Summary
Direct comparisons between potential competing agents often do not exist Initial FDA approval is usually based on comparisons to placebo A new approval does necessarily mean that the new agent is better than existing ones, although this is implied by industry Industry bears all the costs of efficacy trials prior to FDA approval Head to head comparisons are what doctors really need to treat patients Head to head comparisons will require different methodology, larger samples, and could also be failed studies. Industry may be more reluctant to develop new agents which might become only "me too" or second class in a crowded market
Analysis
This article is timely and accurate. For example, in the antidepressant market, we have seen many new drugs approved, each of which entered the market with a better than placebo claim. There still remains no evidence that any one has clear superiority in clinical efficacy to another, hence treatment decisions are often made based on tolerability, rather than efficacy, which would be more desirable.
Unfortunately, NIH funded attempts to address this problem, such as the STAR-D study, have also not yielded clear winners among the comparitors. While STAR-D has shown us a lot of new information about antidepressants, in particular, how much more poorly they perform than they did in the original industry studies leading to FDA approval.
In the atypical antipsychotic schizophrenia market, there are similar problems. With the exception of clozapine, which is FDA approved for refractory schizophrenia and suicide prevention, all of the others share the same "better than placebo" indication. Between the others, Risperdal, Zyprexa, Geodon, Abilify, Seroquel, Invega, none can make a claim of greater efficacy. With the impending emergence of generic risperidone, this may be a major blow to all the brand names.
The NIH attempt to address this, called CATIE, did not fully resolve this question. Although Zyprexa was superior on the primary outcome, and Risperdal was superior to the others (not including Zyprexa) on secondary outcomes, the dose of Zyprexa was above the FDA-approved dosing range while the others were not. This has generated further debate and left many clinicians to select, again based on tolerability.
In the bipolar market, the problem is even greater with very few direct comparisons including basically only industry sponsored studies, some confusion about treatment of acute bipolar mania versus treatment of acute bipolar depression, and considerable confusion about the difference between prevention of mania and prevention of depression. For example, we have 7 first line drugs FDA approved for acute mania with a clear idea of whether any has greater efficacy further complicated by the lack of clarity of whether to use any alone or in combination. For bipolar depression, we have 3 agents FDA-approved, again with no direct comparisons. For bipolar maintenance, we have 4 FDA approved agents, but most doctors are not aware that the efficacy for these was directionally different since the label does not discuss this.
