By Karen Bernstein

If anything has become clear in the past year or so, it is just how tough it is to prove efficacy in many of the diseases being targeted by biotech drugs.

One of those areas is rheumatoid arthritis. Following the receipt last week by Greenwich Pharmaceuticals Inc. of a "not approvable" letter from the FDA for Therafectin, BioCentury surveyed other companies in the clinic with RA drugs to elucidate the issues in RA trials and how companies are coping with them.

The primary issues are the regulatory and ethical impediments to testing new drugs in patients at a sufficiently early stage of disease to show benefit, the variable nature of RA, the problems in conducting lengthy placebo-controlled trials in a patient population that shouldn't be off medication for very long, and the subjective nature of end points.

What's optimum

As in sepsis, investigators believe that one key to showing efficacy is finding the patient population most likely to benefit, and that means patients whose disease is neither too far advanced nor too mild. But in the case of RA, that can clash with the FDA's notions of how RA drugs should be tested and the ethical issues involved in testing potent drugs. At least for initial trials of biologics, several companies said the FDA only feels comfortable allowing testing in more seriously ill patients.