The development of orphan medicines presents many challenges, the main being to obtain sufficient evidence of effectiveness and safety in patients. Apart from the difficulties of funding clinical trials and recruiting competent investigators, the biggest challenge in trials on rare diseases is to recruit the right patients in adequate numbers. A rigid requirement to do studies that completely satisfy the needs of a classic design would prevent many orphan medicines from receiving marketing authorisation. (1)
In the European Union, a disease is defined as rare if its prevalence is five cases or less per 10, 000 of the European population. (2) Rare diseases therefore range from those with a low incidence and poor survival (eg, severe combined immunodeficiency syndrome), through those with a low incidence and relatively long survival (eg, Duchenne muscular dystrophy, cystic fibrosis), to those with a relatively common incidence but short survival (eg, pancreatic and renal carcinomas, myeloma, and glioma).
For diseases categorised as rare because of short survival despite relatively common incidence, classic trial designs are practical, with large numbers of participants and hard outcomes such as survival. By contrast, some rare diseases affect fewer than 100 accessible patients in the European Union. For example, hyperammonaemia associated with N-acetylglutamate synthase deficiency was identified during a 20-year period from 1980 to 2001 in only 42 patients from 28 families.(3) Many other rare diseases are prevalent to the extent of a few thousand people. Under such circumstances, a trial based on classic frequentist design and requiring enrolment of hundreds of patients is impossible. Accordingly, the conduct, analysis, and interpretation of studies in rare disorders are constrained by the prevalence of the disease.
Table: Orphan drugs with marketing authorisation in the European Union
1) Disorders for which drug is indicated
2) Marketing authorisation date
3) Studies done in indicated disorder (number of participants)
Agalsidase beta - Fabry’s disease
May, 2001
Phase I/II (15); phase III pivotal, randomised, double-blind; placebo-controlled multicentre (58); phase III open-label extension (58)
Agalsidase alfa - Fabry’s disease
May, 2001
Phase I and II (106)
Imatinib mesilate - CML, CLL, GIST, dermatofibrosarcoma protuberans (see SPC for full list)
August, 2001
CML: phase I (149); CML: phase II (1027); GIST: phase II (147); DFSP: phase II (12)
Arsenic trioxide - Relapsed or refractory acute promyelocytic leukaemia
Pegvisomant - Acromegaly with incomplete response to surgery, radiotherapy, and somatostatin analogues
November, 2002
Phase II and Phase III (161)
Miglustat - Type 1 Gaucher’s disease in patients for whom enzyme replacement unsuitable
November, 2002
PhaseI/II pivotal (28); pharmacokinetic studies (82); non-comparative study (18);
open comparative study (36)
Carglumic acid - Hyperammonaemia due to N-acetyl glutamatesynthase deficiency
January, 2003
Pharmacokinetic (12); retrospective patient data (20)
Laronidase - Mucopolysaccharidosis I (α-L-iduronidase deficiency)
June, 2003
Phase I/II (10); Phase III (45)
Iloprost - Primary pulmonary hypertension
September 2003
Phase II (76) Phase III (203)
Celecoxib - Familial adenomatous polyposis
October 2003
Phase II (83)
Porfimer sodium - High-grade dysplasia with Barrett’s oesophagus
March 2004
Phase II (48); Phase III (208); uncontrolled studies (86)
Mitotane - Advanced adrenal cortical carcinoma
April 2004
No new studies; fully bibliographic application
Ibuprofen - Patent ductus arteriosus in preterm neonates
July 2004
Dose range study (43); Phase II/III (131)
Patients’ advocacy and support organisations might help by recruiting participants for multicentre or multinational trials. Major patient coalitions, such as the European Organisation for Rare Diseases in Europe and the National Organization for Rare Diseases in the USA, can help access patients and identify specialist clinicians. Web-based resources such as the US National Institutes of Health website and the European site by Orphanet allow potential trial participants to access information about planned studies.
Randomised, double-blind controlled clinical trials are usually thought to provide the best evidence from which to assess the efficacy of a medical treatment. (4) Trials should be powered to allow the testing of a predefined hypothesis of superiority or non-inferiority compared with a comparator treatment. Trial design should identify and minimise potential sources of bias and their conduct should be of a high standard, done by skilled staff , and involving committed participants. (4) Estimation of the number of participants needed for a trial of a particular treatment is conventionally based on a hypothesis of a mean difference between treatments (Δ), allowing for type 1 and type 2 errors. (5) For extremely rare diseases, this estimate might need to be made from animal studies because most of the population with the disease might have been included into the trial, making it a once and only chance study.
Usual power calculations to estimate the number of participants needed for a trial assume normally distributed responses to treatment and control, which is not always true for rare diseases. Therefore, great care should be taken to avoid heterogeneity in the diagnosis, stage, and manifestations of the disease so that the variance in baseline characteristics is kept to a minimum. Adjustments to power calculations to obviate the assumption of normality might well not be helpful, since they tend to increase the sample size. Often when designing a trial of an orphan medicine with a small accessible sample, it is helpful to estimate the size of likely effects that might be detected at a reasonable power (say 80%) and α level (5%). The investigator might then assess whether these effects need to be too large to make the trial feasible. Although use of a continuous variable such as the measure of difference between two groups should further save on sample size compared with event-based outcomes, it is often not useful in trials for rare diseases to use the surrogate endpoints that this frequently requires. Fortunately, some treatments for some rare diseases are so effective that they are considerably better than previously available (control) treatments, so that the numbers of participants needed are small. For example, results of a trial of stiripentol (n=21) compared with placebo (n=20) added to valproate and clobazam in severe myoclonic epilepsy showed a response in 15 (71%) patients on stiripentol and in one (5%) on placebo (difference 66%, 95% CI 42·2–85·7%; p<0·0001). (3) Here, careful diagnosis and selection of participants to avoid heterogeneity decreased the number of participants needed. (3)
There has been interest in other approaches to trial design to allow for smaller numbers to be entered into trials for rare diseases, (6) such as the use of Bayesian approaches, (7,8) N-of-1, (9–14) crossover, (10,15) sequential, (16,17) and adaptive (15) (eg, play the winner) designs. However, although each design might have a role in addressing a particular question, none is a universally applicable panacea for the small numbers of patients. For trials without a very large response difference between treatment and control, these designs are not likely to greatly decrease the number of patients needed.
Sometimes, despite optimum organisation of recruitment and the most sophisticated design to best use available patient numbers, a randomised controlled clinical trial in a very rare disease will be severely underpowered. However, as a basic principle, patients with rare diseases have rights to safe and effective treatment. The overriding role of medicine regulators is to protect public health by assuring availability of safe and effective medicines of adequate quality. Thus, the frequent but limited perception that regulators function only as a barrier (assuring safety, effectiveness, and quality) is incorrect. They also carry part of the responsibility to ensure that patients are not denied vital treatment.
A clear tension exists between accelerating patients’ access to treatments and the need to make the best possible scientific assessment of the risks and benefits of new orphan medicines. Best possible implies that, for each new orphan medicine, developers and sponsors make a convincing case that the evidence they present for its efficacy and safety is the best that can be assembled in a reasonable time. The helpful guidelines produced by the European Medicines Agency (EMEA) (6) clearly establish that there is no absolute requirement for any particular kind of trial design when presenting an application for marketing authorisation of a specific drug. The practical application of this requirement to risk assessment of an orphan medicine is judged case by case, and investigators should always avail of the free scientific advice and protocol assistance provided by the EMEA before starting a trial.
In some instances, orphan medicines might have been used extensively in clinical practice for decades—for example, trientine for Wilson’s disease, (18) caffeine for neonatal apnoea of prematurity, (19) and mitotane for adrenal cortical carcinoma. (20,21) Substantial published studies exists for these drugs, which mostly consist of case reports and clinical trials, many of which were probably not done to Good Clinical Practice standards. However, despite obvious limitations, a systematic review of published work can add substantially to the risk–benefit assessment.
The EMEA lists a detailed summary of all evidence presented to them to support applications for marketing approval (as European Public Assessment Reports or EPARs) on their website. These reports show that the European regulator has taken an eclectic approach to the levels of acceptable evidence for licensing orphan products (table). They show that studies supporting marketing authorisation for orphan drugs consisted of numbers of treated patients ranging from as few as 12 to several hundred. In the instance of one drug, there was complete reliance on reported data only and no new studies were done. For all other drugs, at least one clinical study was included. For carglumic acid, only one clinical study (a pharmacokinetic one) was done. This study included only 12 volunteers, but there was also a retrospective patient data collection (n=20) and a commitment to collect further data and follow-up. Although most marketing authorisations for oncologyrelated orphan drugs were granted on the basis of large studies in commonly incident diseases, most of those for genetic disorders were based on much smaller studies, including some in which no new trials were done (table).
Difficult as it is to establish effectiveness of an orphan treatment, it is usually more challenging to establish the limits of its safety beyond that shown in non-clinical studies. Clearly, the number of patients included in all studies presented for any given authorised orphan drug is far too small to allow reliable detection of adverse effects that occur with a frequency of less than about 1% (a sample size of 500–1000 would be needed). Therefore, knowledge related to the safety of an orphan medicine will usually be gained only after it has entered into the market and into widespread clinical use. Hence, a prospectively designed, highly structured programme of postmarketing surveillance is essential to continuously assess safety of all orphan medicines.
Medicines might receive approval in the European Union under any of three different headings: normal approval, approval under exceptional circumstances, and conditional approval. Approval under exceptional circumstances might be given when comprehensive data cannot be provided, for instance because of the rarity of the disease or because of ethical barriers. Such an approval is granted on the basis of specific obligations on the licence holder to inform the regulator about safety and efficacy with the passage of time. EMEA might grant conditional approval for 1 year, renewable, when the data set submitted is incomplete, but there is a positive risk–benefit balance evident from that available as long as the licence holder provides comprehensive clinical data after approval. Assessment of the benefits and risks of this approach will take some time to emerge.
Scientists, clinicians, industry, and regulators should help in the development of safe and effective treatments for patients with rare diseases. It is not easy to satisfy this obligation without developing new ways to allow assessment of orphan medicines in patients. Novel statistical techniques and recruitment that are more efficient will assist, but will not solve the fundamental truism that rare diseases yield few patients for clinical trials. Therefore, regulators do the best that they can with the limited information available when attempting to assess risks and benefits for orphan drugs. The prospective operation of systematic, coordinated, and comprehensive postmarketing surveillance of all orphan drugs might validate the eclectic approach taken so far.
Lancet 2008; 371: 2051–55
European Centre for Clinical Trials in Rare Diseases
University College Cork
Cork, Ireland
(Prof B M Buckley FRCPI)
Correspondence to:
Prof Brendan Buckley
European Centre for Clinical Trials in Rare Diseases
BMB is chairman of the Irish Medicines Board’s Advisory Committee on Human Medicines and a director of the board. He was formerly a member of the Committee for Orphan Medicinal Products of EMEA. He has received research funding on behalf of his Centre from the Government of Ireland, the Commission of the European Union, Baxter, Bristol Myers Squibb, Merck, Pfizer, Sanofi -Aventis, and Univar. He has received speaker fees and assistance with travel and accommodation for scientific purposes from AstraZeneca, Bristol Myers Squibb, Merck, Pfizer, and Sanofi -Aventis.
The Myelin Project wants to thank Dr. Astrid James and the publisher of The Lance for granting us permission to post these articles.
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