Issues in the design of new clinical trials for rheumatoid arthritis therapeutics.

Rheumatoid arthritis (RA) is a chronic, heterogeneous disease, for which there has traditionally been few reliable prognostic indicators or simple clinical outcome measures with which to adequately assess disease status or clinical improvement. These challenges have hindered the assessment of new therapeutic agents. Investigators in rheumatology have, therefore, attempted over the past two decades to develop new approaches and scoring systems to facilitate the study and development of therapies. As a result of these efforts, the efficacy of almost all new agents tested in clinical trials are now assessed with widely accepted scoring systems that measure improvement in three important areas. First, changes in patient signs and symptoms are measured via composite indices of both clinical and laboratory parameters. Second, the progression of structural damage is assessed by radiographic imaging. Finally, long-term improvement in patient function is measured via patient-reported outcomes. These changes to clinical trial design have been adopted by health authorities around the world. Further challenges, however, must be overcome in order for progress to continue.

Regulating biopharmaceuticals under CDER versus CBER: an insider's perspective.

The FDA has recently transferred jurisdiction for the regulation of certain biopharmaceuticals from the Center for Biologics, Evaluation and Research to the Center for Drugs, Evaluation and Research, where they will be reviewed in the same FDA divisions as are traditional pharmaceutical agents. With this transfer, sponsors of investigational biopharmaceuticals should expect changes in the regulatory requirements the FDA imposes on the clinical development plans, including an increase in the size and number of pivotal studies; more consistent requirements for conducting preclinical tests in two animal species; increased emphasis on organ structure and function as components of primary endpoints; more emphasis on characterizing dose-ranging and pharmacology; more intense scrutinizing of product advertising; and decreased direct communication with the review team.

Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept.

OBJECTIVE: Two tumor necrosis factor alpha (TNFalpha) antagonists were recently licensed in the US. Infliximab was licensed in 1998 for the treatment of Crohn's disease (CD), and since 1999, it has been licensed in combination with methotrexate for treatment of rheumatoid arthritis (RA). Etanercept was licensed in 1998 for treatment of RA and, more recently, for juvenile RA and psoriatic arthritis. Because of potential immunosuppression related to use of anti-TNFalpha agents, we sought to identify postlicensure cases of opportunistic infection, including histoplasmosis, in patients treated with these products. METHODS: The US Food and Drug Administration's (FDA) passive surveillance database for monitoring postlicensure adverse events was reviewed to identify all reports received through July 2001 of histoplasmosis in patients treated with either infliximab or etanercept. RESULTS: Ten cases of Histoplasma capsulatum (HC) infection were reported: 9 associated with infliximab and 1 associated with etanercept. In patients treated with infliximab, manifestations of histoplasmosis occurred within 1 week to 6 months after the first dose and typically included fever, malaise, cough, dyspnea, and interstitial pneumonitis. Of the 10 patients with histoplasmosis, 9 required treatment in an intensive care unit, and 1 died. All patients had received concomitant immunosuppressive medications in addition to infliximab or etanercept, and all resided in HC-endemic regions. CONCLUSION: Postlicensure surveillance suggests that acute life-threatening histoplasmosis may complicate immunotherapy with TNFalpha antagonists, particularly infliximab. Histoplasmosis should be considered early in the evaluation of patients who reside in HC-endemic areas in whom infectious complications develop during treatment with infliximab or etanercept.