The Clinical Trial that must Never be Repeated

The NP001 Trial - Wrong on so many Levels The attached blog post* from our good friend at www.alsadvocacy.com describes a disturbing trial design that must never be repeated. One cannot help but feel the pain and anguish of trial participants whose conditions improved while receiving the trial drug yet were denied access to the treatment at the end of the trial. The laborious post hoc analysis of trial results by statisticians, researchers, pharma executives, and bureaucrats can take months or even years, but trial participants who have ALS can readily describe their results. If Hope NOW for ALS had existed at the time, we would have fought vigorously for patients and an Accelerated Approval pathway. The subject trial was relatively small and therefore would not have met the FDA’s rigid standard for efficacy and approval. However, there was a subset of patients for whom the FDA’s traditional efficacy standard (P=.05) may have been met. These patients had elevated levels of an inflammatory marker protein called IL-18. Unfortunately, they were a small group in an already-small phase 2a trial; furthermore, the trial wasn’t designed to require elevated IL-18 levels for participation or to track moderation of these levels as an endpoint for evidence of success. The IL-18 factor wasn’t discovered until post hoc analyses. Nevertheless, it was clear during the trial that significant improvement was occurring in a subset of patients. This underscores the need for smarter and more humane “adaptive trials.” Researchers should monitor patient data during the trial so that new knowledge can be incorporated into the trial. A few researchers have begun proposing adaptive trial designs to the FDA - but this should be standard practice to both hasten discovery and to treat patients as people, not as subjects. If this gets you upset – wait, there's more. Neuraltus is a small biotech where capital is typically scarce. Several years have passed since the trial and they still haven’t attracted the venture capital necessary to conduct the large 300+ patient Phase 3 clinical trial traditionally required for FDA approval. Because ALS is a "small market," investors are reluctant to risk tens of millions of dollars on smaller companies like Neuraltus. Meanwhile, some of the patients who benefitted from NP001 crashed hard when the trial ended and died; countless others with elevated IL-18 levels who might benefit go untreated. Right to Try (RTT) legislation doesn’t improve the situation if a drug company can’t sell their treatment to recover research costs or protect themselves from considerable risk. If RTT is only approved at the state level, what drug developer is going to risk everything by violating a federal law? Furthermore, the ability to get a drug approved may end abruptly if a patient has an adverse reaction (even if caused by lack of adherence to the protocol). Patients who want to try unapproved therapies bear all the costs since Medicare and insurance won’t cover the treatment or its administration (medical facilities, doctors and nurses, equipment, lab work, etc.). This could cost the patient tens of thousands. Accelerated Approval (AAP)? This is the best way for patients to access promising treatments and no new legislation should be needed. But so far, the FDA has refused to utilize it for ALS - even though Congress clearly directed the FDA to apply it to treatments for fatal diseases that have no other treatment options. FDASIA, passed in 2012, directs the FDA to utilize clinical or surrogate endpoints as evidence of efficacy. Expanded Access (EAP)/Compassionate Use options have the same problem as Right To Try. Formal Expanded Access Programs allow companies to recover limited costs and are conducted similar to clinical trials, but without classifying the patients participating (stratification), the science isn’t advanced and companies still assume a huge risk for future approval. For people with ALS, access to any treatment outside a formal clinical trial is nearly impossible. The ALS Association (ALSA) offered $1.5 million to fund another trial. Unfortunately this won’t nearly fund the large Phase 3 trial the FDA wants and the community called for back in 2014. We are left hoping for a miracle. A Phase 3 trial for NP001 would likely cost around $35 million. How are organizations to know which projects have a good chance of being successful? Those with the money to invest in promising trials, like ALSA, need a means to evaluate smaller trials in order to confidently make bigger bets and truly help these treatments get into trials. The mathematical model we are developing to evaluate small trials is designed for that. Until such a system is in place, investors will be reluctant to make the large bets the ALS research community desperately needs. Phase 3 is where treatments go to die. We need a way to predict in advance, using more than guess-work, which drugs have a viable chance of success. And we must reduce the cost of Phase 3 trials to make them more realistic to fund. SUMMARY 1. We need a better means of analyzing data produced by small trials so the ALS community understands which drugs/treatments have a better shot at approval. 2. We need the community and the investment banks to back the most promising treatments and place larger bets strategically to fully fund the next trials. 3. We need adaptive trials - the flexibility to examine the data during the trial to allow identification of positive trends and to allow for changes to benefit current and future enrollees. If trials can be stopped for reasons of danger, they can likewise be modified in cases of favorable trends so that those patients experiencing benefits maintain access and are studied to determine the reason for the positive response. At the minimum we need crossover-style trials where placebo and active drug assignments are switched so all participants have access to the drug. 4. We need patient participation in clinical trial design to ensure that trials are conducted humanely and that patients aren't left to endure cruel "dry out" periods watching their disease inexorably strip away their independence and dignity, never to return. Hope NOW for ALS is actively engaged with data analytics firms and ALS researchers to develop and promote smarter and more humane trial designs. Modernizing clinical trials along with the other reforms mentioned, will allow smaller, faster (hence cheaper), and more accurate clinical trials that are also more humane. We believe we can turn the odds in favor of the patients and not the entrenched so-called “house”. The life of every person with ALS today depends on it. *The NPOO1 Trial: http://als-advocacy.blogspot.com/2016/03/this-was-simply-wrong-on-so-many-levels.html