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The Journal of RareDISORDERS


Demissie Alemayehu, PhD; Marcia Levenstein, DSc; and Charles Knirsch, MD, MPH

Pfizer Inc, New York, NY 10017


Proper design and repor ng of clinical trials in rare diseases typically require nonstandard sta s cal approaches that may generally be op onal in conven onal large clinical trials. The small size of the target popula on, coupled with the challenges of recrui ng eligible study subjects from mostly vulnerable popula ons, makes tradi onal design framework and large sample–based sta s cal methods nonop mal to generate minimally acceptable eviden ary data for licensing and approval. In this ar cle, we outline some key sta s cal points for considera on in the design, analysis, and repor ng of such trials, with par cular reference to adap ve designs, exact procedures, and the perils of small‐sample inference.


Drug development in rare diseases poses both prac cal and methodologic challenges and opportuni es.1 From a sta s cal perspec ve, most of the issues emanate from the small size of the target study popula on and the logis c problems associated with the conduct of the study. In some cases, the natural history of the disease under study may not be well established, adding to the complexity of sample‐size determina on, dose selec on, defini on of outcome measures, and specifica on of other study protocol components.

Although there have been numerous measures taken by regulatory agencies to encourage research in rare diseases,2‐5 the eviden ary standard to bring safe and effec ve medicines to these pa ents is s ll rela vely high. Accordingly, there is a need to assess the adequacy of conven onal sta s cal approaches to tackle the issues that arise in rare disease clinical trials, and to apply or develop novel design and analy c techniques that are appropriate in small trial se ngs.

In this ar cle, we evaluate alterna ve design approaches and analy c techniques for rare diseases, and highlight steps that need to be taken to ensure proper dissemina on of trial results. Alterna ve design schemes for small trials are provided, and nonstandard analy c approaches and the repor ng of results are discussed.


In rare disease drug development, the tradi onal paradigm of randomized controlled trials involving fixed samples and rigid criteria for study conduct may not be op mal. Thus, alterna ve approaches that consider the accumulated data without compromising trial integrity should be considered. One such approach is the

implementa on of adap ve designs that permit flexibility to update various aspects of the study (including randomiza on scheme, number of treatment groups, and number and frequency of interim analyses) using prespecified and sta s cally sound criteria.6,7

From a drug development perspec ve, adap ve seamless designs can help to reduce the melines for drug approval, combining data from different stages. Seamless phase 2/3 designs, for example, leverage data from the 2 phases to learn and confirm by trea ng both phases as a single study conducted in 2 stages.8 In a typical applica on, such designs may be used in dose‐finding trials, in which op mal doses selected based on the available informa on at interim are studied further in the second stage. For the final analysis, in which pa ents from both stages are included, appropriate sta s cal methods should be used to account for the combina on of data from the 2 stages, because a naive combina on of data from the 2 stages may result in inflated type I error rates. In addi on, suitable measures should be taken to minimize the poten al for bias from the informa on obtained from the analysis at the end of stage 2.

The u lity of a seamless phase 2/3 trial is, of course, a func on of the strength of the informa on obtained at the interim and the infrastructure that is put in place to ensure trial integrity. In par cular, there should be a clear understanding of who performs the analysis (eg,Data and Safety Monitoring Board or sponsor), and how blinding is preserved (including blinding of pa ents, inves gators, and trial sponsor staff) to minimize opera onal bias.

In early‐phase drug development, dose selec on and risk –benefit assessment may require modified versions of

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the approaches used in nonrare disease trials. For example, adap ve dose‐finding methods may be used to obtain informa on on dose response earlier in development and maximize the probability of technical success. One common approach is the so‐called con nual reassessment method (CRM), which unlike tradi onal cohort designs, permits selec on of a dose level sequen ally, upda ng the dose–toxicity rela onship based on the pa ents’ response data using Bayesian methods. However, careful a en on should be paid to the implementa on of the CRM in rare disease research, including the appropriateness of the dose–toxicity model in small samples, the target toxicity/response rate, and the stopping rules.9,10

In late‐phase development, group sequen al designs have increasingly been used to enhance decision making, as they allow for early termina on of a trial either for efficacy or fu lity, based on interim analyses. However, most procedures are based on large‐sample theory, and therefore may require appropriate modifica ons for a small sample.

Providing the ra onale for sample‐size calcula ons is always a challenge in rare disease research. When there is uncertainty about effect size or variability for sample‐ size determina on, adjustments to the ini al sample size may be made based on a review of accumula ng data. In adap ve sample‐size rees ma on, a major issue is preserva on of the overall type I error at the me of the final analysis. Some approaches have been proposed by Bauer and Kohne 11 and Lehmacher and Wassmer,12 involving combining the P values obtained before and

aer the adapta on, with prespecified weights; by Cui, Hung, and Wang,13 in which the Wald sta s cs are combined with prespecified weights; and by Chen, DeMets, and Lan,14 permi ng use of conven onal test sta s cs in connec on with increased sample size based on posi ve interim results. In small trials, when internal pilots are used to reassess nuisance parameters, appropriate adjustments should be made for possible bias.15,16

Because adequate knowledge about the rare disease under study may not be available at the design stage, it may also be essen al to change other aspects of the protocol, including the test sta s c, primary end point, and inclusion/exclusion criteria, based on interim data. In the context of regulatory review and approval, any such adapta on would require extreme cau on, owing to the

poten al for bias. Accordingly, all expected changes to any aspect of the protocol should be prespecified, be adequately jus fied, and, to the extent possible, garner mutual agreement and understanding between the sponsor and regulatory agencies.

With proper implementa on and execu on, novel randomiza on schemes can also prove advantageous in small trials. For example, adap ve randomiza on permits flexible probability of treatment assignment based on pa ent characteris cs and observed response to treatment.17,18 In response adap ve randomiza on, in which alloca on probability is based on responses observed in previous pa ents, one would expect that exposure to more efficacious treatment would be maximized. In covariate adap ve randomiza on, in which the alloca on probability is a func on of the covariate balance between groups, the effects of confounders are minimized, thereby permi ng valid inference about treatment‐effect differences.

In general, assessment of the opera ng characteris cs of an adap ve trial may involve nontradi onal procedures, including simula on under varying assump ons about effect size and other design features. In the context of rare diseases, some of the available methods may require appropriate modifica ons, taking into account the small number of events or subjects involved.19

Crossover designs, in which par cipants serve as their own control, are a rac ve op ons for rare diseases provided that the study involves a chronic condi on and no carryover effect, and that a rela vely rapid response to interven on is a realis c assump on. Such designs generally require fewer subjects and involve less variability than their parallel group counterparts. However, they may be unreliable in the face of poten al carryover of treatment effects or if the disease under study is not stable over me. Moreover, they cannot be implemented in certain situa ons in which the interven on may not be reversible or the outcome of interest may be terminal, eg, all‐cause mortality.

In recent years, use of enriched designs has been advocated as a viable op on to enhance drug development by targe ng a subgroup of the pa ent popula on. Enriched designs have the benefit of reducing variability or increasing effect size by carefully selec ng homogenous and responsive subgroups, respec vely. In rare disease research this is par cularly relevant, because enrichment generally may increase the

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chance of demonstra ng treatment effect with limited sample size. One major limita on of such a strategy is the ability to establish generalizability of findings to the wider pa ent popula on. In addi on, in rare diseases the enrichment may also lead to a reduc on of the available pa ent pool, thereby posing recruitment and other logis c problems.


As in large clinical trials, implementa on of a given sta s cal procedure is heavily dependent on the validity of the assump ons underlying the procedure. One key dis nc on that handicaps the analysts in a small trial is the inability to implement alterna ve approaches that rely on large‐sample theory. For example, when distribu onal assump ons cannot be jus fied to implement parametric methods, one o en resorts to nonparametric approaches in the analysis of large trials. In small trials, methods that rely on large‐sample theory may not be a subs tute when the validity of standard approaches is in ques on.

Given the small size of studies in rare diseases, exact procedures should be used, to the extent possible, in analyzing the data. Most sta s cal so ware packages, such as StatXact, provide exact hypothesis tests, exact confidence intervals, and exact power and sample‐size calcula ons.

Hierarchical models are useful in small trials involving 2‐ stage sampling, including prospec ve longitudinal studies. With longitudinal data, analy c strategies based on the last‐observa on‐carried‐forward approach are generally inefficient. When model assump ons are sa sfied, mixed‐effect models for repeated measures (MMRM) for con nuous responses, and marginal (eg, generalized es ma ng equa ons [GEE]) and random‐ effects (eg, generalized linear mixed models [GLMM]) approaches for categorical responses and count data, may be used to increase efficiency, especially in small trials. In the presence of missing values, the validity of these methods depends on the pa ern of ‟missingness” (eg, the likelihood‐based methods [MMRM and GLMM] and some weighted GEE models are

applicable under “missing completely at random” (MCAR) and “missing at random” assump ons, while the usual GEE models require MCAR assump ons).20

In small clinical trials, Bayesian approaches may be advantageous for a number of reasons. With small samples, inferences are easy to formulate and solve by Bayesian methods. Sequen al analyses are readily implemented in a Bayesian paradigm, without the need to adjust for mul plicity, because the posterior distribu on can be updated using the current posterior distribu on as the prior for the next update. Bayesian hierarchical models allow informa on to be combined from different sources, thereby gaining strength. However, in small samples, different prior opinions may lead to different conclusions, because the influence of the choice of priors on the posterior probability distribu on is a func on of sample size.21 Therefore, the choice of priors should be considered carefully.

Lastly, in view of the uncertain es inherent in small clinical trials, the primary analysis results should be corroborated with alterna ve sta s cal analyses, to ensure the robustness of the results to departures from model assump ons.


Compared with large trials, inves ga ons in rare diseases provide limited scien fic evidence about the safety risk– benefit profile of a treatment op on. Accordingly, the researchers involved in such endeavors should exercise extreme cau on in interpre ng and repor ng the results of a small trial. In par cular, the results of the study should be interpreted with fair balance, highligh ng the limita ons of the study and analy c strategy, the biological plausibility of the findings, and the consistency of the findings with established knowledge of the drug class.

The requirement to present the results with fair balance should not be viewed as an unnecessary measure intended to s fle innova on and research in rare diseases. In fact, it is an essen al means of dissemina ng results, so that pa ents, regulatory agencies, health care providers, and other stakeholders can evaluate the strength of evidence when making informed decisions about the risks and benefits of a drug.


In this ar cle, we highlighted points to consider when designing, analyzing, and repor ng a clinical trial in rare diseases. While some of the issues raised are generally

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per nent to most clinical trials, studies in rare diseases pose addi onal problems as a result of the features that are inherent in the limited size of the target popula on. To achieve regulatory and scien fic objec ves, it is therefore important to enhance and employ best sta s cal prac ces established for tradi onal trials while taking into account the special challenges associated with rare diseases, including the small pa ent numbers, paucity of knowledge about the disease, and recruitment and reten on of study subjects.


The authors would like to thank Jack Cook of Pfizer for helpful sugges ons and feedback at various stages of manuscript development.


1.Kesselheim AS, Myers JA, Avorn J. Characteris cs of clinical trials to support approval of orphan vs nonorphan drugs for cancer. JAMA. 2011;305:2320‐2326.

2.US Food and Drug Administra on. Developing orphan products: FDA honors Rare Disease Day. h p:// www.fda.gov/downloads/ForIndustry/ DevelopingProductsforRareDiseasesCondi ons/ UCM202027.doc. Accessed January 20, 2014.

3.Na onal Ins tutes of Health, NIH News, "Therapeu cs for Rare & Neglected Diseases," h p:// www.ncats.nih.gov/research/rare‐diseases/trnd/ trnd.html. Na onal Center for Advancing Transla onal Sciences. Therapeu cs for Rare and Neglected Diseases. Accessed March 28, 2014.

4.Rubinstein YR, Gro SC, Bartek R, Brown K, Christensen RA, Collier E, et al. Crea ng a global rare disease pa ent registry linked to a rare diseases biorepository database: Rare Disease‐HUB (RD‐HUB) Contemp Clin Trials. 2010;31(5):394–404.

5.European Medicines Agency. Guideline on clinical trials in small popula ons. Doc. ref. CHMP/EWP/83561/2005. Published July 27, 2006. h p://www.ema.europa.eu/ docs/en_GB/document_library/

Scien fic_guideline/2009/09/WC500003615.pdf. Accessed January 20, 2014.

6.Meurer WJ, Lewis RL, Berry DA. Adap ve clinical trials: a par al remedy for the therapeu c misconcep on? JAMA. 2012;307:2377‐2378.

7.Chow SC, Chang M, Pong A. Sta s cal considera on of adap ve methods in clinical development. J Biopharm

Stat. 2005;15:575‐591.

8.Inoue LY, Thall PF, Berry DA. Seamlessly expanding a randomized phase II trial to phase III. Biometrics. 2002;58:823‐831.

9.Garre ‐Moyer E. The con nual reassessment method for dose‐finding studies: a tutorial. Clin Trials. 2006;3:57‐

10.Ishizuka N, Ohashi Y. The con nual reassessment method and its applica on: a Bayesian methodology for phase I cancer clinical trials. Stat Med. 2001;20:2661‐ 2681.

11.Bauer P, Kohne K. Evalua on of experiments with adap ve interim analyses. Biometrics. 1994;50:1029‐ 1041.

12. Lehmacher W, Wassmer G. Adap ve sample size

calcula ons in group sequen al trials. Biometrics.1999;55:1286‐1290.

13.Cui L, Hung HM, Wang SJ. Modifica on of sample size in group sequen al clinical trials. Biometrics. 1999;55:853 ‐857.

14.Chen YH, DeMets DL, Lan KK. Increasing the sample size when the unblinded interim result is promising. Stat Med. 2004;23:1023‐1038.

15.Proschan MA, Wi es J. An improved double sampling procedure based on the variance. Biometrics. 2000;56:1183‐1187.

16.Kairalla JA, Muller KE, Coffey CS. Combining an internal pilot with an interim analysis for single degree of freedom tests. Commun Stat Theory Methods. 2010;39:3717‐3738.

17.Karrison TG, Huo D, Chappell R. A group sequen al, response‐adap ve design for randomized clinical trials. Control Clin Trials. 2003;24:506‐522.

18.Rosenberger WR, Lachin JM. The use of response‐ adap ve designs in clinical trials. Control Clin Trials. 1993;14:471‐484.

19.Chow SC, Chang M. Adap ve design methods in clinical trials―a review. Orphanet J Rare Dis. 2008;3:11.

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20.Mallinckrodt CH, Lane PW, Schnell D, et al. Recommenda ons for the primary analysis of con nuous endpoints in longitudinal clinical trials. Drug Informa on J. 2008;42:303‐319.

21.Gelman A, Carlin JB, Stern HS, Rubin DB. Bayesian Data Analysis. London, UK: Chapman & Hall; 1995.

Address Correspondence To:

Demissie Alemayehu, PhD (corresponding author)

235East 42nd Street/219‐7‐47 Pfizer Inc.

New York, NY 10017 alemad@pfizer.com (212) 573‐2084

Journal of Rare Disorders Vol. 2, Issue 1, 2014


Editorial Board

Nkechi Azie, MD, MBA

Sr. Medical Director

Astellas Pharma US Inc.,

Deerfield, IL

Sukirti Bagal MD, MPH

Director, Rare Disease Specialist Medical Affairs and Clinical Development

Pfizer, Inc.

New York, NY

Nicole Boice


Global Genes | RARE Project

Dana Point, CaliforniaJonathan Bui, MD, PhD

University of California San Diego

La Jolla, CA

Stephen Eck, MD, PhD

Vice President & Global Head

Oncology Medical Sciences

Astellas Pharma Global Development, Inc.

Deerfield, IL

Phyllis Frosst, PhD

Director of Collaborative Operations

NIH Center for Translational Therapeutics, NIH

Bethesda, MD

Richard Haas, MD

Professor of Neurosciences and Pediatrics

University of California San Diego Medical Center

La Jolla, CA

Marlene E. Haffner, MD, MPH

Health Policy and Global Drug Development Consultant

Rockville, MD

Joanna C. Jen, MD, PhD

Associate Professor of Neurology

David Geffen School of Medicine at UCLA

Los Angeles, CA

Cathleen Lutz, PhD

Director, Mouse Resources

Rare and Orphan Disease Center - The Jackson Laboratory

Bar Harbor, ME

David Lynch, MD, PhD

Professor, Neurology and Pediatrics

The Children’s Hospital of Philadelphia

Philadelphia, PA

Anne Pariser, MD

Consulting Physician

Alexandria, VA

Reed E. Pyeritz, MD, PhD

Vice-Chair for Academic Affairs, Dept. of Med.

Director, Center for the Integration of Genetic Healthcare Technologies

Prof. of Medicine & Genetics, Raymond and Ruth Perelman School of Med at the Univ of Penn

Philadelphia, PA

Margaret Ragni, MD

Professor of Medicine, Division of Hematology/Oncology

Director, Hemophilia Center of Western PA

Pittsburgh, PA

Professor Aly Rashid, MD

Medical Director LLR Cluster NHS, Leicester City

Leicester, Northamptonshire, United Kingdom

Peter L. Saltonstall

President and CEO

National Organization for Rare Disorders

Danbury, CT

Dhruv Sareen, Ph.D

Regenerative Medicine Institute

Director, Induced Pluripotent Stem Cell (iPSC) Core Facility

Research Scientist I-Faculty, Department of Biomedical Sciences

Cedars-Sinai Medical Center

Los Angeles, CA

Sharon F. Terry, MA

President and CEO

Genetic Alliance

Washington, DC

Barbara Wuebbels, RN, MS

Associate Director Patient Advocacy and Investigator Relations

BioMarin Pharmaceutical Inc.

Phoenix, AZ






John Ansell, MA, and Glenn Tillotson, PhD

TranScrip Partners, Reading, United Kingdom  



The US Food and Drug AdministraTIon (FDA) now provides 4 different methods for expediting approval of new drugs. This article examines how companies employed these options to win FDA approval last year for 17 orphan drugs and examines the diverse issues encountered. For the first time, in 2014, the Priority Review option was used by all companies whose orphan drugs were successfully registered. This represented a sharp increase in its usage, given that just under half of all companies gaining approval for orphan products had used this opTIon in both 2012 and 2013. In contrast, since 2013 there has been little change in the extent to which the other 3 methods for expedited approval have been used for orphan products.  Other than the universal use of the Priority Review option, we find remarkable variation in the options taken for expedited approval for orphan drugs in 2014: no less than 7 different combinations of the 4 methods were taken. Consequently, we believe this indicates that the options are neither fully understood by orphan drug companies or are not being used optimally by them—with this marked variation relating less to a correct analysis of likelihood of qualification than to companies’ internal attitudes toward the ease of proceeding via each method. It is also unclear why companies do not avail themselves more of the four options. Limited resources or inexperience with the different methods could well be playing a role. We suggest that there is now a case for granting automatic Priority Review status for all drugs granted orphan status and the scope for rationalizing, unifying, and thereby simplifying the 4 methods. This would benefit developers of all types of drugs, but particularly of orphans, as well as reduce the impact of increasing usage of FDA resources.  


Orphan drug status applies to drugs that are developed for a specific condition or disease (there are more than 7000 recognized rare diseases) affecting fewer than 200,000 Americans. In the United States, the Office of Orphan Products Development administers the major provisions of the Orphan Drug Act, which provide incentives for sponsors to develop products for rare diseases. The Orphan Drug Act has been very successful—more than 400 drugs and biological products for rare diseases have been brought to market since 1983. In contrast, the decade prior to 1983 saw fewer than 10 such products reach the market. This regulatory status has several benefits for the sponsor, including marketing the drug without competition for 7 years and possible qualification for clinical trial tax incentives. Awareness of orphan

conditions has increased significantly over the past decade for a number of reasons, not least of which is the response by the US Food and Drug Administration (FDA) to enhancing or simplifying the process for approval. The European Union (EU) has enacted similar legislation, Regulation (EC) No 141/2000, in which pharmaceuticals developed to treat rare diseases are referred to as "orphan medicinal products." The EU's definition of an orphan condition is broader than that of the FDA’s, in that it also covers some tropical diseases that are primarily found in developing nations. In Europe the medicine must treat, prevent, or diagnose a life‐threatening or chronically debilitating condition, and this condition must affect fewer than 5 in 10,000 people in the EU. Alternatively, if a condition affects more than 5 in 10,000 people in the EU, it may still be considered for orphan designation. Notably, for a treatment to qualify for orphan designation, there must be no existing approved treatments for the indicated condition, or if there are, the product in question must offer significant improvements over the other options.  Orphan drug status granted by the European Commission gives marketing exclusivity in the EU for 10 years after approval.  The EU's legislation is administered by the Committee on Orphan Medicinal Products of the European Medicines Agency. In 2014, seventeen orphan drugs were approved for clinical use in Europe, a remarkable increase compared with previous periods.2



Orphan drug status, in itself, provides various benefits to drug development companies that include measures to expedite approval. But, in addition, as for all drugs, orphans can qualify for any of the FDA’s 4 methods of expedited approval. This article examines how companies with orphan drugs approved in 2014 are availing themselves of these options.   The box shows the 4 different methods of expedited approval available to drug developers. The methods have much in common; in particular, all 4 methods target therapies intended to treat a serious aspect of a condition or a serious condition. Also, all require that a new compound address an unmet medical need.3



In 2014 the FDA approved 41 new drug applications, of which 17 were orphans, all from different companies.4 Details are shown in the table. The 17 orphan drugs dominated successful usage of the 4 different methods for expedited approval that have evolved: Variety of Options Taken for Orphan Products All 17 orphan drugs approved in 2014 had been granted Priority Review status (compared with only a third of non ‐orphan products that were granted this status). This is a recent development: in both 2012 and 2013, just under half of all orphan drugs approved (6/13 and 4/9, respectively) were granted this status. There was also considerable, though lesser, use of the other 3 options for orphan drugs, as shown in Figure 1:10 received Fast Track status, 8 had Accelerated status, and 7 were designated as Breakthrough. For each of these methods, the proportions of orphan drugs approved in 2014 were similar to those in the 2013 cohort. The extent to which companies used different options varied enormously. Figure 2 depicts the distribution of use for each of the 4 methods. Only 2 companies used all 4 methods, 7 used 3 methods, and 5 used 2 methods. Three companies used just 1 method.  

Underlining the degree of variety of approaches used was the remarkable diversity in combinations of methods used. These are shown in Figure 3. As mentioned previously, all 4 options were used by just

2 of the companies whose orphan drugs, Opdivo (nivolumab) and Zydelig (idelalisib), were approved in 2014. As Figure 3 shows, no less than 7 combinations of the 4 possible expedited approval methods were used. All 3 possible combinations of the 4 options were used, and 2 types of combinations of just 2 of them. However, the only method used alone was Priority Review. Thus, there was a very wide variety of patterns of usage of the 4 methods. Although the most popular of the 7 different combinations was Priority + Accelerated reviews, this was still only used for 4 of the 17 orphan products. It is interesting that whereas the Breakthrough process is envisaged by the FDA as only to be granted to a subset of those products eligible for Fast Track status that especially merit it, 3 products in 2014—Blincyto (blinatumomab), Keytruda (pembrolizumab), and Zykadia (ceritinib)—gained the former status without being granted the laƩer. Perhaps the companies concerned just did not apply for it.   We suggest that some companies might have considered that Breakthrough status superseded or gave them no advantage over Fast Track status. Indeed, the FDA has even expressly stated that new drugs receiving Breakthrough therapy designaTIon are eligible for all of the features of the Fast Track designaTIon.2 On the other hand, 4 orphan drugs approved in 2014 did have Fast Track as well as Breakthrough status. These products were Opdivo, Zydelig, Ofev (nintedanib), and Esbriet (pirfenidone).  



Current expedited approval methods employed by companies with successfully registered orphan drugs vary greatly. It is not clear why such a degree of difference exists. Also, it appears to us, on examining the data presented, that some companies might have benefited if they had applied for more of the 4 options. Kepplinger3 and Jae5 have thoroughly reviewed this perspective. We conclude that it is unlikely that the 4 different methods are being used by companies optimally. A further factor could conceivably be contributing to this diverse usage. The summary criteria for the 4 expedited approval methods have much in common; however, it could be that the FDA is applying different degrees of stringency to similar approval criteria when it addresses eligibility for the different methods.6 The areas of overlap in assessing eligibility among the 4 methods would appear to offer the FDA opportunities to rationalize, unify, and thereby simplify these expedited approval systems—not just for orphans but for all types of drugs. It has already been proposed recently that the Breakthrough Therapy and Accelerated Approval processes be merged,4, 5 and we believe this could be a sensible first step.  Another, specific area for resource savings relates to Priority Review.  In 2014, for the first time, all 17 orphan drugs approved had been granted Priority Review status. We consider that there is now a case for waiving the Priority Review assessment process for all drugs granted orphan status and suggest that they should be granted Priority Review status automatically. A more unified system that reduces the current duplication of assessment processes would reduce resources required by the FDA, which is important as use of the 4 expedited approval methods is increasing. It should at the same TIme be advantageous to companies making submissions, particularly those developing orphan drugs, whose resources—personnel,  time, and financial—are often particularly limited.



We wish to thank our colleagues at TranScrip Partners, Paul Branthwaite, Dr. Bob Milsted, and Louise Whitley, for their helpful comments, as well as Nicolette Theriault for graphics preparation.  



JA and GT are both employees of Transcrip Partners; they do not have any financial relationship with the companies or products mentioned in this article.


Priority Review: Just over two‐thirds (17/25) of all Priority Review   approvals were orphans. Fast Track:   Just over half (10/17) of all Fast Track approvals were of orphan drugs. Accelerated Approval:   All 8 of the Accelerated approvals were orphans. Breakthrough Therapy: Over two‐thirds (7/9) of all Breakthrough approvals were orphans.

The 4 Different Expedited Approval Methods   

Priority Review status is granted when the Center for Drug Evaluation and Research determines that a drug could provide a significant advance in medical care; it sets a target to review the drug within 6 months instead of the standard 10 months. There has to be potential for significant improvement in safety or efficacy. Unlike the other 3 methods, the US Food and Drug Administration (FDA) classifies all original new drug applications (NDAs) and biologics license applications (BLAs) for Priority Review whether or not the sponsor requests Priority Review.  Fast Track can speed new drug development and review, for instance, by increasing the level of communication FDA allocates to drug developers and by enabling CDER to review portions of a drug application ahead of the submission of the complete application. An unmet need has to be demonstrated to qualify. Accelerated Approval allows early approval of a drug for a serious or life‐threatening illness that offers a benefit over current treatments. To qualify, there must be a likelihood of meaningful advantage over available therapies. Breakthrough Therapy designaTIon includes all of the Fast Track program features as well as more intensive FDA guidance on an efficient drug development program. It is granted for a subset of fast‐tracked products. Breakthrough status is designed to help shorten the development time of a promising new therapy. To gain this status, preliminary clinical evidence must indicate a substantial improvement over available therapies on a clinically significant endpoint. This method first appeared as an option taken for orphan drugs approved in 2013.


Table 1. Orphan drugs approved by the FDA in 2014  



Generic Name Indication Company Fast  









T‐cell lymphoma 





Acute lymphoblastic leukemia 





Gaucher disease 





Non‐small cell lung cancer 

Eli Lilly          




Idiopathic pulmonary fibrosis 





Sleep‐wake disorder 











Merck & Co    




Ovarian cancer 










Neurogenic orthostatic hypotension





Idiopathic pulmonary fibrosis 

Boehringer Ingelheim




Metastatic melanoma 

Bristol Myers Squibb




Multicentric Castleman’s disease

Janssen Biotech



elosulfase alfa 

Mucopolysaccharidosis type IVA 





B‐cell blood cancer





Non‐small cell lung cancer 



Chronic lymphocyTIc leukemia, follicular B‐cell non‐Hodgkin lymphoma and relapsed small lymphocytic lymphoma. Source: FDA3 and other sources.



  1. Developing products for rare diseases & condiTIons. US Food and Drug AdministraTIon Web site. http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesCondiTIons/ucm2005525.htm. Updated February 26, 2015. Accessed June 3, 2015.
  2. Orphan drugs in the EU: a record‐breaking year. Regulatory Affairs Professional Society Web site. http://www.raps.org/Regulatory‐Focus/News/2015/01/13/21063/Orphan‐Drugs‐in‐the‐EU‐A‐Record‐Breaking‐Year/. Accessed June 3, 2015.
  3. Kepplinger EE. FDA’s expedited approval mechanisms for new drugs products. Biotechnol Law Rep. 2015;34 (1):15‐37.  
  4. Clinical development. TotalOrphanDrugs Web site. http://www.orphan‐drugs.org/category/clinical‐ development/  Accessed June 3, 2015.
  5. Jae VS. Simplifying FDASIA: the "fast track" to expedited drug approval efficiency. Admin Law Rev. 2014;66(1):173‐198.  
  6. New drugs at FDA: CDER’s new molecular entities and new therapeutic biological products. US Food

and Drug Administration Web site. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovaTIon/ucm20025676.htm. Updated April 14, 2015. Accessed June 3, 2015.

Address Correspondence To:

Glenn Tillotson, PhD  

2941 Honeymead Road, Downingtown, PA 19335 USA

E‐mail: glenn.TIllotson@transcrip‐partners.com

Phone: (610) 383 5705





The Fundamental Diseases Partnership



Press Release: Findacure launches Online Toolkit for Rare Disease Patients For immediate release.

UK charity Findacure is pleased to announce that this week it has launched an innovative online toolkit- a series of interactive modules, which are aimed at rare disease patient groups to help them develop the skills and knowledge they need to grow their organisations. The toolkit has been built by expert clinicians, fundraisers, drug developers and academics. The modules cover a broad range of topics pertaining to rare disease patient advocacy; there are guides on fundraising, on patient recruitment, on getting involved in clinical trials, on working with academia and on effective PR and communications. We would like to invite rare disease patients to sign up for use of this tookit, which can be accessed at findacure.gather.io/d/sign-up Nick Sireau, the founder of Findacure and father of two boys with ultra rare disease Alkaptonuria (or ‘Black Bone Disease’) said “There are around 7,000 rare diseases and only around half of them have patient groups dedicated to helping them. The remainder of them are isolated, with little hope of cures or little hope of a future. Those that do have patient groups are often ‘kitchen table groups’, set up by patients, their friends and families, desperately striving to make a difference. That’s why we’ve launched this online toolkit for rare disease patient groups – it will provide a range of resources where rare disease patients can go if they’re in need of advice.” Currently, rare disease patient groups are chronically underfunded. They do not usually have access to the skills required to move forward with their aims of funding research and finding treatments. Findacure was set up in 2012, following founder Nick Sireau’s experience of running a patient group for the rare disease affecting his two sons, Alkaptonuria. He was faced with an uphill struggle of raising funds, setting up research, and learning how to run clinical trials and support patients, and realised there was a huge need for practical, hands on advice for patient groups to achieve their aims. Through this online toolkit, Findacure aim to do exactly that.


Contact details: For further information, please contact Louisa Ackermann at Findacure on

01223 222767 or louisa@findacure.org.uk




International research team develops new methods for therapy evaluation in rare diseases


Aachen, 02.09.2013 – In the EU diseases that affect on average not more than 5 in 10,000 people are called rare. Worldwide, more than 7,000 such rare diseases are registered. The resulting groups of patients who are affected by a specific rare disease can be very small. A significant number of diseases occur in only 1-2 patients (e.g. obesity due to prohormone convertase-I deficiency), Orphanet (2012). In the EU 6 to 8 % of the population - that is, from 27 to 36 million people – suffer from at least one of the 5,000 to 8,000 different rare diseases. According to information from the European Society of paediatric oncology, 75% of rare diseases affect children, of whom 30% die before reaching their fifth birthday. 


The ability of conventional statistical methods to evaluate new therapeutic approaches for any given rare diseases is limited due to the small number of patients concerned. This means that established statistical approaches to demonstrate the efficacy and safety of therapies may fail in this situation. Thus, there is an urgent need not only to develop new therapeutic approaches to treat diseases, but also to develop new statistical methods to establish which approaches work. The aim is to use and bring together all possible sources of information in order to optimize the process. This is the point of departure for IDEAL ("Integrated Design and Analysis of small population group trials") research project. The project will explore new methods for design and analysis of clinical studies and to integrate and and synthesize these into an effective strategy, so that the efficiency of clinical trials evaluating therapies for rare diseases can be significantly increased. An international researcher-team under the coordination of Professor Ralf-Dieter Hilgers of the Uniklinik RWTH Aachen, will jointly develop new designs and sophisticated analysis methods for the evaluation of therapies for rare diseases, supported by the EU Projektmanagement Office der RWTH Aachen. The research is funded by the 7.th Framework Programme of the European Union (FP7-HEALTH2013-INNOVATION-1, No. 602 552) with 3 million. €. The consortium consist of Professor Ralf-Dieter Hilgers, Uniklinik RWTH Aachen, Professor Holger Dette, Ruhr University Bochum, Franz König, Medical University of Vienna, Professor France Mentré, Institut National de la Santé et de la Recherche Medicale in Paris, Professor Stephen Senn, Centre de Recherche Public de la Santé Luxembourg, Professor Mats Karlson, Uppsala University, Uppsala, Professor Malgorzata Bogdan, Polytechnika Wroclawska, Warsaw, Dr. Carl-Fredrik Burman, Chalmers Tekniska Hoekskola AB, Goeteburg, Professor Geert Molenberghs, University Hasselt, Hasselt and Professor Christoph Male, Medical University of Vienna. The research programme is divided into 11 work packages. The work packages focus on the assessment of randomization, the extrapolation of dose-response information, the study of adaptive trial designs, the development of optimal experimental designs in mixed models, as well as pharmacokinetic and individualized designs, simulation of clinical studies, the involvement and identification of genetic factors, decision-theoretic considerations, as well as the evaluation of biomarkers. 


Two work packages provide support for project management and the dissemination of results. The IDEAL project is accompanied by an advisory board of international experts with different professional backgrounds, representing both patients' interests, the views of the pharmaceutical industry as well as clinical and regulatory aspects. The ability to use mathematical and statistical techniques for the evaluation of new treatments where standard methods fail to be successful is a challenge and motivation for all of us. We all look forward to this exciting collaboration. 


Über die Uniklinik RWTH Aachen (AöR)

Die Uniklinik RWTH Aachen verbindet als Supramaximalversorger patientenorientierte Medizin und Pflege, Lehre sowie Forschung auf internationalem Niveau. Mit 34 Fachkliniken, 25 Instituten und fünf fachübergreifenden Einheiten deckt die Uniklinik das gesamte medizinische Spektrum ab. Hervorragend qualifizierte Teams aus Ärzten, Pflegern und Wissenschaftlern setzen sich kompetent für die Gesundheit der Patienten ein. Die Bündelung von Krankenversorgung, Forschung und Lehre in einem Zentralgebäude bietet beste Voraussetzungen für einen intensive interdisziplinären Austausch und eine enge klinische und wissenschaftliche Vernetzung. Rund 6.000 Mitarbeiterinnen und Mitarbeiter sorgen für patientenorientierte Medizin und eine Pflege nach anerkannten Qualitätsstandards. Die Uniklinik versorgt mit 1.240 Betten rund 47.000 stationäre und 153.000 ambulante Fälle im Jahr. Weitere Informationen bei: Universitätsklinikum Aachen (AöR) Prof. Dr. rer. nat. Ralf-Dieter Hilgers Institut für Medizinische Statistik

Tel.: 0241 80-89359


Universitätsklinikum Aachen (AöR)

Melanie End Stabsstelle Unternehmenskommunikation Pauwelsstraße 30

52074 Aachen

Tel.: 0241 80-85778





An Open Access Journal


New Methods for Evaluation of Therapy

By: Rare Disorders


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Aachen, 9/2/2013-In the EU diseases that affect 5 in 10,000 people or less are defined as rare.  Worldwide more than 7,000 such rare diseases are registered. The resulting groups of patients who are affected by a specific rare disease can be very small.  The ability of conventional statistical methods to evaluate new therapeutic approaches for any given rare disease is limited due to the small number of patients.  Thus, there is an urgent need not only to develop new therapeutic approaches to treat diseases, but also to develop new statistical methods to establish which approaches work.