Dr. Lynn Kramer
Chief Clinical Officer and Chief Medical Officer, Neurology Business Group, Eisai Inc.
In general terms, data extrapolation is the process of estimating future trends or effects based on previous observations. When speaking about evaluating epilepsy therapies for use as monotherapy, for example, data extrapolation analyzes clinical trial results in antiepileptic drug (AED) adjunctive therapy to establish safety and efficacy equivalence for the same medications when used alone.
Why use extrapolation as opposed to placebo-controlled trials to demonstrate a drug’s safety and/or efficacy? When it comes to epilepsy, placebo-controlled trials raise ethical concerns about having patients who experience seizures – which are potentially life-threatening – go without drug therapy if they were to be randomized to placebo.
Extrapolation for Monotherapy in Partial Onset Seizures (POS)
Nearly one-third of those living with epilepsy have seizures that are still not controlled. In some cases, physicians are able to treat their patients using a single drug (monotherapy), rather than a multi-drug (adjunctive or add-on) regimen. Monotherapy may also be desirable for certain patient populations, including women, the elderly and patients with comorbid conditions who are at increased risk for antiepileptic drug toxicity and drug interactions. However, only a few AEDs are approved as monotherapy, limiting the number of available therapeutic options for patients.
In September 2016, the FDA released a General Advice letter to AED NDA holders, stating “it is acceptable to extrapolate the efficacy and safety of drugs approved as adjunctive therapy for the treatment of partial-onset seizures (POS) to their use as monotherapy for the treatment of POS.” According to the FDA letter, for monotherapy to be considered using extrapolation for POS, a manufacturer must provide a comparative analysis that demonstrates that the proposed dosages of the AED, when used as monotherapy, result in exposures that are similar to those that were demonstrated to be safe and effective when the drug was used as add-on therapy for the treatment of POS.
Eisai is proud to be the first company to have received an approval for monotherapy use in POS following the FDA regulatory pathway of extrapolation that was based on the agency’s careful review of existing data generated in monotherapy and adjunctive therapy trials.
Extrapolation for Efficacy in Pediatric Patients with POS
Our progress utilizing extrapolation also includes another important part of the epilepsy population – children. Currently, more than 450,000 American children and adolescents live with epilepsy. In November 2015, the FDA issued a communication to sponsors that allowed companies “to extrapolate to pediatric patients 4 years of age and older the effectiveness of drugs approved for the treatment of partial-onset seizures (POS) in adults.” Under this policy, drug manufacturers must also provide long-term, open-label safety data in patients 4 years and older, the data that one of our ongoing open-label studies is designed to provide.
Extrapolation for Efficacy in Pediatric Patients with PGTC Seizures
In April 2017, at the American Academy of Neurology annual meeting, one of the largest neurology meetings in the U.S., Eisai announced positive data from a meta-analysis evaluating the feasibility of extrapolating efficacy data from adults to children with PGTC seizures. These data are particularly important because there has been limited research in pediatric patients due to the challenges of conducting clinical trials in children with epilepsy.
At Eisai, we are proud to be at the forefront of scientific advances, both in the discovery and development of epilepsy medicines and in finding ways to best serve the patients who need us. We’re very pleased that the FDA, in collaboration with the epilepsy community, forged a new pathway using extrapolation, which may potentially speed patients’ access to much-needed, additional safe and effective therapies. This effort is consistent with Eisai’s broader mission of addressing the unmet needs of patients and making sure our therapies are available to those who need them in a timely manner.