Pivotal Clinical Trials of Migraine Drugs: Are We Measuring the Same Thing?

By Neil Andrews | September 21, 2023 | Posted in

An analysis of dozens of trials reveals important differences in endpoint selection and timing.

Researchers, clinicians, and people with migraine have seen several successes in recent years for both acute and preventive treatment of the condition. That includes a number of gepants and monoclonal antibodies that target calcitonin gene-related peptide (CGRP) or its receptor, as well as ditans, which target the serotonin 1F receptor. Along with these newer drugs, doctors can also look to older medications like triptans and non-steroidal anti-inflammatory drugs (NSAIDs) to help their patients.

But how is a physician to choose which drug to use? And how are patients to understand the differences among the various treatment options? In both instances, unfortunately, the answer is often “not easily.” One of the main problems is that the pivotal clinical trials – those that are the basis for FDA approval – of migraine drugs use different endpoints to assess efficacy.

Now, researchers led by Leigh Sharpless and Jonathan Darrow, Brigham and Women’s Hospital, Boston, MA, have precisely characterized the nature of variation in the endpoints used in pivotal trials of migraine drugs. They found that the endpoints varied considerably among trials, identifying five primary endpoint types and three combinations of co-primary endpoints. The timing of endpoints also differed among trials.

By delineating these disparities, the investigators are bringing further attention to an issue that the migraine field needs to grapple with, to ensure that patients receive the best care and that new drugs in the pipeline have a measuring stick against which investigators can compare them.

The authors “have provided a window into the heterogeneity of primary endpoints that resulted in the FDA approvals of recent migraine treatments,” wrote Juliana VanderPluym, Mayo Clinic, Scottsdale, US, in an accompanying editorial.

She continued, “It has been very exciting witnessing the expansion of treatment options but disheartening to see the confusion created for patients, clinicians, and payers to compare amongst these options. Over time, we are seeing increasing adherence to the trial design guidelines. As a field, the goal will be to continue striving toward comparing apples to apples to shorten the time to improved patient outcomes, reduce cycling from one medication to another and exposure to side effects, and increase informed utilization of healthcare resources.”

The research and editorial appeared September 5, 2023, in Neurology.

Migraine pivotal trials are not the same
“We have had a number of grants that are intended to facilitate investigation into pharmaceutical policy in the United States,” said Darrow, a drug policy expert and former assistant professor of medicine at Harvard Medical School, in an interview with Migraine Science Collaborative.

One focus of that work is pivotal trial endpoints. Previous research in other therapeutic areas such as oncology had revealed variations in those endpoints, so Darrow and colleagues approached Serena Orr, a migraine researcher and clinician at the University of Calgary, Canada, to look specifically at pivotal trial endpoints in the migraine field.

“It’s fairly rare that we get head-to-head drug comparison trials in our field, and I think in most others. Trials are expensive to do, and, generally, to get FDA approval you just need to show superiority over placebo,” Orr told Migraine Science Collaborative.

Migraine drugs were a good candidate for this approach, considering that there are a manageable number of pivotal trials available for analysis. In addition, the field has a mix of older and recently approved medications, making it important to understand how pivotal trials might compare.

The researchers would go on to identify 16 medications that had been approved by the FDA between January 2001 and September 2022 for acute or preventive treatment of migraine, based on 45 pivotal trials. These medications, which work by a variety of mechanisms, included anti-CGRP antibodies, gepants, triptans, NSAIDs, ditans, onabotulinumtoxinA, and topiramate.

Amongst the trials, the team identified five primary endpoint types, including change in mean monthly migraine days from baseline; change in mean monthly migraine attacks from baseline; change in mean monthly headache days from baseline; mild to no pain after two hours; and pain-free at two hours.

There were also three groups of co-primary endpoints, including headache pain free at two hours and most bothersome symptom free at two hours; pain-free at two hours and sustained pain-free from 2-24 hours post-dose; and pain-free at two hours and 2-24 hours sustained pain free and two-hour pain relief.

Considerable variation among trials in terms of primary endpoint timing also became apparent. That is, some trials calculated patient outcomes based on the final month of treatment, but others did so based on the entire treatment period, or on a portion of the treatment period.

These inconsistencies were observed within drugs that had the same indication (episodic or chronic migraine), worked by the same mechanism, or had the same route of administration.

Still a long way to go
The investigators also saw that pivotal trials for newer medications for acute migraine treatment adhered to FDA guidance issued in 2018, and to guidelines from the International Headache Society (IHS).

Of that finding, VanderPluym wrote in her editorial, “Finally and potentially most importantly, this study acknowledges the interaction of time and the resulting changes in regulatory and IHS clinical trial recommendations. As such, much of the heterogeneity observed may be a relic of times past since recent studies are generally following trial design guideline recommendations around endpoint selection.”

“We do see some improvement over time with the more recent trials that have been published,” Orr said. “But it’s not perfect. Even with those very clear, very well-known published guidance documents, there still are some deviations among trials that could frustrate comparisons of drugs,” of the sort that the new study identified.

Even assuming that the recommendations and guidance don’t change over the years – which is not a given – other problems with the standardization of pivotal trials still remain.

One issue Darrow emphasized is that having common endpoints for newer and future drugs still doesn’t address the need to compare those drugs to medications that have been on the market for a long time – and that may be a lot cheaper, too.

“We need to have comparisons with older, cheaper drugs. It’s not enough to just be able to compare the new, expensive drugs, because that really leaves you without an economic choice. You may have a therapeutic choice, which may be fine from the physician’s perspective, but if you are thinking about the patient’s wallet and the insurance company and the premiums that the patient is paying every month, the patient wants a financial choice in addition to a therapeutic choice,” Darrow said.

One way to address this issue, he said, would be to test new drugs up for approval not only against placebo but also against an older drug using a three-arm trial design, for example.

Another remaining hurdle is that endpoints, of course, are only one aspect of clinical trials. Darrow pointed to the indication for a drug, the demographics of the study population, and the drug dose as a few examples of other factors that could impede standardization.

Finally, the migraine field is fortunate to also have non-drug treatments, such as neuromodulation. Ideally, trials for those therapies, too, would have the same endpoints as drug trials in order to facilitate comparisons, according to Orr.

“I’m really interested in looking at comparisons between neuromodulation and pharmaceutical interventions. In our lab, we actually are running a pilot trial that’s comparing a neuromodulation device to an intravenous acute migraine therapy in the emergency department.”

The patient aspect
As in other areas of medicine, the migraine field has increasingly recognized the importance of including people with the condition of interest in the research process. For example, the FDA-funded Migraine Clinical Outcome Assessment System (MiCOAS) is a project working to develop patient-centered outcome measures for clinical trials.

This is important work since what matters to individuals who have migraine – including the endpoints that are important to them – may differ from what trial investigators deem critical.

It also adds a new complexity to clinical trial standardization, since the endpoints that patients value would need to be standardized across trials, too.

Darrow pointed to other ways that clinical trials could be standardized for the benefit of patients.

“A lot of folks who advocate for comparative testing suggest that patients and physicians want to know whether drug A is better than drug B. I do not think that is enough. Decision-makers need to know how much better a drug is,” Darrow said.

“What I would like to see with migraine medicines – and this is no different than what I would like to see with all medicines – is a presentation of the data in a quantitative manner using measures that patients can understand,” Darrow said. Right now, “we have almost zero transparency and patients really have no idea of the amount of benefit that they can even hope to get.”

The financial imperative
One challenge for the standardization of clinical trials could be how willing companies are to support it, considering the financial and marketing pressures they face.

“As someone who has studied business and worked with businesspeople, I think the dominant factor when selecting endpoints is going to be, How can I differentiate my product in the market?” said Darrow. “Ensuring that trials cannot easily be compared – whether through use of different endpoints or other trial characteristics – will continue to be a priority for drug developers, and proposing changes to guidance documents or preferred patient-reported outcomes, shortly before patents expire, is one way that businesses know they can achieve this.”

Absent that ability to distinguish a new treatment from a competitor’s treatment, “businesspeople would be much less interested in developing new drugs. On the other hand, standardization of trial design, including endpoints and dosing, would allow the consumer to easily compare the drugs and potentially pay a much lower price.”

However the tension among business interests, the need for innovation, and providing the most benefit to patients plays out, there is reason for optimism that the migraine field is heading in the right direction and may be better able to avoid the inconsistencies among trial endpoints that the new study identified.

“I’m hopeful that we’re getting closer to a unified approach that will be sustainable rather than something that has to be changed every five to 10 years that then results in this kind of historical problem,” said Orr.

Neil Andrews is a science journalist and executive editor of the Migraine Science Collaborative. Follow him on Twitter @NeilAndrews

References
Variation in endpoints in FDA medication approvals: A review of acute and preventive migraine medications.
Sharpless et al.
Neurology. 2023 Sep 5;101(10):e989-e1000.

Variation in endpoints in FDA approvals for acute and preventive migraine medications: Striving to compare apples to apples.
VanderPluym JH.
Neurology. 2023 Sep 5;101(10):417-19.

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Neil Andrews is a science journalist and editor based in New York City. He has over two decades of experience covering science and medicine for expert and non-expert audiences alike. He is also the executive editor of the Migraine Science Collaborative, where he manages the day to day operations of the site. Previously he was the executive editor of the Pain Research Forum.

When not thinking and writing about neuroscience, Neil spends much of his free time on his Peloton and exploring NYC. He is also on a quest to satisfy his coffee cravings by visiting every independent coffee shop in the city. Follow him on Twitter @NeilAndrews.

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