Leopards in the Temple: Restoring Scientific Integrity to the Commercialized Research Scene

AG New York v. GlaxoSmithKline , June 2, 2004 at paragraph. 38. 2. Id. [emphasis in claim].

Seroxat/Paxil – Adolescent Depression. Position Piece on the Phase III Clinical Studies, October 1998. Document obtained from David Healy and in author's files.

The British agency had explicitly advised against prescription of SSRIs other than fluoxetine (Prozac). British Medicines and Healthcare Products Regulatory Agency, “Safety review of antidepressants used by children completed,” (Reference 2003/0505), available at <http://www.mhra.gov.uk/news/ssri_101203.htm>.

Health Canada had issued a formal warning that SSRIs were not approved for use in children and adolescents. Health Canada, “Health Canada advises Canadians under the age of 18 to consult physicians if they are being treated with newer anti-depressants,” (February 3, 2004) (advisory), available at <http://www.hc-sc.gc.ca/english/protection/warnings/2004/2004_02.htm> (last visited October 24, 2004).

American College of Neuropsychopharmacology, Executive Summary: Preliminary Report of the Task Force on SSRIs and Suicidal Behavior in Youth (January 21, 2004), available at <http://www.acnp.org/exec_summary.pdf> (last visited October 24, 2004). It is interesting that only this executive summary of the preliminary report is available and that 9 months after this release, the full report has not come out yet.

The document contains extensive conflict of interest statements. Five were members of at least one speaker bureau of a pharmaceutical company. See id., at 19–22.

Healy D. , Letter to Peter J. Pitts, Associate Commissioner for External Relations, Food and Drug Administration, February 19, 2004 (copy in files of author).

Harris G. , “FDA Panel Urges Stronger Warning on Antidepressants,” New York Times, September 15, 2004, at A-1. U.S. Food and Drug Administration, “FDA Launches a Multi-Pronged Strategy to Strengthen Safeguards for Children Treated With Antidepressant Medications,” (October 15, 2004) (news release). Available at <http://www.fda.gov/bbs/topics/news/2004/NEW01124.html> (last visited November 1, 2004).

Vedantam S. , “FDA Urged Withholding Data on AntiDepressants,” Washington Post, September 20, 2004, at A-02.

Healy D. and Cattell D. , “Interface Between Authorship, Industry and Science in the Domain of Therapeutics,” British Journal of Psychiatry 183 (2003): 22–27.

Angell M. , The Truth About the Pharmaceutical Industry: How They Deceive Us and What to Do About It (New York: Random House, 2004): at 166. The fact that advertising agencies took the lead in these acquisitions highlights some of the developments in medical research described further. See infra.

See Healy D. , Let Them Eat Prozac (Toronto: James Lorimer, 2003).

See Hastings Center Report (March 2000) with contributions by Elliott C. Healy D. Kramer P. Edwards J. and DeGrazia D. .

Goldbloom D.S. , Letter to David Healy, April 20, 2001. The letter has been posted with other relevant correspondence on the internet. Available at <http://www.pharmapolitics.com/index.html> (last visited October 24, 2004).

Healy D. , “Conflicting Interests in Toronto: Anatomy of a Controversy at the Interface of Academia and Medicine,” Perspectives in Biology and Medicine 45 (2002): 250–63; and Healy , supra note 13, at 311–321.

Nemeroff Charles Dr. was also the focus of a high profile controversy over his lack of disclosure of significant financial interests in a review for Nature Neuroscience. See infra.

I discuss some specific aspects of this case in a forthcoming article in Monash Bioethics Review.

World Health Organization, “Depression” (2003), available at <http://www.who.int/mental_health/management/depression/definition/en/print.html> (last visited October 24, 2004).

Healy D. , The Anti-Depressant Era (Cambridge, Mass.: Harvard University Press, 1997).

Elliott C. , Better than Well: American Medicine Meets the American Dream (New York: Norton, 2003): at 124.

Shorter E. , A History of Psychiatry: From the Era of the Asylum to the Age of Prozac (New York: John Wiley and Sons, 1997): at 290.

See Healy , supra note 13, at 117.

For a detailed investigative journalism report on the Fen-Phen controversy, see Mundy A. , Dispensing with the Truth: The Victims, the Drug Companies, and the Dramatic Story Behind the Battle over Fen-Phen (New York: St. Martin's Press, 2001).

Duffy S.P. , “Judge Approves Fen-Phen Settlement,” The Legal Intelligencer, August 29, 2000, at 1. The court saga continues, though. In the coming months, more than 5,800 cases are expected to go to trial in New Jersey alone. See Toutant C. , “N.J. Judge Readies First Batch of Fen-Phen Lawsuits for Trial,” New Jersey Law Journal, August 10, 2004.

Kolata G. and Petersen M. , “Hormone Replacement Study a Shock to the Medical System,” New York Times July 10, 2002, at A-1.

Petersen M. , “Court Papers Suggest Scale of Drug's Use,” New York Times, May 30, 2003, at C-1; Emery T. , “Whistleblower's Law Suit Being Closely Watched by Industry,” Associated Press, August 10, 2003; Kowalczyk L. “Pfizer Drug Strategy Probed: States Question Marketing Tactics for Neurontin,” Boston Globe, October 18, 2002, at D-2.

Topol E.J. , “Failing the Public Health – Rofecoxib, Merck, and the FDA,” New Engl. J. Med. 351 (2004): 1707–1709, at 1707.

Kaufman M. , “FDA Official Alleges Pressure to Suppress Vioxx Findings,” Washington Post, October 8, 2004, at A-23.

Editorial, “Vioxx: An Unequal Partnership Between Safety and Efficacy,” The Lancet 364 (2004): 1287–1288, at 1288.

See Bodenheimer T. , “Uneasy Alliance: Clinical Investigators and the Pharmaceutical Industry,” New Engl. J. Med. 342 (2000): 1539–1544; and Rettig R.A. , “The Industrialization of Clinical Research,” Health Affairs 19, no. 2 (2000): 129–146. For two recent books on the subject, see Krimsky S. , Science in the Private Interest: Has the Lure of Profit Corrupted Biomedical Research? (Lanham: Rowman & Littlefield, 2003); and Angell , supra note 12.

Act of Dec. 12, 1980, Pub. L. No. 96-517, Section 6(a), 94 Stet. 3015, 3019–28 (1980) (codified as amended at 35 U.S.C. Sections 200–212 (2994).

See Rai A.K. , “Regulating Scientific Research: Intellectual Property Rights and the Norms of Science,” Northwestern University Law Review 77 (1999): 77–152, at 93–94.

See e.g. Canadian Institutes for Health Research, CIHR: Towards A National Health Research Agenda (2001) at 10, available at <http://www.cihr-irsc.gc.ca/e/publications/revolution.pdf>; and CIHR, Transforming Health Research In Canada, available at <http://www.cihr-irsc.gc.ca/e/publications/cbj_supplement_e.pdf> (last visited October 24, 2004). This publicity appeared as a supplement in the magazines Canadian Business and Actualité.

Genome Canada and The Canadian Networks of Centres of Excellence Program (CNCEP) are the best examples of such initiatives. See the discussion in “Les conflits d'intérêts dans le temple de la science médicale: diagnostic et options thérapeutiques” in Gendreau Ysolde , ed., Dessiner la société par le droit/Mapping Society Through Law (Montréal, Les Éditions Themis, 2004): 77–115. For Genome Canada, see <http://www.genomecanada.ca/GCgenomeCanada/enBref/index.asp?l=e>. The CNCEP “fosters powerful partnerships between university, government and industry” and is “aimed at turning Canadian research and entrepreneurial talent into economic and social benefits for all Canadians.” See <http://www.nce.gc.ca/about_e.htm>. One of its recently funded centers is the Stem Cell Network which, as requested by the agency, has a dual mandate to promote high quality health research as well as the development of a vibrant biotechnology sector around stem cell research and which is currently planning to set up a commercial stem cell venture.

McCoy M. , “Bristol-Myers Study Backfires,” Chemical and Engineering News 82, no. 11 (2004): 8.

Winslow R. , “For Bristol-Myers, Challenging Pfizer Was A Big Mistake,” Wall Street Journal, March 9, 2004, at 1.

Elliott S. , “Viagra and the Battle of the Awkward Ads,” New York Times, April 25, 2004, at 3–1.

Editorial, “Depressing Research,” The Lancet 363 (2004): At 2088.

Willman D. , “Stealth Merger: Drug Companies and Government Medical Research,” Los Angeles Times, December 7, 2003, at A-1; Willman D. , “Ex-NIH Director Now Favors Limiting Drug-Company Ties,” Los Angeles Times, March 13, 2004, at A-21.

See infra notes 116–117 and text there.

For a critical analysis of industry's use of patient advocacy groups, see Mintzes B. , Blurring the Boundaries: New Trends in Drug Promotion (Amsterdam: Health Action International, 1998): Ch. 1, available at <http://www.haiweb.org/pubs/blurring/blurring.intro.html> (last visited October 24, 2004).

Mills F. , Patient Groups and the Global Pharmaceutical Industry: The growing importance of working directly with the consumer (Urch Publishing: London, 2000). Abstract available at <http://www.mindbranch.com/listing/product/R410-0024.html>.

In a recent full-page advertisement in the New York Times, the American Alzheimer's Association invited people to support “further research into prevention and a cure,” to “help ensure that our memories of Ronald Reagan live on.” The advertisement, which contains the questionable statement that “treatments are available,” was sponsored by two producers of Alzheimer drugs, Pfizer and Eisai – not surprisingly also the major contributors to the Association. New York Times, June 11, 2004 at A-17.

For a discussion of the use of Phase IV trials to boost drug prescription, see Angell , supra note 12, at 161–169.

See Krimsky , supra note 31, at 79–81.

Id. at 80.

Department of Health and Human Services, Office of Inspector General, Recruiting Human Subjects: Pressures in Industry-sponsored Research (June 2000), available at <http://oig.hhs.gov/oei/reports/oei-01-97-00195.pdf>.

See Angell , supra note 12, at 101.

See Lemmens T. and Elliot C. , “Guinea Pigs on the Payroll: The Ethics of Paying Research Subjects,” Accountability in Research 7 (1999): 3–20, for a discussion of problems and for further references related to the use of payment to subjects. For a discussion of, and references to, the use of finder's fees to promote recruitment, see Lemmens T. and Miller P.B. , “The Human Subjects Trade: Ethical and Legal Issues Surrounding Recruitment Incentives,” Journal of Law, Medicine & Ethics 31 (2003): 398–418.

Goldner J.A. , “Dealing with Conflicts of Interest in Biomedical Research: IRB Oversight as the Next Best Solution to the Abolition Approach,” Journal of Law, Medicine & Ethics 28 (2000): 379–404. See also Silberner J. , “A Gene Therapy Death,” Hastings Center Report 30, no. 2 (2000): 6.

Committee on Assessing the System for Protecting Human Research Participants, Institute of Medicine, Responsible Research: A Systems Approach to Protecting Research Participants (Washington D.C.: National Academies Press, 2001), at 38.

Id. at 10–11.

Association of American Medical Colleges, Task Force on Financial Conflicts of Interest in Clinical Research, Protecting Subjects, Preserving Trust, Promoting Progress: Policy and Guidelines for the Oversight of Individual Financial Conflict of Interest in Human Subjects Research (2001): at 3, available at <http://www.aamc.org/members/coitf/start.htm>.

Department of Health and Human Services, Financial Relationships and Interests in Research Involving Human Subjects: Guidance for Human Subject Protection, (2004) 69 Federal Register 26393 at 26394 [DHHS, Guidance Document]. See also Emanuel E.J. , “Oversight of Human Participants Research: Identifying Problems to Evaluate Reform Proposals,” Annals of Internal Medicine 141 (2004): 282–291.

For the impact of commercial recruitment practices, see e.g. Department of Health and Human Services, Office of Inspector General, Recruiting Human Subjects: Pressures in Industry-sponsored Research (2000). For further references, see the articles supra note 50.

Association of American Medical Colleges, supra note 54.

See Lexchin J. “Pharmaceutical Sponsorship and Research Outcome and Quality: Systemic Review,” British Medical Journal 326 (2003): 1167–1177; and Bekelman J.E. Li Y. and Gross C.P. , “Scope and Impact of Financial Conflicts of Interest in Biomedical Research,” JAMA 289 (2003): 454–465 at 463.

Krimsky , supra note 31, at 148–149.

Hilts reports how concerns about advertising revenues led the American Medical Association to stop publishing lists of fraudulent and useless drugs in the early 1950s. The association was losing the revenue of drug advertisements in its publications. Protecting America's Health: The FDA, Business, and One Hundred Years of Regulation (New York: Alfred Knopf, 2003): at 127.

See Drazen J.M. and Curfman G.D. , “Financial Associations of Authors,” New Engl. J. of Med. 346 (2002): 1901–1902.

Nemeroff C.B. and Owens M.J. , “Treatment of Mood Disorders,” Nature Neuroscience 5, suppl. (2002): 1068. See the discussion of the controversy in Brownlee S. , “Doctors Without Borders,” Washington Monthly 36, no. 4 (2004): 38–43.

Editorial, Nature Neuroscience 6 (2003): 997.

See Petersen , supra note 26.

See Willman (2003), supra note 40.

See Rennie D. and Flanagin A. , “Authorship! Authorship! Guests, Ghosts, Grafters, and the Two-Sided Coin,” JAMA 274 (1994): 469–471; Bodenheimer , supra note 31; Carpenter W.T. , “From Clinical Trial to Prescription,” Archives of General Psychiatry 59 (2002): 282–285.

Flanagin A. “Prevalence of Articles with Honorary Authors and Ghost Authors in Peer-Reviewed Medical Journals,” JAMA 280 (1998): 222–224.

Supra note 12 at 157–161.

See e.g. supra note 55.

See e.g. Medical Research Council of Canada (MRC), Natural Sciences and Engineering Research Council of Canada (NSERC), Social Sciences and Humanities Research Council of Canada (SSHRC), Tri-Council Policy Statement (Ottawa: Minister of Supply and Services, 1998), at Art. 4.1. In the section dealing with clinical trials, the Policy Statement also explicitly requires REBs to examine the budgets of clinical trials (see Art. 7.3).

Regulations Amending the Food and Drug Regulations (1024 – Clinical Trials), P.C. 2001–1042, C. Gaz. 2001.II.1116, at 1131. See the discussion in Lemmens and Miller , supra note 50.

Editorial, supra note 39.

See Healy supra note 20.

Dowling H. , cited in Hilts , supra note 60, at 125.

Id. at 126.

See text supra at note 41 and 65.

The Cochrane Group keeps, for example, a detailed evidence-based database of various therapeutic products. Available at <http://www.cochrane.org/indexO.htm>.

See Drummond R. , “Fair Conduct and Fair Reporting of Clinical Trials,” JAMA 282 (1999): 1766; and Sniderman A.D. , “The Need for Greater Involvement of Regulatory Agencies in Assessing Adverse Drug Reactions,” Canadian Medical Association Journal 162 (2000): 209.

De Angelis C. “Clinical Trial Registration: A Statement from the International Committee of Medical Journal Editors,” New Engl J. Med. 351 (2004): 1250–51. The committee includes the editors of the Journal of the American Medical Association, the New England Journal of Medicine, the Lancet and the Canadian Medical Association Journal.

Id., at 1251.

Office of Inspector General, Department of Health and Human Services, Institutional Review Boards: A Time for Reform (Boston, MA: Office of Inspector General, 1998); U.S. National Bioethics Advisory Commission, Ethical and Policy Issues in Research Involving Human Participants (Bethesda, MD: National Bioethics Advisory Commission, 2001); Committee on Assessing The System for Protecting Human Research Participants, Institute of Medicine, Responsible Research: A Systems Approach to Protecting Research Participants (Washington DC: National Academies Press, 2001). Similar criticism can be found in the Canadian context. See: Law Commission of Canada, The Governance of Health Research Involving Human Subjects, McDonald Michael M. , ed. (Ottawa: Law Reform Commission of Canada, 2000).

See the discussion in Waring D.R. and Lemmens T. , “Integrating Values in Risk Analysis of Biomedical Research: The Case for Regulatory and Law Reform,” University of Toronto Law Journal 54 (2004): 249–290 at pp. 277–282.

Cambell E.G. , “Characteristics of Medical School Faculty Members Serving on Institutional Review Boards: Results of a National Survey,” Academic Medicine 78 (2003): 831–836, at 833–834.

See Francis L. , “IRBs and Conflicts of Interest,” in Spece R.G. Shimm D.S. and Buchanan A. E. , eds, Conflicts of Interest in Clinical Practice and Research (New York: Oxford University Press, 1996): 418–436; Cho M.K. and Billings P. , “Conflict of Interest and Institutional Review Boards,” Journal of Investigative Medicine, 45 (1997): 154–159; Lemmens T. and Freedman B. , “Ethics Review for Sale? Conflict of Interest and Commercial Research Review Boards,” Milbank Quarterly 78 (2000): 547–584.

See Lemmens T. and Thompson A. , “Non-Institutional Research Review Boards in North America: A Critical Appraisal and Comparison with IRBs,” IRB: Ethics and Human Research 23, no. 2 (2001): 1–12; and Lemmens and Freedman , id.

DHHS, Guidance Document, supra note 55, at 26396.

Association of American Medical Colleges, supra note 54; and Association of American Medical Colleges, Task Force on Financial Conflicts of Interest in Clinical Research, Protecting Subjects, Preserving Trust, Promoting Progress II – Principles and Recommendations for Oversight of an Institution's Financial Interests in Human Subjects Research (2002), available at <http://www.aamc.org/members/coitf/2002coireport.pdf> (last visited October 24, 2004).

Gelsinger P. , “Uninformed Consent,” in Lemmens T. and Waring D.R. , eds., New Directions in Biomedical Research: Regulation, Conflict of Interest, and Liability (Book manuscript under review, University of Toronto Press).

See Van McCrary S. , “A National Survey of Policies on Disclosure of Conflicts of Interest in Biomedical Research,” New Engl. J. Med. 343 (2000): 1621–1626; and Cho M.K. , “Policies on Faculty Conflicts of Interest at US Universities,” JAMA 284 (2000): 2203–2208.

See Thompson J. Baird P. and Downie J. , The Olivieri Report: The Complete Text of the Report of the Independent Inquiry Commissioned by the Canadian Association of University Teachers (Toronto: James Lorimer, 2001); see Lemmens and Miller , supra note 50 at 412 and references there.

Schulman K.A. , “A National Survey of Provisions in Clinical-Trial Agreements between Medical Schools and Sponsors,” New Engl. J. Med. 347 (2002): 1335–1341, at 1339.

McCabe A.R. , “Note: A Precarious Balancing Act – The Role of the FDA as Protector of Public Health and Industry Wealth,” Suffolk University Law Review 36 (2003): 787–819.

Willman D. , “How A New Policy Led to Seven Deadly Drugs,” Los Angeles Times, December 20, 2000, at A-1, available at <http://www.drugawareness.org/Archives/Miscellaneous/122002Howanew.html>.

See Angell , supra note 12, at 209.

See Topol , supra note 28, at 1708.

Pub. L. No. 102-571, Title I, 102–105 Stat. 4491 (codified at 21 U.S.C. 379g, 379h). The permission to use user fees was renewed in the Food and Drug Administration Modernization Act of 1997, 21 U.S.C. 301 (1997). For a discussion of this Act, see Kulynych J. , “Will FDA Relinquish the ‘Gold Standard’ for New Drug Approval? Redefining ‘Substantial Evidence’ in the FDA Modernization Act of 1997,” Food Drug Law Journal 54 (1999): 127–149, at 127.

See the discussion in Angell , supra note 12, at 210. See also Hilts , supra note 60, at 276–290; and McCabe , supra note 91, at 792–794.

Hilts , id., at 280. Marcia Angell states bluntly that the drug regulatory agencies have become “big pharma's handmaiden.” Supra note 12, at 243.

Pomper S. , “Drug Rush: Why the Prescription Drug Market is Unsafe at High Speeds,” Washington Monthly 32, no. 5 (2000): 31–37, available at <http://www.washingtonmonthly.com/features/2000/0005.pomper.html>.

Eisenberg R. , “The Robert L. Levine Distinguished Lecture Series: Patents, Product Exclusivity, and Information Dissemination: How Law Directs Biopharmaceutical Research and Development,” Fordham Law Review 72 (2003): 477–491, at 489.

Id., at 477- For a discussion of the effect of these statutory provisions, see also Angell , supra note 12, at 173–192.

Orphan Drug Act of 1983, Pub. L. No. 97-414, 96 Stat. 2049 (1983) (codified as amended in sections of 15, 21, 26 U.S.C.). See the discussion in McCabe , supra note 91, at 795–796.

Pub. L. No. 98-417, 98 Stat. 1585 (1984) (codified as amended at 15, 21, 28, 35 U.S.C.).

Pub. L. 105–115, 111 Stat. 2296 (1977).

See Eisenberg , supra note 100.

21 C.F.R. 54 (1998).

See the discussion by Baram M. , “Making Clinical Trials Safer for Human Subjects,” American Journal of Law & Medicine 253 (2001): 271–283, at 262 and 274.

The label determines the official purpose for which a drug can be prescribed. It does not prevent physicians from prescribing the drug for other use – opening the door to various promotional tactics for off-label use. Promotion of off-label prescription was one of the controversial practices in the case of Neurontin (see supra).

Baram , supra note 107, at 262.

Id. at 253.

Health Canada only gives access to the much less informative official product monograph. See Lexchin J. , “Secrecy and the Health Protection Branch,” Canadian Medical Association Journal 159 (1998): 481–483, at 482–483.

See Angell , supra note 12, at 112.

See Healy , supra note 13 at 85.

Garland E. J. , “Facing the Evidence: Antidepressant Treatment in Children and Adolescents,” Canadian Medical Association Journal 170 (2004): 489–492; Whittington C.J. , “Selective serotonin reuptake inhibitors in childhood depression: Systematic review of published versus unpublished data,” The Lancet 363 (2004): 1341–1345.

See Healy , supra note 13, at 83–90; and Angell , supra note 12, at 112–113.

See Healy , id., at 116–119.

See Angell , supra note 12, at 210.

See id. and reference there. As mentioned, this is not unique to the drug regulatory agency. Marris E. , “Ethics Review Slams Government Panels Over Conflicts of Interest,” Nature 431 (2004): At 3.

Noah Lars , for example, seems to have confidence in the current REC review system because of the existence of complementary regulatory regimes. See “Deputizing Institutional Review Boards to Police (Audit?) Biomedical Research,” Journal of Legal Medicine 25 (2004): 267–293, in particular at 273–275.

See Krimsky , supra note 31, at 229.

Commission on the Future of Health Care in Canada, Building on Values: The Future of Health Care in Canada, Final Report (2002), in particular at 199–210, available at <http://www.hc-sc.gc.ca/english/pdf/romanow/pdfs/HCC_Final_Report.pdf

See Angell , supra note 12, at 244–247.

Neilson S. , “Healy and Goliath: The Creation of Psychopharmacology,” Canadian Medicial Association Journal 170 (2004): 501–502.

Dickens B. , “Conflicts of Interest in Canadian Health Care Law,” American Journal of Law & Medicine 21, No. 2-3 (1995): 259–280, in particular at 273–274.

Kalb P.E. and Koehler K.G. , “Legal Issues in Scientific Research,” JAMA 287 (2002): 85–91.

See Lemmens & Miller , supra note 50.

Krasner Jeffrey , “SEC focusing on drug makers: Full disclosure of tests called key,” Boston Globe, September 27, 2004, at C-4.

Press E. and Washburn J. , “The Kept University,” Atlantic Monthly (March 2000): 39–54, at 54.