Toward a Jurisprudence of Drug Regulation

Food and Drug Administration Amendments Act of 2007, Pub. L. No. 110, § 801, 121 Stat. 823, 904–22 (2007) [hereinafter FDAAA 2007].

European Commission, Communication from the Commission Regarding the Guideline on the Data Fields Contained in the Clinical Trials Database Provided for in Article 11 of Directive 2001/20/EC to be Included in the Database on Medicinal Products Provided for in Article 57 of Regulation (EC) No 726/2004, 2008 Official Journal of the European Union C 168/3, C 168/3 (2008), available at <http://ec.europa.eu/health/files/eudralex/vol-10/2008_07/c_16820080703en00030004_en.pdf>(last visited April 14, 2014).

Editorial, “European Medicines Agency – More Transparency Needed,” The Lancet 375, no. 9728 (2010): 1753;.

Psaty B. M. Furberg C. D. , “Editorial: Rosiglitazone and Cardiovascular Risk,” New England Journal of Medicine 356, no. 24 (2007): 2522–2524.

Doshi P. Jefferson T. Del Mar C. , “The Imperative to Share Clinical Study Reports: Recommendations from the Tamiflu Experience,” PLoS Medicine 9, no. 4 (2012): 1–6;.

Gøtzsche P. C. , “Commentary: Why We Need Easy Access to All Data from All Clinical Trials and How to Accomplish It,” Trials 12, no. 249 (2011): 1–14;.

Gøtzsche P. C. Jorgensen A. W. , “Opening Up Data at the European Medicines Agency,” British Medical Journal 342 (2011): 1184–1186;.

Strech D. Littmann J. , Commentary, “Lack of Proportionality: Seven Specifications of Public Interest That Override Post-Approval Commercial Interests on Limited Access to Clinical Data,” Trials 13, no. 100 (2012): 1–5;.

Groves T. Godlee F. , “Editorial: The European Medicines Agency's Plans for Sharing Data from Clinical Trials,” British Medical Journal 346 (2013): f2961;.

Rodwin M. A. Abramson J. D. , “Clinical Trial Data as a Public Good,” JAMA 308, no. 9 (2012): 871–872.

For simplicity, I will refer to products that are withdrawn by the manufacturer during research and development as “abandoned” products, and reserve the term “withdrawn drugs” or “withdrawals” for drugs that are removed from the market after they have received market authorization from a regulator. In the literature, however, the term “withdrawn” is used in respect of drugs that are withdrawn pre- and post-market entry.

My use of the term jurisprudence may appear odd to legal scholars given that the term traditionally refers to a body of court decisions or a philosophy of law. I am using the term in a more strategic sense, first, to emphasize the complex nature of regulatory decision-making regarding health products such as drugs and, second, to highlight the body of knowledge regarding the benefits, risks, etc., of drugs that could begin to evolve if regulators were to adopt and adhere to the four features of a jurisprudence of drug regulation that I outline in the second half of the paper.

European Medicines Agency, Committee for Medicinal Products for Human Use, Publication of CHMP Negative Opinion and Refusal of Marketing Authorisation Applications for Human Medicinal Products, Doc. Ref. EMA/311355/2005, adopted Jan. 24, 2007.

European Medicines Agency, Committee for Medicinal Products for Veterinary Use, Reflections Paper on the Publication of the CHMP's Negative Opinion and Refusal to Recommend the Granting of a Marketing Authorisation for Veterinary Medicinal Products, Doc. Ref. EMA/CVMP/459912/2006, adopted Jul. 12, 2007;.

Tafuri G. Trotta F. Leufkens H. G. Pani L. , “Disclosure of Grounds of European Withdrawn and Refused Applications: A Step Forward on Regulatory Transparency,” British Journal of Clinical Pharmacology 75, no. 4 (2013): 1149–1151.

See, for example, Government of Canada, Health Canada, Summary Basis of Decision Phase II: Posting of the Summary Report of External Consultations, May 7, 2012, available at <http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/sbd_ext_consult_sbd-eng.php>(last visited April 14, 2014).

These arguments build on recent work by other scholars, in particular, Rebecca Eisenberg and Trudo Lemmens. See Eisenberg R. S. , “The Role of the FDA in Innovation Policy,” Michigan Telecommunications and Technology Law Review 13, no. 2 (2007): 345–388;.

Unlu M. , “It Is Time: Why the FDA Should Start Disclosing Drug Trial Data,” Michigan Telecommunications and Technology Law Review 16, no. 2 (2010): 511–545;.

Lemmens T. , “Pharmaceutical Knowledge Governance: A Human Rights Perspective,” Journal of Law, Medicine & Ethics 41, no. 1 (2013): 163–184.

Two of these three jurisdictions are of primary interest here because regulators in the United States and Europe carry significant influence, in terms of practices, over other regulators. The third jurisdiction, Canada, is of interest largely for comparative purposes. Generic references to “regulators” throughout the paper are intended to refer to these three regulators unless explicit reference to another jurisdiction is made.

Asamoah A. K. Sharfstein J. M. , “Transparency at the Food and Drug Administration,” New England Journal of Medicine 362, no. 25 (2010): 2341–2343;.

Merrill R. A. , “The Architecture of Government Regulation of Medical Products,” Virginia Law Review 82, no. 8 (1996): 1753–1866.

Young J. H. , The Toadstool Millionaires: A Social History of Patent Medicines in America before Federal Regulation (Princeton: Princeton University Press, 1961): At 93–124;.

Haycock D. B. Wallis P. , “Quackery and Commerce in Seventeenth-Century London: The Proprietary Medicine Business of Anthony Daffy,” Medical History Supplement 25 (2005): 1–216.

See Merrill , supra note 10.

Id.

Id.

Topol E. J. , “Failing the Public Health–Rofecoxib, Merck, and the FDA,” New England Journal of Medicine 351, no. 17 (2004): 1707–1709.

See Merrill , supra note 10.

Pugsley L. I. , “The Administration and Development of Federal Statutes on Foods and Drugs in Canada,” Medical Services Journal Canada 23, no. 3 (1967): 387–449.

See, for example, Vitry A. Lexchin J. Sasich L. Dupin-Spriet T. Reed T. Bertele V. Garattini S. Toop L. Hurley E. , “Provision of Information on Regulatory Authorities' Websites,” Internal Medicine Journal 38, no. 7 (2008): 559–567.

Government of Canada, Interagency Advisory Panel on Research Ethics, TRI-COUNCIL POLICY STATEMENT: ETHICAL CONDUCT FOR RESEARCH INVOLVING HUMANS 2010, Article 11.3; available at <http://www.pre.ethics.gc.ca/eng/policy-politique/initiatives/tcps2-eptc2/Default/>(last visited April 14, 2014) [hereinafter TCPS2].

Government of Canada, Health Canada, Evaluation of Phase I of the Summary Basis of Decision Project, January 29, 2010, available at <http://www.hc-sc.gc.ca/dhp-mps/pubs/drug-medic/sbd_er_smd-eng.php>(last visited April 14, 2014) [hereinafter HC, Evaluation of Phase I].

See FDAAA 2007, supra note 1.

Id.

United States Government Accountability Office, FDA Advisory Committees: Process for Recruiting Members and Evaluating Potential Conflicts of Interest, September 2008, available at <http://www.gao.gov/new.items/d08640.pdf>(last visited April 14, 2014).

European Medicines Agency, European Medicines Agency Policy on Access to Documents (Related to Medicinal Products for Human and Veterinary Use), November 30, 2010, available at <http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/11/WC500099473.pdf>(last visited April 14, 2014).

European Commission, Regulation (EC) No. 726/2004 of the European Parliament and of the Council of 31 March 2004 Laying Down Community Procedures for the Authorisation and Supervision of Medicinal Products for Human and Veterinary Use and Establishing a European Medicines Agency, 2004 O.J. (L136)1 [hereinafter Regulation (EC) No. 726/2004].

Id., at articles 13(3), 12(3), and 11, respectively.

United States Food and Drug Administration, Phase II Transparency Report, May 19, 2010, available at <http://www.fda.gov/downloads/AboutFDA/Transparency/PublicDisclosure/GlossaryofAcronymsandAbbreviations/UCM212110.pdf>(last visited April 14, 2014) [hereinafter FDA, Transparency Report].

European Medicines Agency, European Medicines Agency Announces Plan to Publish Committee Agendas and Minutes, Press Release, July 18, 2012, available at <http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2012/07/WC500130054.pdf>(last visited April 14, 2015).

A recent decision by the Supreme Court of Canada is illustrative of this emergent transparency. The majority held that the confidential business information exemption from disclosure under the Access to Information Act, R.S.C. 1985, C. A-1, s. 20(1)(b), did not apply on the facts of the case because the information in dispute was, to a large extent, publicly available via the FDA's website.

See Merck Frosst Canada Ltd. v. Canada (Health) 2012 SCC 3 at para. 182 [hereinafter Merck Frosst]. Also, in draft proposals intended to increase the transparency of its decision-making, the FDA has specifically highlighted greater levels of transparency at the EMA as a reason to pursue policy change.

See FDA, Transparency Report, supra note 27.

Law M. R. Kawasumi Y. Morgan S. G. , “Despite Law, Fewer Than One in Eight Completed Studies of Drugs and Biologics Are Reported on Time on ClinicalTrials.gov,” Health Affairs 30, no. 12 (2011): 2338–2345;.

see also Gill C. J. , “How Often Do US-Based Human Subjects Research Studies Register on Time, and How Often Do They Post Their Results? A Statistical Analysis of the Clinicaltrials.gov Database,” BMJ Open 2, no. 4 (2012): 1–9, available at <http://bmjopen.bmj.com/content/2/4/e001186>(last visited April 14, 2014).

Mathieu S. Boutron I. Moher D. Altman D. G. Ravaud P. , “Comparison of Registered and Published Primary Outcomes in Randomized Controlled Trials,” JAMA 302, no. 9 (2009): 977–984;.

Sekeres M. Gold J. L. Chan A.-W. Lexchin J. Moher D. Van Laethem M. L. P. Maskalyk J. Ferris L. Taback N. Rochon P. A. , “Poor Reporting of Scientific Leadership Information in Clinical Trial Registers,” PLoS ONE 3, no. 2 (2008): e1610;.

Viergever R. F. Ghersi D. , “The Quality of Registration of Clinical Trials,” PLoS ONE 6, no. 2 (2011): e14701;.

Jones C. W. Platts-Mills T. F. , “Quality of Registration for Clinical Trials Published in Emergency Medicine Journals,” Annals of Emergency Medicine 60, no. 4 (2012): 458–464.e1;.

Scherer R. W. , “Can We Depend on Investigators to Identify and Register Randomized Controlled Trials?” PLoS ONE 7, no. 9 (2012): e44183;.

Prayle A. P. Hurley M. N. Smyth A. R. , “Compliance with Mandatory Reporting of Clinical Trial Results on ClinicalTrials.gov: Cross Sectional Study,” BMJ 344 (2012): d7373.

cf. Huser V. Cimino J. J. , “Evaluating Adherence to the International Committee of Medical Journal Editors' Policy of Mandatory, Timely Clinical Trial Registration,” Journal of the American Medical Informatics Association 20, e1 (2013): e169–e174.

See TCPS2, supra note 19.

Zarin D. A. Tse T. , “Commentary: Moving toward Transparency of Clinical Trials,” Science 319, no. 5868 (2008): 1340–1342;.

Kimmelman J. Anderson J. A. , “Should Preclinical Studies Be Registered?” Nature Biotechnology 30, no. 6 (2012): 488–489.

Lurie P. Almeida C. M. Stine N. Stine A. R. Wolfe S. M. , “Financial Conflict of Interest Disclosure and Voting Patterns at Food and Drug Administration Drug Advisory Committee Meetings,” JAMA 295, no. 16 (2006): 1921–1928.

Lexchin J. O'Donovan O. , “Prohibiting or ‘Managing’ Conflict of Interest? A Review of Policies and Procedures in Three European Drug Regulation Agencies,” Social Science & Medicine 70, no. 5 (2010): 643–647.

For instance, Regulation (EC) No. 726/2004, supra note 23, art. 13(3), states:.

The Agency shall immediately publish the assessment report on the medicinal product for human use drawn up by the Committee for Medicinal Products for Human Use and the reasons for its opinion in favour of granting the authorization, after deletion of any information of a commercially confidential nature. [emphasis added].

Sinha G. , “Trade Secrets in Balance as Agencies Issue New Transparency Rules,” Nature Biotechnology 29, no. 2 (2011): 98–99.

Drazen J. M. , “Transparency for Clinical Trials – The TEST Act,” New England Journal of Medicine 367, no. 9 (2012): 863–864;.

Dickersin K. Rennie D. , “The Evolution of Trial Registries and Their Use to Assess the Clinical Trial Enterprise,” JAMA 307, no. 17 (2012): 1861–1864;.

see Kimmelman Anderson , supra note 33.

Eichler H.-G. Abadie E. Breckenridge A. Leufkens H. Rasi G. , “Open Clinical Trial Data for All? A View from Regulators,” PLoS Medicine 9, no. 4 (2012): e1001202.

See Abbvie Inc. and Abbvie Ltd. v. European Medicines Agency, Order of 25 April 2013, T-44/13. The EMA is nevertheless moving forward with public consultations surrounding open access to clinical trial data.

See European Medicines Agency, European Medicines Agency Receives Interim Decisions of the General Court of the EU on Access to Clinical and Non-clinical Information, Press Release, April 30, 2013, available at <http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/04/WC500142837.pdf>(last visited April 14, 2014).

See European Medicines Agency (EMA) v AbbVie Ltd, [2013] EUECJ C-389/13 (November 28, 2013).

European Medicines Agency (EMA) v InterMune, Inc, [2013] EUECJ C-390/13 (November 28, 2013).

Rabesandratana T. , “European Parliament Approves Bill to Increase Clinical Trial Transparency,” Science Insider, April 3, 2014, available at <http://news.sciencemag.org/europe/2014/04/european-parliament-approves-bill-increase-clinical-trial-transparency>(last visited April 28, 2014).

See also European Parliament, “European Parliament legislative resolution of 2 April 2014 on the Proposal for a Regulation of the European Parliament and of the Council on Clinical Trials on Medicinal Products for Human Use, and Repealing Directive 2001/20/EC (COM(2012)0369 – C7–0194/2012 – 2012/0192(COD)) (Ordinary Legislative Procedure: First Reading),” available from <http://www.europarl.europa.eu/plenary/en/texts-adopted.html>(last visited April 28, 2014).

Murray J. , “AbbVie Withdraw Case against European Medicines Agency,” BMJ Group Blogs, April 16, 2014, available at <http://blogs.bmj.com/bmj/2014/04/16/jim-murray-abbviewithdraw-case-against-european-medicines-agency/>(last visited April 28, 2014).

See Holmes D. , “Transparency Battle Resurfaces as EU Trial Revamp Wraps Up,” Nature Medicine 19, no. 7 (2013): 797.

Castellani J. , “Are Clinical Trial Data Shared Sufficiently Today? Yes,” BMJ 347 (2013): f1881.

cf. Goldacre B. , “Are Clinical Trial Data Shared Sufficiently Today? No,” BMJ 347 (2013): f1880.

Nisen P. Rockhold F. , “Access to Patient-Level Data from GlaxoSmithKline Clinical Trials,” New England Journal of Medicine 369, no. 5 (2013): 475–478.

In Canada, for example, it should be difficult to establish that such information is “confidential information” because regulators' decisions are not “supplied by” manufacturers per se, although the decisions may be based, in part, on information that is in fact supplied by manufacturers. See Frosst Merck , supra note 29, at para. 152–158.

See FDA, Transparency Report supra note 27.

None of the draft proposals relating to the FDA's decisionmaking (e.g., abandoned products) have been implemented to date. The last update provided by the FDA is dated 2011. See United States Food and Drug Administration, Phase II Progress Report, available at <http://www.fda.gov/AboutFDA/Transparency/TransparencyInitiative/ucm273854.htm>(last visited April 14, 2014).

See Castellani , supra note 45.

It is worth noting that regulators such as the FDA do publish guidance documents, for example, about classes of drugs, which can give insight into the regulator's thinking. See United States Food and Drug Administration, Guidances (Drugs), available at <http://www.fda.gov/Drugs/GuidancecomplianceRegulatoryInformation/Guidances/default.htm>(last visited April 14, 2014). However, these guidance documents are not legally binding and even if they could explain a particular regulatory outcome, we have no way of knowing whether the guidance actually does so given the current lack of transparency for product-specific decision-making.

The SBD project has recently undergone significant changes, which will be discussed infra. See Government of Canada, Health Canada, Notice – Launch of Phase II of the Summary Basis of Decision Project, June 29, 2012, available at <http://www.hc-sc.gc.ca/dhp-mps/prodpharma/activit/announceannonce/sbd_notice_launch_phaseii_smd_lance_avis-eng.php>(last visited April 14, 2014) [hereinafter HC, Launch of Phase II].

For further information regarding SBDs, see HC, Evaluation of Phase I, supra note 18;.

and, Lexchin J. Mintzes B. , “Transparency in Drug Regulation: Mirage or Oasis?” CMAJ 171, no. 11 (2004): 1363–1365.

See Tafuri , supra note 6.

It is important to note that news of failed drug submissions does surface through notable media reports such as the Wall Street Journal and informal industry channels. See, for example, Rockoff J. D. Wang S. S. , “Alzheimer's Drug From Pfizer, J&J Fails in Late-Stage Trial,” Wall Street Journal, August 6, 2012. But these news reports generally lack a level of clinical or scientific detail as to why the drug failed. My claim is that regulators could supply this level of detail if there was greater transparency.

DiMasi J. A. Feldman L. Seckler A. Wilson A. , “Trends in Risks Associated with New Drug Development: Success Rates for Investigational Drugs,” Clinical Pharmacology & Therapeutics 87, no. 3 (2010): 272–277.

Id. Unfortunately, the article does not provide new data in this regard. The one-third figure is based upon research published in 2001.

See DiMasi J. A. , “Commentary: Risks in New Drug Development: Approval Success Rates for Investigational Drugs,” Clinical Pharmacology & Therapeutics 69, no. 5 (2001): 297–307.

It also raises a series of ethical issues, including breach of informed consent, respect for participants, and harm to downstream users. See Rogwaski M. A. Federoff H. J. , “Disclosure of Clinical Trial Results When Product Development Is Abandoned,” Science Translational Medicine 3, no. 102 (2011): 102cm29;.

Kimmelman Anderson , supra note 33;.

Cleophas R. C. Cleophas T. J. , “Is Selective Reporting of Clinical Research Unethical as Well as Unscientific?” International Journal of Clinical Pharmacology and Therapeutics 37, no. 1 (1999): 1–7.

Id.;.

Rising K. Bachetti P. Bero L. , “Reporting Bias in Drug Trials Submitted to the Food and Drug Administration: Review of Publication and Presentation,” PLoS Medicine 5, no. 11 (2008): 1561–1570;.

Turner E. H. Matthews A. M. Linardatos E. Tell R. A. Rosenthal R. , “Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy,” New England Journal of Medicine 358, no. 3 (2008): 252–260.

Edwards A. M. Isserlin R. Bader G. D. Frye S. V. Willson T. M. Yu F. H. , “Too Many Roads Not Taken,” Nature 470, no. 7333 (2011): 163–165;.

Boudreau K. Guinan E. Lakhani K. Riedl C. , “The Novelty Paradox & Bias for Normal Science: Evidence from Randomized Medical Grant Proposal Evaluations,” Harvard Business School Working Paper, No. 13, December 2012, available at <http://hbswk.hbs.edu/item/7173.html>(last visited April 28, 2014).

For instance, most R&D in the realm of rare diseases (which now make up approximately one third of FDA drug approvals) is clustered in the area of oncology. See Wellman-Labadie O. Zhou Y. , “The US Orphan Drug Act: Rare Disease Research Stimulator or Commercial Opportunity?” Health Policy 95, no. 2 (2010): 216–228.

Cowley A. J. Skene A. Stainer K. Hampton J. R. , “The Effect of Lorcainide on Arrhythmias and Survival in Patients with Acute Myocardial Infarction: An Example of Publication Bias,” International Journal of Cardiology 40, no. 2 (1993): 161–166 [hereinafter Crowley et al., Publication Bias].

Rogwaski Federoff , supra note 57.

See, generally, Barratt M. J. Frail D. E. , Drug Repositioning: Bringing New Life to Shelved Assets and Existing Drugs (Hoboken, NJ: John Wiley & Sons, 2012).

Eichler H.-G. Petavy F. Pignatti F. Rasi G. , “Access to Patient-Level Clinical Trial Data – A Boon to Drug Developers,” New England Journal of Medicine 369, no. 17 (2013): 1577–1579;.

Crowley , supra note 61;.

Selker H. P. Ruthazer R. Terrin N. Griffith J. L. Concannon T. Kent D. M. , “Random Treatment Assignment Using Mathematical Equipoise for Comparative Effectiveness Trials,” Clinical and Translational Science 4, no. 1 (2011): 10–16;.

Kent D. M. Hayward R. A. Griffith J. L. Vijan S. Beshansky J. R. Calif R. M. Selker H. P. , “An Independently Derived and Validated Predictive Model for Selecting Patients with Myocardial Infarction Who Are Likely to Benefit From Tissue Plasminogen Activator Compared with Streptokinase,” American Journal of Medicine 113, no. 2 (2002): 104–111.

Several commentators have pointed out that these various forms of market protection can be co-extensive. See Eisenberg R. , “Data Secrecy in the Age of Regulatory Exclusivity,” in Dreyfuss R. C. Strandburg K. J. , eds., The Law and Theory of Trade Secrecy: A Handbook of Contemporary Research (United Kingdom: Edward Elgar Publishing, 2012);.

Herder M. , “Unlocking Health Canada's Cache of Trade Secrets: Mandatory Disclosure of Clinical Trial Results,” Canadian Medical Association Journal 184, no. 2 (2012): 194–199;.

Lemmens T. Telfer C. , “Access to Information and the Right to Health: The Human Rights Case for Clinical Trials Transparency,” American Journal of Law & Medicine 38, no. 1 (2012): 63–112.

See supra note 47.

Canadian courts have excluded information that provides insight into the regulatory process such as reviewers' notes from the scope of “confidential information” or information that would harm a company's competitive position. See Astra-Zeneca Canada Inc. v. Canada (Health), 2005 FC 1451 at para. 95, aff'd 2006 FCA 241.

endorsed in Merck Frosst Ltd. v. Canada (Health), [2012] 1 S.C.R. 23 at para. 218.

Hood C. , “Transparency in Historical Perspective,” in Hood C. Heald D. , eds., Transparency: The Key to Better Governance? (New York: Oxford University Press, 2006): At 3–23.

Id., at 5–7.

See FDA, Transparency Report, supra note 27.

Roberts A. , “Dashed Expectations: Governmental Adaptation to Transparency Rules,” in Hood C. Heald D. , eds., Transparency: The Key to Better Governance? (New York: Oxford University Press, 2006): At 107–125;.

see HC, External Consultations, supra note 7;.

FDA, Transparency Report, supra note 27.

For example, FDA advisory committee deliberations are publicly available, but they tend to be populated by individuals that are invested, as patient representatives or expert researchers, to some degree, in the regulatory outcome. Deciphering whether advisory committees are shaped by special interests versus accountable to otherwise interested publics is therefore difficult. Wood S. F. Mador J. K. , “Uncapping Conflict of Interest?” Science 340, no. 6137 (2013): 1172–1173.

The English philosopher Jeremy Bentham's “panopticon” took this performance-based rationale for transparency to the extreme, advocating in the late 18th and early 19th centuries for exposure of every government agent to outside scrutiny through an all “inspective-architecture.” See Hood , supra note 67, at 9–10.

In Canada, for example, several recent decisions by the Supreme Court of Canada acknowledge that, depending on the administrative context, limited reasons may suffice or a duty to give reasons may not even exist. See, for example, Canada (Attorney General) v. Mavi, [2011] 2 S.C.R. 504;.

Alberta (Information and Privacy Commissioner) v. Alberta Teachers' Association, [2011] 3 S.C.R. 654;.

and, Newfoundland and Labrador Nurses' Union v. Newfoundland and Labrador (Treasury Board), [2011] 3 S.C.R. 708.

Shapiro M. , “The Giving Reasons Requirement,” University of Chicago Legal Forum (1992): 179–220, at 180 [emphasis added].

Baker v. Canada (Minister of Citizenship and Immigration), [1999] 2 S.C.R. 817 at para. 39.

Lexchin J. , “Withdrawals of Drugs for Safety Reasons: How Do Regulators Decide If They Are Too Unsafe?” Adverse Drug Reaction Bulletin (February 2006);.

Clarke A. Deeks J. J. Shakir S. A. W. , “An Assessment of the Publicly Disseminated Evidence of Safety Used in Decisions to Withdraw Medicinal Products from the UK and US Markets,” Drug Safety 29, no. 2 (2006): 175–181;.

Lexchin J. , “Notice of Compliance with Conditions: A Policy in Limbo,” Healthcare Policy 2, no. 4 (2007): 114–122.

The core focus in administrative law disputes regarding the purpose and scope of the requirement to give reasons is on the party immediately affected by a given administrative decision. In some cases, courts have broadened the rationale for giving reasons to include providing guidance to other members of a regulated industry. For instance, the Canadian Federal Court of Appeal has explained:.

…in the case of a regulated industry, the regulator's reasons for making a particular decision provide guidance to others who are subject to the regulator's jurisdiction. They provide a standard by which future activities of those affected by the decision can be measured.

See VIA Rail Canada Inc. v. Lemonde, [2001] 2 F.C. 25 (F.C.A.), at para 20.

But there is little attention to the idea that giving reasons might, by opening up those reasons to scrutiny by independent experts, improve the quality of the administrative agency's decision-making over time.

Zuckerman H. Merton R. K. , “Patterns of Evaluation in Science: Institutionalisation, Structure and Functions of the Referee System,” Minerva 9, no. 1 (1971): 66–100. Zuckerman and Merton write in reference to the institution of peer review at the Royal Society:.

The practice of having scientific communications assessed by delegated members of the Royal Society might have affected the quality of those communications. Communications intended for publication would ordinarily be more carefully prepared than private scientific papers, and all the more so, presumably, in the knowledge that they would be scrutinized by deputies of the Society.

Id., at 73.

These normative commitments to “open, disinterested, sceptical” inquiry are meant to map onto three of the four norms (communism, disinterestedness, and organized skepticism) as originally described by Merton Robert Merton R. K. , “A Note on Science and Democracy,” Journal of Legal and Political Sociology 1 (1942): 115–126. Merton's fourth norm, universalism, which holds that scientific work is to be judged by pre-established criteria, has less relevance in the context of this paper because determining what criteria should be used to judge the adequacy of a regulatory decision-making is premature in the absence of greater transparency.

Mitroff I. I. , “Norms and Counter-Norms in a Select Group of the Apollo Moon Scientists: A Case Study of the Ambivalence of Scientists,” American Sociological Review 39, no. 4 (1974): 579–595;.

Merton R. K. , “Priorities in Scientific Discovery: A Chapter in the Sociology of Science,” American Sociological Review 22, no. 6 (1957): 635–659.

Neuman J. Korenstein D. Ross J. S. Keyhani S. , “Prevalence of Financial Conflicts of Interest among Panel Members Producing Clinical Practice Guidelines in Canada and United States: Cross Sectional Study,” BMJ 343 (2011): d5621;.

Zinner D. E. Bolcic-Jankovic D. Clarridge B. Blumenthal D. Campbell E. G. , “Participation of Academic Scientists in Relationships with Industry,” Health Affairs 28, no. 6 (2009): 1814–1825;.

Lurie , supra note 34.

See GAO, supra note 21;.

Government of Canada, Health Canada Policy on External Advisory Bodies (2011), November 7, 2011, available at <http://www.hc-sc.gc.ca/ahc-asc/public-consult/res-centre/poli-eab-oce-eng.php>(last visited April 16, 2014). Some scholars have argued that, rather than reflecting a genuine attempt to engage experts and members of the public in its decision-making, the FDA's use of advisory committees are instead better characterized as an attempt by the FDA to enhance its reputation and power while being seen as consultative.

See Moffitt S. L. , “Promoting Agency Reputation through Public Advice: Advisory Committee Use in the FDA,” Journal of Politics 72, no. 3 (2010): 880–893.

United States Food and Drug Administration, Advisory Committees: Critical to the FDA's Product Review Process, August 12, 2011, available at <http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm143538.htm>(last visited April 16, 2014).

Okie S. , “What Ails the FDA?” New England Journal of Medicine 352, no. 24 (2005): 1063–1066;.

Mundy A. , “Political Lobbying Drove FDA Process,” Wall Street Journal, March 6, 2009, at A1.

Avorn J. , “Keeping Science on Top in Drug Evaluation,” New England Journal of Medicine 357, no. 7 (2007): 633–635.

See Lurie , supra note 34.

For a helpful discussion of how these rules work, see Kellogg I. J. , “Prescription for a Cure: Does the FDA's Draft Guidance Adequately Manage Advisory Committee Members' Conflicts of Interest?” Stanford Law & Policy Review 19, no. 2 (2008): 300–327.

See Lurie , supra note 34.

See Wood Mador , supra note 71.

Zuckerman D. M. , FDA Advisory Committees: Does Approval Mean Safety? (National Research Center for Women and Families, Washington, D.C., 2006), available at <http://www.center4research.org/wp/wp-content/uploads/2010/05/fda_report_9–2006.pdf>(last visited April 16, 2014).

The International Conference on Harmonization is a private forum originally comprised of representatives from the FDA, the EMA, and Japan's medicines regulator, as well as regional associations of the pharmaceutical industry, which meets to discusses regulatory challenges and advocate for the application of common technical standards, including safety and efficacy. See International Conference on Harmonization, History, available at <http://www.ich.org/about/history.html>(last visited April 16, 2014).

See Gøtzsche Jorgensen , supra note 3.

European Medicines Agency, Publication and Access to Clinical-Trial Data, Policy/0070: Draft for Public Consultation, June 24, 2013, available at <http://www.ema.europa.eu/docs/en_GB/document_library/Other/2013/06/WC500144730.pdf>(last visited April 16, 2014).

See FDA, supra note 27, at 39.

United States Food and Drug Administration, Guidance for Industry and Food and Drug Administration Staff – In Vitro Companion Diagnostic Devices, July 14, 2011, available at <http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm262292.htm>(last visited April 14, 2014).

Dunoyer M. , “Accelerating Access to Treatments for Rare Diseases,” Nature Reviews Drug Discovery 10, no. 7 (2011): 475–476;.

Saltonstall P. L. , Letter to the Editor, “Clinical Trials of Orphan Drugs for Cancer,” JAMA 306, no. 14 (2011): 1545;.

Stewart D. J. Whitney S. N. Kurzrock P. , “Equipoise Lost: Ethics, Costs, and the Regulation of Cancer Clinical Research,” Journal of Clinical Oncology 28, no. 17 (2010): 2925–2935.

Two recent studies suggest the evidence behind approved orphan medicines for cancers and neurological conditions depart significantly from important experimental standards, including randomization and blinding. See Kesselheim A. S. Myers J. A. Avorn J. , “Characteristics of Clinical Trials to Support Approval of Orphan vs Nonorphan Drugs for Cancer,” JAMA 305, no. 22 (2011): 2320–2326;.

Mitsumoto J. Dorsey E. R. Beck C. A. Kieburtz K. Griggs R. C. , “Pivotal Studies of Orphan Drugs Approved for Neurological Diseases,” Annals of Neurology 66, no. 2 (2009): 184–190.

See Roberts , supra note 70.

Id., at 111–114.

Trotta F. Leufkens H. G. M. Schellens J. H. M. Laing R. Tafuri G. , “Evaluation of Oncology Drugs at the European Medicines Agency and US Food and Drug Administration: When Differences Have an Impact on Clinical Practice,” Journal of Clinical Oncology 29, no. 16 (2011): 2266–2272. Other studies have similarly revealed differences between regulatory outcomes, but are not able to explain why the differences occurred due to a lack of transparent information.

See Lexchin J. , “International Comparison of Assessments of Pharmaceutical Innovation,” Health Policy 105, no. 2 (2012): 221–225.

See Id. ( Trotta ), at 2271 [emphasis added].

Abraham J. Sheppard J. , “Complacent and Conflicting Scientific Expertise in British and American Drug Regulation: Clinical Risk Assessment of Triazolam,” Social Studies of Science 29, no. 6 (1999): 803–843.

Id., at 823 [emphasis in original].

Id., at 831–832.

Id., at 828–831.

However, several news reports document instances where advisory committees, replete with conflicts of interest, played a key role in getting a drug to market. Harris G. Berenson A. , “10 Voters on Panel Backing Pain Pills Had Industry Ties,” New York Times, February 25, 2005, at A1;.

Willman D. , “New FDA: How a New Policy Led to Seven Deadly Drugs,” Los Angeles Times, December 20, 2000, at A1.

Kim J. W. , “Arbiter of Science: Institutionalization and Status Effects in FDA Drug Review 1990–2004,” Strategic Organization 10, no. 2 (2012): 128–157.

Abraham J. Davis C. , “Drug Evaluation and the Permissive Principle: Continuities and Contradictions between Standards and Practices in Antidepressant Regulation,” Social Studies of Science 39, no. 4 (2009): 569–598;.

Abraham J. Ballinger R. , “The Neoliberal Regulatory State, Industry Interests, and the Ideological Penetration of Scientific Knowledge: Deconstructing the Redefinition of Carcinogens in Pharmaceuticals,” Science, Technology & Human Values 37, no. 5 (2011): 443–477;.

see also, Abraham J. Reed T. , “Progress, Innovation and Regulatory Science in Drug Development: The Politics of International Standard-Setting,” Social Studies of Science 32, no. 3 (2002): 337–369.

Epstein S. , “Activism, Drug Regulation, and the Politics of Therapeutic Evaluation in the AIDS Era: A Case Study of ddC and the ‘Surrogate Markers’ Debate,” Social Studies of Science 27, no. 5 (1997): 691–726.

Id., at 719 [emphasis added].

Fisher E. , “Transparency and Administrative Law: A Critical Evaluation,” Current Legal Problems 63, no. 1 (2010): 272–314;.

Jasanoff S. , “Transparency in Public Science: Purposes, Reasons, Limits,” Law & Contemporary Problems 69, no. 3 (2006): 21–46.

For background information about this project, see references provided at note 52.

See Vitry , supra note 18;.

Schwartz L. M. Woloshin S. , “Lost in Transmission – FDA Drug Information That Never Reaches Clinicians,” New England Journal of Medicine 361, no. 18 (2009): 1717–1720;.

Habibi R. Lexchin J. , “Quality and Quantity of Information in Summary Basis of Decision Documents Issued by Health Canada,” PLoS ONE 9, no. 3 (2014): e92038.

Note that prior events, such as the filing of an application to investigate a drug in a clinical trial, or halt a trial, also typically invite responses from regulators. These prior events in the research and development process are not the focus here, however, as existing clinical trial registration requirements should, in principle, make the pertinent details (e.g., indications being tested) transparent.

One of the guidance documents regarding Phase II of the SBD initiative notes that “submissions/applications for a new use of [an already approved] product [will be published] whether Health Canada's decision was negative or positive….” As a result, this limited subset of negative decisions may, with time, become publicly known. See Health Canada, supra note 7.

Government of Canada, Health Canada, Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II, available at <http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/sbd_qa_smd_fq-eng.php#a11‘>(last visited April 16, 2014).

See Health Canada, supra note 7.

See Schwartz Woloshin , supra note 112.

Frey P. , United States Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Benefit-Risk Considerations in CDER: Development of a Qualitative Framework, June 28, 2012, available at <http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProd-uctsandTobacco/CDER/UCM317788.pdf>(last visited April 16, 2014).

See Lexchin , supra note 76;.

Clarke , supra note 76.

FDA, Structured Approach to Benefit-Risk Assessment in Drug Regulatory Decision-Making, available at <www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM329758.pdf>(last visited April 16, 2014).

see Frey , supra note 106;.

Sukkar E. , “Sunshine at the European Regulator,” BMJ 344 (2012): e976.

Note that these reasons do not encompass information that has been found to be proprietary, such as details of manufacturing processes and any sales or marketing related information.

If this type of coaching is common, it arguably underscores the claim that regulator's reasons are not manufacturer's proprietary information.

Government of Canada, Health Canada, Prochymal: Notice of Compliance with Conditions - Qualifying Notice, May 17, 2012, available at <http://www.hc-sc.gc.ca/dhp-mps/prodpharma/notices-avis/conditions/prochymal_qn_aa_150026-eng.php>(last visited April 16, 2014).

Government of Canada, Health Canada, Summary Basis of Decision (SBD) for PROCHYMAL, October 5, 2012, available at <http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2012_prochymal_150026-eng.php>(last visited April 16, 2014).

Cyranoski D. , “Canada Approves Stem Cell Product,” Nature Biotechnology 30, no. 7 (2012): 571–571.

See Health Canada, supra note 123;.

Government of Canada, Health Canada, Report of the Expert Advisory Panel on Prochymal, January 26, 2012, available at <http://www.hc-sc.gc.ca/dhp-mps/brgtherap/activit/sci-consult/prochymal/report-rapport-eng.php>(last visited April 16, 2014).

See Health Canada, supra note 123.

See Cyranoski , supra note 124.

See notes 107 and 108 and corresponding text.

See Schwartz Woloshin , supra note 112;.

Barbui C. Baschirotto C. Cipriani A. , “EMA Must Improve the Quality of its Clinical Trial Reports,” BMJ 342 (2011): d2291;.

Bauschke R. , “Regulatory Agencies, Pharmaceutical Information and the Internet: A European Perspective,” Health Policy 104, no. 1 (2012): 12–18.

See Schwartz Woloshin , supra note 112.

See Habibi Lexchin , supra note 112.

See Barbui , supra note 129.

See Schwartz Woloshi , supra note 112;.

Baushke , supra note 129.

Schwartz L. M. Woloshin S. Welch H. G. , “Using a Drug Facts Box to Communicate Drug Benefits and Harms: Two Randomized Trials,” Annals of Internal Medicine 150, no. 8 (2009): 516–527.

See Health Canada, supra note 115.

Avorn J. , “Paying for Drug Approvals – Who's Using Whom?” New England Journal of Medicine 356, no. 17 (2007): 1697–1700;.

Lexchin J. , “Harmony in Drug Regulation, But Who's Calling The Tune? An Examination of Regulatory Harmonization in Health Canada,” International Journal of Health Services 42, no. 1 (2012): 119–136;.

Lexchin J. , “Drug Approval Times and User Fees,” Pharmaceutical Medicine 22, no. 1 (2008): 1–11.

Lexchin J. , “Relationship between Pharmaceutical Company User Fees and Drug Approvals in Canada and Australia: A Hypothesis-Generating Study,” Annals of Pharmacotherapy 40, no. 12 (2006): 2216–2222.

See Lexchin , supra note 136;.

United States Government Accountability Office, Food and Drug Administration: Effect of User Fees on Drug Approval Times, Withdrawals, and Other Agency Activities, September 17, 2002, available at <http://www.gao.gov/products/GAO-02-958>(last visited April 16, 2014).

Id.;.

Lexchin J. , “New Drugs and Safety: What Happened to New Active Substances Approved in Canada between 1995 and 2010?” JAMA Internal Medicine 172, no. 21 (2012): 1680–1681.

See Avorn , supra note 136.

Kramer D. B. Kesselheim A. S. , “User Fees and Beyond – The FDA Safety and Innovation Act of 2012,” New England Journal of Medicine 367, no. 14 (2012): 1277–1279.

See Lurie , supra note 34;.

Lexchin O'Donovan , supra note 35;.

GAO, supra note 21;.

Sukkar , supra note 120;.

Anonymous, “European Medicines Agency: Riddled with Conflicts of Interest,” Prescrire International 21, no. 132 (2012): 278.

See Lurie , supra note 34.

See Wood Mador , supra note 71.

Id.

This appears to occur most frequently during post-market surveillance. See Harris G. , “Potentially Incompatible Goals at FDA,” New York Times, June 11, 2007, at A14.

see Okie , supra note 84;.

Willman , supra note 105;.

The Adequacy of the FDA to Assure the Safety of the Nation's Drug Supply: Hearing Before the H. Subcomm. on Oversight and Investigations, Comm. on Energy and Commerce, 110th Cong. 191 (2007) (statement of Rep. Bart Stupak).

As explained by Health Canada:.

The SBDs will continue to be drafted by Health Canada technical writers, based upon Health Canada's regulatory review reports. The SBD draft will be sent to the Health Canada review team for comment and possible revision, in order to ensure that review conclusions are appropriately reflected and contained within the SBD. The completed SBDs will then be sent to the sponsor/manufacturer for review; feedback will be limited to inaccuracies of data and it is expected that only minor revisions, if any, will be made to the document as a result of industry feedback received.

See Health Canada, supra note 115.