In order to gain FDA approval of New Drug Application for a new chemical entity initially marketed in Controlled Release Dosage forms (as with all other similar products), clinical studies in patients establishing the safety and efficacy of each particular dosage form are required.
For drugs that have been previously approved as safe and effective in controlled release dosage forms, data are required to establish bioavailability / bioequivalence to an approved controlled release drug product. Single dose bioavailability studies are acceptable for determining the fraction of the amount absorbed, lack of dose dumping, lack of food effects etc.
Pharmacokinetic studies, performed under steady-state conditions are acceptable to demonstrate comparability to an approved immediate release drug product, occupancy time within a therapeutic window, percent fluctuation etc. The specific types of in-vivo studies include:
- Fasted single dose studies
- Post prandial study
- Multiple dose steady-state studies.
Regulatory Considerations for Specialized CRDDS:
Novel CRDDS evolved in recent years viz. Ocusert, Oros, Copper and Progesterone releasing IUD’s and transdermal systems are considered new drugs requiring full new drug applications (NDA) as a basis of drug approval. In addition to safety and efficacy considerations which includes an understanding of the drug input function, plasma blood level oscillation and the drug’s pharmacodynamics, there are biopharmaceutic and pharmacodynamic issues that need to be addressed by the manufacturer such as :
- Reproductivity of the new drug delivery system by in-vivo or in vitro studies.
- A defined bioavailability profile which rules out dose dumping.
- Demonstration of reasonably good absorption relative to an appropriate standard and which considers important elements e.g. obviating of first pass gut or liver metabolism.
- A well-defined pharmacokinetic profile to support drug labeling.
- In vitro characterization (when possible).