by Ben Goldacre
83 This is a vast story, told well elsewhere. Start with Curfman GD, Morrissey S, Drazen JM. Expression of concern reaffirmed. N. Engl. J. Med. 2006 Mar 16;354(11):1193.
84 Opinion: Misleading Drug Trials. The Scientist [Internet]. [cited 2012 May 15]. Available from: http://thescientist.com/2012/05/14/opinion-misleading-drug-trials/
85 The Yale Open Data Archive project, or YODA, is one good example of how this might look in the future.
Chapter 2: Where do New Drugs Come From?
1 I recommend the classic medical student textbook ‘Rang and Dale’: Rang & Dale’s Pharmacology. 6th ed. Churchill Livingstone; 2007. But also this, on the regulatory process around early drug development: Friedhoff LT. New Drugs: An Insider’s Guide to the FDA’s New Drug Approval Process for Scientists, Investors and Patients. 1st ed. PSPG Publishing, 2009.
2 Elliott C, Abadie R. Exploiting a research underclass in phase 1 clinical trials. New England Journal of Medicine. 2008;358(22):2316.
3 Cohen LP. To screen new drugs for safety, Lilly pays homeless alcoholics: it’s ‘quick cash’ to habitues of Indianapolis shelters; it vanishes quickly, too. Wall St J (East Ed). 1996 Nov 14;A1, A10.
4 Abadie R. The Professional Guinea Pig: Big Pharma and the Risky World of Human Subjects. 1st ed. Duke University Press, 2010.
5 Helms R, editor. Guinea Pig Zero: An Anthology of the Journal for Human Research Subjects. 1st ed. Garrett County Press; 2006.
6 Tucker T. Great Starvation Experiment: Ancel Keys and the Men Who Starved for Science. 1st University of Minnesota Press Ed. University of Minnesota Press; 2008.
7 Gorkin L, Schron EB, Handshaw K, Shea S, Kinney MR, Branyon M, et al. Clinical trial enrollers vs. nonenrollers: The Cardiac Arrhythmia Suppression Trial (CAST) Recruitment and Enrollment Assessment in Clinical Trials (REACT) project. Controlled Clinical Trials. 1996 Feb;17(1):46–59.
8 Sheppard VB, Cox LS, Kanamori MJ, Cañar J, Rodríguez Y, Goodman M, et al. BRIEF REPORT: If You Build It, They Will Come. J Gen Intern Med. 2005 May;20(5):444–7.
9 ACRO – CRO Market [Internet]. [cited 2012 Feb 11]. Available from: http://www.acrohealth.org/cro-market1.html.
10 MacDonald T, Hawkey C, Ford I. Time to treat as independent. BMJ. 2010 Nov 30;341(nov30 2):c6837–c6837.
11 Kassirer J. On the Take: How Medicine’s Complicity with Big Business Can Endanger Your Health. Ch 8. 1st ed. Oxford University Press, USA; 2004.
12 Pharmaceutical CSO – Pharmaceutical Commercialization – Quintiles [Internet.] Available from: http://www.quintiles.com/commercial-services/
13 DRUG TESTING GOES OFFSHORE – August 8, 2005 [Internet]. [cited 2012 Feb 11]. Available from: http://money.cnn.com/magazines/fortune/fortune_archive/200 5/08/08/8267653/index.htm
14 Thiers FA, Sinskey AJ, Berndt ER. Trends in the globalization of clinical trials. Nature Reviews Drug Discovery. 2008 Jan;7(1):13–4.
15 All of the issues around trials in developing countries are well covered in two books, Shah S. BODY HUNTERS, THE: Testing New Drugs on the World’s Poorest Patients. SCIE. THE NEW PRESS; 2007. And Petryna A. When Experiments Travel: Clinical Trials and the Global Search for Human Subjects. 1st ed. Princeton University Press; 2009.
16 Ethical and Scientific Implications of the Globalization of Clinical Research Seth W. Glickman, M.D., M.B.A., John G. McHutchison, M.D., Eric D. Peterson, M.D., M.P.H., Charles B. Cairns, M.D., Robert A. Harrington, M.D., Robert M. Califf, M.D., and Kevin A. Schulman, M.D. N Engl J Med 2009; 360:816–823. February 19, 2009.
17 Bansal N. The opportunities and challenges in conducting clinical trials globally. Clinical Research and Regulatory Affairs. 2012 Feb 9;1–6.
18 Ethical and Scientific Implications of the Globalization of Clinical Research Seth W. Glickman, M.D., M.B.A., John G. McHutchison, M.D., Eric D. Peterson, M.D., M.P.H., Charles B. Cairns, M.D., Robert A. Harrington, M.D., Robert M. Califf, M.D., and Kevin A. Schulman, M.D. N Engl J Med 2009; 360:816–823. February 19, 2009
19 Hyder AA, Wali SA, Khan AN, Teoh NB, Kass NE, Dawson L. Ethical review of health research: a perspective from developing country researchers. J Med Ethics. 2004 Feb;30(1):68–72.
20 Zhang D, Yin P, Freemantle N, Jordan R, Zhong N, Cheng KK. An assessment of the quality of randomised controlled trials conducted in China. Trials. 2008;9:22.
21 FDA Requires Foreign Clinical Studies be in Accordance with Good Clinical Practice to Better Protect Human Subjects by W. Thomas Smith – American Bar Association Health eSource October 2008 Volume 5 Number 2 [Internet]. [cited 2012 Feb 11]. Available from: http://www.americanbar.org/newsletter/publications/aba_healt h_esource_home/Volume5_02_smith.html
22 WikiLeaks cables: Pfizer ‘used dirty tricks to avoid clinical trial payout’ – Business – The Guardian [Internet]. [cited 2012 Feb 11]. Available from: http://www.guardian.co.uk/business/2010/dec/09/wikileaks-cables-pfizer-nigeria
23 US embassy cable Monday 20 April 2009, 16:00, Abuja 000671 ‘Pfizer reaches preliminary agreement for $75m settlement’ [cited 2012 Feb 11]. Available from: http://www.guardian.co.uk/world/us-embassy-cables-documents/203205
24 WikiLeaks cables: Pfizer ‘used dirty tricks to avoid clinical trial payout’ – Business – The Guardian [Internet]. [cited 2012 Feb11]. Available from: http://www.guardian.co.uk/business/2010/dec/09/wikileaks-cables-pfizer-nigeria
25 Jonathan Kimmelman, Charles Weijer, and Eric M Meslin, ‘Helsinki discords: FDA, ethics, and international drug trials,’ The Lancet 373, no. 9657 (January 3, 2009): 13–14.
26 Goodyear MDE, Lemmens T, Sprumont D, Tangwa G. Does the FDA have the authority to trump the Declaration of Helsinki? BMJ. 2009 Apr 21;338(apr21 1):b1559–b1559.
Chapter 3: Bad Regulators
1 Royal College of Physicians, London UK. INNOVATING FOR HEALTH. Patients, physicians, the pharmaceutical industry and the NHS. February 2009. Report of a Working Party.
2 If you’re very confused about the European Medicines Agency, and the UK MHRA, and how they relate to each other, it’s fairly simple. The MHRA used to approve drugs, now the EMA do, but they farm out some of the local work to the old national regulators, especially monitoring and communication, as well as some of the approval stuff.
3 I recommend the work of John Abraham, collected here: http://www.sussex.ac.uk/profiles/6
4 Owen BM, Braeutigam R. The Regulation Game: Strategic Use of the Administrative Process. Ballinger Pub Co; 1978. Via Abraham J. On the prohibition of conflicts of interest in pharmaceutical regulation: Precautionary limits and permissive challenges. A commentary on Sismondo (66:9, 2008, 1909–14) and O’Donovan and Lexchin. Social Science & Medicine. 2010 Mar;70(5):648–51.
5 http://www.alter-eu.org/sites/default/files/documents/lonngrendoc.pdf
6 http://www.alter-eu.org/sites/default/files/documents/lonngrendoc.pdf
7 http://www.alter-eu.org/fr/press-releases/2011/02/25/conflict-of-interest-case-involving-ex-ema-director
8 http://www.corporateeurope.org/publications/block-revolving-door
9 Lurie, P., Almeida, C., Stine, N., Stine, A. R., & Wolfe, S. M. (2006). Financial conflict of interest disclosure and voting patterns at food and drug administration drug advisory committee meetings. JAMA, 295, 1921e1928.
10 If you’re interested in starting on this, the following are a good place to start: http://www.nytimes.com/2009/09/25/health/policy/25knee.html?_r=1; http://www.nytimes.com/2005/02/25/politics/25fda.html. And the work of the Project On Government Oversight is excellent, led by the researcher who worked on Senator Grassley’s reports into the pharmaceutical industry: http://www.pogo.org/investigations/public-health/fda.html; http://pogoblog.typepad.com/pogo/2011/08/fdas-janet-woodcock-the-substance-behind-her-nonsubstantive-substantive-ties-to-industry.html
11 Light D, editor. The Risks of Prescription Drugs (A Columbia/SSRC Book. Columbia University Press; 2010).
12 Survey of FDA Scientists Shows They Feel Pressure to Exclude…: Oncology Times [Internet]. [cited 2012 May 6]. Available from: http://j
ournals.lww.com/oncologytimes/Fulltext/2006/08250/Survey_of_FDA_Scientists_Shows_T hey_Feel_Pressure.8.aspx
13 USATODAY.com – Survey: FDA scientists question safety [Internet]. [cited 2012 May 6]. Available from: http://www.usatoday.com/news/health/2004-12-16-fda-survey-usat_x.htm
14 European Journal of Clinical Pharmacology 2011 10.1007/s00228-011-1052-1 Anything new in EU pharmacovigilance? Silvio Garattini and Vittorio Bertele’.
15 Goldberg NH, Schneeweiss S, Kowal MK, Gagne JJ. Availability of Comparative Efficacy Data at the Time of Drug Approval in the United States. JAMA: The Journal of the American Medical Association. 2011 May 4;305(17):1786–9.
16 Bertele’ V, Banzi R, Gluud C, Garattini S. EMA’s reflection on placebo does not reflect patients’ interests. European Journal of Clinical Pharmacology [Internet]. 2011 Dec 2 [cited 2012 Feb 13]; Epub ahead of print. Available from: http://www.springerlink.com/content/4j733734v35381jk/
17 Garattini S, Chalmers I. Patients and the public deserve big changes in evaluation of drugs. BMJ. 2009 Mar 31;338(mar31 3):b1025–b1025.
18 Van Luijn JCF, Gribnau FWJ, Leufkens HGM. Availability of comparative trials for the assessment of new medicines in the European Union at the moment of market authorization. Br J Clin Pharmacol. 2007;63(2):159–162.
19 Stafford RS, Wagner TH, Lavori PW. New, but Not Improved? Incorporating Comparative-Effectiveness Information into FDA Labeling. N Engl J Med. 2009 Aug 12;NEJMp0906490.
20 Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991 Mar;324(12):781–788.
21 ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA. 2000 Apr;283(15):1967–1975.
22 Lenzer J. Spin doctors soft pedal data on antihypertensives. BMJ. 2003 Jan 18;326(7381):170.
23 Vilsboll T, Christensen M, Junker AE, Knop FK, Gluud LL. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ. 2012 Jan 11;344(jan10 2):d7771–d7771.
24 Grimes DA, Schulz KF. Surrogate end points in clinical research: hazardous to your health. Obstet Gynecol 2005;105:1114–8.
25 This graph is from Chapter 7 of an excellent (though long and serious) history of the FDA: Carpenter D. Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA. Princeton University Press; 2010.
26 Mitka M. FDA Takes Slow Road Toward Withdrawal of Drug Approved With Fast-Track Process. JAMA. 2011 Mar 9;305(10):982–4.
27 Press Announcements > FDA Proposes Withdrawal of Low Blood Pressure Drug [Internet]. [cited 2012 May 7]. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm222580.htm
28 United States Government Accountability Office. September 2009. NEW DRUG APPROVAL. FDA Needs to Enhance Its Oversight of Drugs Approved on the Basis of Surrogate Endpoints. http://www.gao.gov/new.items/d09866.pdf
29 Davis C, Abraham J. Desperately seeking cancer drugs: explaining the emergence and outcomes of accelerated pharmaceutical regulation. Sociology of Health & Illness. 2011 Jul 1;33(5):731–47.
30 Barbui C, Cipriani A, Lintas C, Bertel V, Garattini S. CNS drugs approved by the centralised European procedure: true innovation or dangerous stagnation? Psychopharmacology. 2006 Nov 22;190(2):265–8.
31 There is a good, free summary of the issues around this area in this PDF from the WHO: Aidan Hollis. Me Too Drugs: is there a problem? http://www.who.int/intellectualproperty/topics/ip/Me-tooDrugs_Hollis1.pdf
32 NICE, ‘CG17 Dyspepsia: full guideline,’ Guidance/Clinical Guidelines, http://guidance.nice.org.uk/CG17/Guidance/pdf/ English. But also, if the NICE guideline and its references aren’t enough for you (it’s from 2004) please do waste an hour of your time browsing other more recent trials. There’s nothing magical happening here for esomeprazole.
33 http://www.nytimes.com/2004/10/12/business/media/12drug.html
34 http://www.mediapost.com/publications/?fa=Articles.showArticle&art_aid=92473
35 http://www.forbes.com/forbes/2010/0412/opinions-healthcare-nexium-hmo-prescriptions-heads-up.html
36 Here I should declare an interest: I sit on the funding panel to address this exact question, every quarter, for the NHS ‘Health Technology Assessment’ programme. This funding stream exists specifically to identify trials that need to be done, but which no company would fund, comparing one drug against another, and if you are aware of any important areas where we don’t know which of two important treatments is best, you should submit a request (or if you’re lazy, email it to me).
37 If you’re very interested in this issue, there is a serious problem in the detail. The International Society of Drug Bulletins, which represents the academics and pharmacists producing friendly summaries of data for doctors, has been campaigning for five years to have access to something called Signal, a WHO publication which reports drug-safety issues raised by the raw case reports data. WHO has consistently refused, insisting that only ‘National Health Authorities’ are allowed to see it, but in 2012 they changed their mind, and are now planning wider access for other independent groups. This, sadly, does not end the saga. Drug companies are still allowed early access, to ‘read and comment’ prior to publication. And Signal is just a publication describing findings, it is not the individual case reports, which are held in something called VigiBase, and that still remains secret. The UK and US data are more easily available, but the EU data, as you might expect, is not. You can read more in the ISDB press release and website: http://www.isdbweb.org/publications/view/pharmacovigilance-data (‘Broadening access to signal is a positive step, but access to VigiBase is also needed’, ISDB, February 15th 2012).
38 Hazell L, Shakir SAW. Under-reporting of adverse drug reactions : a systematic review. Drug Saf. 2006;29(5):385–96.
39 L. Härmark and A. C. Grootheest, ‘Pharmacovigilance: methods, recent developments and future perspectives,’ European Journal of Clinical Pharmacology 64, no. 8 (June 4, 2008): 743–752.
40 FDA warns Pfizer for not reporting side effects – Reuters [Internet]. [cited 2012 May 8]. Available from: http://www.reuters.com/article/2010/06/10/us-pfizer-fdaidUSTRE6586PE20100610
41 Healy D: Let them eat Prozac. New York: New York University Press; 2004. Furukawa TA: All clinical trials must be reported in detail and made publicly available. BMJ 2004, 329:626. Via Gøtzsche PC. Why we need easy access to all data from all clinical trials and how to accomplish it. Trials. 2011 Nov 23;12(1):249.
42 Serena Frau et al., ‘Risk Management Plans: are they a tool for improving drug safety?,’ European Journal of Clinical Pharmacology 66, no. 8 (June 25, 2010): 785–790.
43 Giezen TJ, Mantel-Teeuwisse AK, Straus SMJM, Egberts TCG, Blackburn S, Persson I, et al. Evaluation of post-authorization safety studies in the first cohort of EU Risk Management Plans at time of regulatory approval. Drug Saf. 2009;32(12):1175–87.
44 Andrew Herxheimer, ‘Looking at EU pharmacovigilance,’ European Journal of Clinical Pharmacology 67, no. 11 (November 2011): 1201–1202.
45 Schwartz LM, Woloshin S. Communicating Uncertainties About Prescription Drugs to the Public: A National Randomized Trial. Arch Intern Med. 2011 Sep 12;171(16):1463–8.
46 EMA Press Office, 2 February 2012, EMA/30803/2012
47 Garattini S, Bertele’ V. Anything new in EU pharmacovigilance? Eur. J. Clin. Pharmacol. 2011 Nov;67(11):1199–200.
48 Garattini S, Bertele’ V (2010) Rosiglitazone and the need for a new drug safety agency. Br Med J 341:c5506. doi:10.1136/bmj.c5506
49 http://www.nap.edu/catalog.php?record_id=11750#orgs
50 http://www.iom.edu/Reports/2006/The-Future-of-Drug-Safety-Promoting-and-Protecting-the-Health-of-the-Public.aspx
51 Carpenter D. Reputatio
n and Power: Organizational Image and Pharmaceutical Regulation at the FDA. Princeton University Press; 2010.
52 European Journal of Clinical Pharmacology 2011 10.1007/s00228-011-1052-1 Anything new in EU pharmacovigilance? Silvio Garattini1 and Vittorio Bertele’1
53 Uncommon knowledge. Drug and Tuerapautics Bulletin. 2009 Nov 1; 47(11):121
54 Schwartz LM, Woloshin S, Welch HG. Using a Drug Facts Box to Communicate Drug Benefits and Harms Two Randomized Trials. Ann Intern Med. 2009 Apr 21;150(8):516–27.
55 Germany’s tough reimbursement rules cause drug companies to consider alternative drug trial solutions – FT.com [Internet]. [cited 2012 Feb 15]. Available from: http://www.ft.com/cms/s/2/d458d470-4696-11e1-89a8-00144feabdc0.html#axzz1mTzZ2jdb.
Chapter 4: Bad Trials
1 Anesthesiology News – Fraud Case Rocks Anesthesiology Community [Internet]. [cited 2012 Feb 12]. Available from: http://www.anesthesiologynews.com/ViewArticle.aspx?d= Policy per cent2B per cent26amp per cent3B per cent2BManagement&d_id=3&i=March per cent2B2009&i_id=494&a_id=12634&ses=ogst
2 This story is well covered in Wells F. Fraud and Misconduct in Biomedical Research. Chapter 5, Fourth ed. RSM Books; 2008. I highly recommend this book if you want to get started reading about fraud detection and management. Beware that it’s an academic book, and therefore appallingly expensive.
3 Rothwell PM. External validity of randomised controlled trials: ‘To whom do the results of this trial apply?’ The Lancet. 2005 Jan 1; 365(9453):82–93.
4 Pratt, C.M. & Moye, L.A., 1995. The Cardiac Arrhythmia Suppression Trial : Casting Suppression in a Different Light. Circulation, 91(1), pp.245–247.
5 Travers, J. et al., 2007. External validity of randomised controlled trials in asthma: to whom do the results of the trials apply? Thorax, 62(3), pp.219 –223.
6 Zimmerman, M., Chelminski, I. & Posternak, M.A., 2004. Exclusion criteria used in antidepressant efficacy trials: consistency across studies and representativeness of samples included. The Journal of Nervous and Mental Disease, 192(2), pp.87–94.
