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On April 7, Simeon Bennett from Bloomberg reported that individual members of the European Union are attempting to control the cost of medical care by containing the reimbursement of drugs intended for smaller patient populations, generally called orphan drugs. In Europe, orphan drugs are defined as a medicine to treat no more than 5 in 10,000 inhabitants. Many of these drugs undergo a centralized approval process via the European Medicines Agency (see related blog resource page here.) In practice, however, these drugs may only reach the market when each member state decides that its national health system will reimburse for the drug. For example, 35 orphan drugs reached the market in Belgium, 44 in the Netherlands, and 28 in Sweden in 2008. 35 such drugs reached the market in France and 23 in Italy in 2007.

According to Yann Le Cam, CEO of Eurodis, a French patient advocacy group for patients with rare diseases, "The price of orphan medicinal products is under much more debate. We have seen countries which were providing good access to orphan medicinal products now questioning the continuation of reimbursement."

Written by Brian J. Malkin

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Some examples provided in the Bloomberg report included the Netherlands demanding price reductions for certain therapies such as Sanofi's Myozyme® (alglucosidase alfa), an enzyme replacement therapy for patients with Pompe disease, which costs 700,000 euros ($909,000). As we previously reported from MassBio's Annual Meeting, Myozyme® was the largest research and development effort in the history of Genzyme, which was later acquired by Sanofi, and the result of a concerned father of two children with Pompe's disease pushing the promising therapy along to help it reach the public. Another example mentioned in the report included Ireland recommending against the government paying for Vertex Pharmaceuticals, Inc.'s Kalydeco® (ivacaftor) for cystic fibrosis until the company significantly reduced the price for the drug product. Yet another example was the rejection by the United Kingdom ("UK") to expand use of Alexion Pharmaceuticals, Inc.'s drug Soliris® (eculizumab) for two blood disorders, despite the recommendation for this use by an advisory panel. Instead, the government referred the matter to its National Institute for Health and Care Excellence, which we recently blogged on here, as an instrument to encourage value-based medicine in the UK.

On March 14-15, the Massachusetts Biotechnology Council ("MassBio") held its Annual Meeting in Cambridge, Massachusetts. The Meeting also featured a Keynote from FDA Commissioner Margaret A. Hamburg, M.D. (see related blog here). Key themes at the Meeting were the importance of the Cambridge/Boston biotechnology community for advancing new therapies and the unique resources available in the area that have made it an industry leader. Some of the Cambridge/Boston advantages discussed were the intellectual research capital (local universities such as Harvard and Massachusetts Institute of Technology), venture capital, and local biotechnology businesses, such as Biogen Idec and Genzyme, as well as other biotechnology companies that now have offices in the Cambridge/Boston area and are seeking partnerships to develop new products, such as AstraZeneca, Pfizer, Merck, Novo Nordisk, and Sanofi.

On the second day, Hamburg described here "special affection" for the Cambridge/Boston region dating back to her days at Harvard, saying that she hopes D.C. "would be as efficient and congenial as here." Hamburg said that the Cambridge/Boston region is a life sciences enterprise fueled by top notch research and medical care with the top five NIH-funded hospitals and a "biotech supercluster second to none" with "a remarkable 500 biotech and pharma companies here, and some thirty venture capital firms."

Written by Brian J. Malkin

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Hamburg described FDA as striving for true collaboration and regulatory flexibility with industry, including MassBio, and has been hearing that industry wants more clarity, certainty, transparency with decisions. Hamburg said that FDA is trying to have creative approaches--not a one size-fits-all approach. To this end, Hamburg described approaches that FDA has taken with four new products from the Massachusetts area: 1) Inclusig® for two rare forms of leukemia, 2) Juxtapid® (an orphan drug), 3) Linzess® for irritable bowl syndrome, and 4) Kalydeco® for cystic fibrosis. In addition, Hamburg highlighted new provisions in the Food and Drug Administration Safety and Innovation Act ("FDASIA") for expedited approvals, citing 31 breakthrough therapy designation requests, of which 9 have been granted, 10 denied, 11 pending, and 1 withdrawn. To help with more companies taking advantage of this new process, FDA will be publishing a new guidance shortly, Hamburg announced.

On March 14-15, the Massachusetts Biotechnology Council ("MassBio") held its Annual Meeting in Cambridge, Massachusetts. The Meeting featured key topics such as biosimilars and a Keynote from John Crowley, Chairman and CEO of Amicus Therapeutics.

On the first day of the conference, Crowley exemplified many of the speakers' entry in biotechnology, which originated with a family member or friend with a disease requiring development of a biotechnology product. For Crowley, it was his two children Megan and Patrick, were diagnosed with a severe neuromuscular disorder, Glycogen storage disease type II, known as Pompe's disease. Rather that sitting still to wait for a cure, Crowley became involved in the process, first moving to Princeton, New Jersey, to be close to doctors specializing in the disease and leaving his job with Bristol-Myers Squibb. He later took a position as CEO of Novazyme Pharmaceuticals, a biotechnology research company located in Oklahoma City founded by Dr. William Canfield, which was conducting research on a new experimental treatment for the disease. Novazyme was acquired by Genzyme Corporation, which was then the world's third largest biotechnology company. Crowley was put in charge of Genzyme's global Pompe program, becoming the largest research and development effort in the company's history.

Written by Brian J. Malkin

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Through these efforts, an experimental enzyme replacement therapy was developed, and Megan and Patrick Crowley received the therapy, which Crowley credits with saving his children's lives. Crowley went on to become President and CEO of Orexigen Therapeutics and was named the President and CEO of Amicus Therapeutics, based in Cranbury, New Jersey, which he helped take public in 2007. Crowley's efforts were documented in a Wall Street Journal article and other publications, which ultimately resulted in Harrison Ford working to bring the story to life in a major motion picture, Extraordinary Measures.

On November 28-29, 2012, the American Conference Institute ("ACI") held in Boston, Massachusetts, its inaugural conference: "Orphan Drugs and Rare Diseases: Maximizing Opportunities and Overcoming Stumbling Blocks in the Designation and Development Process". The Conference was well attended and featured a pre-conference boot camp on the Orphan Drug Act as well as a post-conference master class on overcoming clinical trial challenges and proving the safety and efficacy for orphan drugs.

One highlight of the conference was Timothy R. Cote, M.D., M.P.H., Principal, Cote Orphan Consulting (Director of FDA's Office of Orphan Drug Products Development (2007-2011)). Cote provided a back drop for how the Orphan Drug Act came about, emphasizing that while for each individual disease the afflicted patient population is small, when all of the orphan diseases are pooled together, actually the population is sizable and a rapidly-growing area. Dr. Cote described orphan drug development as a "high touch" field where the need for new therapies are often driven by families with afflicted members and typical "big pharma" strategies are less effective. Calling it "scrappy not crappy" science, Cote explained that unlike big pharma projects that involve thousands of patients and hundreds of millions of dollars to develop new therapies, orphan drugs often can be developed for under $10 million--in part because there are so few patients who are candidates for clinical studies and treatment. Cote said while approximately 60% of orphan drug designation requests are approved, the success stories are the products that obtain new drug application approval and win the highly-coveted seven-year exclusivity for the first orphan indication ("a horse race"). More importantly, the basic research required to find cures for orphan drugs often provides valuable medical knowledge in how our bodies work, which he called "pharma karma."

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Another highlight of the conference was Christopher-Paul Milne, D.V.M., M.P.H., J.D., Associate Director, Tufts Center for the Study of Drug Development, Tufts University. Milne said that while the initial orphan market was thought of as relatively small, there are often higher rates of return than more "mainstream" diseases, particularly for diseases with more options for treatment. One phenomena that he tracked was the "ultra orphans," where the orphan population for treatment, which is restricted to less than 200,000 when applied for orphan drug designation in the United States, can get closer to the 200,000 number, and sometimes can expand to more mainstream numbers, if the therapy is later found to have non-orphan treatment options. While certain disease areas such as various cancers have good orphan drug representation, other therapeutic areas, such as neurology, have had less success stories, Milne reported. Milne added that amidst the tension of competition versus collaboration, it has often been important for unlikely partners to work together, with the help and motivation of patient groups, such as the National Organization for Rare Diseases ("NORD").

Frommer Lawrence & Haug LLP Partner Brian J. Malkin will present on "Mastering the Intricacies of the Orphan Drug Designation Process: A Step-by-Step Guide to Navigating the Pathway" on November 29, 2012. Mr. Malkin's presentation is part of ACI's inaugural conference, "Orphan Drugs and Rare Diseases: Maximizing Opportunities and Overcoming Stumbling Blocks in the Designation and Development Process" in Boston, Massachusetts from November 28-29, 2012. Mr. Malkin's presentation will include how to assess whether a compound/indication qualifies for orphan drug designation, what benefits may be achieved by obtaining an orphan drug designation prior to product/indication approval, and how to respond to a rejection for an orphan drug designation request, including demonstrating clinical superiority. For more information, see here.

American Conference Institute (ACI) will be holding its inaugural Legal, Regulatory and Compliance Guide to Orphan Drugs and Rare Diseases in Boston at the Hyatt Regency on November 28-29, 2012. This unique program features a distinguished faculty of over two dozen leading legal and regulatory orphan drugs and rare diseases experts - including the former director of FDA's Office of Orphan Products Development, senior in-house pharmaceutical counsel, leading patient advocates, and preeminent FDA and patent attorneys - who will address the intricacies of the FDA's orphan drug designation process as well as the challenges affecting orphan drug development and commercialization and overall patent portfolio considerations.

The ACI conference provides a comprehensive forum for the industry to discuss the latest legal and regulatory developments affecting orphan products and therapies for rare diseases and to analyze the strategic considerations in drug development aimed at providing patients facing an unmet medical need with safe and effective life changing therapy. In light of recent cases concerning FDA enforcement of orphan exclusivity, the conference will also feature a spotlight session on "Protecting Orphan Drug Designation and Proactively Guarding Against Potential Liability."

More information about this event, including a full agenda, faculty list, and brochure can be accessed at www.AmericanConference.com/orphandrug

FDA Lawyer's Blog discount code: FDA 200

K-V Pharmaceutical Company ("K-V") has taken the fight over its preterm-birth prevention drug, Makena® (17-hydroxypreogesterone caproate solution) ("HPC"), to the International Trade Commission ("ITC"). In its complaint, K-V asks the ITC to: (1) issue a temporary general exclusion order prohibiting any unauthorized importation of HPC and (2) issue a temporary cease and desist order stopping owners, importers, and consignees from importing, selling, offering for sale, distributing, or soliciting any HPC unless authorized by K-V.

K-V states that its merits argument will focus on the importation of HPC for the purpose of making compounded versions of Makena®. K-V argues that importation of HPC for use in compounding copies of Makena® is a violation of Section 337 of the Tariff Act of 1930. According to Section 337, "[u]nfair methods of competition and unfair acts in the importation of articles . . . in the United States, or in the sale of such articles by the owner, importer, or consignee, the threat or effect of which is . . . to destroy or substantially injure an industry in the United States," are "unlawful." 19 U.S.C. § 1337(a)(1)(A). K-V argues that, because all HPC in the United States comes from abroad, and the only use for HPC is in the manufacture of Makena® or allegedly unlawful copies of Makena®, the importation of HPC undermines federal law and K-V's statutory orphan drug exclusivity and "is clearly an unfair act and an unfair method of competition."

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According to the Complaint, all the requisites for temporary relief are present. First, there will be immediate and irreparable harm to K-V because the pharmacies compounding copies of Makena® have diverted so much potential revenue from K-V that the drug company has had to file for Chapter 11 bankruptcy. Second, as mentioned above, there is a likelihood of success on the merits. K-V argues that the importation of HPC for the use in compounding violates the prohibition against mass-scale compounding and undermines K-V's statutory orphan drug exclusivity. These unfair acts and unfair methods of competition are threatening to destroy K-V, i.e., the domestic industry. Third, K-V argues that the following public interest factors favors granting the desired relief: (1) prevention of preterm births; (2) ensuring safe and effective drugs; (3) preservation of a domestic industry; and (4) effectuating Congress's intent to promote development of treatments for rare conditions. Finally, K-V states that it faces the balance of hardships. K-V argues that the compounding pharmacies have few, if any, protectable rights, whereas K-V has a "Congressionally-granted seven-year exclusive right to market Makena." Additionally, K-V notes that its business's survival depends on the success of Makena®, whereas the proposed respondents compound many other products and will survive if they are unable to compound Makena® during the exclusivity period.

Orphan Drugs and Rare Diseases
Maximizing Opportunities and Overcoming Stumbling Blocks in the Designation and Development Process
November 28-29, 2012
Hyatt Regency, Boston, MA

Developing drugs and investing in research and development can be risky business in general, and it can be even more so for small populations with unique disease states. Our faculty of leading experts from Pfizer, Shire, Medicis, GSK, Emergent BioSolutions and many more will give you strategies to offset potential risks inherent to orphan drug development including:

• Understanding and factoring in the unique incentives, including favorable exclusivity, pricing, and tax benefits, for companies who decide to pursue designation

• Replenishing product pipelines in the face of the patent cliff through novel therapies

• Preparing for eventual pharmacovigilance and labeling issues downstream as designation takes off

• Designing clinical trials end points and proving safety and efficacy in a smaller population

• Protecting orphan drug status and keeping competitors at bay post-Makena

For more information, please visit our website: www.americanconference.com/orphandrugs

FDA Lawyers blog readers are entitled to a discount when referencing the code: FDA 200

by Howard E. Rosenberg, Ph.D.

Today, FDA held its first-ever Rare Disease Patient Advocacy Day, because of its recognition of the need for therapies for rare diseases. The day was designed to help patients and caregivers engage with the FDA on issues related to drug and medical device development for rare diseases and conditions. Debra Lewis, Deputy Director of FDA's Office of Orphan Products Development ("OOPD"), said, "Today gives rare disease patient advocates the opportunity to meet with FDA staff and learn more about how FDA works. And, as we come together with colleagues, families, patients and advocacy groups, it gives FDA a moment to reflect on recent news in helping people with rare diseases." She also highlighted a new study published in Pediatrics by Chandana Thorat et. al. which carried out a ten-year analysis of the effect of the Orphan Drug Act of 1983 ("ODA"). The study reports that from 2000 to 2009, 1138 "orphan" drugs were designated and 148 received FDA approval, of which 38 were for pediatric diseases. The proportion of approvals for pediatric products increased from 17.5% in the first half of the decade, to 30.8% in the second.

Stephen C. Groft, Pharm.D., Director, NIH Office of Rare Diseases Research, gave an overview of the available resources to researchers and patients alike in this area and highlighted that the considered best approach to carry out research and to look into solving the problems of these rare diseases is to engage in collaborative efforts. Thus the use of disease specific steering committees between academic research investigators and medical specialists, together with the patient advocacy groups and philanthropic foundations and working with offices such as the Office of Rare Diseases Research is the right way to achieve the goals, Groft explained.

The ODA has been viewed as the single biggest catalyst for encouraging research for orphan drug diseases with FDA approving more than 390 orphan products for the treatment of rare diseases since the legislation came into effect. EU legislation followed in 2000 and has also helped to incentivize research. Further, as we reported here, FDA has decided to expand OOPD's staff to reflect the increasing proportion of orphan drug applications that the Agency has been receiving lately, reflecting over a third of new drug applications in 2011, as we reported here.

by Brian Malkin

On February 16, Leerink Swann's Global Healthcare Conference 2012 featured two presentations and several more private discussions featuring Center for Drug Evaluation and Research ("CDER") Director Janet Woodcock, M.D., as well as her colleagues, Steven Kozlowski, M.D., CDER's Director of Office of Biotechnology Products, and Keith Own Webber, Ph.D., CDER's Deputy Director, Office of Pharmaceutical Science, Acting Director, Office of Generic Drugs. The trio presented a discussion "Biosimilars Take the Stage" followed by Woodcock's Keynote Address on New Trends in Drug Regulation and Innovation, and several smaller question-and-answer-format meetings regarding these topics and more. This is part two of a two-part series and concerns the Keynote Address and followup presentations. Part one may be found here.

During Woodcock's Keynote Address, Woodcock addressed the swinging pendulum of new drug review, focusing on the impact of the various iterations of the Prescription Drug User Fee Acts ("PDUFAs") and FDA's road to shortening review cycles while providing increased transparency in the review process. Woodcock chronicled the shifting focus to drug safety to coincide with the shorter review cycles, stating that FDA now has better tools such as its Sentinel Initiative, providing "the same intensity as the pre-market review process."

Sentinel is a active network monitoring pharmaceutical use in over 100 million lives to date (about one-third the U.S. population), which provides FDA with important safety signals to investigate and respond to if an actual safety problem exists. Woodcock noted that a large part of FDA's post marketing review now includes monitoring for prescription drug abuse, which has become an "epidemic" problem that includes prescriber and end user failures, as well as ongoing problems of antibiotic resistance and improper offlabel use. Sentinel, for example, has already provided FDA with a very powerful finding that rare adverse events often reflect individuals with a particular genetic makeup that may permit previously-abandoned "bad" drugs to return, as long as there is a way to remove those individuals with genetic makeups that suggest the negative outcomes from using the products.

by Scot B. Pittman

According to an article in last week's The Washington Post, orphan drugs accounted for 11 of the 30 new drug approvals in 2011. This represents the highest percentage in the last thirty years. Specifically, last year saw new drug treatments for lupus and Hodgkin's lymphoma for the first time in 50 years and 30 years, respectively.

The Orphan Drug Act defines a "rare disease or condition" as one that affects less than 200,000 people in the United States, or one that affects more than 200,000 people in the United States but there is no reasonable expectation that the costs of developing and making available the drug will be recovered from its sale in the US. See 21 U.S.C. § 360bb. Applicants may petition FDA to give a particular drug orphan drug status. If FDA determines the drug meets the criteria required for orphan drug status, the applicant may enjoy the following benefits: (1) seven years of market exclusivity, (2) tax credits, (3) no user fees, (4) help on the costs of clinical testing, and (5) a shorter review period.

Another reason for the increase in orphan drug approvals appears to be the looming expiration of numerous patents covering more traditional ailments. EvaluatePharma Ltd., a London research firm, notes that the patents of drugs generating around $250 billion in annual sales are set to expire in 2016. With the expectation that generic versions of these drugs will flood the market, innovator drug companies are hoping the orphan drug market, where there are often fewer treatment options, can provide replacement revenue. Even with smaller numbers of patients taking these drugs, they often demand higher prices. Some drugs cost in the hundreds of thousands of dollars for a year's worth of treatment.

by Brian Malkin

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by Brian Malkin

On October 19, FDA published in the Federal Register proposed amendments to its 1992 Orphan Drug Regulations. According to the notice, the amendments "are intended to clarify regulatory provisions and make minor improvements to address issues that have arisen since those regulations were issued." FDA said it has reviewed over 3,350 orphan-drug designation requests since the 1992 regulation became final. This proposed rule follows FDA's announcement of boosting its orphan drug program, as we reported here. Comments are due by January 17, 2012 on the proposed rule.

The specific issues addressed in the proposed rule include:

(1) Demonstration of an appropriate "orphan subset" of persons with a particular disease or condition that otherwise affects 200,000 or more people in the United States, for the purpose of designating a drug for use in that subset;

(2) Eligibility for orphan-drug designation of a drug that is otherwise the same orphan-drug indication as a previously-approved drug;

(3) Eligibility for multiple orphan-drug exclusive approvals when a designated orphan drug is separately approved for use in different subset of the rare disease or condition;

(4) Requirement for demonstrating clinical superiority for the purpose of orphan-drug exclusive approval;

(5) Requirement for submitting the name of the drug in an orphan-drug designation request;

(6) Required drug description and scientific rationale in a designation request;

(7) Required information in a designation request relating to the sponsor's interest in the drug;

(8) Timing of a request for orphan-drug designation;

(9) Responding to a deficiency letter from FDA on an orphan-drug designation request;

(10) FDA publication of information regarding designated orphan drugs;

(11) FDA recognition of orphan-drug exclusive approval;

(12) Miscellaneous terminology changes; and

(13) An address change.

by Scot Pittman

A recently released draft, five-year plan from the FDA includes procedures aimed at increasing the Agency's involvement in the area of orphan diseases. Rare, or orphan, diseases are those that affect less than 200,000 people in the United States; but with more than 7,000 known rare diseases, they are anything but rare and affect a significant number of people in the U.S. (30 million) and worldwide (250 million). Many of these diseases, however, lack meaningful treatment options for those afflicted.

FDA's draft, five-year plan includes meaningful steps to address the lack of treatment options for orphan diseases. Starting next year, FDA will complete a staffing and implementation plan for the Rare Disease Program of the Center for Drug Evaluation and Research ("CDER"). This will include adding five staff members and a liaison in the Rare Disease Program for the Center for Biologics Evaluation and Research ("CBER").

The draft plan outlines a continual program of guidance and policy dissemination that will aid FDA reviewers in staying informed about the latest in development of drug and biologic treatments for orphan diseases. The Rare Disease Program staff will also increase its outreach to the industry through public meetings seeking input on complex issues involved in the approval of drugs for these rare diseases.

by Rachael P. McClure

A recent publication in the Orphanet Journal of Rare Diseases calls for FDA to improve access to its accelerated approval pathway for orphan drugs. The Orphan Drug Act, passed in January 1983, defines orphan drugs as products used for the diagnosis, treatment, or prevention of diseases and conditions that affect fewer than 200,000 people in the United States. It was intended, in part, to encourage pharmaceutical companies to develop drugs directed towards small patient populations. FDA's Office of Orphan Products Development ("OOPD") is tasked with advancing evaluation and development of such products by providing incentives, including tax incentives for clinical research, exemption from filing fees, and grant funding, to sponsors of orphan drug projects.

The accelerated approval ("AA") pathway, available to orphan drugs and drugs for other serious illnesses, was created in 1992 to help deliver treatments to patients with rare life-threatening diseases as soon as possible. It allows new drug applications ("NDAs") to be approved using "surrogate endpoints" before traditional indicators of effectiveness are available. Surrogate endpoints are laboratory measurements, such as blood or urine tests, or physical signs that predict that a drug will improve a patient's condition. To gain accelerated approval, applicants must demonstrate that surrogate endpoints are "reasonably likely" to provide a clinical benefit. FDA then continues to monitor AA-approved drugs until their efficacy is confirmed in post-approval trials.

The Orphanet paper, written by Brigitta Miyamoto and Emil Kakkis of the Kakkis EveryLife Foundation, says that while twenty-six new cancer drugs and twenty-nine new human immunodeficiency virus ("HIV") drugs have been approved under the AA pathway since its creation, only one orphan drug has passed muster. They attribute this to the complicated nature of orphan drug development--the lack of understanding of a rare disease and insufficient patient data can make it very difficult to support surrogate endpoints as predictors of benefit.