49
or condition is not subject to the Prescription Drug User Fee Act (PDUFA) unless the
application includes an indication for another, non-orphan disease or condition. In the
intervening years, 282 orphan drugs and biological products, providing treatment for
more than 14 million patients, have come to market. In the eight to 10 years before 1982,
only 10 treatments for rare diseases had been approved by the agency and brought to
market.5
Because of the limited number of patients diagnosed with a rare disease and the
inability to recruit sufficient trial subjects, current clinical trial methods (hypothesis test-
ing) cannot detect or exclude clinically worthwhile differences between treatments with
standard levels of statistical confidence. Clinicians must rely upon observational studies,
historical controls, anecdotal information, limited clinical experience and the perception
of biological plausibility.6 The problem has been partially solved by changing the level
of statistical certainty and employing the Bayesian approach. This method enumerates
the probabilities of effects of different sizes and the trial is analyzed as data accumulate.7
(There are a number of references to Bayesian methods on FDA’s website.)
Small patient populations have thus not presented a major problem in the approval
process. For example, the clinical trial for bovine pegademase (Adegen) used in the treat-
ment of severe immunodeficiency syndrome of the adenosine deaminase type involved
just eight patients, and only 14 people had the disease at that time. A historical control was
used in the trial, and the drug proved 100% effective.8
Ongoing Research
A number of rare disease studies are currently enrolling patients. Studies include
argininosuccinate lyase deficiency, Rett syndrome, polyarteritis nodosa, Wegener’s granu-
lomatosis, Churg-Strauss syndrome, heparininduced thrombocytopenia, Angelman’s
syndrome, Andersen-Tawil syndrome, myelodysplastic syndromes and large granular
lymphocyte leukemia. Future studies will include trials for rare lung diseases, thrombotic
defects and urea cycle disorders. A complete list can be found on the rare diseases network
website.9 Information about metabolic disorders and newborn screening tests, including
the types offered by various states and hospitals, and test methods can be accessed on the
KidsHealth website.10 Other news regarding orphan drug designations and approvals is
available on the FDA website.11
References
1. HaffnerME.“Adoptingorphan drugs—twodozenyearsof treating rare diseases.” NEJM 2006 354(5):445-7.
2. Patton MA.“Usefulinformationaboutrare inheriteddisorders.” BMJ 2003 326:612-3.
3. “IndepthGuidetoRare Diseases.” The Lancet 2003,361:1663.
4. Murphy W. Orphan Diseases—New Hope for Rare Medical Conditions. Twenty first Century Books, Brookfield,
CT, 2002.
5. Op cit 1.
6. Lilford RJ et al. “Clinical trials and rare diseases.” BMJ 1995 311:1621-5.
7. BerryDA.“A case forBayesianismin clinical trials.” StatMed 1993 12:1377-93.
8. Op cit 1.
9. http://rarediseasesnetwork.epi.usf.edu/. Accessed 24 January 2012.
10. http://kidshealth.org. Accessed 24 January 2012.
11. http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/default.htm. Accessed 24
January 2012.
Published in Regulatory Affairs Focus, June 2007. Copyright © 2007 Regulatory Affairs Professionals Society.
Rare Diseases
or condition is not subject to the Prescription Drug User Fee Act (PDUFA) unless the
application includes an indication for another, non-orphan disease or condition. In the
intervening years, 282 orphan drugs and biological products, providing treatment for
more than 14 million patients, have come to market. In the eight to 10 years before 1982,
only 10 treatments for rare diseases had been approved by the agency and brought to
market.5
Because of the limited number of patients diagnosed with a rare disease and the
inability to recruit sufficient trial subjects, current clinical trial methods (hypothesis test-
ing) cannot detect or exclude clinically worthwhile differences between treatments with
standard levels of statistical confidence. Clinicians must rely upon observational studies,
historical controls, anecdotal information, limited clinical experience and the perception
of biological plausibility.6 The problem has been partially solved by changing the level
of statistical certainty and employing the Bayesian approach. This method enumerates
the probabilities of effects of different sizes and the trial is analyzed as data accumulate.7
(There are a number of references to Bayesian methods on FDA’s website.)
Small patient populations have thus not presented a major problem in the approval
process. For example, the clinical trial for bovine pegademase (Adegen) used in the treat-
ment of severe immunodeficiency syndrome of the adenosine deaminase type involved
just eight patients, and only 14 people had the disease at that time. A historical control was
used in the trial, and the drug proved 100% effective.8
Ongoing Research
A number of rare disease studies are currently enrolling patients. Studies include
argininosuccinate lyase deficiency, Rett syndrome, polyarteritis nodosa, Wegener’s granu-
lomatosis, Churg-Strauss syndrome, heparininduced thrombocytopenia, Angelman’s
syndrome, Andersen-Tawil syndrome, myelodysplastic syndromes and large granular
lymphocyte leukemia. Future studies will include trials for rare lung diseases, thrombotic
defects and urea cycle disorders. A complete list can be found on the rare diseases network
website.9 Information about metabolic disorders and newborn screening tests, including
the types offered by various states and hospitals, and test methods can be accessed on the
KidsHealth website.10 Other news regarding orphan drug designations and approvals is
available on the FDA website.11
References
1. HaffnerME.“Adoptingorphan drugs—twodozenyearsof treating rare diseases.” NEJM 2006 354(5):445-7.
2. Patton MA.“Usefulinformationaboutrare inheriteddisorders.” BMJ 2003 326:612-3.
3. “IndepthGuidetoRare Diseases.” The Lancet 2003,361:1663.
4. Murphy W. Orphan Diseases—New Hope for Rare Medical Conditions. Twenty first Century Books, Brookfield,
CT, 2002.
5. Op cit 1.
6. Lilford RJ et al. “Clinical trials and rare diseases.” BMJ 1995 311:1621-5.
7. BerryDA.“A case forBayesianismin clinical trials.” StatMed 1993 12:1377-93.
8. Op cit 1.
9. http://rarediseasesnetwork.epi.usf.edu/. Accessed 24 January 2012.
10. http://kidshealth.org. Accessed 24 January 2012.
11. http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/default.htm. Accessed 24
January 2012.
Published in Regulatory Affairs Focus, June 2007. Copyright © 2007 Regulatory Affairs Professionals Society.
Rare Diseases