Manipulation of Prescription Drug Research Data: Merely an Ethical Breach or a Fraudulent Claim?
Pharmaceutical companies are intimately involved in the modern research and development (R&D) world. They conduct clinical trials to satisfy the Food and Drug Administration’s (FDA) regulatory requirements to file new drug applications (NDAs), prove the efficacy of new “uses” for existing products, and often design trials which compare the safety and effectiveness of their product to a competitor. These trials have the dual effect of advancing a body of evidence surrounding a particular therapy and serving as powerful advertising and marketing pieces. According to an insider article, “For a pharmaceutical company, getting research published in a peer-reviewed medical journal is like winning a stamp of approval from its most influential audience. It’s an automatic validation unmatched by any other medium.” 1 This research is used as a selling tool to validate claims made about prescription drugs, assuage worries about negative product effects, and at times, to provide proof that a product is superior to its competitor. At first blush, selling with peer-reviewed clinical trials seems to be the pharmaceutical industry’s way of presenting impartial scientific data about their products. However, when one looks behind the scenes as to how some of these trials are brought to fruition by the industry, it is prudent to question the ethics of this process and whether it is misleading to healthcare professionals (HCPs) and consumers.
The process of generating a string of clinical trials in the pharmaceutical industry has been referred to as “publication planning”. 2 This consists of a timeline of clinical trials studying the efficacy of a specific medical endpoint. This plan takes into account market dynamics, competitors, and other factors that may have an effect on a product throughout its post-NDA life cycle. It ostensibly predicts at what point in time the release of these publications will have the optimal promotional effect. Accounting for the above factors, a publication team determines not only publication timing, but also which authors will make the study most impressive and in what journal the article will be submitted. 3
In terms of authorship, many pharmaceutical companies employ in-house medical writers merely to refine articles and shorten time-to-publication while the principal investigator does most of the writing. In fact, some companies have drafted internal policies to reflect that this is the proper role of a medical writer. However, there is ample evidence that in many cases, internal pharmaceutical company publication teams, or external contract research organizations (CROs) are shaping every facet of the publication process – employing a process known as “ghostwriting. Throughout this article ghostwriting will refer to the process by which a pharmaceutical company or a CRO generates the methods by which data will be accumulated and analyzed; creates an outline for the manuscript; names a cherry-picked author to approve the final product; and pays that author to be listed on the journal submission. 4 Ghostwriting in the prescription drug arena is troublesome because it can conceal bias of the true author and in this context, where listed authors have contributed only marginally, if at all, to writing the manuscript, can constitute plagiarism. 5
An additional concern exists at the point of publication. It has been brought to light by several studies reviewing the medical literature that a significant proportion of safety and efficacy data generated and published in industry-sponsored clinical trials is biased in favor of that company’s product. 6 Furthermore, there is evidence that there has been considerable under-publication of unfavorable data by pharmaceutical companies with respect to specific products. 7 For example, it was recently reported that a German-based pharmaceutical company withheld from federal drug officials the results of a large clinical study indicating a widely used heart surgery drug increased the risks of death and stroke. 8 This is noteworthy because responsible treatment decisions founded on evidence-based medicine are only medically valuable when they rely on data that accurately presents the risk-benefit ratio for a particular product. Prescription by HCPs based on allegedly fraudulent data can pose a serious public health risk, as well as impose an unjust fiscal burden on federal healthcare programs such as Medicare.
To date there have been no legal sanctions against pharmaceutical companies for extreme forms of publication planning, including ghostwriting or underreporting of negative publication results. However, the scientific community has been clear about its position on these issues for some time and the industry has begun to follow. 9 In 2003, the International Committee of Medical Journal Editors (ICMJE), whose chief concern is to address ethical principles with relation to publication in biomedical journals, updated its non-binding uniform requirements for manuscripts submitted to biomedical journals. Applying the narrowest reading of the ICMJE guidelines, ghostwriters fall outside of their recommendations for ethical authorship. In virtually all cases, ghostwriters fail to meet ICMJE’s recommendation that authors make substantial contributions to conception and design of the trial. 10 It is evident that the industry is responsive to the ethical concerns surrounding ghostwriting as the Pharmaceutical Manufacturers of America (PhRMA) recently adopted the ICMJE’s guidelines as conditions for authorship as a suggested standard throughout the pharmaceutical industry. 11
While much of the scientific community, and now the pharmaceutical industry, has recognized that ghostwriting is outside the bounds of medical ethics, the question of whether this practice is fraudulent remains in a grey zone. With increased scrutiny by members of Congress and a political environment in which the government is emphasizing the importance of curbing fraud and abuse in the Medicare and Medicaid systems, it seems likely that an example could be made of a company involved in a ghostwriting scandal – particularly when it can be shown that a company not only hires ghostwriters, but has also keeps unfavorable scientific data from reaching the medical literature. 12
It is possible to get an idea about how the federal government is currently thinking about the issue of ghostwriting by noting Senator Charles Grassley’s recent inquiry into this practice. Senator Grassley has written several letters to several healthcare players, including a pharmaceutical company inquiring about ghostwriting. 13 It is interesting to note how the Senator frames his concerns. In each case, he characterizes ghostwritten studies as “subtle advertisements rather than publications of independent research”, and noted the significant impact this could have on physicians’ prescribing behavior, “which in turn affects the American taxpayer because the Medicare and Medicaid programs pay billions of dollars for prescription drugs.” 14 In short, the Senator seems to be following the federal dollars and subtly pointing out to parties benefiting from taxpayer funds that the practice of ghostwriting is unethical at best. Furthermore, Senator Grassley also uses language in his letter to a pharmaceutical company suggesting that taxpayer dollars should only be spent on those prescription drugs that are “safe and effective”. 15 This language tracks the Federal Food, Drug, and Cosmetics Act (FDCA) which mandates that each use of an approved prescription drug must be found to be safe and effective on the basis of adequate and well-controlled clinical trials. 16
Based on where this issue currently stands, attorneys may craft arguments alleging that these practices violate provisions of the False Claims Act (FCA). 17 Specifically, it may be argued that when a company submits a body of evidence skewed in its favor and reported in ghost-authored studies to the FDA for NDA-approval, the company is fraudulently and falsely inducing the FDA into believing that the risk-benefit calculus for its product is more favorable than the totality of the evidence demonstrates and is thus not safe and effective under the FDCA. Alternatively, under FDA’s exclusivity around “uses” regime, one could raise the argument that a company has been granted a new indication for its existing product based on fraudulent data as above. This can be construed as off-label promotion, which has been demonstrated to have severe FCA implications. 18 In both of the above scenarios, products determined to be unsafe and ineffective for any indication are ineligible for reimbursement under Medicare or Medicaid. Any federal dollars that have been spent on reimbursement for those products could be found to have been fraudulently induced under the FCA.
While there is ample room for pharmaceutical companies to defend themselves against these allegations, the current environment is one in which it is only a matter of time before research practices in the industry come under intense scrutiny – the adoption of new PhRMA guidelines suggests that this time has already come. Whether claims of fraudulent research practices will prevail under the FCA is unclear. What is also certain is the propensity for this type of publicity to have a significant negative impact on the image of pharmaceutical companies, as well as an undermining of the public’s trust in the integrity of the medical research system as a whole.
The new guidelines issued by PhRMA strengthening disclosure obligations for authors of medical manuscripts and adopting ICMJE guidelines for authorship is a step in the right direction. 19 While these guidelines have been criticized as doing no more than increasing the burden to disclose conflicts, they do recommend a thorough description of the study sponsor’s influence on study design, data collection and writing of the publication. 20 They do not go as far as banning third party authoring of manuscripts, but they do go a long way in increasing the transparency of the process. It is in the interest of corporate leaders to compare their research practices to the guidelines set forth by PhRMA and continue to question whether their research practices are developing an accurate body of evidence upon which to promote their products.
|1||Wendy Balter et al., The P’s and Q’s of Publication Planning, 23 Pharm. Exec. 130 (2000).|
|2||Adriane Fugh-Berman & Susanna J. Dodgson, Ethical Considerations of Publication Planning in the Pharmaceutical Industry, 4 Open Med. 33, 33 (2008).|
|4||Sergio Sismondo, Ghost Management: How much of the Medical Literature is Shaped behind the Scenes by the Pharmaceutical Industry, 9 PLoS Med. 286, 286 (2007).|
|5||Sheldon Krimsky, When Conflict-of-Interest is a Factor in Scientific Misconduct, 26 Med. & L. 447, 452 (2007).|
|6||Sismondo, supra at note 4.|
|7||Erick H. Turner, Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy, 358 N. Eng. J. Med. 252, 252 (2008).|
|8||Gardiner Harris, F.D.A. says Bayer failed to reveal drug risk study, N.Y. Times, Sept. 30, 2006.|
|9||Natasha Singer & Duff Wilson, Medical Editors Push for Ghostwriting Crackdown, N.Y. Times, Sept. 18, 2009 at B1.|
|10||International Committee of Medical Journal Editors, Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication (2003), http://www.icmje.org/urm_full.pdf.|
|11||Pharmaceutical Research and Manufacturers of America, Principles on Conduct of Clinical Trials, Communication of Clinical Trial Results (2009), http://www.phrma.org/files/042009_Clinical%20Trial%20Principles_FINAL.pdf.|
|12||John K. Inglehart, Finding Money for Health Care and Reform – Rooting Out Waste, Fraud, and Abuse, http://healthcarereform.nejm.org/?p=416#|
|13||Letter from Senator Charles Grassley, Ranking Member, Senate Committee on Finance, to DesignWrite Inc. ( Dec. 12, 2008), http://finance.senate.gov/press/Gpress/2008/prg121208a.pdf.|
|14||Letter from Senator Charles Grassley, Ranking Member, Senate Committee on Finance, to Wyeth Pharmaceuticals ( Dec. 12, 2008), 008/prg121208.pdf. (replies were received by Senator Grassley’s office responding to his inquiry surrounding their ghostwriting policies. In January 2009, Senator Grassley re-introduced S.301, Physician Payments Sunshine Act of 2009. The bill would amend Title XI of the Social Security Act to provide for transparency in the relationship between physicians and manufacturers of drugs, devices, biologicals, or medical supplies for which payment is made under Medicare, Medicaid, or SCHIP. This bill has been referred to the Senate Committee on Finance.|
|16||Federal, Food, Drug, and Cosmetics Act § 505(b)(1)(a), 21 U.S.C. § 355 (2000).|
|17||31 U.S.C. § 3729(a) (2008).|
|18||Press Release, Department of Justice, Justice Department Announces Largest Health Care Fraud Settlement in its History – Pfizer to Pay $2.3 Billion for Fraudulent Marketing ( Sept. 2, 2009), http://www.fbi.gov/pressrel/pressrel/pressrel09/justice_090209.htm.|
|19||Pharmaceutical Research and Manufacturers of America, supra at note 8.|