Meet the Attorney

frankVITAL SIGNS

NAME: Frank J. Sasinowski, MS, MPH, JD

POSITION: Director, Hyman, Phelps & McNamara, PC; Member, Board of Directors, National Organization for Rare Disorders (NORD)

EDUCATION: JD, Georgetown University Law Center; MS, Nutritional Sciences, University of California at Berkeley; MPH, University of California at Berkeley; BS, Biological Sciences and Genetics, Cornell University

HOBBIES: Contemplation and meditation (see www.onewednesday.org)

Mr. Frank Sasinowski has dedicated his career to helping patients and companies bring new therapies for rare diseases to market. He recently shared his work, his hopes for orphan drug development, and his advice for researchers and companies with HD Insights. The following is an edited transcript of the conversation.

HD INSIGHTS: How did you become interested in orphan drug development?

SASINOWSKI: I worked at the Food and Drug Administration (FDA) when Congress enacted the orphan drug law. I was asked to investigate how to make it work, because initially it wasn’t working. My research led to the 1984 and 1985 amendments to the original 1983 law that made it as positive, constructive, and beneficial as it has proven to be. I drafted the original implementing regulations before I left the FDA in 1987. After that, I helped companies through the FDA pre-approval gauntlet for getting new orphan drugs to the market and patients in need. Due to my experience with the orphan drug law, I had a particular passion for helping with therapies for patients who are afflicted with rare conditions. I had also worked on developing the accelerated approval track for therapies for AIDS, because in the mid-1980s, the AIDS crisis was upon us. Fast Track is essentially a way to get drugs approved on the basis of a surrogate endpoint, where the ultimate clinical endpoint can be proven in a confirmatory post-approval trial. I helped Berlex Pharmaceuticals (now Bayer Healthcare Pharmaceuticals) with Betaseron (interferon beta-1b), the first therapy approved for multiple sclerosis. Betaseron was the first therapy ever approved by the FDA for a condition other than AIDS or cancer that relied upon this new system for accelerated approval. It was really ground-breaking, not only for patients with multiple sclerosis, but also as a trail blazer for other FDA regulatory precedents.

HD INSIGHTS: How did you become interested in HD?

SASINOWSKI: I have a long history of working with HD therapies. I was involved in the Care-HD study, the largest HD study that had yet been conducted. I was actually there 15 years ago when Drs. Karl Kieburtz and Ira Shoulson, professors at the University of Rochester and principle investigators for the study, broke the blind and announced the results. I represented VitaLine, one of the two companies that had therapies being investigated. VitaLine’s Coenzyme Q10 (see HD Insights, Vol. 6) showed a 13% slower decline in the Total Function Capacity subscore of the Unified Huntington’s Disease Rating Scale (UHDRS) compared to placebo. This was startling to the investigators, because a 13% between-group difference was by far the largest they had ever witnessed.

More recently, I helped Prestwick Pharmaceuticals with getting FDA approval for tetrabenazine for treatment of chorea associated with HD (see HD Insights, Vol. 7). The company showed positive results in a single trial on its primary endpoint, and an effect on global impression, a secondary endpoint, but the FDA was also impressed with patients’ stories. You will not find this talked about in the labeling for the product, nor if you scour the FDA medical reviews or statistical reviews. However, we found in our interactions with the FDA that they were impressed by anecdotal reports that some patients whose chorea was so severe that they needed help in feeding themselves were able to self-feed after treatment with tetrabenazine. This demonstrates that the FDA wants to see that a therapy is going to improve how a patient feels or functions on a daily basis, or survives. Also related to HD, I aided Avanir Pharmaceuticals with its dextromethorphan and quinidine (NUEDEXTA®) therapy for pseudobulbar affect, which was approved in 2010.

Significantly, this was before the FDA Safety and Innovation Act (FDASIA) of July 8th, 2012, which represents the first time in the history of our drug laws that the word “patient” appears. Our drug law started with the 1906 Pure Food and Drug Act, and one would think that in over a century of law-making, it would be impossible that the law would never mention patients, but it is true. Congress relied on the medical community and the regulators to decide what was best for patients. There was a shift in 2012, and Congress told the FDA—and in effect the medical and patient communities—that patients need to have a role in approval of new drugs. I have had about 10 meetings this year with the FDA division of neurology, and they want companies not just to rely upon measurements of physiological outcomes that have an unclear connection with a patient’s daily life, but to discover how a new therapy affects how that patient is feeling on a daily basis, and how they are engaging in their activities of daily living.

HD INSIGHTS: The Orphan Drug Act has been a great policy success. What are some of the remaining policy and regulatory challenges, especially as they might apply to HD?

SASINOWSKI: A major initiative in the evolution of drug development is just now emerging: the engagement of the patient voice in all drug development issues. FDASIA mandated that FDA hold hearings to bring patients’ voices into the regulatory process, and I think getting patients’ voices into the conversation remains a challenge. The HD community has the Huntington’s Disease Society of America, which was invited to be at that unveiling of the Care-HD study results 15 years ago. This is an example of how visionary people such as Drs. Kieburtz and Shoulson were already looking out for patient interests, but I think that kind of engagement has been slow in coming from the broader research community. We are on this cutting edge, and I predict that we will see more and more collaboration: for example, researchers and sponsors going out to patient groups as they plan trials to ask, “What do you think? What is important to you in your daily life?”

HD INSIGHTS: Are there current examples of this engagement in development of therapies for orphan neurological conditions?

SASINOWSKI: One of my fellow NORD board members, Pat Furlong, is the founder of a group called Parent Project Muscular Dystrophy. They devised their own draft guidelines on developing therapies for Duchenne muscular dystrophy and presented them to the FDA, who published the guidelines for public comment. That is an example of a patient-driven, patient-initiated effort to help define what key elements should be considered, what populations should be enrolled in studies, what kind of endpoints should be considered, and what kind of safety risks should be prominently and sensitively monitored.

I’ll give you one more example. About a year ago, the FDA published a guidance document on migraine that said in effect, “We all know that the most prominent feature of migraine is pain, but we need to have other symptoms that will be relieved by any therapy in development, because we do not want to approve drugs such as opioids that might treat only pain. There are three or four other prominent symptoms such as photophobia, phonophobia, nausea, and vomiting. Why don’t you, as a sponsor, let each patient decide for themselves what is the most bothersome second symptom?” Why is this different? Let’s say you have a therapy and you need to come up with a second endpoint, aside from pain. Normally, you would say, “Well, maybe it’s photophobia, so I need only screen those who say that their most prominent second feature is light sensitivity.” Thus, you enrich your study population with those who are just light sensitive, and then ask, “How did you do on pain?” and “How did you do on light sensitivity?” and hopefully show a difference. But you have severely limited who can enroll in your trials. The FDA is saying, “Open the floodgates, let them all in, but let them define for themselves what is the most troublesome second symptom after pain,” demonstrating a sensitivity to letting patients drive the drug development system.

HD INSIGHTS: In 2012, you published an analysis of FDA approvals for rare and orphan diseases, demonstrating variability in the application of evidence standards.1 What are the implications of your research for companies that are developing drugs for rare and orphan diseases?

SASINOWSKI: The exchanges that I routinely heard at public advisory committee hearings for orphan drugs would baffle me. Normally, sponsors need two adequate, well-controlled studies that each hit a P value of less than 0.05 on the primary endpoint in order to even talk to the FDA about approval. For an orphan disease, the sponsor would often come in with something short of that. The chairman of the committee would turn to the FDA and say, “We know that this is not a situation like a new drug for treating hypercholesterolemia or high blood pressure, where you have an unlimited pool of potential subjects to enroll in trials. We know that there are severe constraints on who can be enrolled. So what are we to do with this?” The FDA would answer, “The Orphan Drug Act did not change the rules for how much evidence of treatment benefit needs to be presented for drug approval.” This left the advisory committee in a quandary, because it seemed that they should be more flexible, but the FDA said that the law did not allow it. This bothered me. When the FDA held its first-ever public hearing on orphan drugs in June 2010, I was invited to speak on behalf of NORD. I said that the FDA ought to articulate a policy that explains how they would deal with this conundrum. The Orphan Drug Act did not change the quantum of evidence that is required for drug approval, but every orphan drug is different and every rare disease patient population is different. I suggested that if they could not enunciate a generalized statement of policy, at a minimum they could catalogue everything done with all the orphan drugs so that the world could see what has happened over time and what the evidentiary basis had been for all prior orphan drug approvals by FDA.

The FDA approached me after the hearing and said, “We think your idea to catalogue it all is brilliant, but we do not have the time.” I knew then that if anybody were to do it, it would have to be me. I printed off all the labeling, medical reviews, and statistical reviews for the 135 new chemical entities for rare diseases, other than cancer, that the FDA had approved from 1983 through June 2010. I took 27 boxes of documents with me to a secluded place in the mountains where I read and catalogued all 27 boxes, to see whether or not they met the usual criteria for approval for a prevalent disease. If they did not, I recorded whether these approvals represented some flexibility in the quantum of evidence, demonstrating that the FDA exercises some discretion while still relying upon good science. I found that two-thirds of all these orphan drug approvals showed some signs of flexibility with regard to the number and scope of trials required. This was eye-opening to everyone, particularly to the FDA, who did not realize they had been acting this way. I’ve since written an update that shows the same degree of flexibility. In orphan drugs approved between June 2010 and July 2014, the same ratio of about two-thirds of all approvals show some evidence of FDA flexibility.2

HD INSIGHTS: Is there any advice that you have for HD researchers or drug developers regarding current regulatory matters in front of the FDA?

SASINOWSKI: I think that the FDA is being extraordinarily sensitive to the needs of individuals who suffer from rare, chronic, debilitating, life-threatening diseases such as HD. Sponsors should realize that working with the FDA is extremely beneficial. For researchers and patients, it is important to think about ways to deepen an understanding of the natural history of the disease. We need collaboration between patients and the research community to figure out ways in which everyone will measure the same things under the same conditions. Currently, there is tremendous incentive for people to come up with their own ways of doing things; every major research institution wants to have its fingerprint so that it can publish a paper that says, “This is how we do it.” That doesn’t help, because that means everybody is evaluating everything differently.

HD INSIGHTS: When you are not helping companies develop treatments for orphan diseases, how do you spend your time?

SASINOWSKI: I recently set up a program called One Wednesday, which hosts community gatherings for 30 minutes of silence every month. Looking at the suffering of patients tells me that we live in a divided world; we divide ourselves between healthy and unhealthy, between economic classes, political factions, religions and even within religions. One Wednesday is one effort to try to bring people to understand a fundamental truth, and that is that we all are one.

HD INSIGHTS: Thank you for all your efforts to help us get better treatments for individuals suffering with rare conditions.


1Sasinowski FJ. Quantum of effectiveness evidence in FDA’s approval of orphan drugs: cataloging FDA’s flexibility in regulating therapies for persons with rare disorders. Drug Information Journal. 2012; 46(2):238-263.

2Sasinowski FJ, Panico EB, Valentine JE. Quantum of Effectiveness Evidence in FDA’s Approval of Orphan Drugs: Update, July 2010 to June 2014. Therapeutic Innovation & Regulatory Science. 2015.


Editor’s Desk: The Orphan Drug Act, 1983-2015

Orphan diseases are rare conditions which affect less than 200,000 individuals in the United States. The NIH Office of Rare Diseases website currently lists over 7,000 orphan conditions that affect a total of 25-30 million individuals in the US. Approximately one-fifth of these conditions are neurological.1 The 1983 Orphan Drug Act encourages pharmaceutical firms to develop new therapies for orphan diseases through several incentive programs, including tax breaks, grant funding, FDA fee waivers, and longer market exclusivity for companies. In the 32 years since the passage of the Orphan Drug Act, the FDA has issued approvals for 463 orphan indications (some compounds are approved for multiple indications), 34 of which are for neurological conditions (see Figure).2 Only one, tetrabenazine, is for HD.

figure 11

1Murphy SM, Puwanant A, Griggs RC. Unintended effects of orphan product designation for rare neurological diseases. Ann Neurol 2012;72:481-90.

2U.S. Food and Drug Administration (FDA). Orphan Drug Product designation database. Available from accessdata.fda.gov/scripts/opdlisting/oopd/. Accessed May 4, 2015.