FDA recently finalized a Guidance for Industry to help guide the development of new products for patients with amyotrophic lateral sclerosis (ALS). The original draft guidance was published early in 2018 (see our previous post here).
ALS, colloquially known as Lou Gehrig’s Disease (ALS forced the baseball player to retire in 1939), is a progressive neurodegenerative disease that deteriorates nerve cells in the brain and spinal cord. About 5,000 people in the U.S. are diagnosed with ALS each year. Early symptoms can include stiff or weak muscles, twitching or spasms, fatigue and trouble walking. Eventually it leads to difficulty in speaking, breathing and swallowing, as well as loss of voluntary movement with premature death often within 2-5 years after diagnosis. This disease is sporadic, typically with no known pattern of inheritance or familial patterns, although gene mutations have been identified in some sporadic ALS patients. This disease can affect multiple body systems including cognitive and behavioral changes.
This guidance focuses on specific clinical drug development and trial design issues that are unique to ALS. One of the changes that is immediately noticeable is the emphasis on drug developers communicating with people affected by ALS. This is part of the ongoing emphasis of the FDA on greater patient engagement at every phase of drug development. The guidance states that, “Sponsors should understand how affected patients view treatment goals and risk tolerance.”
Additionally, the FDA encourages broader inclusion in clinical trials of patients at every age and at every stage of the disease. They suggest enrolling the broad population of affected individuals with ALS and possibly conducting a primary analysis on a specified subset of those enrolled and using the totality of the data collected as secondary and supportive. This advice is in sync with the FDA guidance published in June of this year on the topic of broadening inclusion criteria in clinical trials.
Another significant change from the draft guidance is the emphasis on greater flexibility in the review of drugs for this devastating rare disease. This emphasis reflects the Agency’s continued evolution in flexible approaches to approving drugs for patients with serious and unmet needs. The FDA is committed to providing flexibility which is supported by statute. 21 CFR 314.105 states:
While the statutory standards apply to all drugs… the many kinds of drugs… and the wide range of uses for those drugs demand flexibility in applying the standards. Thus FDA is required to exercise its scientific judgment to determine the kind and quantity of data and information an applicant is required to provide for a particular drug to meet the statutory standards.
As the prospect of gene therapies continues to grow, FDA advises sponsors to meet with the staff at the Center for Biologics Evaluation and Research (CBER) when planning phase 1 clinical trials. Gene therapy trials must start slowly to ensure there are no immediate safety concerns or off-target effects from the intervention which is usually irreversible once administered. This advice reflects similar advice given in the 2015 guidance “Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products.”
The draft ALS guidance was somewhat rigid and recommended that sponsors conduct randomized, placebo-controlled, double-blind studies for ALS. In the spirit of flexibility and concern for patient well-being, the final guidance has modified that directive. The final guidance states that no patient should be denied effective therapies by being randomized to a placebo-only arm of the study. The Agency also suggests that everyone in a study be given a treatment that has previously been shown to be effective so that no one in the study is on placebo alone. They also state that placebo-controlled studies can be designed as time-to-event trials so that if a participant in the placebo arm worsens, they can be transitioned to open-label study drug. The final guidance maintains that using historical controls as a control group can be very challenging in ALS since there is tremendous variability in disease course.
Regarding efficacy endpoints, FDA has added emphasis on engaging with patients in developing any new measures being considered. It is refreshing to see how consistently the Agency is asking industry to inquire about the patient perspective at all points in drug development. One of the specific suggestions they make for endpoints is related to the measurement of the key symptom of ALS – loss of strength. This can include effects on the ability to perform activities of daily living (ADLs) where any improvement might be significant to patients. The guidance also suggests considering measuring respiratory function as a potential treatment benefit. Consistent with the draft guidance, mortality will be an important outcome to be measured in all patients.
ALS strikes people between the ages of 40 and 70 and there are approximately 16,000 Americans who are sick at any given time. ALS takes away a person’s ability to walk, to write, to dress, to swallow and eventually to breathe. This disease is devastating to individuals and families with affected loved ones. This final guidance will help guide and expedite the development of new treatments for people with ALS.
* Not admitted to the Bar. Work supervised by the firm pending Bar admission.