Studying Drug Interactions with Combined Oral Contraceptives
November 20, 2020 St Louis Park, MN
The FDA has issued a new Draft Guidance for Industry “Clinical Drug Interaction Studies With Combined Oral Contraceptives” which can be found on the FDA website at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-interaction-studies-combined-oral-contraceptives-guidance-industry. This document discusses the need for drug-drug interaction (DDI) studies with combined oral contraceptives (COCs) containing an estrogen and a progestin when used to prevent pregnancy. The FDA reports “COCs are highly effective in preventing pregnancy when used correctly.” Unfortunately, interactions between COCs and other drugs may increase pregnancy risk or compromise patient safety by changing estrogen or progestin metabolism. For example, this guidance states increased estrogen and/or progestin levels “can increase” the risk of blood clots in veins which is a “rare but serious adverse event.”
Women of childbearing age often use COCs and other drugs concurrently and safely; however, DDIs between COCs and investigational new drugs have not been well studied in the past. This guidance is intended to help sponsors determine (1) when DDI studies between investigational drugs and COCs are needed, (2) how COC DDI studies should be designed and conducted and (3) what DDI data should be communicated on the drug labelling. The FDA is putting forward their “current thinking” about the types of in vitro (benchtop experiments) and/or clinical (human trials) assessments which will be needed for investigational new drug approval in the future. This guidance details the need to evaluate enzymes involved in progestin and estrogen metabolism including cytochrome P450 3A (CYP3A).
For new drugs the labeling must describe “clinically significant” DDI risks and should recommend not to use the new drug at the same time a woman is using estrogen/progestin-containing COCs for new drugs which increase estrogen levels or to use a back-up/alternative method of contraception for drugs which decrease progestin levels. Alternatively, when no clinically significant DDI risks are found, the drug labeling should include a statement similar to: “No clinically significant differences in [drug substance] pharmacokinetics were observed when Drug-X was used concomitantly with Drug-Y.”
This guidance suggests enrolling both pre- and post-menopausal women into these COC DDI studies using a “Fixed sequence”, “randomized crossover” or “parallel study design”. COCs containing drospirenone with ethinyl estradiol are recommended “as a worst-case scenario for CYP3A inhibition” and the treatment “should be given at the highest proposed therapeutic dose and… duration to ensure…” maximum metabolic effects are seen during the investigational drug use.
Interested parties may submit comments on the draft guidance by February 22nd, 2021 for FDA consideration as the final guidance document is developed.