Last week, The New York Times reported widespread panic among the pharmaceutical industry with the expiration of patents looming in the near distance. As the articles states, “…because of patent expirations, the drug industry will lose control over more than 10 megamedicines whose combined annual sales have neared $50 billion.” At the same time, pipelines for new drugs have been drying up. In other words, there are few new candidates to replace the expiring blockbusters.
There are many angles to explore here in terms of the ethics and economics of drug development: the tricky practices for extending drug patents, the role of generics in spurring innovation, the tendency for pharmaceutical companies to buy up smaller companies as a way to propel themselves forward, the focus on “me too” drugs, whether the pressure on the drug industry to lower prices will ever result in any tangible decrease in healthcare costs, whether or not marketing budgets play a role in the cost of a drug, how legislation to restrict conflicts of interest is impacting innovation, what really goes on at the FDA, how much does it actually cost to develop and manufacture a new chemical or biologic drug, and more. Oh how I would love to unravel all these topics. Slowly, slowly catch the monkey.
On the one hand, it’s fascinating to look at what is currently happening, whether the end is nigh and if so, why. But it’s equally compelling to see what new approaches could genuinely make a difference. Because I’m on a clinical trials kick at the moment, here’s a look at one possible shift that the pharmaceutical industry could take: collaborative clinical trials.
In a recent Perspectives piece in the New England Journal of Medicine, researchers from the University of Rochester Medical Center’s Multicenter Research Group look at the potential benefits of taking a collaborative approach to conducting clinical trials. Collaboration? Among companies developing competing drugs or devices? Yes, you read correctly.
The authors cite the same issues raised elsewhere about the current clinical trials environment: the high costs, regulatory requirements proliferating like The Blob, and the overall slim chance that a new compound will actually make it from the laboratory to the pharmacist’s shelves.
They also raise an interesting point about patient enrollment, which is commonly slow. Increasingly, diseases are being classified in narrower and narrower ways—breast cancer, any breast cancer expert will now tell you, is not one disease, but a collection of many different diseases, each with a unique genetic signature. These more rigorously defined disease categories are expected to enhance the development of targeted therapies, but could also impede trials: the more specific the therapeutic target, the longer it can take to enroll the numbers needed to cocnduct a statistically rigorous study. The incorporation of biomarkers—surrogate biologic indicators that signal an individual’s prognosis, likelihood of benefiting from a particular treatment or other relevant characteristic of his or her disease—into clinical trials could also slow down enrollment.
Even in the absence of these limiting factors, there are clear problems with competitive trials. The authors give the example of the search for new anticoagulant medications. The various phase III studies conducted over the past decade all required large study populations, which led to competition over enrollment sites and patients, which delayed the work at hand. The use of different endpoints to measure the benefit of each medication makes comparing the drugs to one another difficult. In other words, for several reasons, it is no longer making sense to simultaneously conduct several clinical trials of comparative treatments for the same patient populations.
In many situations, the authors argue, a collaborative approach could be warranted. What if one single anticoagulant study had been done? What if the companies had gotten together and said, look, we all want what’s best for the patients, let’s figure out a way to test our drugs in a single study so that we can figure out which drug is best for which situation quickly and efficiently, without wasting time and money?
Now before you leave your comment asking me what I’m smoking, the authors actually cite successful examples of the collaborative approach. There was the Cardiac Arrhythmia Suppression Trial, testing three different antiarrhythmic drugs at once (completed over 15 years ago). The Sudden Cardiac Death in Heart Failure Trial compared two different experimental approach at once (also done years ago). Researchers from Wake Forest University recently conducted a “three-way, double-blind, triple-dummy crossover trial” for asthma in need of something beyond inhaled glucocorticoid.
My personal favorite is The Biomarkers Consortium, a public-private research group conducting all kinds of clinical trials, such as the I-SPY 2 study for breast cancer (sorry, a round-up of silly clinical trial names is a subject for another post). This Consortium is experimenting with a truly collaborative approach to clinical trials that seems to be taking the entire concept of personalized medicine into something tangible. And the entire success of the approach hinges on collaboration.
A collaborative approach means the need for only one control group versus several experimental arms, direct comparison of new therapeutics, the elimination of potentially confounding variables that make comparing different patient populations murky, and speedier and less costly research.
Of course it’s not so easy-breezy. Collaborative clinical trials would likely require changes in FDA review requirements, extremely careful management of conflicts of interest and any incentives that could bias the study toward one drug or another, and somehow not getting bogged down the predictable mountain of legal documents that everyone would require for confidentiality and patent protection. The approach would also require … collaboration. A slowly caught monkey if ever there was one.
Clearly there are many factors to tackle when it comes to understanding the future of drug development, and I’m no expert at knowing what the state of affairs really is, and what is truly needed. Yet it is hard to not be wooed by the thought that greater collaboration in the conduct of clinical trials could be a piece of the puzzle.
Last week, the news came out that a compound being tested for the treatment of lung cancer had failed its phase III study with 913 patients. The drug, aflibercept (sorry, a round-up of awkward generic drug names for another post), did extend progression-free survival and improve response rates, but it did not improve survival time beyond that seen with chemotherapy alone. In another post, I hope to explore this particular study, to understand whether an alternative trial design could have shortened the research time, diminished the cost, or limited the study population. Right now, I don’t know, and it may be that the standard trial approach was exactly what was needed here. But in light of this most recent example of a phase III disappointment, it’s hard not to wonder about other ways of proceeding.
ps: new twitter page: @jessicawapner