To the Editor:
Last October, the European Medicines Agency (EMA) adopted a new policy that clinical study reports (CSRs) submitted as part of a marketing application in 2015 or later will be published—with redactions of commercially confidential information—once a decision is made on the application1. Earlier in 2014, the European Parliament and Council passed a regulation to similar effect2. Meanwhile, the US Food and Drug Administration (FDA) has proposed new rules that would require disclosure of masked and de-identified patient-level data3. The drug industry has responded with its own transparency projects, including initiatives by GlaxoSmithKline, AstraZeneca, Sanofi, Pfizer and others4. These developments reflect a growing policy consensus favoring disclosure, which promotes independent verification of drug safety and efficacy data, provides a better framework for precompetitive collaboration and increases public trust in drugs and industry and the possibility of facilitating large cross-border clinical trials for, inter alia, rare diseases5. Despite these benefits, the costs and concerns associated with opening up trial data are also substantial—for patients (patient privacy), for research (related to misuse of clinical trial data in poor-quality analyses) and for industry (fewer incentives to invest in innovative R&D owing to reduced competitive edge and increased exposure to litigation owing to trolling of these data by class-action tort lawyers)6. Here we highlight another area where clinical trial disclosure may have adverse effects: the development of new uses for already approved drugs5.
Drugs frequently have multiple effects; for instance, interferon-α, developed to treat hairy-cell leukemia, is now also used to treat hepatitis C and metastatic melanoma5. Finding and developing additional medical uses for older drugs minimizes concerns about whether a physiologically potent molecule can be made into a safe, stable drug7. In principle, human trial disclosure should help this goal: with more carefully controlled drug data, third-party drug companies or independent researchers can identify new uses for testing and development. However, many new uses would still require costly clinical trials to receive market approval. Firms typically only make such investments if they can expect a sufficient exclusivity period after approval5. And herein lies the challenge: clinical trial disclosure severely limits the patentability of new uses in both the United States and the European Union.
Under US law, methods of new drug uses can only be patented if the use has not been disclosed publicly. A disclosure focusing on one treatment but revealing another effect will block later patents on that use; for example, an article describing a method of skin treatment that noted the disruption of hair follicles was enough to block a patent on using the method for hair depilation8. Applied to the issue of clinical trial disclosure, if a drug in clinical trials had a second effect that was noted and disclosed in a CSR, it would probably be impossible to later patent the second use of the drug (Fig. 1). Even for uses not precisely disclosed, a second use, if it would be obvious to someone skilled in the relevant field, would be unpatentable.
Under European law the effect is the same, although through slightly different reasoning. Although Article 54 (4) & (5) of the European Patent Convention allows patenting of a known product's new medical uses, these uses must still demonstrate novelty and an inventive step under Articles 52 and 56, as determined in the European Patent Office's decisions in T128/82 (Pyrrolidin-Derivate)9 and G2/08 (Dosage regime/Abbott Respiratory)10.
New and non-obvious uses discovered during clinical trials would still be patentable. Frequently, though, such uses are discovered after the original drug's approval, or they are noted but not adequately appreciated before disclosure would be required—too late to be patented5 (Fig. 1). Furthermore, disclosure crosses international borders: European disclosures will block US patents, and vice versa.
Without patents and with little or no data exclusivity available for originator companies, companies will have little incentive to invest in validating new uses and bringing them into widespread use5. Similar challenges may arise even for completely new drugs, such as innovative biologics, where the broad increase to the 'prior art' and 'common general knowledge' created by clinical trial disclosure may render many related new drugs unpatentably obvious.
The new regulations take some account of this. US proposals involve masking the identity of tested drugs; the much-debated11 new EMA policy and EU regulation protects commercially confidential information. But secondary effects of unrecognized importance are unlikely to be held confidential and would probably still be disclosed under these proposals.
More flexible regulatory data and market exclusivities, enforced by the FDA or EMA, could provide incentives to replace unavailable patents. Even so, firms could still use that clinical trial disclosure for market approvals in countries without equivalent regimes for regulatory exclusivity, potentially leading to contention in trade agreements. Additional clashes may arise with new trade secrecy legislation in the United States and European Union. In particular, the European Commission (EC) recently published a draft directive attempting to harmonize and enhance trade secret protection in Europe12; the European Federation of Pharmaceutical Industries and Associations welcomed it and stressed the importance of protecting the “proprietary know-how” of drug development, including in clinical trials13. The overlap between these proposals remains wholly unresolved.
Why have these concerns not been sufficiently addressed despite substantial debate on clinical trial disclosure in general? Simply put, few parties have both expertise and incentives in regulatory and intellectual property issues. Regulatory agencies and patent adjudicators each lack the other's expertise and mandate, and large innovator drug companies have few incentives to help smaller companies patent new uses. But to reap the full benefits of clinical trial disclosure, policymakers must consider the overlap between disclosure mandates and intellectual property law. Effective pharmaceutical innovation requires reasonable incentives engaging both private and public actors. We should not block new cures by pursuing a laudable initiative without full consideration.
European Medicines Agency. Publication of clinical reports. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/10/news_detail_002181.jsp&mid=WC0b01ac058004d5c1 (2 October 2014).
The Council of the European Union. Council adopts new rules on clinical trials. http://www.consilium.europa.eu/uedocs/cms_data/docs/pressdata/en/lsa/142181.pdf (14 April 2014).
US Food and Drug Administration. Fed. Reg. 78, 33421–33423 (2013).
Mello, M.M. et al. N. Engl. J. Med. 369, 1651–1658 (2013).
Roin, B.N. Social Science Research Network http://dx.doi.org/10.2139/ssrn.2337821 (October 10, 2013)
Doshi, P. Br. Med. J. 347, f6754 (2013).
DiMasi, J.A., Reichert, J.M., Feldman, L. & Malins, A. Clin. Pharmacol. Ther. 94, 329–335 (2013).
MEHL/Biophile Int'l Corp. v. Milgraum, 192 F.3d 1362 (1999).
T128/82 (Pyrrolidin-Derivate) Case T 128/82 - Hoffman-La Roche/Pyrrolidine-derivatives O.J. EPO 1984, 164 (Jan. 12, 1984)
G2/08 (Dosage regime/Abbott Respiratory) Case G 2/08 - Dosage regime/Abbott Respiratory 2010 O.J. EPO 456 (Feb. 19, 2010)
Torjesen, I. Br. Med. J. 348, g3432 (2014).
EU Commission, COM/2013/0813 final - 2013/0402 (COD), Proposal for a Directive of the European Parliament and of the Council on the protection of undisclosed know-how and business information (trade secrets) against their unlawful acquisition, use and disclosure. http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:52013PC0813 (Nov. 28, 2013)
European Federation of Pharmaceutical Industries and Associations. EFPIA welcomes the Commission's Proposal on the protection of undisclosed know-how and business information (“Trade Secrets”). http://www.efpia.eu/mediaroom/129/44/EFPIA-welcomes-the-Commission-39-s-Proposal-on-the-protection-of-undisclosed-know-how-and-business-information-quot-Trade-Secrets-quot (28 November 2013).
The authors wish to thank I. Glenn Cohen and the Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School for support and advice.
The authors declare no competing financial interests.
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Price, W., Minssen, T. Will clinical trial data disclosure reduce incentives to develop new uses of drugs?. Nat Biotechnol 33, 685–686 (2015). https://doi.org/10.1038/nbt.3243
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