How Low in Sample Size Can We Go? FDA approves ultra-orphan drug on a 4-patient trial

The development of the orphan drugs has been red hot in recent years due to the favorable regulatory environment and the government incentives. It is well know that it is challenging to conduct the clinical trials in orphan diseases. The rigorous statistical rules and principles may not be feasible to be followed in drug trials in rare diseases. The sample size in rare diseases are usually small, but how low in sample size can we go? A recent FDA approval gives an answer.

Recently, FDA approved a new orphan drug to treat rare autosomal recessive disorder. The drug called Xuriden was approved for treating patients with Hereditary orotic aciduria – an ultral orphan disease. According to FDA’s announcement:

“The safety and effectiveness of Xuriden were evaluated in a single arm, six-week, open-label trial in four patients with hereditary orotic aciduria, ranging in age from three to 19 years of age, and in a six-month extension phase of the trial. The study assessed changes in the patients’ pre-specified hematologic parameters during the trial period. At both the six-week and six-month assessments, Xuriden treatment resulted in stability of the hematologic parameters in all four clinical trial patients.”

It looks like that the company (Wellstat Therapeutics) initially planned to enroll 10 subjects. I guess that due to the enrollment challenge, only 4 subjects were enrolled. Wellstat presented the data from 4 subjects and got the green light from FDA. According to the clinicaltrials.gov, the study protocol is titled "Open-Label Study of Uridine Triacetate in Pediatric Patients With Hereditary Orotic Aciduria" and the primary and secondary outcome measures are biomarkers or PD markers:

Primary Outcome Measures:

•  Stability of predetermined principal hematologic parameters

Secondary Outcome Measures:

• Levels of orotic acid and orotidine in urine 
• Levels of uridine in the plasma

With the results from four patients, it is not possible to perform any inferential statistical analysis. The approval is essentially based on the summary results or data listings from the outcome measures in 4 patients. See Clinical Studies section in Xuriden package insert.

As part of the approval, the manufacturer of Xuriden (Wellstat therapeutics) was also granted a rare pediatric disease priority review voucher. The priority review voucher itself worthies millions dollars and probably will be more than enough to recoup all the investment costs that the company has invested in the development of Xuriden.

With the emphasis on precision medicine and personalized medicine, we will see a trend of conducting more smaller trials. In the future, every drug is so specifically targeted that it would apply to only a few people worldwide. If we can really achieve the precision medicine, more and more medicines will be classified as orphan drugs.

Some backgrounds about the orphan drug is summarized in one of my previous articles "Drug for Treating Rare Diseases: Orphan Drug, Orphan Disease, Orphan Subset". Similarly a presentation by Dr Lawrence J. Lesko from FDA gave a good introduction about the rare diseases and orphan drugs. Rare and ultra-rare diseases, often referred to as orphan and ultra-orphan diseases, affect very small numbers of patients. In the United States, a disease is defined as rare if it affects fewer than 650 patients per million of population, and the European definition of a rare disease is one that affects fewer than 500 patients per million of population. In contrast, a disease is generally considered to be ultra rare if it affects fewer than 20 patients per million of population (or, one patient per 50,000 people)—and most ultra-rare diseases affect far fewer than this—as few as one per million or less.