Ralph Kuncl and Elizabeth Logue
Ethical Issues in Drug Development
Prepared by Anne Dalke
Additions, revisions, extensions are encouraged in the Forum
FDA and Drug Discovery | Historical Developments Affecting Industry’s Role in Drug Research
Having been invited to "tell a scientific story about a relevant public issue," Ralph had decided to "report in from the military industrial complex." He began with a current news story of a "minature epidemic," the recent deaths of four women who had taken the abortion pill RU-46. The primary source of this news, The New England Journal of Medicine, makes the point that the incidence of death from use of this drug is approximately 1 in 100,000; deaths related to pregnancy and surgical abortion are much higher. Although you "wouldn't know it from reading the newspaper article," these four deaths resulted from the "alignment of many stars." The newspaper headlines named the drug as the single causal factor in these deaths, but multiple other factors were equally important contributors. Since most of us get our science and public policy information from cursory reading of such articles, we are often misinformed. For instance, the common public report that "Vioxx causes heart attacks" is a simplified version of what the primary literature reports: that a single study linked the drug to an increased risk of hypertension (which is just one factor contributing to heart attacks).
Ralph then spent some time explaining the "mystery of how drugs get developed in this country." He walked us through the four stages of preclinical testing (on animals), clinical testing (on humans), review by the food and drug administration, and the final step of postmarketing surveillance. At the point at which the FDA approves a drug for limited application, only several thousand patients have been exposed to it. Since it's impractical to test millions of patients before the drug goes on the market, most serious consequences are not discovered in early testing. However, the "clock starts ticking" on patent protection at the very beginning of this process, long before it is determined whether a drug is either safe or efficacious. Patents are good for 17 years; it takes 11 years for the average drug to get to the market. By the time information about the most serious consequences is discovered, the drug company has already invested huge amounts of resources in the process, and needs to generate profits to cover not only the costs of the drug currently under development, but also the costs for the hundred or more drugs that "didn't get through the pipeline." Drug companies plow 5-15% of their yearly gross profits back into research and development.
Liz followed this account of the "nature of drug development in America" with a report of the ethical problems, as seen "from the liberal left." The top ten drug companies are richer than the next 40 combined, so we really need not be concerned about protecting their profitability. It is typically said that it costs $800 million to develop a new pill. However, the really costly part of drug development is the 15-20 year process of finding the disease mechanism, and this is not included in that figure. Liz had a number of stories to tell about the troubling consequences of research funded by pharmaceutical companies. For example, financial investment is significantly linked to trial outcomes: there is a 9-out-of-10 chance that research will come out in favor of a drug being marketed by the company that authorizes its study. There are many problems related to academic freedom: whistle-blowers who call attention to the dangers of a drug have been sued.
A number of important historical developments--increasing regulations to assure that products work, and are safe--have increased the costs to drug companies. With the tax revolt of the 1980s, government funding to universities was cut back, and the pharmaceutical industry began determining the academic research agenda. In order to promote the transfer of technology, a company that funds research gets exclusive marketing rights to the products being developed; universities often have equity interest in the company, and share its profits. There has been a proliferation of contract research organizations, which are cheaper and faster than universities: they design and implement studies, analyze data, run and write up clinical trials--and now dictate the terms to university investigators, who find themselves in competition with organizations that are investigating the drugs they themselves will bring to market.
These pharmaceutical companies have education divisions, with responsiblity for ghost-writing articles for medical journals; they provide packets of material for journal authors, and pay for supplements to publications like The New England Journal of Medicine, which depends on such companies for advertising revenue. The "folks putting in the money," rather than the researchers or the public, determine the research agenda. (For example, Nike withdrew $30 million in research funding from the University of Oregon, when the school began investigating working conditions in the Nike plants.) The sponsor of a study, rather than the investigators, have the main responsibility and decision-making ability about when and if the research is published.
Nurse practitioners are increasingly exhorted to diagnose and treat patients according to the research; they must have a research base for their practice. But with increased industry funding, the quality of quality of this research is questionable, and public confidence in it is likely to erode. If people are recruited for studies which are not brought to fruition, what is the ethical justification for exposing them to risk? As clinical research becomes increasingly complex, it requires the involvement of multiple centers; a researcher may have no communication with another; the authorizing company can collect all the data and then "deep-six the study" based on marketing decisions. Keeping the drug from the market also means preventing patients from getting reimbursed for its use. It may be decades before secondary usage of a drug is studied and approved. Whenever a drug is about to go "off-patent," minor alterations are made to it, in order to preserve the right to exclusive marketing.
Social scientists are bewildered by all the ethical questions raised by this report; there is a need for a lot of further discussion about the organizational structure of the chemical industry, and about its relations to the government and the private sector. There is a theory about the appropriate things that patent law is "supposed to be doing," but these things are not happening; much improvement of education and communication is needed. The sorts of large public conversations in the electorate which happen, for instance, in Ireland--about who gets medical care, and on what basis, or about prioritizing operations in hospitals--is never heard in this country. The dialogue needs to continue, and to deepen.
Discussion concluded with the observation that we all--patients, academicians, governmental officials and the pharmaceutical industry--share a desire for safe and efficacious drug to get to market. How can we realize that goal? Who will do most of the talking about ethics? Patients don't know enough; the pharmaceutical industry is (appropriately enough) focused on its shareholders, and the government on its citizens. It is academicians who should be the most motivated to carry on that conversation; we have a special responsibility to change the public story.
The conversation is invited to continue on-line.
The semester's brown bag series on "Rethinking Science in Society" will conclude next Friday, December 9, when Wendy Sternberg (Haverford Psychology) and Peter Brodfuehrer (Bryn Mawr Biology) will lead the discussion on the hot topic of "Pain and Foetuses." The discussion will focus on the neurobiology/psychology of pain in the context of pain/suffering surrounding prenatal/neonatal procedures. An overview of nervous system mechanisms of nociception, pain, and pain modulation will be given to help frame the discussion. To start you thinking about the issues, please take a look at Fetal Pain: A Systematic Multidisciplinary Review of the Evidence", JAMA 294, 8 (August 24/31, 2005): 947-954.