Clinical and Regulatory Webinar and Extended Q&A Now Available

A recording of last week’s Cure SMA Clinical and Regulatory Webinar is now available online.


Our thanks again to our three panelists—Dr. Tim Franson, Dr. Tim Miller, and Dr. Tom Murray—for their expertise and for their generosity with their time. Our thanks also to everyone from our community who joined in.

We received a number of excellent questions and, unfortunately, time did not permit us to answer all of them during the webinar. Below, we have included an extended Q & A, with answers to many of the questions that we did not get to cover.

Extended Q&A

Is it possible that in the Phase 3 trial there are two different doses and placebo investigating? And is it possible that this information is secret?

Phase 3 trials are typically conducted as blinded-randomized placebo controlled trials. Therefore, some patients are given drugs and some are given a sham treatment or a placebo. This means that the drug company, the site principal investigator (PI), and the patient do not know whether they are receiving drug or placebo. This trial design is considered to be the gold standard in determining the true benefit of a drug, as it has been shown that significant percentage of benefit in clinical trial can come from a placebo effect. Please see page 15 of our clinical trial booklet for more information on placebos.

Considering the obvious and established deterioration of SMA patients, why wasn’t the natural history of SMA used instead of placebo/sham controls?

Many studies have shown the placebo effect is real and significant. Thus, placebo controlled studies are considered the gold standard for drug development. However, good natural history data can be used in registration trials, for example. In addition, natural history data can and has been used to reduce the number of individuals who are placed in a placebo group in a clinical trial—for example, a 2:1 treatment to placebo ratio.

Another consideration is the fact that SMA natural history data has been changing over the last decade. The National Institutes of Health (NIH) has funded the largest and most well controlled natural history study in infants under six months of age, which will be completed over the next few months. Once the results become available in 2016, that will open up more opportunities to use this data.

I was hoping to find out more about the results from the trials being conducted now. Can that be discussed?

Cure SMA regularly posts updates on clinical trials, including information on new trials, recruitment, and results. Please visit our news section and click on “Clinical Trials” in the right sidebar.

What is the probability that drug trials will open to patients with SMA type III?

While there are currently no trials open to SMA type III patients, Cytokinectics recently announced that they will open a trial in 75 teens and adults with SMA type II, III, or IV—both ambulatory and non-ambulatory. We will post additional details as soon as they become available, as well as any updates on future trials for all types of SMA.

When is the FDA is going to be satisfied with the cure?

The FDA needs to see robust data to be convinced the benefit of a drug outweighs the risk in specific patient populations. The best possible measure for this is a blinded, randomized placebo-controlled trial. However, there are mechanisms to speed this up, such as accelerated approval, where drug approval can be sought from a surrogate marker or from Phase 2 trial data. Often this data would need to be more robust than sought from placebo-controlled results of a Phase 3 trial. In addition, drug sponsors are continually speaking with the FDA about when their data warrants a NDA submission for marketing approval. In fact, designations like fast-track and breakthrough are intended to give drug sponsors greater access to the FDA for such ongoing discussions, in the cases of rare or orphan diseases.

The FDA will also look at information from families and individuals affected by SMA to determine the impact that a potential treatment will have. Treatments may slow disease progression, stop it, or reverse it. The FDA will take into account the community’s input on how each of these outcomes could affect their daily lives.

Because the patho-physiology of SMA is well known and increasing/correcting the SMN2 protein is a known target for drug therapy, would increased measurements of patients csf SMN2 protein combined with obvious and measurable clinical improvements not suffice for required FDA drug approval criteria?

Surrogate markers can be used as primary endpoints for accelerated approval, provided it is proven that the marker correlates with disease severity. SMN fits many of those considerations, but several major questions remain unanswered, making its use as a surrogate challenging right now. Researchers need to learn more about when and where SMN is needed, particularly in patients who are already showing symptoms of SMA. This is one of the many reasons why basic research is so important, even with multiple drugs already in clinical trials. Several ongoing basic research projects are working to answer these critical questions about SMN protein.

At what point would the FDA consider not filing a NDA unethical?

Timing and data requirements for FDA submission are generally negotiated with the FDA before hand for rare diseases. In fact, this is particularly true if a drug program has a fast-track or breakthrough designation, as Dr. Franson discussed during the webinar. These designations provide for many more discussion points with the FDA, and greater collaboration on what needs to be in a NDA and when enough data has been collected to support the NDA filing.

Can orphan status help expedite reviews/approvals for a therapy/drug?

Having orphan status gives a drug candidate priority review by the FDA at the time when the new drug application (NDA) for marketing approval is submitted to the FDA. This shortens the NDA review process at the FDA from 10 months down to six months.

Does Cure SMA have a projected timeline for all of the compounds in phase 3 that would outline the FDA review/decision of each compound and supply chain of molecule if sm molecule or large molecule?

The figure on page 13 of our booklet, Learning About Clinical Trials, explains in more detail each phase of the drug development/clinical trials process and how long each of those phases might take. In addition, 2-3 times per year, Cure SMA releases an updated drug pipeline showing the stage of each program. Taken together, these pieces can provide a rough estimate of when a given program might reach NDA status.

However, it’s important to keep in mind that many things can either speed up or slow down the process for a drug. And, perhaps most important of all, only 10% of drugs that begin the clinical trial process will reach the NDA stage. In fact, 40% of drugs with good Phase 2 data will fail in Phase 3. The continued progress of a drug will depend on the data that is generated through the clinical trials.

As far as expanded access use, is it limited to the type of patient population currently being studied in a clinical trial, or can it be applied to a broader patient population that may not have met inclusion criteria of a trial?

It depends on the type of expanded access protocol (EAP) being sought. Some EAPs are for one patient only. Others are for a group that has been tested in clinical trials. And still others are for a wider group, including those who may have been excluded from a clinical trial in the past. The pharmaceutical company and the FDA will look at a number of factors. Has the drug been proven safe, or might there be unknown side effects for other populations that have not yet been tested in clinical trials? Can they manufacture enough of the drug to serve a wider group? Are the clinical trials complete, or might a wider EAP jeopardize enrollment in ongoing Phase 3 trials? The clinical trials section of our website includes a number of resources directly from the FDA that address these sorts of questions.

Are there any drugs for SMA going through the EAP (expanded access protocol) process?

Currently, there are no expanded access programs for SMA drug candidates. These most typically open after positive Phase 3 results have been obtained, during the NDA review process.

The Importance of Clinical and Regulatory Issues

The ultimate goal in drug development is to get treatments approved for as many people as possible, as quickly as possible. The FDA approval process is the best way to reach this goal. And as we get closer to approved treatments, we understand and expect that the frustration in our community will increase.

In some situations, options like accelerated approval can shorten the waiting time. However, though these options may carry potential benefit, they also carry potential risk to our overall goal of getting a treatment approved for as many people as possible, as quickly as possible. These issues must be carefully weighed.

In addition, the timing of these options must fit within the FDA’s requirements for data that proves safety and efficacy—data that is required to support the new drug application (NDA) that must be filed before the FDA will approve a drug. This burden of proof for both efficacy and safety is high.

Because these issues are complex, we want our community to be knowledgeable about the burden of proof required to support an FDA-approved treatment, and how that approval process works. We hope this webinar helps provide our community with important and useful information about this subject.

Additional Resources

Do you like what you're reading?

Help make a difference in the lives of people affected by spinal muscular atrophy.

Leave a Comment

Your email address will not be published. Required fields are marked *

Scroll to Top