Keytruda: what flexibility did regulators accept, and why?

“On the basis of the known association between PD-1 deficiency and increased rates of abortion, FDA agreed with the Applicant’s request to provide a literature assessment of the scientific data of pregnancy outcomes in PD-1 -/- mice in lieu of conducting an embryofetal study in the monkey with MK-3475.”

“This decision was made in part because MK-3475 is not active in any species other than the nonhuman primate.”

“Pembrolizumab is not expected to cause adverse effects in the male and female reproductive system, however as the number of sexually mature male treated with pembrolizumab for a sufficiently long duration (≥ 3 months according to ICH S6(R1) was too low to draw any conclusions about the effect of pembrolizumab on male fertility, a statement has been included in the SmPC section 5.3.”

“The Applicant did not, however, investigate the potential for an exaggerated recall response to an antigen in either the presence or absence of pembrolizumab following a primary response in the presence of anti-PD-1.”

“Understanding this potential may be useful in advising patients on the safety of vaccination during treatment with pembrolizumab, and an additional pharmacology study has been requested as a post-marketing commitment to better define this potential.”

“Given the availability of clinical data from humans, the lack of a non-clinical proof-of-concept at the 2 mg/kg every 3 weeks dose is acceptable.”