FDA consulted a Morquio A patient and several caregivers as it struggled to determine the clinical relevance of Vimizim’s effect on the six-minute walk test, apparently unbeknownst to the product’s sponsor, BioMarin Pharmaceutical Inc.

The consultation during FDA’s active BLA review process shows that patient groups can engage with FDA outside the context of an advisory committee, and reinforces the agency’s interest in patient and caregiver input.

FDA approved Vimizim (elosulfase alfa) Feb. 14 for treatment of Morquio A syndrome, a rare disease also known as mucopolysaccharidosis type IVA, despite the review team’s doubts about the clinical meaningfulness of the six-minute walk test (6MWT) primary endpoint ([A#06141201004]).

Patients taking Vimizim showed a statistically significant mean improvement of 22.5 meters after 24 weeks of treatment compared with placebo.

Early in the review, the agency conducted a teleconference with “patient caregivers and an adult patient” to better understand their personal experiences, according to the clinical review conducted by Tamara Johnson.

The meeting occurred May 21, 2013, less than two months after the application had been filed ([A#06141201001]).

No minutes of the meeting were included in the publicly available Vimizim review documents, but a footnote in advisory committee briefing documents says that patients shared the “clinical signs and symptoms that are most troublesome.”

FDA wanted patient input on the “impact on function,” according to an Oct. 28 email to Pharmaceutical Approvals Monthly.

FDA does not appear to have informed BioMarin that the meeting took place.

A company official said Oct. 21 during the National Organization for Rare Disorders’ Rare Diseases and Orphan Products Breakthrough Summit that the company did not learn of the meeting until FDA posted its application summary, presumably because reviews are confidential.

FDA said in the emailed statement that “reviews often incorporate the patient perspective at varying levels of interactions and phase of drug development.”

BioMarin was not told of the meeting because “FDA independently conducts its review of marketing applications, which may include consultations with both internal and external parties,” the agency said.

The 2012 FDA Safety and Innovation Act directs FDA to look for ways to include patient input throughout the drug development process.

This story is part of a larger Drug Review Profile appearing in Pharmaceutical Approvals Monthly. The Drug Review Profile ongoing series provides a closer look at factors affecting drug reviews and insightful take-aways for other products in development. Other articles in the Vimizim profile include:

([A#06141201004])
Also see "In Manufacturing, Absence Of Evidence Is Not Evidence Of Absence, FDA Tells BioMarin" - Pink Sheet, 19 November, 2014.
Also see "FDA Awaits Data On Clinical Significance Of Vimizim Neutralizing Antibodies" - Pink Sheet, 19 November, 2014.
Also see "Low Survival To Adulthood Key To Vimizim Pediatric Priority Voucher" - Pink Sheet, 19 November, 2014.

Patients already give their input during advisory committee meetings, where a patient representative maintains a seat and has a vote.

But FDASIA mandated that patients be allowed to give input during early FDA meetings with sponsors before an application is filed, and established a process for specific disease workshops to gather patient input Also see "PDUFA Commitment Letter Formalizes REMS Standardization Schedule" - Pink Sheet, 1 September, 2011..

The agency also recently asked for public input on the best ways to involve patients in drug and device development ([A#14141103005]).

Meeting Influential, But How Much?

The patient and caregiver opinions did not appear to definitively calm FDA concerns about Vimizim.

However, the meeting still appeared powerful. Johnson wrote that the common symptoms reported were fatigue, decreased exercise endurance, joint stiffness and pain.

“Patient and patient caregivers wished to see a drug that could improve the endurance and breathing, as well as resolve the short stature,” Johnson wrote.

Those issues, which may be affected by an improvement in the distance walked over a short time, could have swayed Johnson and other agency officials.

Johnson did not state specifically that the patient and caregiver comments changed her mind about the clinical meaningfulness of the six-minute walk test results. She did state her opinion that the test was meaningful to patients.

“This reviewer considers the [six-minute walk test] relevant to the [Morquio A syndrome] population in that it reflects functional limitations in activities of daily living,” Johnson wrote. “But the clinical meaningfulness of the [six-minute walk test] improvement needs to be further explored.”

Advisory committee members also decided that the test was adequate, but said it did not measure a number of other aspects of the disease, such as fatigue Also see "FDA Panel Backs Efficacy Of BioMarin’s Rare Disease Drug Vimizim" - Pink Sheet, 20 November, 2013..

Patients Can Initiate Meetings With Reviewers

The patient teleconference also illustrates another, lesser-known strategy patients and advocates can use to educate or potentially influence agency reviewers, especially if they are struggling with clinical meaningfulness, as in the Vimizim case.

FDA allows patient groups to meet with reviewers to talk about issues related to their disease. James Valentine, an associate at Hyman, Phelps and McNamara, said during the NORD conference that one of those meetings was able to help a client break a stalemate with FDA.

Valentine, who did not reveal specific details of the case he mentioned, said reviewers cannot be expected to be experts on every disease, especially when it comes to rare diseases.

“In this case, the next time our client met with FDA, the first thing FDA told the client was that they had met with the patient advocates or the patient community and that they understood that critical aspect of the disease,” said Valentine, who worked as an FDA patient liaison before going into private practice. “That allowed the client and FDA to resolve that kind of stand-still that they were at and move forward with planning their drug development program.”

It appears from the Vimizim documents that FDA may have initiated the teleconference with patients. But Valentine said in other cases, patients requesting meetings with a review division can allow them to “make a direct impact on drug development in their disease.”

Patient advocacy groups typically are approached to provide recommendations for participants when FDA initiates a patient meeting.

Diane Dorman, NORD VP of public policy, said in an interview that FDA sometimes consults the group when it is having trouble finding patients, although she did not know the specifics of the Vimizim case.

Patient involvement in drug development has been one of the most successful aspects of PDUFA V.

The most visible example of the increased patient voice is FDA’s patient-focused drug development program, which is part of FDASIA. It is likely to include more than the required 20 disease-specific meetings where patients, caregivers and advocates can talk about unmet needs and existing treatments.

FDA also has encouraged patient groups whose diseases are not the subject of any planned meetings to conduct their own events using the agency’s format. FDA will send its staff to listen if schedules allow Also see "Patient-Focused Drug Development At 10: Where Does It Go From Here?" - Pink Sheet, 20 October, 2014..

One patient group used its own patient-focused meeting to write a proposed guidance on drug development that it submitted to FDA ([A#00140707011]).

FDA Quietly Consults Patients To Understand Vimizim's Six-Minute Walk Significance

More from United States

More from North America