by Dr. Vishal Pawar, MD Pharmacology

1. DRUGS FOR RARE DISEASES
BY: DR. VISHAL PAWAR
JR II

2. INTRODUCTION
 There is no single definition of rare diseases
 WHO: 0.65-1/1000 as ‘rare’
 EU: 5/1,00,000 as ‘rare’
 US: <2,00,000 patients as ‘rare’
 Japan: <50,000 patients as ‘rare’

3. RARE DISEASES
 These disorders are found rarely among population
 Includes:
Malformation syndrome
Clinical syndromes
Morphological/Biological Anomalies
Neurological Disorders
Infectious Diseases
Rare Cancers
Hematological Conditions
Endocrine Disorders
Autoimmune Disorders
Genetic Diseases

4.  Rare diseases when taken together aren’t rare
at all
 ‘Rare’  each affects very few people
 Comprise of various disorders
 Most have genetic abnormality
 Data stored  Orphanet

5. ORPHAN DRUGS
 Finance required for developing treatment for rare
diseases is huge
 Cost incurred developing drugs  usable medicine
cannot be recovered by developer
 Government offers  Incentives
 Such drugs when developed by pharmacological
companies  Orphan Drugs

6. PROBLEM STATEMENT

7.  Over half the population affected  Children
 >80%  genetic component
 Global avg. occurrence rare disease  6-8%
 Orphan drugs top list of costliest drugs
 Worldwide sales forecast  $209 Billion (2022)
 Double of overall prescription market

9. ORPHAN DRUG ACT 1983
 First act by US FDA for orphan drugs
 Later adopted by various countries
 Provides for granting special status
 Drugs or biological products to treat rare
disorders
 Upon request of sponsor

10.  Status referred  orphan designation/status
 New orphan drug application  highest priority
at all stages of drug review process
 Manufactures receive incentives
 Help cost of production
 Tremendous surge new orphan drug applications

11. ORPHAN DRUG DESIGNATION
PROCESS
 Sponsors  send request to grant designation
 Send  New Drug Application (NDA) to controlling
authority
 Typical review cycle  90 days
 Once designated, sponsor required to submit
annual reports until drug approval

12. DRUGS APPROVED IN 2016-17Cetylev (Acetyl Cysteine)  PCM overdose
Evomela (Melphan)  Multiple Myeloma
Defetelio (Defebrotide)  Veno occlusive disease
Photrexa (Riboflavin)  Keratoconus
Ocalica (Obeticholic acid)  Biliary Cholangitis
Spinraza (Nusinersen)  Spinal Muscular Atrophy
Lartruvo (Olaratumab)  Soft Tissue Sarcoma

13. CHALLENGES
 Small population for trials
 Lack of standard patient care regimens
 Lack of standardization of usual supportive care
 Novel mechanism, viral vector technique 
?? Long term safety, Durability

14.  Natural History of Rare diseases poorly understood
 Diseases tend 
 Difficult to diagnose (variable presentation, less
previous exposure)
Serious
Progressive
Life limiting
Life threatening

15. Problems due to Rarity
 Scarcity of patients
 Well designed trials to determine efficacy are
difficult to perform
 Large studies to determine serious adverse
effects are impossible to conduct
 Limited financial rewards unless cost of drugs
are increased

16. PATIENT BURDEN
 <1 in 10 receives disease specific treatment
 Approved treatment only available for <5% diseases
 Psychological, financial burden  patients, caregivers
 Receive 2-3 misdiagnoses

17.  Wait few years to be diagnosed due to lack of
disease understanding
 Rare disease often render patient unable to engage
in basic activities
 Necessitates extensive time and care from caregivers
 Thus financially pressed dues to increased healthcare
burden

18. INCENTIVES
Simplification
marketing
authorization
procedures
Research
aids
Tax
aids
Exemption
from fees
Extended
market
exclusivity

19. DEVELOPMENT IN GENETICS
 Cost of powerful techniques – next generation
sequencing, whole genome screening
 They identify genetic components in patho-physiology
of rare diseases
 Helps in drug discovery and development
 Genes responsible for half of rare monogenic disorders
 already identified

20.  Recent advances in rare cancer research
 >40% of FDA approved drugs  orphan drug
designations
 Research may  development of drugs for more
common diseases
 Example: Sclerostin antibodies for osteoporosis
originating from research on Sclerosteosis

21. CLINICAL PHARMACOLOGY
AND RARE DISORDERS

22.  Clinical pharmacologists  skilled in basic
pharmacology and its link to clinical medicine
 Essential component  Involved in all stages of
drug development
 Contribute to delineation of genetic factors
 Determine clinical outcomes of pharmacological
interventions

23.  Develop biomarkers
 Design, perform clinical trials
 Assist regulatory decision making
 Conduct post marketing surveillance
 Conduct pharmaco-epidemiological and
pharmaco-economical assessments

24. EVALUATION FRAMEWORK

25.  Suitability depends:
 Adequate evidence from trials
 Threshold for rarity
 Next steps:
 Long term effects is then integrated into disease
model
 Costs are evaluated as part of budget impact
model
Reviewing
natural
history of
disease
Consistency
Temporal
relationship
Dose
response
Potential
effectiveness
of treatment

26. BENEFITS OF NEW TREATMENT
 Direct patient health benefit
 Reduced complexity  significant improvement in disease
outcome
 Significant reduction in caregiver burden
 Novel mechanism, approach  successful treatment of who
have failed with other available treatments
 Significant impact and improvement on overall productivity

27. FDA MODERNIZATION PLAN
 To eliminate backlog
 To respond in timely fashion efficiently grant new
drug designation requests
 Goal 1  in 90 days: complete review of pending
requests
 Goal 2  all new requests will receive a response
 Approvals: >40% from that 2015-16

29. DRUGS IN PIPELINE
Binimetinib  Melanoma
Brigatinib  NSCLC
Durvalumab  Bladder Cancer
Dupilumab  Atrophic Dermatitis
Romosozumab  Osteoporosis
Ocrelizumab  Multiple Sclerosis

30. PROMISE OF TARGETED
THERAPIES
 Personalised medicine, treatment, diagnoses
increased from 13 in 2006  126 in 2015
 Biopharmaceutical companies committing to
advancing development of targeted therapies
 Researchers increasingly able to pursue therapeutics
aimed at genetic composition of diseases

31.  Allows them to develop medicines for more
targeted population
 Offers hope to patients with rare diseases
 Suggested  to cost: NGOs can be involved
 Breakthrough cancer research designation:
 Review time 3 months faster
 Development time 2.2 years less

32. ORGANIZATION FOR RARE
DISEASES INDIA (ORDI)
 Objectives:
 Definition of rare diseases in India: <1 in 5,000
 70 million affected in India
Sponsored clinics
Annual conference
Bio specimen registry
Patient registry
Helpline and Helpdesk
Funding

33. Lessons Learned In Rare Disease
Drug Development
 Early natural history studies are invaluable
 Especially with protocol driven, rigorous, consistent
objective endpoints
 Need to consider randomization and placebo
controls from the very beginning

34. How Orphan Drugs Have Impacted Life
Expectancy for Select Rare Diseases.
Disease Life Expectancy
Before Available
Treatment
Life Expectancy
Now
Cystic Fibrosis <1 years 37 years
Gaucher’s Disease 11 years 50 years
Hemophilia <30 years 68 years-Normal

35. CONCLUSION
 Over past few decades, there has been substantial
improvement in treatment of rare diseases
 However, there’s still significant gap in understanding
of underlying pathology and treatment
 Limited viable treatment options exist for many
patients with rare diseases
 But with complete understanding of genomic basis of
pathophysiology of most genetic disorders, new
treatments are being found

36.  Drug Development for Orphan diseases uses
expedited review to a great degree
 Targeted Medicines are increasing and common
among therapies for Orphan diseases with both
advantages and challenges
 Patient centered drug development is important in
orphan disease
 There’s an increased level of global collaboration
on rare diseases

37. REFERENCES
 Serge Cremers and Jeffrey K. Aronson; Drugs for rare disorders,
British Journal of Clinical Pharmacology (2017) 83 1607–1613
 PhRMA. (2017). Medicines in Development for Rare Diseases: A
Report on Orphan Drugs in the Pipeline. Retrieved from
http://phrma-
docs.phrma.org/sites/default/files/pdf/medicines-in-
development-report-rare-diseases.pdf.
 Daniel A. Ollendorf, Rick Chapman, Steven D.; Assessing the
Effectiveness and Value of Drugs for Rare Conditions, Institute
for clinical and economic review May 2017
 PhRMA. (2016). Great Strides Against Rare Diseases. Retrieved
fromhttp://phrma-
docs.phrma.org/sites/default/files/pdf/great-strides-against-
rare-diseases.pdf

38.  Richard Moscicki, CDER 2016 Update for Rare Diseases, US FDA
 Andreas Hadjivasiliou, Evaluate Pharma Orphan Drug Report
2017, 4th Edition, February 2017
 Global Genes, Allies in Rare Disease. (2015). RARE Diseases: Facts
and Statistics. Retrieved from https://globalgenes.org/rare-
diseases-facts-statistics.
 Aronson J. Rare diseases and orphan drugs. Br J Clin Pharmacol.
61(3): 243-245
 Shire. (2013). Rare Disease Impact Report: Insights from patients
and the medical community. Retrieved from
https://globalgenes.org/wp-
content/uploads/2013/04/ShireReport-1.pdf
 Gammie, T., Lu, C. Y., & Babar, Z. U. (2015). Access to Orphan
Drugs: A Comprehensive Review of Legislations, Regulations and
Policies in 35 Countries. PLoS One, 10(10), 1-24

39. THANK YOU