FEATURE ARTICLE

Tampering with the Evidence

By James Dolan, MD

The press and politicians have showered much attention on the shameful state of affairs whereby the richest country in the world finds almost a sixth of its population without health insurance. Meanwhile, big business and people with coverage have been ratcheting up the complaints about their share of the ever-increasing cost. Locally we seem to be entering a crisis phase in terms of access to providers. Despite all the turmoil on these fronts, I suggest that the most urgent challenge to American medicine today is not the aging of our population, the morass of reimbursement, or the embarrassment of access to care. The dagger pointed at the heart of our profession, threatening our ability to care for our patients, is the influence wielded by the medical-industrial complex in research and education.

Our patients may fret about the lack of access and the growing cost of care, but they still have faith in our trustworthiness–more than they have for most other professions.[1] Many patients hold the insurance companies in contempt and have little love for the pharmaceutical industry, but they continue to regard us as above the fray. In their view, we are purveyors of healing and—while somewhat tainted by the influence of pharmaceutical and medical-device money—essentially ethical and worthy of trust. If our patients realized that much of what we offer is based on evidence that is often tainted and sometimes nearly bankrupt, a crisis in confidence would be the logical response.

Physicians are familiar with the HRT, Vioxx and Vytorin stories. We have seen the studies about the influence of PhRMA money on our prescribing practices,[2] and our gut tells us that the drug industry, which recently achieved the highest gross and net profits of any in the world,[3] would not spend over $7 billion a year on us if the payments did not affect its bottom line. Nonetheless, we still want to trust the elegant studies published in the hallowed journals of our profession. We ourselves are products of the medical schools, and we are inclined to put our faith in the medical knowledge that emanates from these great institutions. We are also prone to accepting the evidence that shows we can positively influence our patients’ health; we want to believe that our pills work. We know that studies can be unfairly contrived, results buried, and researchers bought; but we are loathe to admit that academia and expert panels are to a troubling extent beholden to PhRMA and the medical-device makers.[4] The evidence they produce and the guidelines they promulgate are often designed more to further sales than to improve the health of our patients.

Four years ago, the International Committee of Medical Journal Editors found that “selective reporting of [clinical] trials does occur, and it distorts the body of evidence available for clinical decision-making.”[5] These editors (of JAMA, NEJM, Annals of Internal Medicine, Lancet and others) established a requirement that any study to be published in their journals would be required to register publicly prior to enrolling human subjects. Certainly this requirement represents a step in the right direction, but it offers only minimal protection from the misrepresentations found in the Vytorin fiasco, or from the years of distorted evidence behind statins and antidepressants, or from the drug companies’ almost complete takeover of the research agenda.

The Vytorin scandal stands out as an egregious example of what happens when those who stand to profit from clinical trials are responsible for undertaking them. The delay in releasing the results of the Vytorin study (which was completed in April 2006 but only partially reported in January 2008, after prompting from Congress) allowed for the continued prescribing of the medication under faulty assumptions–to the tune of $8.9 billion.[6] Much of the concern in the medical community has been to reassure patients that there is no risk from continued use of Vytorin. Perhaps a more appropriate response would be a combination of confusion and outrage: confusion as to why we are spending billions of dollars a year on a medicine whose effectiveness in altering outcomes that matter remains questionable, and outrage that Merck and Schering-Plough were allowed to delay publication of damaging results until they were forced to do so. We have been misled by commercial interests and have thereby unwittingly misled our patients. The mistake is not so much in having recommended Vytorin to our patients, but rather in continuing to put our faith in corrupt research and in not demanding systemic reform.

The case of the ubiquitous statins provides more evidence of the guiding hand of industry sponsors when the financial stakes are high. A large body of evidence supports the use of HMG-coA reductase inhibitors for secondary prevention, and for primary prevention in high-risk men. However, the drive to expand the market to include low- and moderate-risk men and women reveals the extent to which both research and conclusions have been influenced by the drug companies.

A recent analysis of 95 randomized controlled trials comparing the efficacy of a chosen statin drug to another statin or non-statin therapy discovered that the odds ratio of results in favor of the trial sponsor’s brand was greater than 20.[7] Many explanations for this effect are possible, but they all involve intentionally manipulating factors that influence the results. An analysis of cost-effectiveness studies of statin therapy published between 1995 and 2003 revealed that 100% of the conclusions favored the sponsor’s brand.8 The same analysis found that industry-sponsored studies claimed cost-effectiveness ratios far below independent studies.

More fundamentally, the expert panel behind the National Cholesterol Education Program, which in 2001 called for an almost three-fold increase in the number of Americans recommended for statin therapy, was composed of five members with extensive ties to pharmaceutical companies. The composition of the panel may or may not explain in part why the panel extrapolated findings in men to include women in their recommendations, even though there was no evidence of benefit for primary prevention in women. The panel’s composition may also explain why the panel ignored the evidence from the study best equipped to measure the effect of primary prevention on men at moderate risk (AFCAPS/TexCAPS), which concluded that statins had no effect on all-cause mortality; and why the panel contradicted its own conclusion that $100,000 per QALY saved was too expensive, since the data upon which they based their therapy recommendations demonstrated that the cost for treating most of these patients far exceeded this number. Finally, the panel’s relationship with pharmaceutical companies may help to explain why the panel neglected to update its recommendations when subsequent results from the ALLHAT and PROSPER trials seemed to question the rationale for and certainly the economics behind primary prevention in low- or moderate-risk patients.[9]

The story behind the marketing of antidepressant medication is no less instructive. Pills that promised to ameliorate everything from true clinical depression to low mood were the bestselling class of drugs between 1999 and 2001, generating over $10 billion a year for the pharmaceutical companies, based on data which demonstrated that the pills worked on average less than 10% better than placebo.[9,10] If that were the end of the story, we might simply wonder if we had been conned into a poor financial deal. Closer inspection, however, reveals a more troubling truth.

A recent review of FDA files evaluating twelve antidepressants found that 31% of the studies were never published.[11] Unsurprisingly, 97% of the positive studies were heralded; but 22 negative studies never saw the light of day, and another 11 studies were twisted to show a positive effect. Shockingly, only 51% of the studies demonstrated a positive effect. By ignoring the negative studies, the overall increase in the apparent effectiveness of the 12 antidepressants studied was 32%. Reasonable people can disagree about the value of the benefit achieved–whether it offsets the morbidity from adverse effects and the neglect of more beneficial therapy—but most should agree that we have been intentionally misled and by extension have unwittingly done the same to our patients.

Acknowledging that corporate-sponsored research is tainted may not be much of a stretch for many people; accepting how deeply this influence reaches into the halls of academia can be a shock. The inexorable trend over the past few decades has been from majority NIH-sponsored research to majority corporate-sponsored research—currently over 80%.[9] This trend was accelerated by the Bayh-Doyle Act of 1980, which encouraged researchers and universities to patent their discoveries and enjoy the proceeds from commercial exploitation.[4] Up until that point, the predominant attitude among researchers had been disdain for commercial influence; but when the profits began pouring in, the stampede was on.

What ensued was a self-perpetuating race to the ethical bottom, defended in the name of survival. The descent was epitomized by the dilemma facing Harvard Medical School in the late 1990s. The “strict” guidelines at that time limited faculty from owning more than $20,000 in stock of companies whose products they were investigating. The guidelines came under fire not for their laxity but because of concerns about losing the most “prestigious” researchers.

In 2000, New England Journal of Medicine editor Marcia Angell stated that finding experts to write an editorial on depression therapy for the journal had become a challenge as “we found very few who did not have financial ties to drug companies that make antidepressants.” [4] She further insisted that the problem was widespread, particularly in specialties “that involve the heavy use of expensive drugs and devices.”

Two inevitable outcomes of this wholesale purchase of academia have been realized. First, the focus of research is now skewed toward areas that promise healthy remuneration rather than health (think erectile dysfunction vs. malaria). Second, the panels that create the guidelines we are encouraged to follow are often dominated by “experts” on the payroll of PhRMA.[9]

The above examples represent only the tip of an iceberg of corrupted evidence. They call into question a significant but unknowable share of our understanding of medicine. They also call into question many of the guidelines upon which we base our daily practice, upon which our patients bank their health, and for which we are all paying a painful percentage of our wealth. Unsurprisingly, the higher the monetary stakes involved, the more likely the data have been influenced.

The urgent question facing our profession is how to deal with the morass of misinformation before we do any more unintentional harm to patients. The solution to this problem is bigger than any single one of us and will challenge even our professional associations, as the obstacles are great and powerful. But if we do not take concerted action soon, we run the risk of losing the invaluable confidence our patients place in us–the trust which is so necessary for a healing relationship.

References

1. “Doctors and teachers most trusted among 22 occupations and professions,” The Harris Poll #61 (Aug. 8, 2006).
   
2. Wazana A, “Physicians and the pharmaceutical industry: Is a gift ever just a gift?” JAMA, 283:373-380 (2000).
   
3. Angell M, The Truth About the Drug Companies, Random House (2005).
   
4. Angell M, “Is academic medicine for sale?” NEJM, 342:1516-18 (2000).
   
5. DeAngelis C, et al, “Clinical trial registration: A statement from the International Committee of Medical Journal Editors,” NEJM, 351:1250-51 (2004).
   
6. Johnson L, “U.S. inquiry widened on delay in releasing data on cholesterol drug,” International Herald Tribune (Feb. 13, 2008).
   
7. Baro L, “Factors associated with findings of published trials of drug-drug comparisons,” PLoS Medicine, 4;6:184 (2007).
   
8. Messori A, “Cost effectiveness of statins for primary prevention of cardiovascular events is questionable,” BMJ, 327:808-809 (2003).
   
9. Abramson J, Overdosed America, Harper (2005).
   
10. Khan A, et al, “Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials,” Arch Gen Psychiatry, 57:311-317 (2000).
    
11. Turner E, “Selective publication of antidepressant trials and its influence on apparent efficacy,” NEJM, 358:252-260 (2008).