Five Un-Easy Pieces of Pharmaceutical Policy Reform

For some classic discussions of the pharmaceutical industry, see Dowling H. F. , Medicines for Man: The Development, Regulation and Use of Prescription Drugs (New York: Alfred A. Knopf, 1970); Temin P. , Taking Your Medicine: Drug Regulation in the United States (Cambridge: Harvard University Press, 1980). For more recent critiques, see Angel M. , The Truth About Drug Companies: How They Deceive Us and What to Do about It (New York: Random House, 2004); Kassirer J. P. , On the Take: How Medicine's Complicity with Big Business Can Endanger Your Health (New York: Oxford University Press, 2005).

Lessig L. , “Two Conceptions of ‘Corruption,’” in Republic, Lost: How Money Corrupts Congress – and a Plan to Stop It (New York: Twelve-Hackette Book Group, 2011): At 226–247; Thompson D. F. , Ethics in Congress: From Individual to Institutional Corruption (Washington, D.C.: Brookings Institution Press, 1995).

For discussion of the misalignment of incentives for drug development and marketing and ways to address that problem, see Gagnon M.-A. , “Corruption of Pharmaceutical Markets: Addressing the Misalignment between Financial Incentives and Public Health,” Journal of Law, Medicine & Ethics 41, no. 3. (2013): 571–580; Light D. W. Lexchin J. Darrow J. , “Institutional Corruption of Pharmaceuticals and the Myth of Safe and Effective Drugs,” Journal of Law, Medicine & Ethics 41, no. 3. (2013): 590–600. See also Sismondo S. , “Key Opinion Leaders and the Corruption of Medical Knowledge: What the Sunshine Act Will and Won't Cast Light On,” Journal of Law, Medicine & Ethics 41, no. 3. (2013): 635–643; Miller J. E. , “From Bad Pharma to Good Pharma: Role of Accreditation, Certification, and Rating,” Journal of Law, Medicine & Ethics 41, no. 3. (2013): 601–610.

Center for Drug Evaluation & Research, Manual of Policies and Procedures 6020.3 (2007). Some me-too drugs do offer slightly fewer risks or slightly greater benefits than the original. Me-too drugs also do increase competition, but the price reductions are small because, typically, both the original and the me-too are patented. The FDA grants higher priority to reviewing drugs that offer important therapeutic advances. This alone, however, is not a strong incentive for investment in challenging and high-risk research. Ashburn T. T. Thor K. B. , “Drug Repositioning: Identifying and Developing New Uses for Existing Drugs,” Nature Reviews Drug Discovery 3, no. 8 (2004): 673–683.

A study of new drugs introduced in France from 1981 to 2001 found that only 12 percent were therapeutic advances. See “Drugs in 2001: A Number of Ruses Unveiled,” Prescrire International 11, no. 58 (2002): 58–50. When Prescrire evaluated drugs introduced beween 2002 and 2011, it found that only about 12 percent offered therapeutic advantages and only 1.6 percent offered substanial therapeutic advantages; “New Drugs and Indications in 2011,” Prescrire International 21, no. 126 (2012). One review of new molecular entities introduced between the mid-1970s and the mid-1990s found that only between 11 and 16 percent of new molecular entities produced therapeutic gains. See Light D. Lexchin J. , “Pharmaceutical R&D - What Do We Get for All That Money?” BMJ 344, no. 7869 (2012): E4348.

The key exception is tax subsidies to promote research on orphan drugs, drugs for a medical condition that affect less than 200,000 patients annually.

Ashburn T. Thor K. B. , “Drug Repositioning: Identifying and Developing New Uses for Existing Drugs,” Nature Reviews Drug Discovery 3, no. 8 (2004): 673–683.

Love J. Hubbard T. , “Prizes for Innovation of New Medicines and Vaccines,” Annals of Health Law 18, no. 2 (2009): 155–178; Love J. Hubbard T. , “The Big Idea: Prizes to Stimulate R&D for New Medicines,” Chicago Kent Law Review 1519, no. 3 (2007): 1528–1534; Hubbard T. Love J. , “A New Trade Framework for Global R&D,” PLOS Biology 82, no. 2 (2004): 0147–0150. Comment from Love J. , “Knowledge Ecology Int'l, to the Intergovernmental Working Group on Public Health, Innovation and Intellectual Property, World Health Organization, The Role of Prizes in Stimulating R&D,” September 30, 2007, available at <http://www.who.int/phi/public_hearings/second/contributions_section2/Section2_JamesLove-KEI_prizes.pdf> (last visited July 3, 2013); Love J. , Consumer Project on Tech., Evidence Regarding Research and Development Investments In Innovative and Non-Innovative Medicines (2003). See generally, Baker D. , Center for Economics & Policy Research, The Benefits and Savings from Publicly- Funded Clinical Trials of Prescription Drugs (2008). See generally, Pogge T. , “The Health Impact Fund: More Justice and Efficiency in Global Health,” Australian National University, Crawford School of Public Policy, Development Policy Center, Discussion Paper #7 (2011). See generally, Pogge T. , “The Health Impact Fund: Boosting Pharmaceutical Innovation without Obstructing Free Access,” Cambridge Quarterly Healthcare Ethics 18, no. 1 (2009): 78–86.

Legislation passed in 1962 required demonstrating that new drugs were safe and effective, but regulation specifying that to meet this standard required randomized trials was not promulgated until 1969. Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 351 (2012); U.S. Food and Drug Administration, Hearing Regulations and Regulations Describing Scientific Content of Adequate and Well Controlled Clinical Investigations, Federal Register 35, no. 90 (1970): 7250.

See Hilts P. J. , Protecting America's Health: The FDA, Business, and One Hundred Years of Regulation (New York: Alfred A. Knopf, 2003); Carpenter D. , Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA (Princeton: Princeton University Press, 2010).

See, for example, Interagency Coordination in Drug Research and Regulation: Hearing Before the Subcommittee on Reorganization and International Organization of the Committee on Government Operations, 88th Congress (1963); Examination of the Pharmaceutical Industry: Hearing on Section 3441 and Section 966 before the Subcommittee on Health and the Comm. on Labor and Public Welfare, 93rd Congress (1974); Preclinical and Clinical Testing by the Pharmaceutical Industry: Hearing on Preclinical and Clinical Testing by the Pharmaceutical Industry before the Subcommittee on Health of the Senate and the Subcommittee on Administrative Practice and Procedure and the Committee on Labor and Public Welfare, 94th Congress (1976); Preclinical and Clinical Testing by the Pharmaceutical Industry: Hearing on Preclinical and Clinical Testing by the Pharmaceutical Industry before the Subcommittee on Health of the Senate and the Subcommittee on Administrative Practice and Procedure and the Committee on Labor and Public Welfare, 94th Congress (1975); Drug Regulation Reform Act of 1978: Hearing on S. 2755 before the Subcommittee on Health and Scientific Research and the Comm. on Human Resources, 95th Congress (1978).

See, for example, Chan A. W. Hróbjartsson A. Haahr M. T. Gøtzsche P. C. Altman D. G. , “Empirical Evidence for Selective Reporting of Outcomes in Randomized Trials: Comparison of Protocols to Published Articles,” JAMA 291, no. 20 (2004): 2457–5465; Kesselheim A. S. Mello M. M. , “Confidentiality Laws and Secrecy in Medical Research: Improving Public Access to Data on Drug Safety,” Health Affairs 26, no. 2 (2007): 483–491.

See, Brown A. , “Understanding Pharmaceutical Research Manipulation in the Context of Accounting Manipulation,” Journal of Law, Medicine & Ethics 41, no. 3. (2013): 611–619; Feldman Y. Gauthier R. Schuller T. , “Curbing Misconduct in the Pharmaceutical Industry: Insights from Behavioral Ethics and the Behavioral Approach to Law,” Journal of Law, Medicine & Ethics 41, no. 3. (2013): 620–628.

Rodwin M. A. , “Independent Clinical Trials to Test Drugs: The Neglected Reform,” Saint Louis University Journal of Health Law & Policy 6, no. 1 (2012): 113–165.

Tobbell D. A. , Pills, Power, and Policy: The Struggle for Drug Reform in Cold War America and Its Consequences (Berkley: University of California Press, 2012).

See Rodwin , supra note 14.

Drug firms design and conduct some post-marketing studies because the FDA requires them to do so as a condition for approving sale of the drug.

For a thorough analysis of problems of drug safety, see Avorn J. , Powerful Medicines: The Benefits, Risks, and Costs of Prescription Drugs (New York: Alfred A. Knopf, 2004).

Bodenheimer T. , “Uneasy Alliance: Clinical Investigators and the Pharmaceutical Industry,” New England Journal of Medicine 342, no. 20 (2000): 1539–1542; Angell M. , The Truth About the Drug Companies: How They Deceive Us and What To Do About It (New York: Random House, 2004).

Lundh A. Sismondo S. Lexchin J. Busuioc O. A. Bero L. , “Industry Sponsorship and Research Outcome,” Cochrane Database of Systematic Review 12, no. 12 (2012): MR000033; Davidson R. A. , “Source of Funding and Outcomes of Clinical Trials,” Journal of General Internal Medicine 1, no. 3 (1986): 155–158; Als-Nielsen B. Chen W. Glund C. Kjaergard L. , “Association of Funding and Conclusions in Randomized Drug Trials: A Reflection of Treatment Effect or Adverse Events?” JAMA 290, no. 7 (2003): 921–928; Heres S. Davis J. Maino K. Jetzinger E. Kissling W. Leucht S. , “Why Olanzapine Beats Risperidone, Risperidone Beats Quetiapine, and Quetiapine Beats Olanzapine: An Exploratory Analysis of Head-to-Head Comparison Studies of Second-Generation Antipsychotics,” American Journal of Psychiatry 163, no. 2 (2006): 185–194.

Italy taxes pharmaceutical promotional spending. Bonini S. del Zompo M. Francavilla L. Garaci E. Garattini S. Liberati A. Rupolo G. , “Feasibility and Challenges of Independent Research on Drugs: The Italian Medicines Agency (AIFA) Experience,” European Journal of Clinical Investigation 40, no. 1 (2009): 69–86.

Langreth R. , “Drug Marketing Drives Many Clinical Trials,” Wall Street Journal, November 16, 1998; Pieters T. , “Marketing Medicines through Randomized Controlled Trials: The Case of Interferon,” BMJ 317, no. 7167 (1998): 1231–1233; Greenland P. Lloyd-Jones D. , “Critical Lessons from the ENHANCE Trial,” JAMA 299, no. 8 (2008): 953–955. The FDA tried to prevent drug firms from disseminating articles on off-label uses of their products. Drug firms and the Washington Legal Foundation sued the FDA, alleging that the policy was an unconstitutional restriction of commercial speech. Federal appellate courts held that the FDA policy was unconstitutional. For a summary of the WLF challenge and related cases and current status of the law, see Washington Legal Foundation v. Henney, 202 F.3d 331 (2000) FDA, Decision in Washington Legal Foundation v. Henney, Federal Register 65, no. 52 (2000): 14286–14288, FDA Docket No. 98N-0222.

France has started to allow under some control and evaluation, off-label durg use while a firm seeks approval to market a drug for a new use. See, Emmerich J. Dumarcet N. Lorence A. , “France's New Framework For Regulating Off-Label Drug Use,” New England Journal of Medicine 367, no. 14 (2012): 1279–1281. For a proposal to regulate off-label use in the United States, see, Kesselheim A. , “Off-Label Drug Use and Promotion: Balancing Public Health Goals and Commercial Speech,” American Journal of Law & Medicine 37, nos. 2 & 3 (2011): 225–257.

There would need to be measures to protect privacy. However, pharmaceutical firms already purchase prescription data from pharmacies that reveal the drug prescribed. It might also be possible to obtain this information from electronic medical records, but that would require obtaining much more mining of records from many more sources and it would also raise privacy concerns. See, Rodwin M. A. , “Patient Data: Property, Privacy & the Public Interest,” American Journal of Law & Medicine 36, no. 4 (2010): 586–618.

These issues are discussed in depth in Rodwin M. , “Rooting Out Institutional Corruption to Manage Inappropriate Off-Label Drug Use,” Journal of Law, Medicine & Ethics 41, no. 3. (2013): 654–664.

Vedula S. S. Bero L. Scherer R. W. Dickersin K. , “Outcome Reporting In Industry-Sponsored Trials of Gabapentin for Off-Label Use,” New England Journal of Medicine 361, no. 20 (2009): 1963–1971.

Dwan K. Altman D. G. Arnaiz J. A. Bloom J. Chan A.W. , “Systematic Review of the Empirical Evidence of Study Publication Bias and Outcome Reporting Bias,” PLoS ONE 3, no. 8 (2008): E3081. Chan A. W. Hrobjartsson A. Haahr M. T. Gotzsche P. C. Altman D. G. , “Empirical Evidence for Selective Reporting of Outcomes in Randomized Trials: Comparison of Protocols to Published Articles,” JAMA 291, no. 20 (2004): 2457–2465; Dickersin K. Chan S. Chalmers T. C. , “Publication Bias and Clinical Trials,” Controlled Clinical Trials 8, no. 4 (1987): 343–353; Easterbrook P. J. Berlin J. A. Gopalan R. , “Publication Bias in Clinical Research,” The Lancet 337, no. 8746 (1991): 867–872; Dickersin K. , “The Existence of Publication Bias and Risk Factors for Its Occurrence,” JAMA 263, no. 10 (1990): 1385–1389; Dickersin K. Scherer R. Lefebvre C. , “Identifying Relevant Studies for Systematic Reviews,” BMJ 309, no. 6964 (1994): 1286–1291; Dickersin K. , “How Important Is Publication Bias? A Synthesis of Available Data,” AIDS Education and Prevention 9, no. 1, Supp. (1997): 15–21; Scherer R. W. Langernberg P. Von Elm E. , “Full Publication of Results Initially Presented in Abstracts,” Cochrane Database of Systematic Reviews 2, no. 2 (2007).

Dickersin K. Rennie D. , “Registering Clinical Trials,” JAMA 290, no. 4 (2003): 516–523; Zarin D. Ide N. C. Tse T. , “Issues in Registration of Trials,” JAMA 297, no. 3 (2007): 2112–2120.

DeAngelis C. D. Drazen J. M. Frizelle F. A. , “Clinical Trial Registration: A Statement from the International Committee of Medical Journal Editors,” JAMA 292, no. 11 (2004): 1363–1364. There have been difficulties in enforcing this policy. See, Mathieu S. Boutron I. Moher D. Altman G. Ravaud P. , “Comparison of Registered and Published Primary Outcomes in Randomized Controlled Trials,” JAMA 302, no. 9 (2009): 977–984.

Food and Drug Administration Amendments Act, U.S. Public Law 110–85 (2007).

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, no. 2 (2011): D7373.

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; Chan A. W. Hrobjartsson A. Haahr M. T. Gotzsche P. C. Altman D. G. , “Empirical Evidence for Selective Reporting of Outcomes in Randomized Trials: Comparison of Protocols to Published Articles,” JAMA 291, no. 20 (2004): 2457–2465; 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.

Zarin D. Ide N. C. Tse T. , “Issues in Registration of Trials,” JAMA 297, no. 3 (2007): 2112–2120.

ICH Harmonised Tripartite Guideline, Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use, available at <http://www.pmda.go.jp/ich/m/m4_ctd_betsu1_m4kosei_01_6_21e.pdf> (last visited July 16, 2013); ICH Harmonised Tripartite Guideline, Structure and Content of Clinical Study Reports E3, available at <http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_Guideline.pdf> (last visited July 16, 2013); Doshi P. Jefferson T. Del Mar C. , “The Imperative to Share Clinical Study Reports: Recommendations from the Tamiflu Experience,” PLoS Med 9, no. 4 (2012): E1001201.

Rodwin M. A. Abramson J. , “Clinical Trials as a Public Good,” JAMA 308, no. 9 (2012): 871–872. To enhance public understanding of these studies and to promote FDA accountability, it also makes sense to require the FDA to disclose all of its reviews of applications for marketing new drugs and to disclose all clinical trial data. Turner E. H. , “A Taxpayer-Funded Clinical Trials Registry and Results Database,” Public Library of Medicine 1, no. 3 (2004): 180–182.

For a discussion of the risks of drugs on the market, see Light , supra note 3.

21 C.F.R. §§ 310.3–5.21; 21 C.F.R. § 314.80.

Government Accountability Organization, FDA Needs to Enhance Its Oversight of Drugs Approved on the Basis of Surrogate Endpoints, 2009, GAO-09-866.

Sasich L. D. Lurie P. Wolfe S. M. , The Drug Industry's Performance in Finishing Post-Marketing Research (Phase IV) Studies: A Public Citizen's Health Research Group Report, available at <http://www.citizen.org/hrg1520> (last visited July 16, 2013).

Food and Drug Administration Amendments Act, 21 U.S.C.A. § 301 (2007). The problems with the previous approach to pharmacovigilance are carefully described in the Institute of Medicine, The Future of Drug Safety: The Future of Drug Safety: Promoting and Protecting the Health of the Public (Washington, D.C.: National Academies Press, 2007); Behrman R. E. Benner J. S. Brown J. S. , “Developing the Sentinel System – A National Resource for Evidence Development,” New England Journal of Medicine 364, no. 6 (2011): 498–499.

Oldani M. J. , “Thick Prescriptions: Toward an Interpretation of Pharmaceutical Sales Practices,” Medical Anthropology Quarterly 18, no. 3 (2004): 325–356; Larkin J. M. , “Optimizing Resource Allocations with a Strategic Focus: An Accounting Perspective”, Journal of Business Case Studies 5, no. 5 (2009): 55–60.

Ziegler M. G. Lew P. Singer B. C. , “The Accuracy of Drug Information From Pharmaceutical Sales Representatives,” JAMA 273, no. 16 (1995): 1296–1298, Mintz B. Lexchin B. J. Sutherland J. M. Beaulieu M.-D. Wilkes M. S. Durrieu G. Reynolds E. , “Pharmaceutical Sales Representatives and Patient Safety: A Comparative Prospective Study of Information Quality in Canada, France and the United States,” Journal of General Internal Medicine (2013): 1–8; Lexchin J. , “What Information Do Physicians Receive from Pharmaceutical Representatives?” Canadian Family Physician 43, (1997): 941–945. “Cinq Ans D'observation et Un Constat: Rien a Attendre De La Visite Médicale Pour Mieux Soigner,” La Revue Prescrire 26, no. 272 (2006): 383–389; Bignall J. , “Monitoring Reps in France,” The Lancet 344, no. 8921 (1994): 536.

Armour v. City of Indianapolis, 132 S. Ct. 2073 (2012); San Antonio Independent School Dist. v. Rodriguez, 411 U.S. 1, 41 (1973).

Institute of Medicine, Committee on Planning a Continuing Health Professional Education Institute, Redesigning Continuing Education in the Health Professions (Washington, D.C.: National Academies Press, 2010), available at <http://www.nap.edu/catalog/12704.html> (last visited July 16, 2013).

Steinman M. A. Bero L. A. Chren M. M. , “Narrative Review: The Promotion of Gabapentin: An Analysis of Internal Industry Documents,” Annals of Internal Medicine 145, no. 4 (2006): 284–293. U.S. Government Accountability Office, GAO-08-835, Prescription Drugs FDA's Oversight of the Promotion of Drugs for Off-Label Uses (2008); see also, Rodwin M. A. , “Drug Advertising, Continuing Medical Education, and Physician Prescribing: A Historical Review and Reform Proposal,” Journal of Law, Medicine & Ethics 38, no. 4 (2010): 807–815.

Compliance Program Guidance for Pharmaceutical Manufacturers, Office of Inspector General, 68 Federal Register 86 (U.S. Department of Health and Human Services, 2003). Letter from Max Baucus, Chair, Senate Finance Committee, to Murray Kopelow, ACCME, April 27, 2007. Senate Committee on Finance, Use of Educational Grants by Pharmaceutical Manufacturers, Prt. 110–21. 110th Cong., 1st Session (2007), available at <http://www.finance.senate.gov/newsroom/chairman/release/?id=9b20d8ca-fca3–4cbe-8deb-94bd841eda7d> (last visited July 16, 2013).

See Rodwin , supra note 45.

Rodwin M. A. , “Reforming Pharmaceutical Industry-Physician Financial Relationships: Lessons from the United States, France and Japan,” Journal of Law, Medicine & Ethics 39, no. 4 (2011): 662–670.

Temin P. , Taking Your Medicine: Drug Regulation in the United States (Cambridge: Harvard University Press, 1980): 106–120; Moore D. A. Cain D. M. Loewenstein G. , Conflicts of Interest: Challenges and Solutions from Law, Medicine and Organization Settings (Cambridge: Cambridge University Press, 2004); Cain D. M. Loewenstein G. Moore D. A. , “The Dirt on Coming Clean: Perverse Effects of Disclosing Conflicts of Interest,” Journal of Legal Studies 34, no. 1 (2005): 1–23.

See, Sah S. Fugh-Berman A. , “Physicians under the Influence: Social Psychology and Industry Marketing Strategies,” Journal of Law, Medicine & Ethics 41, no. 3 (2013): 665–672.

“Tap Pharmaceutical Products Inc. and Seven Others Charged with Health Care Crimes; Company Agrees to Pay $875 Million to Settle Charges,” U.S. Department of Justice, available at <http://www.justice.gov/opa/pr/2001/October/513civ.htm> (last visited July 16, 2013); Rodriguez T. A. , “Physicians and the Pharmaceutical Industry: Knowing When to Look a Gift Horse in the Mouth,” in Gosfield A. , ed., Health Law Handbook (St. Paul: West Group, 2003). See also Cosgrove L. Wheeler E. E. , “Drug Firms, Codification of Diagnostic Categories & Bias in Clinical Guidelines,” Journal of Law, Medicine & Ethics 41, no. 3 (2013): 644–653. For a discussion drug marketing through opinion leaders, see Sismondo S. , “Key Opinion Leaders and the Corruption of Medical Knowledge: What the Sunshine Act Will and Won't Cast Light On,” Journal of Law, Medicine & Ethics 41, no. 3 (2013): 635–643; and Snow Landa A. Elliott C. , “From Community to Commodity: The Ethics of Pharma-Funded Networking Sites for Physicians,” Journal of Law, Medicine & Ethics 41, no. 3. (2013): 673–679.

Cosgrove L. Krimsky S. Vijayaraghavan M. “Financial Ties between DSM-IV Panel Members and the Pharmaceutical Industry,” Psychotherapy and Psychosomatics 75, no. 3 (2006): 154–160.

See, Rodwin M. A. , Conflicts of Interest and the Future of Medicine: The United States, France and Japan (New York: Oxford University Press, 2011).

Brown L. D. , “The Fox and the Grapes: Is Real Reform beyond Research in the United States?” Journal of Health Politics, Policy and Law 37, no. 4 (2012): 587–609, at 588.