Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients (53 page)

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. Reputation 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.

7
Keitner, G.I., Posternak, M.A. & Ryan, C.E., 2003. How many subjects with major depressive disorder meet eligibility requirements of an antidepressant efficacy trial?
The Journal of Clinical Psychiatry
, 64(9), pp.1091–3.

8
Jarvinen TLN, Sievanen H, Kannus P, Jokihaara J, Khan KM. The true cost of pharmacological disease prevention. BMJ. 2011 Apr 19;342(apr19 1):d2175–d2175.

9
Van Staa T-P, Leufkens HG, Zhang B, Smeeth L. A Comparison of Cost Effectiveness Using Data from Randomized Trials or Actual Clinical Practice: Selective Cox-2 Inhibitors as an Example. PLoS Med. 2009 Dec 8;6(12):e1000194.

10
Safer DJ. Design and reporting modifications in industry-sponsored comparative psychopharmacology trials. J. Nerv. Ment. Dis. 2002 Sep;190(9):583–92.

11
Califf RM, DeMets DL. Principles From Clinical Trials Relevant to Clinical Practice: Part I. Circulation. 2002 Aug 20;106(8):1015–21.

12
Mueller PS, Montori VM, Bassler D, Koenig BA, Guyatt GH. Ethical Issues in Stopping Randomized Trials Early Because of Apparent Benefit. Annals of Internal Medicine. 2007 Jun 19;146(12):878–881.

13
Bassler D, Briel M, Montori VM, Lane M, Glasziou P, Zhou Q, et al. Stopping Randomized Trials Early for Benefit and Estimation of Treatment Effects: Systematic Review and Meta-regression Analysis. JAMA. 2010 Mar 24;303(12):1180–7.

14
Montori VM, Devereaux PJ, Adhikari NKJ, Burns KEA, Eggert CH, Briel M, et al. Randomized Trials Stopped Early for Benefit: A Systematic Review. JAMA. 2005 Nov 2;294(17):2203–9.

15
Trotta F, Apolone G, Garattini S, Tafuri G. Stopping a trial early in oncology: for patients or for industry? Annals of Oncology [Internet]. 2008 Jan 1 [cited 2012 Feb 14]; Available from: http://annonc.oxfordjournals.org/content/early/2008/04/09/ann onc.mdn042.full

16
Lurie P, Wolfe SM. Misleading data analyses in salmeterol (SMART) study. The Lancet. 2005 Oct;366(9493):1261–2.

17
Rickard KA. Misleading data analyses in salmeterol (SMART) study – GlaxoSmithKline’s reply. The Lancet. 2005 Oct;366(9493):1262.

18
Garcialopez F, Dealvaro F. INSIGHT and NORDIL. The Lancet. 2000 Dec 2;356(9245):1926–1926.

19
Safer DJ. Design and reporting modifications in industry-sponsored comparative psychopharmacology trials. J. Nerv. Ment. Dis. 2002 Sep;190(9):583–92.

20
Gilbody S, Wahlbeck K, Adams C. Randomized controlled trials in schizophrenia: a critical perspective on the literature. Acta Psychiatr Scand. 2002;105:243–251.

21
Montori VM, Jaeschke R, Schünemann HJ, Bhandari M, Brozek JL, Devereaux PJ, et al. Users’ guide to detecting misleading claims in clinical research reports. BMJ. 2004 Nov 6;329(7474):1093–6.

22
Shaughnessy AF, Slawson DC. What happened to the valid POEMs? A survey of review articles on the treatment of type 2 diabetes. BMJ. 2003 Aug 2;327(7409):266.

23
Melander H, Ahlqvist-Rastad J, Meijer G, Beermann B. Evidence b(i)ased medicine – selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications. BMJ 2003;326:1171–3.

24
Vedula, S Swaroop, Lisa Bero, Roberta W Scherer, and Kay Dickersin. ‘Outcome reporting in industry-sponsored trials of gabapentin for off-label use.’ The New England Journal of Medicine 361, no. 20 (November 12, 2009): 1963–1971.