This document summarizes an MMS Expert Insights webinar on rare disease research in the United States. The webinar discusses challenges in rare disease research such as limited patient populations and understanding of diseases. It provides an overview of the regulatory history around orphan drugs and incentives in the US. It also discusses how the FDA flexibly applies regulatory standards for rare disease drug development, including allowing single efficacy studies, modified clinical trial designs, and use of existing data in some cases.

1. MMS Expert Insights Webinars
Rare Disease Series
1

2. Introduction
Dr. Uma Sharma, Chief Scientific Officer & Founder

3. Industry Perspectives

4. MMS Expert Insights Webinars
The Expert Insights webinar series offers learning opportunities
related to current industry trends, best practices and emerging areas
or innovations occurring in the pharmaceutical, biotechnology, and
medical device industries.
Rare Disease Series
• Today’s Webinar: Rare Disease Research in the United States:
Understanding FDA Guidance and Flexibility in the Application
of Regulatory Standards
• Second Installation: [August 31, 2021 at 2 PM EST]
• Upcoming Webinar: Orphan Drug, Rare Pediatric Disease,
and Expedited Program Designations: FDA Incentives to
Promote Rare Disease Drug Development
[October 6, 2021]
FDA Orphan Drug Designation Applications Whitepaper
Quick registration at:
mmsholdings.com/webinars
“Our leadership supports continuous
learning of our colleagues and
increased engagement with our
sponsor partners.”
Pictured: Mohamad Zahreddine, CIO

5. Rare Disease Research in the United States:
Understanding FDA Guidance and Flexibility in the Application of
Regulatory Standards
5

6. 6
Our Presenters
Amanda Beaster
Senior Global Regulatory
Affairs
Ben Kaspar
Senior Manager
Regulatory Strategy

7. 7
Topics for Discussion
Challenges in Rare Disease Research
Legal Framework for Rare Disease Research
Flexible Application of Regulatory Standards
A Path Forward in Ultra-Rare Diseases

8. Challenges in Rare Disease Research
8

9. 9
Rare Disease or Condition
The Orphan Drug Act (ODA) generally defines a rare disease or
condition as one affecting:
• Fewer than 200,000 people in the United States
• More than 200,000 in the United States and for which there is no
reasonable expectation that the cost of developing and making
available in the United States a drug for such disease or condition
will be recovered from sales in the United States of such drug
For more about Orphan Drug Designation and Expedited Development,
join us for the next webinar in this series…

10. 10
Challenges of Rare Disease Programs
• Scientific Data
– Pathogenesis and Pathophysiology
– Natural History
– Genotypic and Phenotypic
Variations
• Regulatory Standards
Inconsistent global
definitions and standards
Limited patient population
to enroll in clinical trials
Limited understanding of
the disease or condition
Limited funds/resources
especially during initial studies

11. 11
Challenges of Rare Disease Programs
Inconsistent global
definitions and standards
Limited patient population
to enroll in clinical trials
Limited understanding of
the disease or condition
Limited funds/resources
especially during initial studies
• Age of patient population
• Severity of disease
• Lack of alternative therapeutics

12. 12
Challenges of Rare Disease Programs
Inconsistent global
definitions and standards
Limited patient population
to enroll in clinical trials
Limited understanding of
the disease or condition
Limited funds/resources
especially during initial studies
• Limited funding
• Limited resources
• Limited experience

13. 13
Challenges of Rare Disease Programs
Inconsistent global
definitions and standards
Limited patient population
to enroll in clinical trials
Limited understanding of
the disease or condition
Limited funds/resources
especially during initial studies
• Terminology
• Prevalence thresholds
• Other requirements and
Benefits of Orphan Drug
Designation

14. Legal Framework for Rare Disease Research
14

15. 15
Regulatory History in the US
*The Office of Orphan Products Development (OOPD) Designation Program
**The OOPD Grant Program
OrphanDrugAct; OOPD;
OrphanDrugDesignation
Program;Clinical Trial
Grant Program**
1983
1990
Humanitarian
Use Device*
Orphan Drug
Proposed Rule of
January 29
1991
1992
Orphan Drug Final
Rule of December 29;
Orphan Drug Regulation:
Codified: 21 CFR part 316
2011
Orphan Drug
Proposed Rule of
October 19
Rare Pediatric
Disease*
2012
Pediatric Device
Consortia**
2009
2013
Orphan Drug
Final Rule of
June 12
Natural History
Grant Program**
2016
2017
Orphan Drug
Modernization
Plan
CDER Rare
Disease Cures
Accelerator
2019
1963
Kefauver-
Harris
Amendments
2020
Orphan Drug
Technology
Modernization
Effort;
CDER NextGen
Portal

16. 16
Regulatory History in the US
*The Office of Orphan Products Development (OOPD) Designation Program
**The OOPD Grant Program
OrphanDrugAct; OOPD;
OrphanDrugDesignation
Program;Clinical Trial
Grant Program**
1983
1990
Humanitarian
Use Device*
Orphan Drug
Proposed Rule of
January 29
1991
1992
Orphan Drug Final
Rule of December 29;
Orphan Drug Regulation:
Codified: 21 CFR part 316
2011
Orphan Drug
Proposed Rule of
October 19
Rare Pediatric
Disease*
2012
Pediatric Device
Consortia**
2009
2013
Orphan Drug
Final Rule of
June 12
Natural History
Grant Program**
2016
2017
Orphan Drug
Modernization
Plan
CDER Rare
Disease Cures
Accelerator
2019
1963
Kefauver-
Harris
Amendments
2020
Orphan Drug
Technology
Modernization
Effort;
CDER NextGen
Portal

17. 17
Regulatory History in the US
*The Office of Orphan Products Development (OOPD) Designation Program
**The OOPD Grant Program
OrphanDrugAct; OOPD;
OrphanDrugDesignation
Program;Clinical Trial
Grant Program**
1983
1990
Humanitarian
Use Device*
Orphan Drug
Proposed Rule of
January 29
1991
1992
Orphan Drug Final
Rule of December 29;
Orphan Drug Regulation:
Codified: 21 CFR part 316
2011
Orphan Drug
Proposed Rule of
October 19
Rare Pediatric
Disease*
2012
Pediatric Device
Consortia**
2009
2013
Orphan Drug
Final Rule of
June 12
Natural History
Grant Program**
2016
2017
Orphan Drug
Modernization
Plan
CDER Rare
Disease Cures
Accelerator
2019
1963
Kefauver-
Harris
Amendments
2020
Orphan Drug
Technology
Modernization
Effort;
CDER NextGen
Portal

18. 18
Regulatory History in the US
*The Office of Orphan Products Development (OOPD) Designation Program
**The OOPD Grant Program
OrphanDrugAct; OOPD;
OrphanDrugDesignation
Program;Clinical Trial
Grant Program**
1983
1990
Humanitarian
Use Device*
Orphan Drug
Proposed Rule of
January 29
1991
1992
Orphan Drug Final
Rule of December 29;
Orphan Drug Regulation:
Codified: 21 CFR part 316
Pediatric Device
Consortia**
2009
Natural History
Grant Program**
2016
2017
Orphan Drug
Modernization
Plan
CDER Rare
Disease Cures
Accelerator
2019
1963
Kefauver-
Harris
Amendments
2011
Orphan Drug
Proposed Rule of
October 19
Rare Pediatric
Disease*
2012
2013
Orphan Drug
Final Rule of
June 12
2020
Orphan Drug
Technology
Modernization
Effort;
CDER NextGen
Portal

19. 19
Regulatory History in the US
*The Office of Orphan Products Development (OOPD) Designation Program
**The OOPD Grant Program
OrphanDrugAct; OOPD;
OrphanDrugDesignation
Program;Clinical Trial
Grant Program**
1983
2020
Orphan Drug
Technology
Modernization
Effort;
CDER NextGen
Portal
1990
Humanitarian
Use Device*
Orphan Drug
Proposed Rule of
January 29
1991
1992
Orphan Drug Final
Rule of December 29;
Orphan Drug Regulation:
Codified: 21 CFR part 316
2011
Orphan Drug
Proposed Rule of
October 19
Rare Pediatric
Disease*
2012
Pediatric Device
Consortia**
2009
2013
Orphan Drug
Final Rule of
June 12
Natural History
Grant Program**
2016
2017
Orphan Drug
Modernization
Plan
CDER Rare
Disease Cures
Accelerator
2019
1963
Kefauver-
Harris
Amendments

20. 20
The ODA Expands the Range of the Law, but Doesn’t Change the
Law
The ODA does not create a statutory standard for the approval of
orphan drugs that is different from standard approval
• Substantial evidence of the drug’s effectiveness for its intended use
(from adequate and well-controlled studies)
• Sufficient information to conclude that the drug is safe for use under
the conditions prescribed, recommended, or suggested in the
proposed labeling

21. 21
Case Study: CDER Novel Orphan Drug Approvals in 2020
Drug
Designation Priority
Review
Approval
Pathway
FT BT
artesunate yes yes yes Traditional
Ayvakit™ yes yes yes Traditional
Blenrep® no yes yes Accelerated
Danyelza® no yes yes Accelerated
Detectnet™ yes no yes Accelerated
Dojolvi® yes no no Traditional
Ebanga™ no yes yes Traditional
Enspryng™ yes yes no Traditional
Evrysdi® yes no yes Traditional
Gavreto® no yes yes Accelerated
Imcivree™ no yes yes Traditional
Inmazeb™ no yes yes Traditional
Inoqovi® no no yes Traditional
Isturisa® no no no Traditional
Koselugo® no yes yes Traditional
Lampit® no no yes Accelerated
Drug
Designations Priority
Review
Approval
Pathway
FT BT
Mojuvi® yes yes yes Accelerated
Orladeyo™ yes no no Traditional
Oxlumo™ no yes yes Traditional
Pemazyre® no yes yes Accelerated
Qinlock® yes yes yes Traditional
Retevmo® no yes yes Accelerated
Sarclisa® no no no Traditional
Tabrecta® no yes yes Accelerated
Tazverik® no no yes Accelerated
Tepezza® yes yes yes Traditional
Tukysa® yes yes yes Traditional
Uplizna® no yes no Traditional
Viltepso® yes no yes Accelerated
Zepzelca™ no no yes Accelerated
Zokinvy® no yes yes Traditional
Sarclisa® (isatuximab)
Isturisa® (osilodrostat)

22. What Does Change?
Therapeutic Context
The disease or condition to be
treated, the population intended
to be treated, and the benefits and
risks of current therapies
22
“An understanding of the
disease(s) or condition(s)
being treated or prevented
and the safety and
effectiveness of current
treatment options is critical
to many aspects of a new
drug review, including the
design of the clinical studies
and the interpretation of
the study results.”
- FDA Instructions for Completing
the NDA/BLA Multi-Disciplinary
Review and Evaluation

23. 23
What Does That Mean For Rare Disease Research?
• Flexible/broad application of regulatory standards
• Scientific judgment - 21 CFR 314.105(c)
• Innovative study designs are encouraged
– Adaptive and seamless trial designs
– Master protocols
– Modeling and simulations
– Real world data
– Other innovative methods

24. Case Study: Givlaari® (givosiran)
Reliance on a Single Adequate and Well-Controlled Efficacy Study to
Support Approval

25. Therapeutic Context and Pharmacology
• Disease: Acute Hepatic Porphyria
– Group of 4 genetic diseases due to increased aminolevulinic acid synthase 1
(ALAS1) activity which result in increased levels of neurotoxic heme intermediates
– Acute painful attacks and chronic symptoms
– Prevalence: 1 in 25,000
• Therapeutic Options: Panhematin® (hemin for injection)
– Approved for treatment of recurrent Acute intermittent porphyria (AIP) attacks
related to the menstrual cycle in affected women.
– Administered as an Infusion
• Drug: small interfering RNA or siRNA that inhibits ALAS1 activity

26. 26
Regulatory Status
• History:
– Orphan Drug Designation
– Breakthrough Therapy Designation
– Priority Review Designation
• Single, adequate and well controlled, multicenter trial in 94 patients
• Evidence of a treatment effect: estimated attack rate per 6 months (double-
blind treatment period) Givlaari: 2 attacks per patient; Placebo: 14 attacks
per patient (70% fewer porphyria attacks with treatment or approximately
10.4 fewer attacks per year)
• Other Benefits: SQ route of administration

27. 27
QUESTION:
What was the outcome and
how was it tied to the rarity of the disease?

28. 28
Outcome
• No Drug Advisory Committee Meeting or other external
consultations were required
• On November 20, 2019, the FDA granted approval for the treatment
of adult patients with acute hepatic porphyria
• Postmarketing Commitment: controlled trial in pediatric patients
(12-17 years old)

29. 29
KEY TAKEAWAY:
A combination of several factors, rather than simply
the rarity of the disease, allowed for reliance on a
single adequate and well-controlled efficacy study
to support approval.

30. Flexible Application of Regulatory Standards
30

31. FDA Flexibility and Scientific Judgment
Common Issues in Drug Development
• not specific to rare diseases
• frequently more difficult to address in the
context of a rare disease
31
“…flexibility extends from
the early stages of
development to the
design of adequate and
well-controlled studies
required to demonstrate
effectiveness to support
marketing approval and
to establish safety data
needed for the intended
use.”
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

32. Key Points and Areas of Flexibility
• Product Quality (CMC)
• Nonclinical Studies
• Existing Data
• Clinical Data
32
Flexible Application of
Regulatory Standards
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

33. Chemistry, Manufacturing and Controls (CMC)
Concurrent, stage appropriate development
• Changes to the manufacturing process and/or
formulation
• Type/extent of manufacturing information
• Late-stage modifications to manufacturing
procedures and purification methods.
33
Flexible Application of
Regulatory Standards:
Product Quality
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

34. Planned Formulation or Manufacturing Changes
Includes changes to
• drug substance manufacturing process
• drug product manufacturing process
• drug product formulation
34
Flexible Application of
Regulatory Standards:
Product Quality
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

35. Type and Extent of Manufacturing Information
5 factors FDA will consider include:
1.product characteristics
2.seriousness of condition / medical need
3.manufacturing processes
4.robustness of quality system
5.strength of risk-based quality assessment
35
Flexible Application of
Regulatory Standards:
Product Quality
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

36. Late-Stage Modifications
• To manufacturing procedures and purification
methods
• Change in responsibility
• Commercial scale up
36
Flexible Application of
Regulatory Standards:
Product Quality
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

37. Quality-by-Design (QbD) Principles
• Systematic approach to development
• Begins with predefined objectives
37
“The robustness of
the quality system
may facilitate
more flexible
regulatory
approaches.”
Pharmaceutical Development
Q8(R2)
FDA Guidance for Industry

38. Nonclinical Studies
• Support for safety of clinical investigations
• Scientific understanding of the drug
38
Flexible Application of
Regulatory Standards:
Nonclinical
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

39. Nonclinical Flexibility
“…it is appropriate to exercise the broadest
flexibility in applying the statutory
standards, while preserving appropriate
guarantees for safety and effectiveness.”
-21 CFR 312.80
39
Flexible Application of
Regulatory Standards:
Nonclinical
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

40. Nonclinical Flexibility
Factors Considered:
• Pharmacological and chemical characteristics
• Proposed study design and objectives
• Anticipated risks to humans
• Existing data
40
Flexible Application of
Regulatory Standards:
Nonclinical
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

41. Relevance of Existing Data
• Drug product constituents
• Dosage form
• Route of administration
• Dose levels
• Dosing regimen
41
Flexible Application of
Regulatory Standards:
Existing Data
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

42. Case Study: Kineret® (anakinra)
Label expansion is a common route for approval in rare indications

43. Case Study: Kineret® (anakinra): Therapeutic Context and
Pharmacology
• Diseases
– Neonatal-Onset Multisystem Inflammatory Disease (NOMID)
• a life-long and severely debilitating disease associated with an overproduction of
Interleukin-1 (IL-1)
• Prevalence: very rare ~100 known cases globally
– Deficiency of Interleukin-1 Receptor Antagonist (DIRA)
• caused by a genetic mutation in the gene encoding the IL-1 receptor antagonist
protein.
• autoinflammatory disease that can an occur in the first weeks of life and may be fatal
• Prevalence: very rare, more common in NW Puerto Rico (1 in 6300 in that region)
• Therapeutic Options: no adequate therapy; supportive care only
• Drug: interleukin-1 or IL-1 receptor antagonist

44. 44
Regulatory Status
• History:
– Orphan Drug Designation
– Breakthrough Therapy Designation
– Priority Review Designation
• Long-term open-label study in 43 NOMID patients
• Long-term natural history study in 9 DIRA patients

45. 45
QUESTION:
What was the outcome and
how was it tied to the rarity of the disease?

46. 46
Outcome
• No Drug Advisory Committee Meeting or other external
consultations were required
• In 2012, the FDA granted approval for neonatal-onset multisystem
inflammatory disease (NOMID)
• In 2020, the FDA granted approval for deficiency of IL-1 receptor
antagonist (DIRA)
• No Postmarketing Commitments/Requirements

47. 47
KEY TAKEAWAY:
Existing data should be carefully evaluated to
determine the feasibility for supporting subsequent
label expansion, which may reduce overall effort
and expedite approval.

48. Clinical Development
• Endpoint Selection
• Evidence of Safety and Effectiveness
• Natural History
48
Flexible Application of
Regulatory Standards:
Clinical
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

49. Clinical Trial Endpoint Selection
49
Flexible Application of
Regulatory Standards:
Clinical
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

50. Clinical Trial Endpoint Selection
50
Exploratory
Clinical Evidence
Flexible Application of
Regulatory Standards:
Clinical
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

51. Clinical Trial Endpoint Selection
51
Exploratory
Clinical Evidence
Clinical Outcomes
vs Surrogate
Endpoints
Flexible Application of
Regulatory Standards:
Clinical
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

52. Clinical Trial Endpoint Selection
52
Exploratory
Clinical Evidence
Clinical Outcomes
vs Surrogate
Endpoints
Minimization of
Bias and Improve
Utility
Flexible Application of
Regulatory Standards:
Clinical
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

53. Clinical Trial Endpoint Selection
53
Exploratory
Clinical Evidence
Clinical Outcomes
vs Surrogate
Endpoints
Minimization of
Bias and Improve
Utility
Development of
Novel Endpoints
Flexible Application of
Regulatory Standards:
Clinical
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

54. Clinical Trial Endpoint Selection
54
Exploratory
Clinical Evidence
Clinical Outcomes
vs Surrogate
Endpoints
Minimization of
Bias and Improve
Utility
Development of
Novel Endpoints
Full Range of
Patients
Flexible Application of
Regulatory Standards:
Clinical
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

55. Case Study: Oxlumo® (lumasiran)
FDA Agreed to Full Approval Based on Evaluation of a Surrogate Endpoint

56. Therapeutic Context and Pharmacology
• Disease: Primary hyperoxaluria type 1 (PH1)
– In both pediatric and adult patients
• Inherited deficiency of the liver enzyme alanine-glyoxylate aminotransferase
or AGT
• Causes recurrent kidney stones and loss of kidney function.
• As kidney function declines, oxalate deposits in other tissues, leading to
arrhythmias and cardiac arrest, gangrene, bone/joint pain and fractures, and
blindness.
• Prevalence: 1 in 58,000
• Therapeutic Options: liver transplant; supportive care only
• Drug: a synthetic, double-stranded small interfering RNA or siRNA that inhibits the
messenger RNA of the hydroxyacid oxidase 1 gene

57. 57
Regulatory Status
• History:
– Orphan Drug Designation
– Breakthrough Therapy Designation
– Priority Review Designation
• Double-blind placebo controlled trial in 39 patients (≥6 years of age)
– Large treatment effect; substantial decrease in urinary oxalate at
Month 6 and urinary oxalate excretion normalized in ~half of
patients treated with Oxlumo
• Single-arm trial in 18 patients (<6 years of age)
– Scientific and clinical justification for use of a surrogate endpoint

58. 58
QUESTION:
What was the outcome and
how was it tied to the rarity of the disease?

59. 59
Outcome
• No Drug Advisory Committee Meeting or other external
consultations were required
• In 2020, the FDA granted approval for PH1
• Rare Pediatric Disease Priority Review Voucher Program
• No Postmarketing Commitments/Requirements

60. 60
KEY TAKEAWAY:
This case study highlights how essential endpoint
selection is and the FDA’s willingness to set
attainable standards in the context of a rare disease
population.

61. Clinical Evidence of Safety and Effectiveness
61
Flexible Application of
Regulatory Standards:
Clinical
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

62. Clinical Evidence of Safety and Effectiveness
62
Adequate and
Well-Controlled
Investigations
Flexible Application of
Regulatory Standards:
Clinical
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

63. Clinical Evidence of Safety and Effectiveness
63
Adequate and
Well-Controlled
Investigations
Historical
(External) Controls
Flexible Application of
Regulatory Standards:
Clinical
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

64. Clinical Evidence of Safety and Effectiveness
64
Adequate and
Well-Controlled
Investigations
Historical
(External) Controls
Early
Randomization
When Feasible
Flexible Application of
Regulatory Standards:
Clinical
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

65. Clinical Evidence of Safety and Effectiveness
65
Adequate and
Well-Controlled
Investigations
Historical
(External) Controls
Early
Randomization
When Feasible
Feasible and
Sufficient Safety
Assessment
Flexible Application of
Regulatory Standards:
Clinical
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry

66. Natural History Studies
66
• “Natural History” - disease course in the
absence of intervention
• “Natural History Study” - patients may be
receiving the current standard of care and/or
emergent care
Flexible Application of
Regulatory Standards:
Clinical
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry
Natural History Studies for
Drug Development
FDA Guidance for Industry

67. Benefit and Use of Natural History
67
• Define the disease
• Identify the patient population
• Selection of endpoints
• Recognition of safety concerns
• Identify critical elements in clinical trial design
Flexible Application of
Regulatory Standards:
Clinical
Rare Diseases:
Common Issues in Drug Development
FDA Guidance for Industry
Natural History Studies for
Drug Development
FDA Guidance for Industry

68. Case Study: Zokinvy® (Lonafarnib)
Utilized a Natural History Study as an External Historical Control

69. Therapeutic Context and Pharmacology
• Disease:
– Hutchinson-Gilford Progeria syndome (HGPS): 1 in 4 million births
– Processing-deficient progeroid laminopathies (PL): fewer than 1 in
25 million
– Serious genetic diseases that cause premature aging and death.
– Accelerated cardiovascular disease from the buildup of defective
progerin or progerin-like protein in cells.
– Many patients die before 15 from heart failure, heart attack or stroke.
• Therapeutic Options: supportive care and symptom management
• Drug: a first – in-class farnesyltransferase inhibitor

70. 70
Regulatory Status
• History:
– Orphan Drug Designation
– Breakthrough Therapy Designation
– Priority Review Designation
• 62 HGPS patients from 2 single-arm trials that were compared to matched, untreated
patients.
• A contemporaneously well-matched untreated cohort from a separate natural history
study.
• One processing-deficient PL patient was included in the treatment group, and this
patient had no matched control.
• Evidence of a treatment effect: Confirmatory evidence from mechanistic studies

71. 71
QUESTION:
What was the outcome and
how was it tied to the rarity of the disease?

72. 72
Outcome
• No Drug Advisory Committee Meeting or other external
consultations were required
• On November 20, 2020, the FDA granted approval for the treatment
HGPS and certain PL in patients ≥1 year of age
• Rare Pediatric Disease Priority Review Voucher Program
• Postmarketing Commitment: requirement for a new thorough QT
study, a carcinogenicity study, and a CYP2C9 drug-drug interaction
study.

73. 73
KEY TAKEAWAY:
Relying on a natural history study as an external
controls may be acceptable when it is not feasible
or ethical to use an internal control, particularly in
rare disease populations.

74. Human Gene Therapy Products
Effect mediated by transcription/translation of transferred
genetic material or by altering human genetic sequences:
• nucleic acids
• genetically modified microorganisms
• engineered site-specific nucleases
• ex vivo genetically modified human cells
74
74
Flexible Application of
Regulatory Standards:
Human Gene Therapy
“…seeks to modify or
manipulate the expression of
a gene or to alter the
biological properties of living
cells for therapeutic use”
Human Gene Therapy for Rare Diseases
FDA Guidance for Industry

75. Chemistry, manufacturing and controls
(CMC) considerations
75
• Importance of well-controlled manufacturing process
and suitable analytical assays
• Innovative strategies for understanding critical quality
attributes
• Early discussion of product-specific considerations
Flexible Application of
Regulatory Standards:
Human Gene Therapy
Human Gene Therapy for Rare Diseases
FDA Guidance for Industry

76. Preclinical Program for Gene Therapy
76
• Overall objectives include
– Identify a biologically active dose range
– Dose justification
– Establish feasibility / reasonable safety of the
route of administration
– Define/support patient eligibility criteria
– Identify potential toxicities/ monitoring needs
– Identify prospect of direct (pediatric FIH)
Flexible Application of
Regulatory Standards:
Human Gene Therapy
Human Gene Therapy for Rare Diseases
FDA Guidance for Industry

77. Gene Therapy Clinical Considerations
77
• Selection of the study population
• Study Design
• Dose Selection
• Safety Considerations
• Efficacy Endpoints
• Patient experience data
Flexible Application of
Regulatory Standards:
Human Gene Therapy
Human Gene Therapy for Rare Diseases
FDA Guidance for Industry

78. Gene Therapy Agency Interactions
FDA recommends communication with OTAT - early in
product development, before submission of an IND.
• Pre-IND meetings prior to submission of the IND and
• INitial Targeted Engagement for Regulatory Advice on
CBER producTs (INTERACT) meetings,
78
“An INTERACT meeting is…
intended for innovative
investigational products
that introduce unique
challenges due to the
unknown safety profiles
resulting from the use of
complex manufacturing
technologies, development
of innovative devices, or
cutting-edge testing
methodologies.”
78
Human Gene Therapy for Rare Diseases
FDA Guidance for Industry

79. A Path Forward for Ultra-Rare Disease Research
79

80. FDA Guidance for Ultra- and Uber-Rare Diseases
• Nonclinical Testing of Individualized Antisense
Oligonucleotide Drug Products for Severely
Debilitating or Life-Threatening Diseases - Guidance
for Sponsor-Investigators
– Abbreviated nonclinical assessments specific to
AOS treatment in rare SDLT disease
“to describe the nonclinical
information that FDA
recommends to
support an investigational
new drug application (IND)
for an antisense
oligonucleotide being
developed to treat a
severely debilitating or life-
threatening (SDLT) disease
caused by a unique
genetic variant where only a
small number of individuals
are prospectively identified
(usually one or two).”

81. FDA Guidance for Ultra- and Uber-Rare Diseases
• Nonclinical Testing of Individualized Antisense
Oligonucleotide Drug Products for Severely
Debilitating or Life-Threatening Diseases - Guidance
for Sponsor-Investigators
– Abbreviated nonclinical assessments specific to
AOS treatment in rare SDLT disease
• Developing Targeted Therapies in Low-Frequency
Molecular Subsets of a Disease Guidance for Industry
– Recommendations on how to group patients in
clinical trials
– Evaluating the benefits and risks of targeted
therapies
“Many clinically defined
diseases are caused by a
range of different molecular
alterations, some of which
may occur at low
frequencies, that impact
common proteins or
pathways involved in the
pathogenesis of diseases.”

82. Case Study: Milasen (TY777)
IND to test a brand-new drug created for a single patient

83. Therapeutic Context and Pharmacology
• Disease: Batten Disease
– Caused in part by insertion of a retrotransposon CLN7 gene
– A rare and fatal neurodegenerative disease
– Prevalence: identified in a single patient
• Therapeutic Options: supportive care
• Drug: antisense oligonucleotides that targets CNS tissue

84. 84
Regulatory Status
• History:
– Orphan Drug Designation
– Breakthrough Therapy Designation
– Priority Review Designation
• Single patient (6 year old girl) treated through expanded access
• Evidence of a treatment effect: reduction in seizures

85. 85
QUESTION:
What was the outcome and
how was it tied to the rarity of the disease?

86. 86
Outcome
• In January 2018, the FDA granted approval for expanded access
treatment of the rare form of Batten Disease caused in part by
insertion of a retrotransposon CLN7 gene

87. 87
KEY TAKEAWAY:
This study is an example of individualized genomic
medicine. A novel therapeutic agent for a patient
with a rare disease was able to be treated through
the expanded access program.

88. 88
Individualized Therapeutics
• CBEr
– Cell and gene therapy
– Phage therapy
• CDER
– Antisense oligonucleotide therapy
Facilitating End-to-End Development
of Individualized Therapeutics
-CBER Public Workshop
Platform Vector Gene
Therapy (PaVe-GT)
-NIH pilot project
Foundations and Research Hospitals

89. Key Takeaway
89

90. 90
Communication and Advance Planning is Key
• Talk to the Agency
• Get the necessary designations

91. MMS Expert Insights Webinars
The Expert Insights webinar series offers learning
opportunities related to current industry trends, best
practices and emerging areas or innovations occurring in the
pharmaceutical, biotechnology, and medical device industries.
Upcoming Webinars
• Orphan Drug, Rare Pediatric Disease, and
Expedited Program Designations: FDA Incentives to
Promote Rare Disease Drug Development [(DATE)]
• Webinar 3 - TC fu’d with Eric. [(DATE)]
FDA Orphan Drug Designation Applications Whitepaper
Quick registration at:
mmsholdings.com/webinars
“Our leadership supports continuous
learning of our colleagues and
increased engagement with our
sponsor partners.”
Pictured: Mohamad Zahreddine, CIO

92. Thank you!
Any questions?
visit
www.mmsholdings.com
email
media@mmsholdings.com

93. 93
Other Precedent Approvals and sources
• Small sample sizes
– Drug Trials Snapshots: XURIDEN | FDA (n =4)
– Estimating cumulative point prevalence of rare diseases: analysis
of the Orphanet database (nih.gov)
Rare-and-Ultra-Rare-Diseases-Prioritisation-and-
Sustainability_230221_FINAL.pdf (amrytpharma.com)