Regulatory Challenges and Threats in Orphan Drug Development Are Ultra Orphans Easy?

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1 Regulatory Challenges and Threats in Orphan Drug Development Are Ultra Orphans Easy? EPLS September 24, 2014 Ulrich Granzer Granzer Regulatory Consulting & Services

2 The Challenge: What needs to be done to cross the bar

3 without leaving too much space? without pushing the bar down?

4 Company obligations: Development plan Target Product Profile: Company definition on where to go Indication Dosing and administration Safety profile Plans for CMC Preclinical Clinical development with consideration of what is necessary throughout the target areas

5 The issues to overcome Three different opinion leading areas: USA Europe (EEA), Germany as a (tiny) part: 5% of global drug market Japan

6 Authorities Local Inspections (young biotechs with small budget and complicated manufacturing process) National: Competent Authorities EEA (European Economic Area): EMA USA Japan

7 Orphans and Ultra-Orphans

8 Guideline on small populations Defines small populations International definition: Less than 5,000 patients Studies easily possible Les than 2,000 patients Studies still possible Less than 200 patients Special investigations possible

9 Very small populations Ultra-orphan diseases Often based on genetic mutations Lysosomal storage diseases Niemann Pick Disease Type C Mucopolysaccharidosis type IIIA (Sanfilippo type A syndrome) Gaucher disease Metabolic diseases Lipoprotein Lipase Deficiencies (LPLD) Phosphatase disorder (Glass bone disease) Retinal disorders Choroideremia Inherited retinal diseases due to several different mutations

10 What needs to be done? CMC As usual What does it mean? GMP is a given Batch sizes might be small Highest amount of drug use often in preclin development Often very new developments pushing the frontier Gene therapies Enzyme replacement therapies: Purification of drug substance often very difficult, esp when E.coli is used for manufacture (Endotoxins, HCPs, like flagellin)

11 Preclinical There is no shortage in No of test animals Preclinical work as usual Long term tox for chronic therapy necessary All other tox testing as in ICH M3 or S6

12 The real challenge: Clinical development Orphans have up to 10 % of living global population in clinical trial database (would be several million patients in non orphan major diseases) Usually between 0.1 and 1% We need to find the patients Rare genetic disorders: Patient interest groups (often parents) Rare non genetic diseases (e.g. rare cancers): no patient groups search for patients 100 centers for 50 patients not uncommon

13 Database size Phase Ib/II/IIII Usually 1,000 10,000 patients prior to registration for classical drugs Classical orphans : patients Ultra orphans: (<10) patients Submission with lowest No of patients: 13 patients in DB

14 Meaning Classical dose finding, statistics, assessment often not possible Primary endpoint at the beginning of pivotal trial often not known Best knowledge of disease often gained during pivotal trial Most often first chosen primary endpoint wrong Example: Friedreich s ataxia Friedreich scale did not show anything, Parkinsin s disease scale did Training effect of tests

15 What can be done? Look at totality of data Assess trends in all endpoints Forest plot of all endpoints measured Biomarkers often important, but almost never validated

16 Regulators Early involvement of authority experts Education of regulators Understanding of disease Need to leave classical pathways Discussion of clinical program Options to be discussed and shown use of video material Best way for development within limited patient population

17 Example: Glybera First ever approved gene therapy outside China Very severe metabolic disease: LPL Deficiency Patients must not eat fat: total of less than 13 g/day Pancreatitis, death Reason: LPLD is the most important enzyme for Chylomicron breakdown Chylomicrons are the most important fat (triglycerid) carriers in the body Blood of patients is yellow, not red, fat content in blood roughly 1000 times increased

18 Therapy Total of 64 i.m. injections into muscle tissue, injection point tattooed. Gene incorporated into muscle via viral carrier 2 4 weeks after inoculation muscle starts manufacture of human LPLD

19 Cholic Acid deficiency Patients are unable to build cholic acid Fat cannot be absorbed in intestine Life expectancy very much reduced Ultra orphan with a few 100 patients in total globally Total of 6 different gene defects

20 Two different registration approaches One with a study of 20 years duration Started prior to real GCP IIT Data needed to be cleaned retrospectively Data showed clear benefit The other via WEU Data from one side in France only Implications on future procedures?

21 Types of approval Conditional Data from phase 2 only prior to approval Exceptional circumstances Classical data may never be generated Prerequisite: MoA known or plausible

22 General issues following approval RMP: Risk Management Plan Registry Collection of safety (and efficacy) data post approval Data to be pooled in data base and reported to regulators at defined time points Efficacy study, if possible Dedicated Prescribing rules: Specialist prescription only Training Manual for treating physicians

23 And the upside: Chance for very small companies to get a drug to market Specialists of global importance to work with during development Sales force can be very small, but needs to be very specialized and very well trained Every Ultra orphan pushes the frontiers of science and regulatory affairs They can be fun! Regulators usually become very helpful during procedure Always direct and intense contact from start of clinicl development to approval

24 Vielen Dank Dr Ulrich Granzer Granzer Regulatory Consulting & Services

25 Welcome to the 7 th European Pharma Licensing Symposium 23 rd & 24 th September 2014