CHM496: Federal Regulatory Affairs: From Discovery to Approval Student Project Choice 3

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CHM496 Federal Regulatory Affairs From
Discovery to Approval Student Project Choice 3

• Pamela Rizos
• 16-Nov-2004

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L-001234567 PR-Virasefor Treatment of Early
Exposures to HIV and Post Inhalation of
AnthraxGeneral Development and Approval
Strategy
PR Pharma Restricted Confidential

• Pamela Rizos
• November 16, 2004

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Overview
PR Pharma Restricted Confidential

• Background / Commercial Value
• Probability of Success
• Regulatory Strategy Areas of Serious, Unmet
  Medical Need
• Showing Safety And Efficacy to Gain FDA Approval
• Target Timeline
• Budget and Resource Requirements
• Conclusion and Recommendation

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Background / Commercial Value
PR Pharma Restricted Confidential

• HIV (Human Immunodeficiency Virus)
• In the US, the estimated number of
• -adults and children living with HIV/AIDS, end
  of 2003950,000
• -deaths, 2003 14,000
• -total deaths of persons with AIDS 501,669
  (496,354 adults and adolescents and 5,315
  children under age 15)
• Globally
• -the number of people living with HIV grew from
  35 million in 2001 to 38 million in 2003.
• -In 2003 alone, 3 million were killed by AIDS

• High Market Value for HIV

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Background / Commercial Value

• Anthrax (Acute Infectious disease caused by
  Bacillus anthracis)
• B. anthracis predominantly a cause of livestock
  disease
• NIAID 236 cases reported between 1955 and 1999
  ( 5 per year)
• Anthrax is a top choice for use as a biological
  warfare agent
• spores remain dangerous for decades
• spores can be processed to become easily airborne
  
• can be produced in large quantities with basic
  technology
• Anthrax was used as a biological weapon in the US
  (AVIP)
• Delivering anthrax was a simple as putting it in
  an envelope and dropping it in the mail
• 7 confirmed and 4 possible cases of cutaneous
  anthrax, all survived
• 11 people contracted inhalational anthrax, 5 died
  
• Emergency Preparedness and Response Strategic
  National Stockpile
• 1999 DHHS CDC established the National
  Pharmaceutical Stockpile,
• which will supply large quantities of medical
  material to states during an emergency within 12
  hours of the federal decision to deploy
• 2003NPS became SNS managed jointly by DHS and
  HHS
• Material stock is rotated and kept within potency
  shelf life limits

• There is also a market for anthrax

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Probability of Success (Scientific Feasibility)
PR Pharma Restricted Confidential

• Promising Compound for both Anthrax and HIV
• Low toxicity
• Contains functional groups that are known to be
  highly anti-resistant to HIV isolates that show
  resistance to currently approved drugs
• Based on the structure of the anthrax toxin, the
  candidate has high potential for the desired
  interference with active sites
• Emerging Data that Earlier Treatment of HIV
  infection Is More Beneficial
• Past Believed that ART should start at gt200
  CD4 cells/uL
• Drug Toxicities were of special concern because
  long-term clinical consequences were unknown
• Fear of Exhaustion of therapeutic options if
  start too early
• Today Emerging data that ART should start at
  gt350 CD4 cells/uL
• Risk of new opportunistic infection or death is
  lower when start ART earlier
• There are newer and safer drugs that are less
  toxic
• Difficult to exhaust therapeutic options as there
  are a lot more approved drugs
• Reduction of sexual transmission

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Regulatory Strategy
PR Pharma Restricted Confidential

• PRIORITY Primary Indication HIV, Secondary
  Indication Anthrax
• Fast Track Drug Development for Both indications
• Designation based on serious and unmet medical
  need
• Serious HIV and anthrax both serious , drug
  intended to affect serious aspects of each (HIV-
  prevention of opportunistic infection or death,
  Anthrax-Survival)
• Unmet Other drugs are available for both
  indications, L-001234567 has possible improved
  benefits (lower toxicity, higher viral
  anti-resistance)
• Will demonstrate drugs potential through
  pharmacologic and animal model data
• 1-Accelerated approval Approval based on
  surrogate endpoints
• HIV HIV-1 RNA and CD4 levels
• Anthrax Bacterial levels in the rhesus monkey
• 2-Priority review Products regulated by CDER are
  eligible if they provide a significant
  improvement compared to marketed products in the
  treatment of disease
• L-001234567, PR-Virase is less toxic and highly
  anti-resistant to HIV-1 mutants
• 3-Rolling Submission Portions of the marketing
  application are accepted for review prior to the
  complete application
• Meetings with the FDA Earlier and More Frequent
  (pre-IND, EOP1, EOP2, pre-NDA, Labeling)

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Showing Safety and Efficacy for HIV
PR Pharma Restricted Confidential

• Pre-Clinical
• In-Vitro Activity and Resistance Studies
• Animal Studies
• Single and repeat dose toxicity studies in rats,
  mice, dogs
• Pre-carcinogenicity and reproductive toxicity
  studies
• Phase I Healthy Subjects Safety and
  Pharmacokinetic Studies
• Single Dose and Multiple Dose
• Phase II Dose- Finding/ Efficacy Studies (In
  Order to Accelerate Limited Ph II program- 3
  studies)
• Two Studies in Therapy- Naïve patients250-500
  subjects of gt 350 CD4 cells/ uL will be
  randomized to receive either PR-virase 200 mg,
  400 mg, 600mg once daily and/or another currently
  approved drug. This study will also provide
  initial data on drug-drug interaction and
  evaluate monotherapy and combination therapy.
• A smaller Ph II study may be conducted in
  treatment-experienced subjects.
• These studies will support dose selection for Ph
  III
• A rollover study may be conducted to collect long
  term safety data

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Showing Safety and Efficacy for HIV
PR Pharma Restricted Confidential

• Phase III
• Several (3-5) Ph III studies will be conducted
  and will consist of 100-1,000 patients (Two of
  the studies will be relatively small 100-300).
• Data will be collected for 24-48 weeks (24 week
  FDA guidance) and safety and Efficacy Will be
  Based On Surrogate markers
• These studies will be randomized,
  multinationalized, open-label or double blind,
  active controlled.
• Several drug-drug interaction studies
• Phase IV (Post marketing) TBD

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Showing Safety and Efficacy for Anthrax
PR Pharma Restricted Confidential

• Pre-clinical Toxicology data required (animal
  toxicity in at least two species)
• These studies will be already completed (for the
  HIV indication)
• In Vitro Microbiology data
• Several strains and multiple isolates will be
  tested
• Testing will be done in 2-3 labs ?
  reproducibility
• Cipro, doxycycline and penicillin-G will be used
  as control drugs
• Clinical studies of inhalational anthrax cannot
  be performed in humans as one cannot ethically
  intentionally expose patients to B. anthracis
• The rhesus monkey model Applicable to the human
  disease
• The study of the human disease that resulted from
  the 1979 outbreak in Sverdlovsk has provided an
  understanding of anthrax that demonstrates that
  the rhesus monkey model is a relevant animal
  model of this disease.
• End Points include survival, bacterial levels at
  different time intervals and microbial burden in
  infected organs and tissues collected at the time
  of necropsy.
• 50-70 moneys in 5-7 groups
• After exposure, animals observed for 3 months
• FDA Priority given to those products already
  approved and have had extensive use

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Target Timeline
PR Pharma Restricted Confidential
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Estimated Budget and Resource Requirements
PR Pharma Restricted Confidential
Budget Manpower
Discovery/Basic Research   30
Biological Screening 140,000,000  
Synthesis 140,000,000  
Preclinical   50
Toxicology/Safety 90,000,000  
Pharmaceutical Dosage Formulation 100,000,000  
Clinical Trials for HIV   150
Ph I, II, III 500,000,000  
Ph IV 140,000,000  
Animal Model Studies for Anthrax 200,000,000 30
Process Development for Manufacturing and QC 120,000,000 75
Regulatory IND, NDA 80,000,000 20
Bioavailability 30,600,000 10
Other 130,000,000 50
Total Estimated Budget Requirements 1,670,600,000 415
1.7 Billion 400

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Conclusions and Recommendations
PR Pharma Restricted Confidential

• Program should be pushed forward through the
  developmental and regulatory fast track for both
  indications with higher priority (in terms of
  efforts and resources) given to the HIV
  indication
• If data does not look promising for the HIV
  indication, the anthrax indication should still
  be pursued
• Orphan Drug Status
• Tax incentives
• 7 year exclusivity
• Meanwhile RD investigation of other possible
  indications

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References

• Application Number 19-537/ S038 (CIPRO)
  approval letter, medical review
• Application Number 2-567 (REYATAZ) approval
  letter ,medical review, microbiology review,
  administrative documents, approved labeling
• Buckheit, R, Specialized Anti-HIV Testing
  Expediting Pre-Clinical Drug Development, Drug
  Information Journal, 19973113
• Chuang-Stein, C, DeMasi R, Surrogate Endpoints in
  Aids Drug Development Current Status. Drug
  Information Journal, 199832439
• Cocchetto, D, The Evolving Paradigm for Clinical
  Development and Regulatory Approval of the
  Antiretroviral Drugs In the United States. Drug
  Information Journal, 199933357
• Code of Federal Regulations 21CFR312, 314
• FDA Guidance for Industry Inhalational Anthrax
  (Post- Exposure)- Developing Antimicrobial Drugs
• FDA Guidance for Industry Fast Track Drug
  Development Programs- Designation, Development,
  and Application Review
• Hammer S, Use of Surrogate Versus Clinical
  Markers in Trials for HIV Infection. Drug
  Information Journal, 1999 33374
• Holmberg, S, Pallela, F, Lichtenstein, K, Havlir,
  D, The Case for Earlier Treatment of HIV
  Infection. Clinical Infectious Diseases,
  2004391699
• Meadows, Michelle. The FDA and the Fight Against
  terrorism. FDA Consumer magazine, 2004 Jan-Feb.
• Meyerfoff, A, Albrecht R, Meyer J, Dionne, P,
  Higgins, K, Murphy D, US Food and Drug
  Administration Approval of Ciprofloxacin
  Hydrochloride for Management of Postexposure
  Inhalational Anthrax. Clinical infectious
  Diseases, 200439303
• Milne, CP, Bergman, E, Fast Track Product
  Designation Under the Food and Drug
  Administration Modernization Act The Industry
  Experience. Drug Information Journal, 2001 3571
• National Institute of Allergy and Infectious
  Disease Factsheet on Anthrax (www.niaid.nih.gov/fa
  ctsheets/anthrax.html)
• Physicians Desk Reference
• UNAIDS/WHO Epidemiological Fact Sheet Update
  United States of America, 2004
• www.anthrax.osd.mil/threat/default.asp
• www.bt.cdc.gov/stockpile
• www.fda.gov

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Thank you for your attention!

• ?Questions?