The below article is Part Two of a series that began in the Winter 2015/2016 edition of the FARA Advocate.
"Drug Development Series: Accelerating Drug Development and Clinical Trials"
By Jane Larkindale, PhD
If there is a common complaint that we hear from patients, it is that the drug development process is so slow. This is not surprising – the process is very deliberate and takes a lot of time. This is so that we can be sure that treatments work and are not too dangerous, or more precisely, that the benefits of the treatment outweighs any risk of taking that treatment.
We have heard patients comment that their disease is so bad that they will accept some risk, but that the FDA insists that they ensure the efficacy and safety of a drug before patients can try it. This is, to some extent true, although the FDA does recognize (and is increasingly trying to understand) how patients view the balance of risk vs. benefit of a new treatment. It has several programs aimed at trying to get urgently needed medications to patients as fast as possible, without letting completely ineffective and/or dangerous drugs go on the market. It should be noted that many drugs fail in trials either because they are proven to cause no benefit to patients (not a good outcome), or worse, that the effects are worse than not taking the medication (e.g. a study of minocycline in ALS made patients worse). That is why trials are necessary.
However, at some point we have to say “good enough” and allow patients to take the drug – before we have the perfect dataset that would take generations of patients to obtain. The FDA does recognize this, particularly in the cases of severe diseases where not treating the disease at all has serious consequences (like FA). The FDA has special programs to accelerate drug development, most of which really affect the time the agency spends on the program. This means both more time early with the FDA giving advice before the trials are run to ensure that the trials are as informative as possible and less time later on where the FDA decision is the only thing holding a drug back from the market. Some of these programs are described below.
Fast Track: expedites the review of drugs that treat serious conditions and fill an unmet medical need (i.e., conditions like FA). A company developing a drug that gets Fast Track Status gets to meet with the FDA more frequently than most and gets more guidance on the development plan, which includes discussions on endpoints and biomarkers (measures of things that could indicate that the drug was working faster than traditional endpoints). It is also allowed a “rolling review,” which means that it can submit its application in sections as it is completed and each section can be reviewed as it comes in, rather than the FDA waiting until it is complete before it starts the review process. This reduces the waiting time. Fast Track drugs may also be eligible for accelerated approval and/or priority review.
Breakthrough Therapy: expedites the development and review of drugs that may demonstrate substantial improvement over available therapy. An FA drug that appeared to significantly affect disease progression, or really changed a significant biomarker (such as frataxin) could receive this designation. The drug must have some human data to apply for this status. A Breakthrough Therapy gets intensive guidance from the FDA throughout the process, including involvement from senior management. It will also get all benefits of being designated as Fast Track.
Accelerated Approval: accelerates approval for drugs that address a serious condition or fill an unmet medical, based on a surrogate or an intermediate clinical endpoint. This kind of approval can really speed up development for a disease like FA. Normally, approval of a new therapy requires proof that the therapy slows down progression of the disease as measured by some endpoint that is determined to be clinically meaningful. That is usually something like how far or fast a patient can walk, survival rates or some composite measure of various functional measures (such as FARS). Measuring a statistically significant change in those measures can take years. Accelerated Approval allows for approval of a drug based on a change that happens more quickly. That is, in theory, a drug might be approved on showing a significant increase in frataxin (shown over months) prior to showing an improvement in a patient’s activities of daily life (which could take a couple of years). The developer of the therapy will still need to provide the data supporting that the drug affects the longer term endpoint, but it can be marketed to patients while the tests continue. This would allow much earlier access to the therapy. However, in practice it is challenging to get to an accelerated approval as the bar set for linking the biomarker (frataxin in my example) to a functional endpoint is very high. FARA is working hard on developing new biomarkers and endpoints to reduce the time of early stage trials now, with an eye to eventually validating them to this standard and opening the field to the possibility of accelerated approvals in the future.
Priority Review: accelerates FDA evaluation of drugs that, if approved, would result in significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions. If a drug is given priority review, the FDA pledges to make a decision on the approval of the drug in 6 months instead of the standard 10. This designation does not affect the time the drug is in trials, but it does speed up the time between a successful trial and the drug getting on the market. This designation is highly valuable to drug companies!