Drugmakers ask FDA to reconsider concomitant treatment in migraine drug guidance

Four drugmakers have asked the US Food and Drug Administration (FDA) to amend some of the requirements in its draft guidance on developing migraine prevention medications, including the preference that 70% of a study population to be off all migraine preventives at clinical trial enrollment.

The draft has been open for public comment since it was posted in early June. While no patients or patient advocacy groups filed comments, four drugmakers (Pfizer, AbbVie, Lundbeck and Eli Lilly) did. FDA’s draft requirements on concomitant medications and its separation of chronic and episodic migraine were among their top concerns.

According to the draft guidance, the use of concomitant treatments should be minimized as much as possible in clinical trials of migraine preventives, because they could mask both response and safety signals.

“Because the use of other preventive migraine treatments may influence the interpretation of both safety and efficacy, no more than 30 percent of the study population should be taking a concomitant medication for the preventive treatment of migraine during the trial,” the agency wrote in the document. “Randomization should be stratified by the use of such concomitant medications.”

That’s going to be tough, wrote Erin Greene of Pfizer’s International Regulatory Sciences and Policy department.

“Restricting concomitant use of preventive migraine treatments to 30% of the population will be challenging in studies focusing on patients with chronic migraine, due to the prevalent use of preventive therapies in that population,” she said in Pfizer’s comment. “Similarly, the use of more than one preventive medication in this population may be unavoidable. We suggest specifying that this does not apply to chronic migraine populations.”

Lundbeck agrees, according to comments filed by Lene Kirstein, the company’s head of regulatory science and policy. Because these medications are such a common part of routine migraine care, the requirement could have broad effects on cohort recruitment.

“The 30% should be considered in the context of the target study population and study design,” Kirstein wrote. “A ‘hard limit’ on percent of patients receiving preventive medications might become a recruitment challenge and not representative for the population in which migraine medications are investigated.”

Another point of contention appears to be FDA’s suggestion that sponsors should consider chronic migraine and episodic migraine separately when developing these drugs. That differentiation is artificial, wrote AbbVie’s Katie McCarty, head of US/Canada regulatory policy and intelligence.

“The distinction between episodic migraine [EM] and chronic migraine [CM] does not describe fundamental biological differences,” she said. “The studies conducted in the past 8 years with monoclonal antibodies and oral calcitonin gene-related peptide [CGR] receptor antagonists indicate that the drugs are effective at the same dose in both EM and CM populations and the safety profiles of the drugs in the two populations do not differ. The response to treatment in the two populations is more similar than different; the placebo-corrected treatment differences for the primary endpoint in the EM and CM populations are similar. The fact that EM patients have more discrete attacks, and CM patients have less discrete attacks, is immaterial since the classification of EM vs. CM is based on the number of ‘ days’ or ‘headache days.’ Additionally, patients frequently move between these two categories, i.e., from CM to EM and EM to CM, both EM and CM being part of the migraine disease spectrum that is nonbinary and manifests as a continuum of disease severity.”

AbbVie recommended revising the draft to say that a sponsor does not need to conduct separate studies in both populations, but that they may consider a single study, or replicate studies, in a population of both EM and CM patients.

Lilly’s Conrad Wong, PhD, agreed. His comment pinpointed the second part of FDA’s CM/EM recommendations, which said that patients with EM might be able to more accurately define the beginning and end of a migraine attack, whereas those with CM might not be able to do so, when a headache continues over several days.

“The guidance should explicitly state that the number of monthly migraine attacks should not be used as inclusion criteria or as an outcome measure for chronic migraine trials. The number of possible migraine attacks may actually be lower in patients who have a very high number of migraine headache days per month,” wrote Wong, Lilly’s executive director of global regulatory affairs in North America. “For example, a patient with migraines 30 days in a month might only be counted as having a single attack since they do not have a migraine-free day between separate attacks. Thus, patients with fewer migraine headache days might be seen to have more migraine attacks … this makes the resulting counting of migraine attacks meaningless in the CM population.”

Wong also recommended deleting a section of the draft that would require prospective trial subjects to be able to differentiate between their headache subtypes – for example, the document says, “If subjects have more than one headache type, they should be able to distinguish their other headache types (e.g., tension-type headaches) from their migraines.

Wong objected to that recommendation. “It is not the patient’s responsibility to distinguish between headache types and sponsors will be unable to determine whether they are able to do so before patients enroll in the trial. The eDiary algorithms should allow the sponsor to identify when a headache is a migraine based on the recorded symptoms and duration. We recommend deleting this sentence.”

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Drugmakers ask FDA to reconsider concomitant treatment in migraine drug guidance

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