An inadequate reproductive safety assessment of Celgene's Revlimid was of central concern to FDA during its review of the myelodysplastic syndromes treatment and helped guide post-approval risk management requirements, review documents show.

"Due to the inadequacy of the reproductive safety assessment, FDA has a concern regarding the risk of teratogenicity and the potential fetal exposure to lenalidomide" (Revlimid), Division of Oncology Drug Products Director Robert Justice concluded in his Dec. 23, 2005 approval memo.

Justice also cited concerns over the "high" 80% incidence of dose reductions and/or delays due to neutropenia and thrombocytopenia observed in Celgene's core Phase II trial supporting Subpart H approval. Grade three or four hematologic toxicities were seen in 80% of patients.

The twin safety concerns with the immunomodulatory drug led FDA to require creation of the RevAssist risk management plan.

The plan is modeled after Celgene's STEPS program (System for Thalidomide Education & Prescribing Safety) to monitor fetal exposure associated with its thalidomide therapy Thalomid , which is known to cause severe birth defects. Revlimid is an analog of thalidomide.

Celgene "should implement a risk management activity similar to the STEPS program until toxicology studies determine that lenalidomide is not a teratogen in species that predict human teratogenicity," Justice said.

Revlimid labeling includes a "black box" warning about the "potential for human birth defects." The warning also cites the risk of "hematologic toxicity (neutropenia and thrombocytopenia)" and "deep venous thrombosis and pulmonary embolism."

A consult by FDA's Office of Drug Safety determined RevAssist to be "acceptable…for interim use until the questionable teratogenicity of lenalidomide is fully characterized and resolved."

Non-clinical reproductive studies in animals examined the effects of lenalidomide on embryo-fetal development, fertility and early embryo development, and pre- and post-natal development.

While FDA points out that "only the embryo-fetal development studies are required for drugs with oncology indications," the studies "have not been adequately conducted at this time," Pharmacology/Toxicology Reviewer Anwar Goheer said.

"The first study, conducted in a rat, showed very slight maternal toxicity and no fetal malformations. The rat, however, is not an adequate species for the full assessment of lenalidomide's developmental effects, given the structural similarity to thalidomide," the pharmacology/toxicology review states.

"Historical data indicate that the rat is not sensitive to the full range of thalidomide's teratogenic effects."

An additional developmental study conducted with rabbits included a concurrent thalidomide dose group. However, "this study had a confounding variable with some rabbits not eating prior to the study and all these rabbits had a negative outcome in the study. Additionally, the highest dose tested did not meet the standard criteria for sufficient drug exposure."

While Goheer ultimately recommended lenalidomide approval, he noted that "adequate reproductive toxicity assessment, specifically embryo-fetal developmental toxicity in two species, needs to be conducted."

Revlimid cleared FDA Dec. 27, 2005 as an orphan drug following a priority review for "treatment of patients with transfusion dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes associated with a deletion 5q cytogenic abnormality with or without additional cytogenic abnormalities" (¹ Also see "Revlimid Approved With Safeguards Against Fetal Exposure" - Pink Sheet, 28 December, 2005.).

[Editors' note: Additional analysis of FDA's review of Revlimid, including Celgene's effort to gain fast track designation, appears in the April issue of FDC Reports' ² Pharmaceutical Approvals Monthly. For a sample copy, contact customer service at 800-332-2181.]

- Jon Dobson

Revlimid Reproductive Safety Concerns Led To Broad Risk Management Plan

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