Meeting with the FDA

On May 12th, fifteen members of the ALS patient community met with senior FDA management to discuss expedited development and approval of new therapies for ALS. The key FDA persons

attending the meeting were Dr. Janet Woodcock, Director of the Center for Drug Evaluation and Research (CDER), Dr. Richard Moscicki, Deputy Director for Science Operations in CDER, and Dr. Ellis Unger, Director of the Office of New Drugs 1 (OND 1). The Division of Neurology Products (DNP), which is the review office that oversees the development of new

drugs intended to treat neurological diseases, resides in OND 1, and is supervised by Dr. Unger. The Director of the DNP, Dr. Billy Dunn, was scheduled to be at the meeting, but did not attend. Several other FDA employees that are not in key decision-making positions associated with the development of neurological drugs also attended the meeting.

We made the following initial points to FDA during the meeting.

  1. ALS is a serious and terminal disease with an extreme unmet medical need, making it clearly eligible for use of the agency’s expedited

    approval authorities, including its Accelerated Approval Program (AAP)

  2. Any unwarranted delay in developing and approving promising drugs for ALS means that thousands of patients are denied an opportunity to see if the drug might help them and to participate in the learning
  3. The FDA’s standard, phased development process is too slow, expensive and uncertain for ALS,

    a

    disease for which only one drug has ever been approved (more than 20 years ago), and which has minimal effect on disease progression

  4. ALS generations are measured on a scale of 2 to 5 years, a timeframe shorter than the FDA’s typical phased development approach, making it unacceptable for use in ALS.

 

We also addressed the FDA’s role in the development program for GM604.

 

A large segment of the ALS patient community is supporting Accelerated Approval for GM604 for the following reasons:

  1. The drug is safe. It has been given to approximately 50 patients and has shown no significant adverse side effects
  2. While not yet conclusively proven, the drug has shown signs of efficacy in regulating biomarkers thought

    to be associated with ALS, and has also shown a positive effect on Forced Vital Capacity (FVC)

  3. The sponsor (Genervon) is the only company attempting to deliver any potentially efficacious treatment to the ALS community now, which means that absent availability of the drug, the current generation of ALS patients (most of whom are not eligible for any

    ongoing clinical trials) have no reasonable treatment option.

  4. The ALS patient community is aware that GM604, or any treatment now in development, may not work as anticipated or may not help everyone who receives it.
  5. The inevitable risk of the disease for most ALS patients (progressive loss of physical function followed by death within 2 to 5 years) far outweighs the risks of treatment with GM604, and the potential for benefit offered by GM604 further enhances the patient perception of the potential benefit versus risk comparison.

 

Furthermore, we made the following points regarding Genervon:

  1. The ALS patient community was not being lead, or mislead, by Genervon in any way. In fact, it was the patient community that asked Genervon to pursue approval of GM604 under FDA’s AAP, and worked with the company on preparing the cover letter and data package that was submitted to FDA requesting feedback regarding the agency’s position on whether it would accept an application for Accelerated Approval.
  2. We expressed our continuing strong support for Accelerated Approval of GM604.
  3. We informed the FDA that Genervon had informed us they were not capable of supporting any significant level of compassionate use or expanded access at this time; consequently (as suggested at one point in the meeting by Janet Woodcock), it is not

    a workable option for meeting the very large and severe unmet medical need for ALS patients.

We reminded FDA that Congress directed the agency to factor the patient perspective of the potential for benefit versus the risks of a new drug and the risks posed by the disease into its decision-making process regarding drug approvals for serious and life-threatening diseases, and to expand the use of its AAP across all such diseases.

Citing the legal prohibition on discussing any information associated with their interactions with sponsors, FDA declined to provide specific responses regarding GM604; however, the FDA did agree that ALS is among the most severe serious and life-threatening

diseases which makes it eligible for use of the agency’s expedited approval mechanisms (including AAP), and that in diseases

like ALS, safety is usually not a concern if there is substantial evidence of efficacy.

Dr. Woodcock pointed out that the agency would likely approve a drug with significant safety issues for ALS if the drug provided an offsetting benefit. The FDA also acknowledged that they have a lot of flexibility under the law with regard to the amount of evidence needed for them to conclude that sufficient evidence to support AAP has been collected.

We went on to propose to FDA that, because of the severe unmet medical need and the devastating effects of the disease, new approaches were needed for all

promising ALS medicines (including GM604), – a new kind of 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 (e.g., more advanced patients, or patients who didn’t qualify for the trial because they were more than two years from diagnosis).

Some specific concepts for confirmatory trials were discussed, and at the conclusion of this discussion, Dr. Unger repeated back to us what we were asking for in relation to a streamlined, parallel approval (using AAP) and a continuing post-approval development process. We made the central point that this type of approach fits squarely into the intent of the agency’s AAP, as intended by Congress.

We expressed our strong dissatisfaction with FDA for failing to respond to Genervon’s request for feedback on whether a New Drug Application (NDA) for GM604 would be accepted for review under the AAP. The point was clearly made that because FDA had not responded to Genervon, more than three months had been wasted – an unacceptably long period of time given the challenges and abbreviated life expectancy of ALS patients.

We requested that senior management (specifically Drs. Richard Moscicki and Ellis Unger) ensure that the Division of Neurology Products respond to Genervon immediately (suggesting that they do it by May 13th), and that whatever personnel training and disciplinary actions needed to ensure that the review division, and more broadly the FDA, never again chose to ignore

a legitimate and appropriate request for feedback from a regulated company trying to develop a new treatment for a serious neurological disease.

We also requested a continuing dialogue with FDA regarding the development of all drugs for ALS, including a continuing dialogue regarding an expedited path through the process for GM604. We expressed a willingness to work with the FDA and drug sponsors to design more creative and effective clinical trials, and flexible, faster drug development and approval pathways for new ALS treatments. We stated that there is not time for development of guidance, which typically takes two years or more at FDA. Dr. Moscicki concurred that guidance development was a lengthy, years-long process at FDA.

We received the following commitments from FDA.

  • FDA would quickly provide a response to Genervon regarding their request

    for feedback and would work with the company on a path forward for GM604.

  • Senior management would determine why Genervon’s request for feedback was

    ignored and take appropriate actions to make sure it does not happen again.

  • The FDA would participate in a continuing dialogue with us regarding the development of new medicines for ALS.

We learned on Friday,

May 15th, that FDA is declining to consider GM604 under

its AAP at this time, but that they do intend to work with Genervon on a path forward for the drug. By separate communication between our technical team and Janet Woodcock of FDA, we have also

learned that the FDA agrees that AAP should be used in the ALS space, that they

have discretion in determining the level of evidence needed to support an Accelerated Approval, and that they are open to new, faster, less expensive approaches to determining efficacy.

We are extremely disappointed that FDA has failed to fully appreciate and concur with the positions we expressed at our meeting, and that they still do not appear to understand the need for immediate action and new regulatory approaches for ALS; however, we are encouraged by the commitments we received from FDA. We will be pressing ahead based on those commitments to work with FDA and Genervon to create a flexible, faster pathway for GM604 and other promising drugs

for ALS, with the goal of submission of an NDA for Accelerated Approval of GM604 within months, instead of what would otherwise be years.

Do we have a fully committed partner in the FDA? It is not yet clear, but we would not have the commitments at all without the powerful efforts and advocacy of the ALS patient community.

Quoting our own Eric Valor: “To our supporters: Our combined activism actually moved the mountain a little and with continued support we firmly believe we together can actually achieve the goal. PALS, CALS, family, and friends are on the verge of changing history for ALS and all other neurological diseases.”

Keep up the pressure! Continue to e-mail the FDA urging them to work flexibly, creatively and

with a sense of urgency with us, Genervon and other drug companies working to bring new treatments to ALS patients!

Let

your elected representatives in Washington know that ALS patients continue to:

  • Wait for the first very promising ALS drug in more than 20 years to reach them!
  • Question whether we have an FDA that is fully engaged with PALS and CALS and understands the need for speed, flexibility and faster delivery

    of

    medical progress!

  • Doubt that FDA has accepted the intent of Congress regarding the use of AAP and the incorporation of the patient perspective into its decision-making for diseases like ALS!

FDA has been given the opportunity to prove itself! Let’s make sure it stays front and center on their radar screen!

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