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CHM496: Federal Regulatory Affairs: From Discovery to Approval Student Project Choice 3. Pamela Rizos 16-Nov-2004. PR Pharma Restricted Confidential. L-001234567 PR-Virase for Treatment of Early Exposures to HIV and Post Inhalation of Anthrax General Development and Approval Strategy.

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chm496 federal regulatory affairs from discovery to approval student project choice 3

CHM496: Federal Regulatory Affairs: From Discovery to ApprovalStudent Project Choice 3

Pamela Rizos

16-Nov-2004

slide2

PR

Pharma

Restricted

Confidential

L-001234567 PR-Virasefor Treatment of Early Exposures to HIV and Post Inhalation of AnthraxGeneralDevelopment andApproval Strategy

Pamela Rizos

November 16, 2004

overview

PR

Pharma

Restricted

Confidential

Overview
  • 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
background commercial value

PR

Pharma

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Background / Commercial Value
  • HIV (Human Immunodeficiency Virus)
    • In the US, the estimated number of

-adults and children living with HIV/AIDS, end of 2003:950,000

-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
slide5

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

      • 2003:NPS 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
probability of success scientific feasibility

PR

Pharma

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Confidential

Probability of Success (Scientific Feasibility):
  • 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 >200 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 >350 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
regulatory strategy

PR

Pharma

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Regulatory Strategy
  • 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 drug’s 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)
showing safety and efficacy for hiv

PR

Pharma

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Showing Safety and Efficacy for HIV
  • 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 patients:~250-500 subjects of > 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
showing safety and efficacy for hiv9

PR

Pharma

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Showing Safety and Efficacy for HIV
  • 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
showing safety and efficacy for anthrax

PR

Pharma

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Showing Safety and Efficacy for Anthrax
  • 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
target timeline

PR

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Target Timeline
conclusions and recommendations

PR

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Conclusions and Recommendations
  • 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: R&D investigation of other possible indications
references
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, 1997:31:13
  • Chuang-Stein, C, DeMasi R, Surrogate Endpoints in Aids Drug Development: Current Status. Drug Information Journal, 1998:32:439
  • Cocchetto, D, The Evolving Paradigm for Clinical Development and Regulatory Approval of the Antiretroviral Drugs In the United States. Drug Information Journal, 1999:33:357
  • 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: 33:374
  • Holmberg, S, Pallela, F, Lichtenstein, K, Havlir, D, The Case for Earlier Treatment of HIV Infection. Clinical Infectious Diseases, 2004:39:1699
  • 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, 2004:39:303
  • Milne, CP, Bergman, E, Fast Track Product Designation Under the Food and Drug Administration Modernization Act: The Industry Experience. Drug Information Journal, 2001: 35:71
  • National Institute of Allergy and Infectious Disease Factsheet on Anthrax (www.niaid.nih.gov/factsheets/anthrax.html)
  • Physician’s 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
  • www.hhs.gov/news/press/2001press/20011010a.html