Tuesday, February 3, 2009

Cost: The neglected adverse event / side effect in trials of for-profit pharmaceuticals and devices

Amid press releases and conference calls today pertaining to the release of data on two trials of the investigational drug pirfenidone, one analyst's comments struck me as subtly profound. She was saying that in spite of conflicting data on and uncertainty about the efficacy of the drug (in the Capacity 1 and Capacity 2 trials - percent change in FVC [forced vital CAPACITY] at 72 weeks was the primary endpoint of the study) IPF is a deadly and desperate disease for which no effective treatments exist (save for lung transplantations if you're willing to consider that an effective treatment) and therefore any treatment with any positive effect however small and however uncertain should be given ample consideration, especially given the relative absense of side effects of pirfenidone in the Capacity trials.

And I thought to myself - "absense of side effects?" Here we have a drug that, over the course of about 1.5 years reduces the decline in FVC by about 60ccs (maybe - it did so in Capacity 2 but not in Capacity 1) but does not prolong survival or dyspnea scores or any other outcome that a patient may notice. So, I'm picturing an IPF patient traipsing off to the drugstore to purchase pirfenidone, a branded drug, and I'm imagining that the cash outlay might be perceived by such a patient as an adverse event, a side effect of sorts of using this questionably effective drug to prevent an intangible decline in FVC. The analyst's argument distilled to: "why not, there's no drawback to using it and there are no alternatives", but this utterly neglected the financial hardships that many patients endure when taking expensive branded drugs and ignored alternative ways that patients with IPF may spend their income to benefit their health or general well-being.

This perspective is even more poignant when we consider the cases of "me-too" drugs that add marginally to the benefits or side effect profiles of existing drugs, and which are often approved on the basis of a trial comparing them to placebo rather than existing generic alternatives. One of the last posts on this blog detailed the case of Aliskiren, and I am reminded of the trial of Tiotropium published in the NEJM in October, among many other entire classes of drugs such as the proton pump inhibitors, antidepressants, antihistamines, inhaled corticosteroids, antihypertensives, ACE-inhibitors for congestive heart failure, and the list goes on.

Given todays economy, soaring healthcare costs, and increasing financial burdens and co-pays shouldered by patients especially those of limited economic means or those hit hardest by economic downturns, we can no longer afford (pun intended) to ignore the financial costs of "me too" medications as adverse events of the use of these drugs when cheaper alternatives exist.

In terms of trial design, we should demand that new agents be compared to existing alternatives when those exist, and we need to develop a system for evaluating the results of a trial that does not neglect the full range of adverse effects experienced by patients as a result of using expensive branded drugs. Marginally "better" is not better at all if it costs ridiculously more, and the uncertainty relating to the efficacy of a drug must be accounted for in terms of its value to patients, especially when costly.


  1. I'm glad you are blogging again.

  2. Excellent points. If it were my dad, I would send him to GNC for acetylcysteine .

    To play devil's advocate and argue on behalf of big pharma (Hey, somebody has to watch out for the big guy.):
    They have a marginally effective drug that may be a basis for development of a future drug that may actually be helpful to patients. If they don't recover some cost from R&D for this one, the future useful drug may never happen.

  3. Thanks, Marilyn and Dr. Jaymez for your comments!

    Dr. J, I agree with you about the NAC. I also acknowledge that this company is done like dinner if the FDA doesn't approve the drug this time around, but I wonder if patients with IPF should subsidize future research on this agent with their payments for subscriptions? What will happen to the agent if the company goes bust? Will the company be capable of objectively testing the agent in phase 4 or post-approval studies if it is conditionally approved contingent upon these? If such studies failed to show efficacy, would approval actually ever be withdrawn? If not, of what practical use would such studies be?

    I have further pondered the issue of cost as a side effect. There are concerns about the rash with this agent and its cost. Suppose it is priced at $6,000 a year or about $20/day. I'm thinking of economic analyses such as "willingness to pay" and I wager that many people would pay $20 per day to accept a rash. Likewise, many people with rash would NOT pay $20 per day to have it treated. So it seems to me that the rash is trivial compared to the cost. Of course, this perspective is diluted markedly if a third-party payer is picking up the cost of the medicine...