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Rezulin, the first thiazolidinedione drug, was withdrawn from the market in 2000. Just three years earlier, the FDA had approved Rezulin through a “fast track” approval process, marking January 1997 as the beginning of a new era in type 2 diabetes management by helping type 2s make use of their own insulin more effectively.
In the human clinical trials for Rezulin, however, a small number of patients experienced some decline in liver function. Not much was made of this, but years later, liver toxicity would play a big part in Rezulin’s downfall. (Out of the estimated 2 million patients who took Rezulin in the three years that it was on the market, it is estimated that 400 patients—or 0.0002 percent—died from causes attributable to the drug.)
Is it fair to blame the pharmaceutical industry for the possible misuse of Rezulin in the real world? Or for the fact that it reached the market despite negative data on liver function? One could speculate that Rezulin’s maker, Warner Lambert, saw there was too much money to lose if the unfavorable liver data were to be well publicized.
The story of Rezulin’s rise and fall inspires the question: Whom should the diabetes community trust when it comes to data demonstrating the efficacy and safety of insulin, oral drugs and cholesterol medications?
‘The Vioxx That Isn’t Going to Happen’
A manufacturer developing a drug or product furnishes a great deal of research that appears in clinical and scientific journals to support a therapy’s efficacy. People who might take this drug need to ask: Is the quality of the research affected by the source of funding? Or, putting it simply: Can scientists on a pharmaceutical company’s payroll be objective when they are studying a drug that is manufactured by the company that also signs their paychecks?
Recently, the FDA refused to approve the experimental diabetes drug Pargluva (muraglitazar), developed jointly by Bristol Myers-Squibb and Merck. While shareholders in both companies cringed at the news, Steven Nissen, MD, of the Cleveland Clinic in Cleveland, Ohio, referred to Pargluva as “the Vioxx that isn’t going to happen.” Nissen’s point was simple: Just as Merck had known early on that Vioxx might be dangerous, Bristol-Myers Squibb and Merck were aware that the risks of Pargluva might outweigh the benefits after conducting animal and human trials.
Only this time, it would not take patient deaths to get the drug withdrawn from the market. Pargluva was dead on arrival.
Interestingly, in most news coverage and discussions surrounding the FDA’s refusal to approve Pargluva, the fact that it was first red-flagged by the FDA in July 2004 received no mention. The FDA’s concern in the summer of 2004 was not cardiovascular disease but cancer risk. Mice exposed to glitazar drugs that had already been abandoned (ragaglitazar and farglitazar) had shown significant tumors compared to controls. In light of safety data generated by rodent studies of Pargluva, the FDA demanded that all companies developing drugs in the glitazar class present two years’ worth of rodent safety data to the FDA before moving on to human trials.
Bristol-Myers Squibb and Merck assured shareholders that they had nearly enough data on hand, and that human trials of muraglitazar would not be significantly delayed as long as the FDA was pleased with the animal data. Ultimately, the animal safety data provided by the companies satisfied the FDA.
However, human trials revealed previously undetected cardiac risks associated with Pargluva. The FDA’s October 2005 decision not to approve Pargluva may demonstrate that although it is not necessarily perfect, the present system of private funding for pharmaceutical research combined with governmental surveillance and regulation can work in the public’s interest.
In Defense of Industry Research Funding
Clinicians, industry representatives, scientists, and laypeople with diabetes all have opinions on the pressing issue of funding for medical research. (See below.) However, many critiques of the current system of funding in the United States do not present a viable alternative. Most of the companies supporting medical research, especially in the field of diabetes, have shareholders to whom they are accountable each quarter, but no nonprofit organizations have emerged with pockets deep enough to take on the burden of funding research.
Some say that the U.S. federal government should play a larger role in medical research funding, but few are eager to pay higher taxes to boost the government’s spending on research. Industry research often does break new ground and does find new therapies and devices. Later trials, however, tend to be designed to show off the qualities of the product for marketing purposes more than to provide the best science.
Susan Fisher, a type 1 from San Francisco, is a former graduate student who knows firsthand how difficult it can be to obtain funding for valid research projects. “While there may be a stigma associated with some sources of funding, the integrity and enthusiasm of the individual researchers is really at stake,” says Fisher.
“It is scary to think of a Nameless Big Drug Company being in charge—but really, real people with PhDs do the research. Important, dramatic breakthroughs are every researcher’s goal, no matter where the funding comes from.”
Is There a Solution?
So how do we improve medical research in the United States? There’s no easy answer to this question. We want new and better drugs that are safe and we want them soon, but thorough testing takes time and it takes lots of money. We want medical research to be conducted with patients’ interests as the top priority, but patients’ interests can’t pay a laboratory’s bills. We want the FDA to prevent risky drugs from getting to market, but we are frustrated when a very promising new treatment is blocked because some study participants developed rare but serious side effects.
We have reason to be cautious when reviewing data generated by pharmaceutical companies, but medical research is expensive and (at present) private companies have the lion’s share of the resources required to conduct it. Is a new and improved system of medical research funding in the pipeline? No. Is a new system needed, or can the present one be fixed? Those are the questions that need to be answered.
I sit on our medical center’s institutional review board, so I see all the human research studies that our multiple sub-institutes and practitioners do.
The majority of these are funded either by pharma or equipment manufacturers. These days, all human clinical research is carefully monitored by multiple entities, both for scientific merit and human subject protection. Despite such protections, problems of course can occur, but I believe they are few. The few disastrous ones get well publicized. And all human research is complex, because humans are complex, so outcomes, results and conclusions are not always clear and sometimes are in conflict.
Furthermore, with some of the new federal regulations and procedures, all or most clinical trials now must be posted on the Internet, whether the results are positive or negative. In the past, some negative studies were not reported, but I think that will be diminished significantly from now on. Moreover, while of course the companies are appropriately profit-oriented, this motivation has resulted in fantastic medical advances.
It is in the companies’ best interests to design valid studies that support their products, and the scientists and consultants who help design and participate in the studies are motivated to keep their reputations intact. All peer-reviewed publications and presentations now disclose any potential or actual conflicts of interest, so the readers or listeners can judge potential bias for themselves.
Gary Arsham, MD, PhD
California Pacific Medical Center
The existing system is perhaps inevitable. Researchers attaining the grants are some of the best scholars on a specific topic and so logically they are sought by the media for commentary. Many publications include a statement that specifies if the expert has a financial relationship with the sponsor.
The media and all publications should do the same in my opinion. But the question still remains: Does the relationship influence the commentary? My common sense suggests that it does. If readers are at least informed of a relationship, then they can decide whether or not [they think there might be any bias] and if so, the extent to which that information may be biased. The state of knowledge in the sciences is expanding at an exponential rate, so regardless of the state of knowledge today, much of it will change. The problem is we don’t know which part that is. Consequently, knowledge in general might be viewed with a grain of salt.
Kris Berg, EdD
Director, Exercise Physiology Lab
University of Nebraska at Omaha
In the 38 years that I have worked with drug companies and professional organizations and publishers, I have seldom experienced any pressure to try to bias a study or a publication.
Any study requiring human subjects is designed and reviewed by the researchers and clinicians. Then it goes to an institutional review board for detailed dissection and evaluation. The review board is composed of scientists, social workers, statisticians, lay members and clinicians. If the study is biased in design or not properly designed in terms of methods or statistical significance, it is rejected and the researcher cannot do the study.
It is possible but seldom occurs that a researcher could interpret results that would bias those results. If the paper is published and it appears to have biased results, the researcher/author quickly loses credibility.
The editorial process of peer-reviewed journals catches improperly researched or biased papers, and the journal rejects the paper. This is one reason that it is important that studies in peer-reviewed journals be respected as they carry more weight than publications that just report news.
An additional safeguard occurs now in most peer-reviewed journals in that authors are required to list any possible conflicts of interest.
R. Keith Campbell, PharmD, CDE
Washington State University
In my field of exercise physiology, many researchers get small grants from manufacturers of dietary supplements that may have the potential to enhance performance. For many of these companies, hard-core science is essential to proving the worth of their products.
For example, there is actually a Gatorade Sports Science Institute that funds studies on sports supplements and drinks (including ones to determine rates of gastric emptying and optimal carbohydrate content of such supplements), and many of these studies are well conducted, solid, scientific research.
Thus, it is my opinion that it is possible to conduct research that is funded by someone with an overlying interest in the outcome of the studies, but care must be taken to remain unbiased. The funding must be given with the explicit understanding that outcomes are not guaranteed to be positive, and the researchers must be allowed to conduct the studies completely independently of the manufacturer supplying the funding.
Sheri Colberg-Ochs, PhD
Associate Professor of Exercise Science
Old Dominion University
There are three major sources of research funding: government, nongovernmental organizations and industry. Years ago, the government was clearly the best source of funding. Money was available and most reasonably good research got funding. Over the years, a few things have happened. First, the amount of money has decreased significantly. Now the National Institutes of Health (NIH) tends to fund only the best projects, often not the stuff that breaks barriers. Prior to the Nixon era, the NIH was virtually apolitical and politics played no role in what got funded. That is no longer the case.
Barry Ginsberg, MD, PhD
Vice President of Medical Affairs
Becton Dickinson Diabetes Care
There is a growing gap in the ratio of investment to diabetic patient. Government funding per diabetic person is declining. Of course, this is due to the rapid increase in the incidence of diabetes but also to the lack of pressure from the public on federal offices responsible for funding. Different from AIDS and cancer, the diabetic patient is not one to stand up in a crowd and say, “I’m a diabetic and I am proud of it, therefore, fund research!” We lack a strong advocacy in government.
A sizeable and important amount of research funding is provided by pharmaceutical and device companies. Obviously these studies support the use of their product either for application to the FDA or to show superiority of theirs over the competition. Since the name of the researcher is attached to these publications and the researcher receives a livelihood from this work, researchers must be careful to be impartial when imparting the findings of their studies.
Besides funding projects that originate from their headquarters, drug and device companies also fund projects that originate outside their walls. The latter are called “investigator initiated trials,” or ITT. Although subject to connection to their products, ITT studies may answer important questions such as “how does this medicine work?” or “how can I predict which patients will respond to this treatment?”
Until government or unrelated organizations fund all research, we must live with pharma-sponsored research. Clearly such sponsorship must be noted in any publication, and non-company-affiliated researchers must maintain their integrity when writing or speaking about the results of these studies.
Allen B. King, MD, FACE, CDE
Diabetes Care Center
I believe that all research has value if done with integrity. The question is, if a pharmaceutical company funds research on its own product, does that cause a conflict of interest in the interpretation of the results of that research?
Of course the answer could be, yes, the results are tainted. However, the companies that have developed good products are definitely the most interested in getting their product out there, used and trusted, and are indeed the most interested in proving their product is worthy. Additionally, they are most often in the best position to finance research on their own product.
If the research is multicentered, done in a double-blind trial with unaffiliated researchers, and if the final publication is published in a peer-reviewed reputable journal, then in spite of the research being funded by the pharmaceutical company, I would take the results seriously. The credence of the study is in the design, integrity of the investigators and interpretation of the data. Of course, it is possible for data to be skewed in any research study, which can cause a misinterpretation of results. Therefore, we have to trust in the integrity of those doing the research. If these elements are in place, I would not be too concerned about where the funding comes from.
Jean Betschart Roemer, CRNP, CDE
Children’s Hospital of Pittsburgh
While universities and nonprofit research institutes should continue to be funded to build the science and understanding that forms the basis of every new treatment, additional grant funding is desperately required to fuel small start-up biotech companies. It is these entrepreneurs who take the next step of synthesizing the basic research and applying it in ways that lead to “commercializability.” This is an important, risky (and expensive) step. There is often a “funding chasm” between the basic science on one side of development and a new therapy’s successful launch and distribution by large pharmaceutical companies.
Loraine V. Upham
Chief Executive Officer
The controversy regarding pharmaceutical company-funded research is understandable. Can researchers be impartial when they are funded by a company that wants to market the product they are studying?
It is prudent, however, for those outside of the study to not only trust but also to verify. A careful review of the study may indicate researcher bias.
I helped establish the American Center for Foot Health Research, through which I have participated in a number of such studies. When possible, the protocol of the study should require double-blinding to keep both the researcher and participant impartial. The study results are what they are—no more, no less.
I believe strongly in the free market. The incentive for research and new product lines is profit. I often tell my patients that I want pharmaceutical companies to make lots of money so they can continue to discover new drugs. I’m getting older and, someday, may benefit from the research they do today.
Neil M. Scheffler, DPM, FACFAS
Baltimore Podiatry Group