The March 12, 2014, Lab seminar was led by Edmond J. Safra Lab Fellow, Jennifer E. Miller. During her second fellowship year, Miller has continued to explore the possibility of addressing prominent ethical concerns and trust gaps in the pharmaceutical industry through a number of reform strategies, particularly policy amendments and a third party rating system. Her seminar presentation, titled, “Bioethical Standards for the Pharmaceutical Industry? Concerns & a Reform Strategy,” updated Lab participants on her efforts to assess the prevalence of ethics problems in pharmaceutical companies and to identify reasonable remedies to address widespread problems in companies today that can adversely impact patient, public and global health.
Miller began her presentation by giving a brief overview of the areas where bioethical concerns commonly arise when pharmaceutical companies bring a drug to the global market. These ethics concerns generally fall into five categories, according to her analysis: Clinical trial design, clinical trial conduct, the communication of clinical trial results, drug marketing, and access to medicines. In regards to clinical trials, one primary concern is that trials may be biased if companies inappropriately cherry pick their research subjects and research settings. Miller provided a compelling anecdote of this practice, which she learned of during her initial qualitative studies with drug company executives. One executive recalled a clinical trial for an osteoporosis drug that was conducted in a small Brazilian town where average levels of calcium in the local population were very low in comparison to the United States. The executive explained that because one of the measurements for success in this particular drug was a marked increase in calcium levels in patients, that the trial results were skewed. Therefore, when the drug was introduced to the American and European markets where levels of calcium are typically higher in patients, it was found to be less effective.
Moving on with the discussion, Miller shifted her attention to the problem of selective reporting and underreporting of clinical trial results by drug companies. In one study, researchers found that 30-50% of trials are unpublished. Perhaps not surprisingly, favorable results are twice as likely to be published. Further, Miller also explained that within the medical literature, 99% of papers have discrepancies. These discrepancies can range from unidentified research subjects to the omission of adverse effects, according to studies. Indeed, the problem of selective reporting and underreporting is so pervasive in the industry that the Institute of Medicine issued a report in 2009 warning that missing information “puts millions of patients at risk of using ineffective drugs and unsafe drugs . . .” This is particularly disconcerting because doctors rely on prescription guidelines, which are formulated from Meta analyses and reviews of the clinical trial literature; which begs the question: how are doctors to properly and effectively treat patients if their body of evidence is corrupted? Aside from the negative impact this selective reporting has on prescribing effective treatments, it can also pose the risk of harm to research patients, as in the case of the TGN1412 clinical trial disaster. In this case, patients in a clinical trial suffered from an acute clinical syndrome, which caused multiple organ dysfunctions. Had the results from a previous clinical trial conducted over a decade before been required to be published, these serious adverse events would most likely have been prevented.
At this point in the seminar, Miller went on to discuss her analysis of average rates of reporting, publication, and FDAAA compliance (Food and Drug Administration Amendments Acts) for 15 approved drugs by the largest pharmaceutical companies by market cap in 2012 (companies such as GSK, Gilead, Pfizer, etc.). Though the results were varied across the spectrum for each company, the average rate of trials with reported results was shockingly low. Less than a quarter of trials have reported results. She explained that this is largely due to the fact that companies are not legally required to disclose all trial results, only a small fraction of their clinical trial results. This in turn led to a discussion of potential reform strategies that would improve primary bodies of objective medical evidence. Some of these strategies might include: passing laws to strengthen existing governmental regulation to increase clinical trial monitoring, implementing private regulatory solutions, and Miller’s new idea of a third-party rating system.
Unlike the ethics accreditation system proposed in her previous fellowship year, Miller explained that a rating system would not require the cooperation of companies to disclose internal data relating to policies that an accreditation system would require. It would rely on government and public data. Further, ratings would be outcome-based, rather than process-based. She also contended that “naming, faming, and shaming” could incentivize companies to increase disclosure standards when bringing a new drug to market. At this point in the Lab seminar, one participant of the Lab encouraged Miller to examine industry indices, such as the MSCI Global Sector Indexes, as a potential example for how an industry accepted analysis framework might serve as a tool or industry benchmark. A former pharmaceutical employee, now a project director for Harvard’s multi regional clinical trial group, expressed concern over unintended public health consequences. For instance, what if an inferior drug scored higher in the transparency ranking over a better performing drug simply because the company disclosed more clinical trial results? Surely this could cause a public backlash. Miller acknowledged this issue and explained that it’s worth considering carefully, but that the medical evidence for determining safety, efficacy, and superiority is directly related to the proportion of disclosed trial information.
In summary, Miller discussed the common areas of drug development in the pharmaceutical industry where trust gaps and ethics concerns are most likely to arise. She then gave an overview of her efforts to measure the prevalence of the perceived ethics problems in companies today – beginning by analyzing disclosure and publication rates by some of the industry’s largest drug companies. This in turn led to a discussion of potential remedies, particularly a rating and ranking system on companies’ ethics and global health footprint. Finally, Lab participants discussed, among other things, competing incentives that Miller’s third-party program might offer to companies and differing methods of implementation, as well as who might be the likely consumer of the ranking results from her pilot rating system, such as medical societies, IRBs, formulary decision-makers, policy makers, investors and/or patient advocates.
-Summary composed by Joseph Hollow
 K. Lee et al, “Publication of Clinical Trials Supporting Successful New Drug Applications: A Literature Analysis,” PLoS Med 5, no. 9 (2008).