Steve Walker of the Abigail Alliance weighs in on the issue of timely commencement of promised Phase IV trials:
"I think in some cases you are probably right about the failure to conduct Phase IV studies being a "self-inflicted" wound, but there is perhaps a bigger problem in the design of a lot of the studies. Once a drug is approved and deemed safe and effective (in many cases proven in compelling fashion despite the absence of a perfect p-value), conducting randomized studies where patients are randomized into treatment arms that do not serve their best medical interests is fraught with all kinds of ethical and practical problems, and challenges for sponsors, physicians and doctors. Coupled with the undeniable fact that after approval the development and learning process about many drugs accelerates dramatically (a good thing that usually leaves the slow-moving FDA far behind) often causes the trials mandated by FDA to become obsolete before they start, and even more commonly before they are completed. When that occurs, the FDA's and other's mandates that the trials be conducted anyway degenerates into nothing but a form over substance pursuit of compliance for no other purpose than compliance. That should not be the purpose of the regulation of medical products because it is harmful to the public health, not to mention a waste of money and patients.
"I think in some cases you are probably right about the failure to conduct Phase IV studies being a "self-inflicted" wound, but there is perhaps a bigger problem in the design of a lot of the studies. Once a drug is approved and deemed safe and effective (in many cases proven in compelling fashion despite the absence of a perfect p-value), conducting randomized studies where patients are randomized into treatment arms that do not serve their best medical interests is fraught with all kinds of ethical and practical problems, and challenges for sponsors, physicians and doctors. Coupled with the undeniable fact that after approval the development and learning process about many drugs accelerates dramatically (a good thing that usually leaves the slow-moving FDA far behind) often causes the trials mandated by FDA to become obsolete before they start, and even more commonly before they are completed. When that occurs, the FDA's and other's mandates that the trials be conducted anyway degenerates into nothing but a form over substance pursuit of compliance for no other purpose than compliance. That should not be the purpose of the regulation of medical products because it is harmful to the public health, not to mention a waste of money and patients.
Even beginning a discussion of what to do about non-compliance with Phase IV trial requirements must be undertaken within the context of the broader discussion about how to modernize FDA's science (which despite all the talk, still isn't occurring at the review policy and practice level) and a recognition that a lot of the Phase IV trials required by FDA make little sense for progress, and even less sense for patients. Should we be forcing sponsors to complete Phase IV clinical trials that we know with a high degree of confidence, or even only strongly suspect, would be harmful to the patients enrolled in those trials? The ethical questions and scientific/medical deficiencies surrounding all of this pile up very quickly once one starts looking at the details of what the FDA is often asking the sponsors to do.
One of the most troubling aspects of the discussion about Phase IV trials is an almost complete dismissal of the effect these mandates have on patients, and the entirely appropriate and correct reaction those patients have, in consultation with their doctors, to avoid some Phase IV trials (usually the randomized ones). The patients and their physicians are actually medically correct to do that in most cases, and denying that fact virtually guarantees failure of the Phase IV system. Patients are simply not going to elect to expose themselves to harm, premature death or loss of control over their health and life in any great numbers when they don't have to, to get what they and their doctors think is the appropriate treatment for them. Combine that with the tight statistical restrictions on entry into randomized Phase IV trials, and you end up with an impossible situation for a lot of these trials.
If we want post-approval trials to work as an effective regulatory tool, and as a means for advancing the science of drug development, it has to be re-thought from the ground up.
Mandating unworkable, unethical ineffective "stupidity" is never the right solution, and all the talk about iron-fisted enforcement of Phase IV trails that fit that definition of "stupidity" is not going to fix the problems. The problem, as is almost always the case, is that FDA almost completely fails to recognize and accommodate reality in its approach to clinical trials, and in particular to Phase IV trials.
The solution of some at FDA has been to delay approval of good cancer drugs until the p-value they want arrives, thus solving the problem of trying to enroll unethical Phase IV trials by simply denying patients access to the drug they need by any other means so they have no choice but to enter the trials in Phase III. This leaves the large majority out of the progress because they don't qualify for the trial, or they don't fit into the trial (fully enrolled), or they can't reasonably get to the trial. This approach has turned the entire enterprise of the regulation of drugs for serious and life-threatening diseases on its head. The goal has to be delivery of progress to patients who have the disease as soon as reasonably possible, not delivery of pro forma p-values to regulators who don't have a disease at all.
If we want Phase IV trials to be enrolled and completed, they have to be useful, necessary, ethical and enrollable. If they become obsolete before they start or finish, the FDA has to be flexible enough to recognize it and adjust to reality, by dropping the requirement or allowing adaptation of the trial design to preserve its usefulness. If they are un-enrollable because they are unethical or unnecessary except as an exercise in regulation (and that is often the case), then they shouldn't have been requested in the first place.
This is much more complex and much more wrapped up with the self-imposed scientific stagnation and negative ethical creep that permeates the FDA and the clinical research community than most people realize.
Just doing more of the wrong thing in the wrong way because most people don't understand it is hardly a solution.
I suspect you understand most if not all of what I explain above, but it didn't come through in your post."
Thanks Steve -- for both the thoughtful comments and for giving me the benefit of the doubt.
Thanks Steve -- for both the thoughtful comments and for giving me the benefit of the doubt.
