Sep 07 2011
The latest issue of the BMJ contains an editorial recommending that regulators (this is in the UK, but the argument applies in the US and elsewhere) should require pharmaceutical companies to provide research on direct comparison to existing therapies as part of the approval process. The authors, Sorenson, Naci, Cylus, and Mossialos, write:
When a drug comes to market, evidence on the comparative risks and benefits is needed to help regulatory authorities to safeguard public health from inferior and unsafe treatments, to ensure that health technology assessment agencies and payers make funding decisions based on the best available evidence of different treatments, and to aid clinicians’ and patients’ understanding of what therapies work best and their appropriate position in the treatment pathway.
They make a persuasive argument, but there are some interesting angles to this topic.
Comparative efficacy research is definitely valuable, for all the reasons stated by the authors above. In order to get approval, typically a new drug has to demonstrate that it is safe and more effective than a placebo treatment. For many common indications there are also often more than one drug for the same indication. Therefore there may be several drugs approved to treat migraine, gastric ulcers, hypertension, etc., all of which have been compared to placebo, but perhaps not to each other (at least not prior to approval).
Clinicians, therefore, may have difficulty in comparing available options. You can compare the relative effect size with respect to placebo, but this is fraught with confounding factors. No two trials are exactly the same: outcome measures may be different, the subject population may be different, etc. and therefore comparing the results of two different trials is problematic. There is no substitute, therefore, for a head-to-head comparison of two or more drugs (or any treatments, for that matter) in the same trial.
The issue is also not simply a matter of which drug is better – each may have different strengths and weaknesses, or be more efficacious or safe in different subpopulations. Comparitive efficacy research is often performed, but it is done post-market. The authors are advocating that such research be required pre-market. The primary criterion they are recommending is lack of inferiority – demonstrating that the new drug is at least as effective as existing treatments.
There are advantages and disadvantages to such regulation, in my opinion. The advantages are outlined above – more information for clinicians, regulators, and payors that cannot be obtained any other way. Further they argue that pharmaceutical companies are often reluctant to initiate or sponsor head-to-head research because it is risky for them if their product comes out on bottom. They would rather have ambiguous evidence that all sides can spin to appear to favor their product.
The one potential downside I see is that it would make the drug research and approval process more expensive and longer than it already is. This could delay or even prevent the introduction of new effective drugs to the market. This is always the trade off – the more evidence we require for approval the safer and better evidenced our drug market will be, but the higher the barriers to getting potentially effective drugs to patients. Would this new requirement (for comparative efficacy research) be worth the higher barriers?
Some have also criticized the practice of pharmaceutical companies producing “copy cat” or “me too” drugs for the market, simply to capture their piece of a lucrative pie. There is some legitimacy to this criticism – decisions about which potential new drugs to research are corporate marketing decisions, not decisions made on the basis of societal welfare. (I am not criticizing the capitalist system we employ in the US for drug development – that is a separate issue I do not intend to explore here – I am simply pointing out one relevant consequence.)
However, I find it very useful to have multiple drug options for a single indication. There are always differences, and this allows for individualization for patients. Some patients may be allergic to one drug, so having another option is critical. And also sometimes one drug simply does not work in a patient while another “copy cat” drug may (perhaps due to genetic differences).
In the end, I find direct head-to-head comparative efficacy research highly valuable, but I am not sure it should be required pre-market. That may be one burden too many on the approval process. Perhaps we should explore other mechanisms to facilitate such research, such as funding independent academic comparative efficacy research (which happens now, but could be increased through funding). Regulations could even require pharmaceutical companies to participate in some way in such research of their drugs, by providing free drugs for the trial or even contribute to funding.
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