There’s a natural tension between wanting the FDA to ensure safety and efficacy before a drug enters the market and wanting to speed up what many view as a glacially slow approval process. The rare disease community tends to fall in the second camp, and has become increasingly vocal in calling for more clinical trials, more flexibility in their design and redefinition of what constitutes a benefit.
ALS advocates, for example, have called for a parallel track, “in which FDA provides an early approval based on limited data, and then continues the learning process in a confirmatory clinical trial and if needed, patient registries to collect additional data from patients receiving the drug outside the clinical trial…”
Recent legislation is encouraging patient engagement in drug development, especially for conditions with profound unmet medical needs. In its 2012 iteration, the Prescription Drug User Fees Act (PDUFA) introduced public meetings to get input from the patient community, captured in a series of informative white papers.
PDUFA 6, to be launched in 2017, calls on the FDA to strengthen staff capacity to develop and use patient-focused methods. It also directs the agency to develop guidance around collecting/reporting/analyzing patient input and incorporating patient-reported outcomes in drug assessments. The 21st Century Cures Act, passed by the House and still lingering in the Senate, also includes patient-focused drug development provisions.
Patients want input in three key areas, outlined in a recent panel co-hosted by Boston Children’s Hospital’s Office of Government Relations and Public Policy and Technology and Innovation Development Office.
Patients and caregivers frequently tolerate more risk and more modest benefits than regulators, especially when good treatments are lacking. In one FDA public meeting, families of children with neurometabolic disorders stressed a willingness to try experimental therapies, since their children are dying. The Parent Project Muscular Dystrophy recently surveyed 119 caregivers and issued Guidance for Industry stating that a drug that only slows clinical deterioration or delays the loss of functional milestones could be worth the risk, even if it doesn’t extend lifespan.
But what about the companies developing the drugs? Will they be comfortable handing the risk/benefit decision off to patients? That’s far from certain, panelists said.
“Companies are looking at ‘what’s required on the regulatory side, to get this approved?’” said Joan Finnegan Brooks, a cystic fibrosis patient and advocate. “And that’s often at odds with the interests of the patient community.”
Defining endpoints for clinical studies
Patients want their views to be considered when deciding what constitutes a meaningful treatment outcome. Parent Project Muscular Dystrophy, for example, states a general flexibility around accepting intermediate endpoints. It has asked for more flexibility around post-hoc analyses — giving credence to outcomes that weren’t initially defined as study endpoints.
Increasingly, patients are defining their own endpoints and aggregating their own outcomes on sites such as Patients Like Me, which was founded by the brothers and friend of an ALS patient and claims more than 80 published research studies.
Sometimes patient groups have been successful in adjusting endpoint measures. Jennifer Helfer, PhD, head of patient affairs at bluebird bio, cited an example from the brain tumor community. Traditionally, brain imaging is used to gauge treatment efficacy, but it has inherent variability, a sticking point with the FDA.
“[The community] came out with an imaging acquisition protocol and had the FDA review it, asking, ‘Will this lessen your concerns?’” Helfer said. “The FDA agreed to try it out as a biomarker.”
But again, is industry on board with this?
“If an endpoint isn’t acceptable to the FDA, no one wants to do the trial,” said Finnegan Brooks.
Development of study protocols
The bottom line is that patients want to be at the table as early as possible, when the protocols are first being developed, and to be regarded as disease experts.
For a start, many patients want to change the way data are collected.
“Do you really think a patient is going to sit in a room for two hours and fill out all these surveys?” asked panelist Ahmet Uluer, DO, director of the Adult Cystic Fibrosis Program at Boston Children’s Hospital.
Patient groups also have called for changing overly narrow clinical trial criteria that make it hard to get sufficient patient numbers. And some, like the Duchenne community, request moving away from the use of placebos.
“In the ALS world, we’ve seen tension between patients and clinicians around ‘How flexible and aggressive can we be in clinical trial design?’” said Dave Zook, chair of FaegreBD Consulting, a national advisory and advocacy firm.
Patients versus parents
It’s an interesting time of flux in the rare disease corner of the drug development world. How far will regulators go in bending to the patient community’s requests? What role should industry be playing?
“It’s all new, and we’re all trying to figure this out,” says Helfer. “We are all really flying blind right now.”
And here’s another twist. In conditions that start in childhood, patients’ views may differ from those of their parents. One young adult Duchenne patient found himself disagreeing with parents advocating for approval of a new experimental drug because of his concerns about drug-induced anxiety and depression.
He is now part of a group seeking to gather data on the mental health of people with Duchenne.