US FDA is now insisting to the pharma industry which is engaged in the drug development of rheumatoid arthritis (RA) to focus on three  aspects. These are dosing regimen, efficacy factors and  drug-device combination product considerations.

The regulatory authority which issued the draft norms in May this year has now received the comments from the industry and is now in the process of reviewing the same to be able to issue its final guidance within a couple of months.

This guidance is a revision of the norms for Clinical Development Programmes for drugs, devices, and biological products for the treatment of rheumatoid arthritis, published in February 1999.  The FDA’s current thinking has been influenced by clinical development programs conducted for RA 32 since the 1999 guidance was published. Several changes in the standard of care for RA have come in with the  availability of many effective treatments.

The revisions include: dosing regimens selection throughout the clinical development program. The regulatory authority has stated that to establish the efficacy in RA, the therapy should be based on signs and symptoms. Therefore use of efficacy endpoints such as clinical remission and prevention of structural damage progression, limiting use of placebo, use of active comparator for safety and efficacy trials are mandated.

In the case of development of drug-device combination products, therapies developed for the treatment of RA include drug products that may require parenteral administration and the use of an accessory delivery unit like for instance an auto injector. In such a case, the manufacturer of the drug product should ensure that the accessory delivery unit is approved for marketing through the device regulatory process which is through a pre-market approval by the Centre for Devices and Radiological Health. If the accessory delivery unit is not already approved for marketing, then it should be cleared at least concurrently with the drug product consent.

Under the dosing regimen selection which is a fundamental component of drug development, the regulator has stated that it should be based on the benefit-to-risk assessment. It should be supported by all available data gathered throughout the  development programme. The regulatory authority has pointed out that it is important to find the appropriate nominal dose and dosing regimen that produces efficacy with an acceptable long- and short-term safety profile.

Many drug products intended to treat RA have the potential to cause serious dose-related adverse reactions, such as opportunistic infections and malignancy, which may not be apparent in short-term  clinical trials. Therefore US FDA in its draft guidance is insisting on the dose-ranging exploration to begin early in the development programme and often should continue throughout definitive efficacy and safety studies.

Smaller early dose-ranging exploratory studies may not be adequate for selection of a single dose or a single dosing regimen. The regulatory authority has called to study a wide range of doses and dosing regimens based on pharmacokinetic and relevant pharmacodynamic considerations.