Industry Want More Clarity on Assessing Crossover Risks of Male API Use

Drugmakers are seeking clarification on the use of in vitro studies to assess the effects of active pharmaceutical ingredients taken by men on their potential offspring.

Commenting on a draft guidance released in June, Celgene and Gilead Sciences say in vitro studies such as genotoxicity assays usually aren’t conducted during clinical trials of a drug so there are no standard assays for sperm or for sperm genetic integrity.

If the FDA retains this section, it should provide more detailed guidance, including whether specific assays are envisioned and when in the clinical development program these tests should be conducted, the companies say.

The guidance focuses on two main risks to potential offspring — developmental problems triggered by an API’s effect on the germ cell before conception occurs and developmental toxicity in the fetus when the API is transferred to a pregnant partner through semen (DID, June 12).

According to the FDA, sponsors should clinically determine the amount of a drug or biologic secreted into semen or perform pharmacokinetic modeling to determine if it could affect the germ cell before conception or developmental toxicity in the fetus of a pregnant partner.

The guidance also says that until the developmental or reproductive risks of an API are known, precautions such as appropriate contraception should be taken to prevent pregnancy or exposure to a potential embryo. Gilead says it’s not clear what the FDA considers proper contraception and suggests that female partners be included in the process.

The International Consortium for Innovation and Quality in Pharmaceutical Development agrees. “If a condom is recommended but a diaphragm is not sufficient, this should be stated,” the group says.

Celgene also wants the FDA to remove a section from the draft dealing with thalidomide, saying the research from the 1960s is outdated.

The firm points to a study from 2014 that shows thalidomide delivered to pregnant rabbits at doses 10,000-fold greater than that found in human semen didn’t result in any developmental abnormalities. The drug was pulled from the market after it was linked to serious birth defects, but was later relaunched as a treatment for certain cancers, HIV/AIDS, rheumatoid arthritis and other conditions. — John Bechtel


$1,695 $1,395


Subscribe to Drug Industry Daily and save $300 off the regular one-year price of $1,695 — plus receive a FREE copy of our webinar CD, Understanding CDER's "Super" Office of Pharmaceutical Quality and Its Effect on You — a $287 Value!

Key Benefits

LINKS TO KEY DOCUMENTS — You get links to key documents that support DID's articles such as draft and final guidances, 483s and warning letters, proposed rules, closeout letter, full text of proposed legislation and GAO reports.

ONLINE ACCESS — Consider our newsletter archive your personal library! Search your current issue — and hundreds of past issues — by keyword and relevancy.