced thousands of pages of documents from clinical study protocols to adverse event data. See e-mail from Cortelyou C. Kenney, Counsel of Record in Treatment Action Group v. FDA, No. 15-cv-976 (D. Conn. Sept. 20, 2016), to Amy Kapczynski, Professor of Law, Yale Law Sch. (Oct. 25, 2016 04:26 EST) (on file with authors). FDA does not comment on ongoing litigation.
4.
This paper does not cover many other possible issues of transparency at FDA. For example, it does not cover issues of transparency about disagreements within FDA, an area in which the Agency has made important progress in recent years. It does not cover transparency about FDA’s internal timelines. The paper does not address veterinary medical products, tobacco products, or food. It does not cover most communications between companies and FDA, including such industry submissions as Periodic Benefit-Risk Evaluation Reports and Periodic Safety Update Reports. In addition, the focus on a practical transparency agenda means that the members of the FDA Transparency Working Group may individually support additional recommendations for transparency not included in this paper.
5.
FDA’s definition of trade secret is: “A trade secret may consist of any commercially valuable plan, formula, process, or device that is used for the making, preparing, compounding, or processing of trade commodities and that can be said to be the end product of either innovation or substantial effort. There must be a direct relationship between the trade secret and the productive process.” 21. C.F.R. 20.61(a).
6.
The report’s recommendations aim to improve proactive disclosure of information by FDA. As a result, the report does not specifically address implementation at FDA of the Freedom of Information Act, a law that provides the opportunity for citizens to request information. In general, FDA policies and regulations that limit proactive transparency also limit the Agency’s ability to share information in response to a request under the Freedom of Information Act.
7.
The relevant regulations include: 21 C.F.R. §312.130(a) (non-disclosure of Investigational New Drug applications for drugs); §601.50 (non-disclosure of Investigational New Drug applications for biological products); §812.38(a) (non-disclosure of Investigational Device Exemptions applications); §314.430(b) (non-disclosure of New Drug Applications prior to approval); §601.51(b) (non-disclosure of Biologics Licenses Applications prior to approval); §814.9(b) & (c) (non-disclosure of Pre-Market Approval applications prior to approval); and §807.95(b) (non-disclosure of 510(k)s where the submitter of the 510(k) certifies that the submitter’s intent to market the device is confidential commercial information).
8.
The ‘sponsor’ of a product subject to FDA regulation is usually the company that controls the rights to that product. A ‘biologic product’ generally is a type of drug that is produced from a biologic source, such as a living cell.
9.
21 C.F.R. §812.30(IDEs),§312.40 (Investigational New Drug applications).
10.
21 C.F.R. §312.42(a) (“A clinical hold is an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing clinical investigation.” (emphasis added)).
11.
FDCA §505(b)(5), 21 U.S.C. §355(b)(5).
12.
Despite the difference in names, which exists for historical reasons, FDA’s review process is similar for both New Drug Applications and Biologics License Applications.
13.
A PMA is “approved” by FDA; a 510(k) is “cleared” by FDA. Several factors, including the equivalence to previously approved devices and the risk of the device, determine whether a device requires a PMA or 510(k). For a low to moderate risk device where there is no existing predicate device that is not within a device type that is class III, a sponsor can submit a de novo.
The Orphan Drug Act of 1983 (ODA) is codified as amended at FDCA §§525-529, 21 U.S.C. §§360aa-360ff. The ODA provides priority review only for potential treatments for rare pediatric diseases. FDCA §529, 21 U.S.C. §360ff. An orphan drug designation does not “alter the standard regulatory requirements and process for obtaining marketing approval.” FDA, Designating an Orphan Product: Drugs and Biological Products, available at <http://www.fda.gov/forindustry/developingproductsforrarediseasesconditions/howtoapplyfororphanproductdesignation/default.htm> (last visited July 12, 2017).
16.
Pub. Law 114-255 (Dec. 13, 2016), §3033.
17.
FDCA §515(d)(5), 21 U.S.C §360e(d)(5); FDA, Expedited Access for Premarket Approval and De Novo Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly Debilitating Diseases or Conditions: Guidance for Industry & FDA Staff (April13, 2015), available at <http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM393978.pdf> (last visited July 12, 2017).
18.
Pub. Law 114-255 (Dec. 13, 2016), §3051.
19.
FDCA 505A, 21 U.S.C. §355a.
20.
21 C.F.R. sec. 20.100 contains a list of specific FDA regulations that provide for non-disclosure of particular milestones in the regulatory process.
21.
FDA proactively releases to the public the ‘background package’ that is provided to an advisory committee. 21 C.F.R. §314.430(d)(1) (disclosure of “selected portions of the safety and effectiveness data” in connection with advisory committee consideration of an New Drug Application); §601.51(d)(1) (similar provision for Biologics License Application advisory committees); §814.9(d)(1) (similar provision for Pre-Market Approval Application advisory committees); FDA, Guidance for Industry: Advisory Committee Meetings — Preparation & Public Availability of Information Given to Advisory Committee Members (August2008), available at <http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm125650.pdf> (last visited July 12, 2017).
22.
Under federal law, FDA is not permitted to disclose trade secret information to advisory committees.
23.
FDCA §526(c),21 U.S.C. §360bb(c)(“Notice respecting the designation of a drug under subsection (a) [as an orphan drug] shall be made available to the public.”)
24.
For example, on August 29, 2016, FDA designated a drug intended to treat neuroblastoma as an orphan drug. On FDA’s website, however, the drug was identified only as ‘131-I-8H9 monoclonal antibody.’ National Cancer Institute, Drug Dictionary: Iodine I 131 monoclonal Antibody 8H9,” available at <https://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=380753> (last visited July 12, 2017).
25.
See FDA TTFR Draft Proposals at page 37. Supra note 1.
26.
FDA TTFR Draft Proposals 8, 9 and 10. Supra note 1.
27.
These include Informa PLC, IMS Health, Evaluate Group, Pharmaprojects, and Springer Nature.
Typically, companies provide information about clinical holds without comment from FDA. See, e.g., Reuters, FDA Places Some Seattle Genetics Drug Trials on Hold after Four Deaths,” December 27, 2016, available at <http://www.reuters.com/article/us-seattle-genetics-fda-idUSKBN14G13V> (last visited July 12, 2017).
32.
In addition to written requests for pediatric studies under the Best Pharmaceuticals for Children Act, FDA is authorized to require submission of pediatric study plans for new drugs and biologics under the Pediatric Research Equity Act. See FDCA §505B, 21 U.S.C. §355c. Others have recently called for these pediatric study plans to be made publicly accessible, as they provide important clinical information that can accelerate pediatric research and improve pediatric care. See F. T.Bourgeois and T. J.Hwang, “The Pediatric Research Equity Act Moves Into Adolescence,”JAMA317, no. 3 (2017): 259-260.
33.
FDA TTFR Proposals 8, 9, and 10. Supra note 1.
34.
Depending on the type of marketing application, these letters have different names (e.g., ‘refuse to file’ ‘refuse to accept, not approvable, or denial). A different procedure is followed for 510(k)s.
35.
FDCA §505(l)(2), 21 U.S.C. §355(l)(2).
36.
Section 505(l)(2)(A) of the FD&C Act (21 U.S.C. 355(l)(2)(A)) states: “(l)Public disclosure of safety and effectiveness data and action package … (2)Action Package for Approval.— (A)Action package. —The Secretary shall publish the action package for approval of an application under subsection (b) or section 262 of title 42 on the Internet Web site of the Food and Drug Administration— (i) not later than 30 days after the date of approval of such application for a drug no active ingredient (including any ester or salt of the active ingredient) of which has been approved in any other application under this section or section 262 of title 42; and (ii) not later than 30 days after the third request for such action package for approval received under section 552 of title 5 for any other drug.”
37.
21 U.S.C. §355(l)(1). This section outlines that ‘safety and effectiveness’ data included in a New Drug Application must be disclosed to the public when the New Drug Application has been abandoned, or FDA determines that the New Drug Application is not approvable, or FDA withdraws approval of the New Drug Application, or on the first date an Abbreviated New Drug Application using the drug covered by the New Drug Application as the Reference Listed Drug (RLD) could be approved. This provision is qualified, however, by the phrase: “unless extraordinary circumstances are shown.”
38.
A. S.Kesselheim and M. M.Mello, “Confidentiality Laws and Secrecy in Medical Research: Improving Public Access to Data on Drug Safety,”Health Affairs26, no. 2 (2007): 483-491.
39.
In the case of an New Drug Application or Biologics License Application, this letter is known as a ‘Complete Response Letter.’ For pre-market approval, this letter is known as a ‘Not to Approve Letter.’ In the case of a 510(k), a different procedure is followed, and the letter is known as an ‘Additional Information Letter,’ or ‘Not Substantially Equivalent Letter’ (NSE). The only time a Complete Response Letter is generally released is in the case that the product is eventually approved. On rare occasions, a Complete Response Letter may be disclosed as part of a background package for an advisory committee. Applications for Approval to Market a New Drug; Complete Response Letter; Amendments to Unapproved Applications. 73(133) fed. reg. 39588, at 39601 (July 10, 2008) (noting “our long-standing presumption that before approval or tentative approval, the existence of an application is confidential commercial information”). Not Substantially Equivalent letters and Additional Information letters are not released even if FDA eventually clears the device.
40.
FDA TTFR Proposals 11, 12, 13, & 15.
41.
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 Announcements from Sponsors: Cross Sectional Study,”BMJ350 (2015): h2758.
42.
Securities Exchange Commission, Biotech Company Misled Investors about New Drug’s Status with FDA, Press Release, March29, 2016, available at <https://www.sec.gov/news/pressrelease/2016-59.html> (last visited July 12, 2017) (charging AVEO Pharmaceuticals with violations of federal securities laws by omitting to disclose to investors that FDA had called for new clinical trial).
FDA, “Availability of Masked & Deidentified Non-Summary Safety & Efficacy Data; Request for Comments,”Federal Register78, no. 107 (June4, 2013): 33421, at 33422
46.
NHLBI Biologic Specimen & Data Repository Coordinating Center (BioLINCC), available at <https://biolincc.nhlbi.nih.gov/home/> (last visited July 12, 2017).
47.
S. A.Coady and E.Wagner, “Sharing Individual Level Data from Observational Studies and Clinical Trials: A Perspective from NHLBI,”Trials14 (2013): 201.
48.
FDA TTFR Proposals 11, 12, 13, and 15. Supra note 1.
A generic drug is approved based on its ‘bioequivalence’ to a previously approved drug, which is known as the ‘Reference Listed Drug’ (RLD).
51.
Special Committee on Aging, U.S. Senate, Sudden Price Spikes in Off-Patent Prescription Drugs: The Monopoly Business Model That Harms Patients, Taxpayers, and the U.S. Health Care System (December2016); R.Gupta, A. S.Kesselheim, N.Downing, J.Greene, and J. S.Ross, “Generic Drug Approvals Since the 1984 Hatch-Waxman Act,”JAMA Internal Medicine176, no. 9 (2016): 1391-1393.
52.
Public Health Service Act §351(k), 42 U.S.C. §262(k).
J. M.Sharfstein and A.Charo, “The Promotion of Medical Products in the 21st Century: Off-label Marketing and First Amendment Concerns,”JAMA314, no. 17 (2015): 1795-1796; J.Avorn, A.Sarpatwari, and A. S.Kesselheim, “Forbidden and Permitted Statements about Medications--Loosening the Rules,”New England Journal of Medicine373, no. 10 (2015): 967-973.
63.
21 C.F.R. §20.82 (FDA Commissioner has discretionary authority to disclose any or all of a record otherwise exempt from disclosure if the disclosure is “in the public interest” and is necessary for the Agency “to pursue its regulatory activities without disruption.” The regulation specifically exempts trade secrets and commercial or financial information that is privileged or confidential, any information for which disclosure would constitute a clearly unwarranted invasion of personal privacy, and any record that is prohibited from public disclosure by statute.) FDA might also consider taking enforcement action if the inappropriate comments represent misbranding under the Food, Drug, and Cosmetic Act.
FDCA §505(o), 21 U.S.C. §355(o) (PMRs for drugs and biologics).
68.
FDCA §506B, 21 U.S.C. §356b (PMCs for drugs and biologics).
69.
I. S.Reynolds, J. P.Rising, A. J.Coukell, K. H.Paulson, and R. F.Redberg, “Assessing the Safety and Effectiveness of Devices After US Food and Drug Administration Approval: FDA-Mandated Postapproval Studies,”JAMA Internal Medicine174, no. 11 (2014): 1773-1779. FDCA §522, 21 U.S.C. §3601 (device surveillance studies); 21 C.F.R. §814.82 & §814.126 (post approval studies for PMA and Humanitarian Use devices).
21 C.F.R. §314.430(c) (prohibiting release of data or information from unapproved applications if the existence of the application has not been publicly acknowledged); §314.430(e)(2) (summaries released after approval “do not constitute the full reports of investigations…on which the safety and effectiveness of the drug may be approved”).
72.
FDA TTFR Draft Proposal 17. Supra note 1.
73.
Institute of Medicine, Sharing Clinical Trial Data: Maximizing Benefits, Minimizing Risk (2015), available at <https://www.nap.edu/catalog/18998/sharing-clinical-trial-data-maximizing-benefits-minimizing-risk> (last visited July 21, 2017). See also H. M.Krumholz, P. E.Bourne, and R. E.Kuntzet al., “Data Acquisition, Curation and Use for a Continuously Learning Health System: A Vital Direction for Health and Health Care,”National Academy of Medicine, September19, 2016, available at <Data Acquisition, Curation and Use for a Continuously Learning Health System: A Vital Direction for Health and Health Care> (last visited July 12, 2017).
74.
M. M.Mello, J. K.Francer, M.Wilenzick, P.Teden, B. E.Bierer, and M.Barnes, “Preparing for Responsible Sharing of Clinical Trial Data,”New England Journal of Medicine369, no. 17 (2013): 1651-1658; PhRMA & European Federation of Pharmaceutical Industries & Associations (EFPIA), Principles for Responsible Data Sharing: Our Commitment to Patients & Researchers (July 18, 2013), available at <http://phrma.org/sites/default/files/pdf/PhRMAPrinciplesForResponsibleClinicalTrialDataSharing.pdf> (last visited July 12, 2017). See also the Yale University Open Data Access (YODA) Project, available at <http://yoda.yale.edu/> (last visited July 12, 2017).
I.Boutron, A.Dechartres, G.Baron, J.Li, and P.Ravaud, “Sharing of Data from Industry-Funded Registered Clinical Trials,”JAMA315, no. 24 (2016): 2729-2730.
NHLBI Biologic Specimen & Data Repository Coordinating Center (BioLINCC), available at <https://biolincc.nhlbi.nih.gov/home/> (last visited July 12, 2017).
82.
S. A.Coady and E.Wagner, “Sharing Individual Level Data from Observational Studies and Clinical Trials: A Perspective from NHLBI,”Trials14 (2013): 201.
83.
The European Medicines Agency aims to publish marketing authorizations, line extensions, and extensions of product indication applications 60 days after the European Commission decision and following the publication of the European Public Assessment Report (EPAR). Withdrawn applications are published 150 days after the receipt of the withdrawal letter. European Medicines Agency — Marketing authorization — Clinical data publication <http://www.ema.europa.eu/ema/?curl=pages/special_topics/general/general_content_000555.jsp> (last visited July 12, 2017).
84.
PhRMA, “Comments on Food and Drug Administration Transparency Task Force,”August7, 2009.
