Journals Must Exercise Their Authority as Gatekeepers

by Vera Sharav

If physicians can’t rely on the unbiased objectivity of journal reports—they cannot practice evidence-based clinically responsible medicine.  Changes are needed to restore credibility to the medical literature.

December, 2005: an editor of The New England Journal of Medicine (NEJM) acknowledged under oath that although editors knew of three unreported Vioxx deaths in the VIGOR-Vioxx study, [1] they decided not to inform physicians.  That acknowledgement, five years after publication, was reported by Forbes, [2] then The Wall Street Journal (WSJ) [3] sending shock waves—but did it change journal policies?

May, 2006: The New York Times (NYT) reported: “Virtually every major scientific and medical journal has been humbled recently by publishing findings that are later discredited." [4]

July, 2006: Just after BMJ editor, Dr. Fiona Godlee’s editorial, Can We Tame the Monster, was posted, [6] the editor of the Journal of the American Medical Association (JAMA) acknowledged publishing two reports whose authors failed to disclose their financial ties to drug manufacturers. [7] The findings reported in JAMA provided a rationale for increased use of psychoactive drugs by women—even during pregnancy. [8] [9]

Less than a week later, the FDA issued two public health advisories warning about evidence of additional lethal risks linked to antidepressant drugs:

(a) persistent pulmonary hypertension in newborn infants whose mothers took antidepressants during pregnancy, [10] http://www.fda.gov/cder/drug/advisory/SSRI_PPHN200607.htm
(b) serotonin syndrome when taken with migraine medications. [11]  http://www.fda.gov/cder/drug/advisory/SSRI_SS200607.htm

These contradictions raise questions about the credibility of not only these two reports, but also of medical journals that clinicians rely on for guidance in their medical practice.  JAMA editor, Dr. Catherine DeAngeles told the WSJ (which broke the news) that she was “misled.” [7] When questioned by the Chicago Tribune, she snapped:  "I don’t give people lie detector tests.  I am not the FBI." [12] 

Do physician /authors and journals bear no moral, professional, or public responsibility when they publish misleading information resulting in preventable deaths?

July 19, 2006: the WSJ exposed the “perfect storm,” involving coalescing conflicts of interest violations. [13]  All eight prominent academic psychiatrists whose names are penned to a report in the official journal of the American College of Neuropsychopharmacolgy (ACNP), failed to disclose that they are paid members of the advisory board of Cyberonics, [14] the manufacturer of VNS (vagus nerve stimulation), an experimental surgically implanted device for the treatment of depression. The ninth author, an employee of the company, disclosed his company connection in the article. The report in Neuropsychopharmacology [15] purports to review the scientific evidence for the efficacy and safety of VNS. Its controversial approval “despite strong objection by FDA’s review team,” was severely criticized in a Congressional report. [16]

The principle author, Dr. Charles B. Nemeroff, "one of the nation’s most prominent psychiatrists" [13] is chairman of psychiatry at Emory University, a past president of ACNP, the editor-in-chief of Neuropsychopharmacology, and chairman of Cyberonics’ Mechanism of Action Advisory Board. [14] An editorial in the NYT [17] described these industry ties as “particularly incestuous.” “It is hard to know whether to be more upset at the journal’s failure to disclose these ties or at its decision to let such interested parties serve as authors in the first place.” The Times notes that “Early drafts of the article were prepared by a professional writer hired by the company.”   In other words, the paper was crafted not by the authors but by a “professional writer” hired by the sponsor.

Since the 1990s editors have known (or should have) that industry’s influence was penetrating journals not only directly (through advertising) but indirectly—by planting  favorable reports often written by professional ghostwriters but “authored” by influential leaders in their field. [18] Academic scientists traded their influence for cash, penning their names to biased, ghostwritten reports of trials they did not conduct, and whose source data they did not analyze. [19] Others, constrained by contractual publication restriction agreements with the sponsoring company, published fraudulent reports based on partial data findings.[20] As two thirds of medical research is now sponsored by industry, [21] the most influential (“high impact”) medical journals have become accomplices, camouflaging the commercial nature of industry promotional reports. [22]

Journals’ failure to take measures to stop this growing malaise provided a shield for corrupt practices that have undermined the integrity of science and the journals themselves.  Dr. Richard Horton, editor of The Lancet, calls medical journals “information laundering operations.” [23] The magnitude of industry’s corrupting influence has put the credibility of the entire academic literature reporting the safety and efficacy of (psychotropic) drugs under a dark cloud. [24]

June 2004: New York State Attorney General, Elliott Spitzer, charged GlaxoSmithKline with fraud for concealing negative data from its pediatric Paxil trials, [25] citing as evidence the dichotomy between published journal reports about and company documents refuting those claimed findings. [26] Only then did drug companies and their accomplices in academia wake up to the fact that their illegitimate practices constitute fraud and are subject to prosecution.  May 2006: GlaxoSmithKline reversed years of denial, acknowledging a six-fold increased suicide risk in adults linked to its antidepressant, paroxetine (Paxil)—thereby discrediting the entire Paxil literature. [5]

Writing about the SSRI antidepressants, Dr. Jonathan Leo observes: [27]
“Doctors accepted these drugs and prescribed them so willingly not because they were given free pens, free dinners, or even free trips. They put their trust in the drugs because they were backed by papers that were: written by professors at the major academic medical centers; approved by peer reviewers; published in the major medical journals; cited in review articles; discussed at meetings; defended by the ACNP…You can hardly fault the average physician for putting faith in them.” 

A Danish review (2006) of head to head studies of so-called atypical antipsychotics found that in 90% (of 33 studies) outcomes favored the sponsor’s drug. “This pattern resulted in contradictory conclusions across studies when the findings of studies of the same drugs but with different sponsors were compared.” [28]

Clearly major journals have not taken meaningful steps to protect the integrity of the scientific literature, or to cleanse it of discredited reports, or to ensure that biased findings are not published in the future.  Academic medicine is tainted because its gatekeepers, the journals, not only turned a blind eye; they joined in the desecration of the scientific foundation of medicine for a 70% profit return from reprints of “favorable” industry-sponsored reports. The NEJM reportedly made $697,000 from VIGOR reprints. [3]

BMJ editor, Dr. Goldee’s call for a separation between drug producers and evaluators is both valid and justified, but journals must exercise their authority as gatekeepers if the integrity of science and safety in medicine is to be restored.

A few suggestions:

1. Require authors to submit protocol and raw data to substantiate reported findings;
2. Post the protocols and data on a website so that independent analysis is possible;
3. Require authors’ to declare details of ties to the sponsor, indicating the nature of  those ties (e.g., consultant, speaker, investment; stock option; advisory board, grant recipient);
4. Require detailed disclosure of author’s contribution to the report: specify who wrote the first draft, and whether any “professional writers” were involved;
5. Publish only reports by authors who have control over the data and control over what is published;
6. Enforce publication policy; adopt penalties for violators barring them for 3 years. 

References:

1. Bombardier C., Laine L., Burgos-Vargas R., Davis B., Day R., Ferraz M. B., Hawkey C. J., Hochberg M. C., Kvien T. K., Schnitzer T. J., Weaver A., Reicin A., Shapiro D. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343:1520-1528.

2. Langreth, R and Herper, M. Merck’s Deleted Data, Forbes, December 8, 2005 http://www.forbes.com/home/sciencesandmedicine/2005/12/08/merck-vioxx-lawsuits_cx_mh_1208vioxx.html.

3. Amstrong, D. Bitter Pill: How the New England Journal Missed Warning Signs on Vioxx: Waited Years To Report Flaws in Article That Praised Pain Drug The Wall Street Journal, May 15, 2006; Page A1.  http://online.wsj.com/article/SB114765430315252591.html

4. Altman, L. For Science’s Gatekeepers, a Credibility Gap, The New York Times May 2, 2006. http://www.nytimes.com/2006/05/02/health/02docs.html?

5. See: GSK. Briefing. Paroxetine Adult Suicidality Analysis. April 5, 2006:  http://www.gsk.com/media/paroxetine_adult.htm; GSK. Letter to healthcare professionals: “Clinical worsening and suicide risk” May 2006:  http://www.gsk.com/media/paroxetine/mi_letter.pdf.

6. Godlee, F. Editor’s Choice: Can we tame the monster? BMJ, July, 2006; 333:

7. Armstrong, D, Drug Interactions: Financial Ties to Industry Cloud Major Depression Study, WSJ. July 11, 2006; Page A1
http://online.wsj.com/article/SB115257995935002947.html

8. Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, Suri R, Burt VK, Hendrick V, Reminick AM, Loughead A, Vitonis AF, Stowe ZN. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment.  JAMA. 2006 Feb 1;295(5):499-507.

9. Kurth, T, Gaziano, MJ, Cook, NR, Logroscino, G, Diener, HC Buring, JE. Migraine and Risk of Cardiovascular Disease in Women  JAMA. 2006;296:283-291.  <http://jama.ama-assn.org/cgi/content/full/296/3/283 >

10. FDA advisory: Pulmonary Hypertensionion: http://www.fda.gov/cder/drug/advisory/SSRI_PPHN200607.htm

11. FDA Advisory: Serotonin Syndrome: http://www.fda.gov/cder/drug/advisory/SSRI_SS200607.htm

12. Japsen, B. and Dow Jones News Wires, Journal tightens rules for authors: Doctors must disclose conflicts of interest, Chicago Tribune, July 12, 2006, http://www.chicagotribune.com/business/chi-0607120198jul12,1,1635801.story?coll=chi-business-hed

13. Armstrong, D Medical Reviews Face Criticism Over Lapses, WSJ. July 19, 2006; B1 http://online.wsj.com/article/SB115322997681109756.html

14. Nemeroff, CB, Mayberg, HS, Krahl, SE, McNamara, J, Frazer, A, Henry, TR, George, MS,  Charney, DS,  and Brannan, SK.  VNS Therapy in Treatment-Resistant Depression: Clinical Evidence and Putative Neurobiological Mechanisms  Neuropsychopharmacology (July, 2006) 31;1345–1355. Published online 19 April 2006.  http://www.nature.com/npp/journal/v31/n7/full/1301082a.html

15. Senator Charles Grassley. Review Of The FDA’s Approval Process For The Vagus Nerve Stimulation Therapy System For Treatment-Resistant Depression. Staff Report. http://finance.senate.gov/press/Gpress/02_2006%20report.pdf

16. See: Cyberonics Press Release, August 13, 2003 at: https://ahrp.org/cms/content/view/293/29   

17. Our Conflicted Medical Journals, NYT, Editorial, July 23, 2006
http://www.nytimes.com/2006/07/23/opinion/23sun2.html?     

18. Flanagin, A; Carey, LA, Fontanarosa, PB,  Phillips, SG,  Pace, BP, Lundberg, GD,  Rennie, D. Prevalence of Articles With Honorary Authors and Ghost Authors in Peer-Reviewed Medical Journals. JAMA. 1998;280:222-224.
 
19. Kaufman, A  and Julien, A. Scientists helped industry to push diet drug. Hartford Courant, April 10, 2000, p. A-1; A8; Peterson, M. Madison Ave. Has Growing Role In the Business of Drug Research, NYT,  November 22, 2002, A-1.

20. Chan, AW, Hróbjartsson, A, Haahr, MT, Gøtzsche, PC, Altman, DG. Empirical Evidence for Selective Reporting of Outcomes in Randomized Trials, JAMA 2004;291:2457-2465; Gøtzsche, PC, Hróbjartsson, A, Johansen, HK,  Haahr, MT,  Altman, DG, Chan, AW. Constraints on Publication Rights in Industry-Initiated Clinical Trials, JAMA 2006;295:1645-1646.

21. Egger M, Bartlett C, Juni, P. Are randomised controlled trials in the BMJ different? BMJ. 2001 Nov 24;323(7323):1253-4.

22. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003; 326: 1167-70.

23. Horton, R. “The Dawn of McScience,” New York Review of Books, March 11, 2004;
Smith R. “Medical Journals an extension of the marketing arm of drug companies,”

24. Healy, D and Cattell, D. Interface between authorship, industry and science in the domain of therapeutics, British Journal of Psychiatry (2003);183:22–27.

25. NYS Attorney General Press Release: https://ahrp.org/infomail/04/06/02.php

26. GSK memo details concealment strategy, 1998: https://ahrp.org/risks/SSRI0204/GSKpaxil/index.php

27.  Leo, J. The SSRI Trials in Children: Disturbing Implications for Academic Medicine Ethical Human Psychology and Psychiatry, Volume 8, Number 1, Spring 2006

28. 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. Am J Psychiatry. 2006 Feb;163(2):185-94.