Orphan Drugs: Where have we been; Where are we now; Where are we going Marlene E. Haffner, MD, MPH Haffner Associates, LLC 11 October, 2011

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Abbey Myers was concerned for – her and other children who could not obtain needed treatments for their disease AND – Hell hath no fury as woman scorned - William Congreve 1697 Marian Finkel, MD – Report “Significant Drugs of Liimited Commercial Value” – Tenets of the current US Orphan Drug Act were born – Laid out incentives including Exclusivity Protocol Assistance Grant Support Tax Incentives Lack of Profitability In the beginning…. Drug Information Association

Success was not immediate - Need to amend profitability statement – 1984; add prevalence 1986: 100 th designation AZT approved for a “new disease” HIV AIDS – 1986 Growth Hormone – what is the same and what is a different drug Concern about cost of orphan products – with growth hormone and AIDS drugs 1988 amendments – must be designated prior to submitting NDA Drug Information Association

Companies began to build around the Orphan Drug Act - Genentech, Enzon, Genzyme, BioMarin - Big Pharma not interested except by happenstance - Some of the new companies became both large and profitable Other countries become interested and pass their on legislation/regulations - Japan – Australia-1998 – and then EU, Taiwan, Singapore, and more Drug Information Association

Horse Races – if the population is big enough; the possibility of a horse race may exist – Digibind vs Digidote – Erythropoietins – Two Factor IX’s – Fabry’s disease – Pneumocystis drugs Regulations published – 1992 – Codified same/different – Not much else that was new Drug Information Association

Biotech becomes increasingly important An increasing number of orphan diseases described – more than 7000 on NIH list NIH Office of Rare Diseases and Research established by law (had already existed in fact) Pediatrics issues increasingly addressed Human Genome project New drugs for diabetes, hypertension, harder to find Realization that not all rare diseases are “that” rare – Oncology and Metabolic diseases very important Then - - Drug Information Association

Passage of PDUFA 2 – establishes waiver of Orphan drugs from user fees for initial reviews > $1.5 million Numbers of designations increase dramatically “Medically plausible” comes to the fore and is still being defined IOM committee studies issues of rare disease research Establishment of Office of Orphan Drugs in the Office of New Drugs/CDER Brownback Brown amendment – 2009 CDER establishes focus on orphan drug review Drug Information Association

Make Mine Rare By Megan Scudellari | August 1, 2011 With mounting interest from biotechs, Big Pharma, and the federal government, research on rare diseases is burgeoning Researchers at the Basel, Switzerland, branch of the Novartis Institutes for BioMedical Research develop therapies for rare diseases,…business is booming. Multiple Articles in popular and scientific Press Drug Information Association

Designations dramatically increase in last 4 years Creating Hope Act - rare Pediatric Diseases NORD petitions for FDA Policy Statement o Orphan Drug Review – Acknowledging that rare diseases have smaller populations with specific issue of drug development – Requests training for reviewers NIH establishes TRND Multiple consortia funded through NIH Office of Rare Disease Research Drug Information Association

Companies investing in orphan product research are multinational Consumer groups are ever more educated and active The human Genome has given rise to better understanding of many diseases – particularly inborn errors of metabolism EU COMP and FDA OOPD having regular discussions to better “harmonize” The World is a Smaller place Drug Information Association

Better understanding of surrogate and biomarkers in the study of rare diseases What are the challenges of small population studies Safety will remain a significant issue with small populations – REMS are exensive Biotech drugs serving a small population (economies of scale) will remain expensive – but must consider benefit risk Drug Information Association And yet to be done -

The future is Bright CDER and OOPD continue to coordinate Multiple international groups working together on behalf on patients with rare diseases – ICORD, IRDiRC Better understanding in CDER of the review process – consistency OOPD to continue outreach Drug Information Association

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16www.diahome.org Drug Information Association In the beginning…

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