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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 l.jpg

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

Pamela Rizos

16-Nov-2004


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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


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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


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PR

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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


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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

      • 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


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PR

Pharma

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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


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    PR

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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)


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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


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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


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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


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    Target Timeline


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    PR

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    Estimated Budget and Resource Requirements


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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


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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, 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



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