Target Product Profiles for Drug-Drug and Drug-Device MPT Products Joe Romano, Ph.D. NWJ Group, LLC Microbicide Trials Network November 3, 2011
Genesis of the Drug-Drug/Drug Device Working Group May 5, 2011 Think Tank USAID, CAMI, AVAC Think Tank Description of a TPP: How a proposed candidate product addresses critical attributes Outline framework for development via target specification range Why a TPP? To define attributes/parameters for MPT products with highest potential public health impact (i.e., prioritization) To Guide donor investment and sponsor development strategies Two working groups formed Drug-Drug/Drug Device Vaccines
Drug-Drug/Drug Device Working Group: P. Harrison (IC), M. Kerrigan (BMGF), J. Manning (USAID), J. Marrazzo (U Wash/MTN), J. Romano (NWJ/MTN), J. Turpin (NIAID/DAIDS) Development Strategies Product/ Technology Survey MPT TPP Beyond the Scope of the Initial Phase of this Effort Primary Deliverable: 1 st Pass: Critical Attributes and Appropriate Parameter Ranges for High Impact MPT Products to be Challenged by the Field* *Conceived as a first step in defining relevant MPT TPP
Initial TPP Development Process and Format: Critical Product Attributes and Parameter Ranges Critical Attribute Minimally Acceptable Preferred Critical Attribute Minimally Acceptable Preferred Indications Adherence Target Population Time to Market Administration Route R&D Costs Product Presentation Reversibility Dosage Form & Schedule Side Effects Efficacy IP Status Storage Conditions Access Potential Shelf Life Other Health Benefits Cost Packaging Disposal/Waste Contra-indications, warnings, precautions, use by preg/lact women
Can a Single TPP for Drug-Drug or Drug-Device MPT Products Be Built? Non- HC Anti- Microbial HC Pro-Biotic Anti- Viral Barrier Anti- Fungal HIV Chlamydia BV HSV Pregnancy Gonorrhea Candida HPV Syphilis Trichomonas Vaginal Film Vaginal Tablets Topical Daily Topical Peri-Coital Oral Tablet Vaginal Ring Non-IVR Device Vaginal Gel Systemic Sustained Topical Sustained Injectable Implantable Oral Daily Oral Peri- Coital
Working Group Approach: Address General Concepts (not specific product configurations) Build/populate alternative tables based on general product concepts (n=5) Other Survey Input Solicit expert review and comment (n= 8-14, R&D/provider/ user experts) Consolidate consensus views around concepts; capture outlier positions Report results for the next round of review
Table 1: Prioritization of Multipurpose Prevention Technology Indications Indication Description Magnitude of priority; public health impact in target populations; definition of most relevant target populations; other HIV Prevention/ Contraception HIV/STI Prevention STI Prevention/ Contraception Single product preventing HIV transmission/ pregnancy Single product preventing HIV/STI transmission Single product preventing STI transmission/ pregnancy Highest Priority: Highest potential for impact to prevent both pregnancy and HIV in low resource settings Medium Priority, determined largely by the specific STI, and relevance to HIV transmission Medium priority, determined largely by the specific STI, and consequent disease burden for women
Table 2: Prioritization of STI Indications for MPT Product Development Target STI in MPT Proposed Priority Rationale HSV Very High High Incidence, HIV co-factor HPV Very High High incidence, burden of disease BV High Incidence, potential enhancement of HIV infection Chlamydia Moderate Incidence, disease burden syndromic management potential Trichomonas Moderate Incidence, disease burden, syndromic management potential Gonorrhea Low Incidence, disease burden Syphilis Low Incidence, disease burden
Tables 1 and 2: Consensus Responses HIV/Contraception slightly higher priority than HIV/STI STI/Contraception not a priority HSV: high priority given role in HIV infection, feasibility prospects, and marketing potential worldwide HPV: moderate to high priority given oncogenic potential Seen addressable via vaccine; availability needs to be increased Possible MPT product to cover all HPV types and bridge gap to vaccine availability BV: high priority given relevance of vaginal health to HIV and other infections
Tables 1 and 2: Consensus Responses (continued) Chlamydia: moderate priority given high prevalence in certain settings; high disease burden potential Curable with cheap antibiotic course Age specific screening and treatment is effective Trichomoniasis: moderate priority given high disease burden, induced inflammation and enhanced HIV shedding Product feasibility challenges recognized for prevention Gonorrhea and Syphilis: low priority Prevalence and curability cited Key factors: Relevance to HIV; technical feasibility; prevalence; treatability; public health burden
Table 3: Routes of Administration and Dosage Forms Route of Administration Topical: Daily Dosage Form(s) Gels, tablets films, etc. Development Priority 2.1 Adherence Potential 3.0 Topical: Peri-coital Gels, tablets, films, etc. 1.3 1.8 Sustained Release Device Injectable Implantable Oral: Daily IVR, barrier device with drug release Single product/ Dual indication Single product/ Dual indication Single pill/ Dual Indication 1.2 2.1 2.5 2.0 1.1 1.2 1.0 2.4 Oral: Peri-coital Single pill/ dual indication 2.0 1.8 Scale: 1= highest priority/potential; 3= lowest priority/potential
Tables 3: Consensus Responses Adherence! Vaginal rings: Highest development priority/highest adherence potential Technical feasibility high; cheap; proven contraception technology Use in menses? User removal? Peri-coital products were higher priority than daily products Adherence burden too high for daily Peri-coital cheaper than daily Peri-coital must be fast acting; technical challenge Component elements for oral daily are available; technically feasible Topical products were higher priority than oral products Topical contraceptives have technical challenges
Tables 3: Consensus Responses (Continued) Injectable: High adherence potential (pending dosing interval) Reversibility issues Long term systemic exposure concerns Technically challenging Skilled provider? Implantable: High adherence potential Technically challenging/low feasibility More reversible than injectable Potentially low uptake in target populations; skilled provider required Other key points: No mention of HC issue and dosage form linkage Efficacy cited as relevant to dosage form preference Side effects via systemic exposure repeatedly cited Peri-coital definition ranged from +/- 30 min to +/- 24 hr
Survey of ARHP Members: Tables 1, 2 & 3 Issues Informally conducted by J. Manning (USAID) ; n= 593 Which of the following combinations of prevention options would be your highest priority for development? Unintended pregnancy & HIV 147 24.8% HIV & other STIs 53 8.9% Unintended pregnancy & other STIs 393 66.3% Preventing which of the following STIs is your highest priority? HIV/AIDS 296 49.9% HSV (Herpes Simplex Virus) 63 10.6% HPV (Human Papillomavirus) 202 34.1% BV (Bacterial Vaginosis) 32 5.4%
Survey of ARHP Members: Tables 1, 2 & 3 Issues Which of the following modes of administration for a comb. product would be most accepted and used by your clients? Topical pericoital (eg: gel, film, or tablet used 8 hrs 46 7.8% before or after sex) Oral (daily or pericoital) 274 46.2% Sustained release device (eg: vaginal ring used 108 18.2% continuously for 3 mos) Injection 78 13.2% Implant 15 2.5% IUD 72 12.1% USA Contraception & STI Oral Dosage Form HPV > HSV Domestic vs. SSA, SEA, Etc. SSA, SEA, Etc. HIV & Contraception/HIV & STI Sustained Release Device HSV > HPV Effect on Pharma Involvement?
Table 4: Product Attributes & Parameters Parameter Range Dosage Forms Topical Sustained Injectable Implantable Oral Release Shelf Life Min 24 mos 24 mos 24 mos 24 mos 24 mos Pref >36 mos >36 mos >36 mos > 36 mos >36 mos Storage Conditions Min 15-30 o C/65% RH 15-30 o C/65% RH 4 o C 4 o C 15-30 o C/65% RH Pref >30 o C/75% RH >30 o C/75% RH >30 o C/75% RH 40 o C/75% RH 15-40 o C/75% RH Schedule/ Dosing Min Daily or Pericoital Monthly 2 mos 3 mos Daily or Pericoital Regimen Pref +/-24 hr of sex Yearly 12 mos >12 mos +/- 24 hr of sex Infrastructure Needs Min Clinic w/medical support Clinic w/medical support Clinic w/medical support Clinic w/ medical support Clinic w/medical support Pref Local Healthcare Provider Local Healthcare Provider Local Healthcare Provider Clinic w/ medical support Local Healthcare Provider
Table 4: Product Attributes & Parameters (Continued) Parameter Range Dosage Forms Topical Sustained Injectable Implantable Oral Release Provision Min Clinic/User Clinic/User Clinic/Phys Clinic/Physician Clinic/User Source and Administration Pref Reversibility timing Local Healthcare Provider or Pharmacy/User Packaging Min Controlled disposal Local Healthcare Provider or Pharmacy/User Trained Healthcare Provider Trained Healthcare Provider Local Healthcare Provider or Pharmacy/User Min 14 days 30 days 90 days 90 days 14 days Pref Immediate <24 hours 14 days?? Feasible? 14 Days?? Feasible? <24 hours Controlled Controlled disposal disposal Pref Concealable, user disposal Concealable, user disposal With all necessary materials for administration With all necessary materials for administration??? Biodegradable? Removable? Concealable, user disposal
Table 4: Consensus Summary Generally accepting of parameters as posed All attributes considered high priority except: Reversibility timing (medium) and packaging (low)- no consensus Strong preference for 40 o C storage temp 4 o C seen as potentially not feasible Preference for 36 month shelf life Resupply issues, access to testing/monitoring, cold chain storage needs all cited as relevant Concerns re: Packaging (sterility) and storage (temperature) for injectable and implantable Dosing interval also of concern
Table 4: Consensus Summary (continued) Potential for local uptake and support of specific product dosage forms in specific settings was raised Level of healthcare provider expertise and involvement Monica s Challenge Do the access strategies and product education activities need to change to support the development of effective products that traditionally did not achieve high uptake due to the dosage form?
Table 5: General Issues Parameter Minimally Acceptable Preferred Target Efficacy HIV 40%-70% pending product >80% type/indication Contraception Current levels w/ recommended use >current levels per contraceptive form STI 40% >80% Side Effects Contraindications, warnings, use w/ pregnancy, etc OTC with no pregnancy or major systems warnings or contraindication with other vaginal products Time to licensure 8-12 years 5 years R&D costs <$400M <$150M Yearly MPT product cost per user <$100/year <$50/year
Tables 5: Consensus Summary HIV Efficacy: Minimally acceptable- 40-50%; Typical use- 60%; Perfect use >80% Contraception Efficacy: Current levels with recommended use Efficacy-STI: Minimally acceptable- 40-50%; no comments on posed >80% preferred target Side Effect Issues: Acceptable to most women and generally no worse than comparable single use products No effects on daily activities Difficult to answer in the absence of other details (e.g., product efficacy) Continued concerns expressed regarding systemic exposure/resistance
Tables 5: Consensus Summary (continued) Contraindications, Warnings, Use with Pregnancy: Equal standards for drugs and devices in the developed world General concerns about ARV during pregnancy and breast feeding Different recommendations for Rx vs OTC products Time line to licensure: 5 years preferred; 8-12 years minimally acceptable R&D Costs: No comments provided Preferred Costs: $12-40/year
Summary Findings from the TPP Survey for Drug-Drug and Drug-Device MPT Products Priority Indications: HIV/Contraception followed closely by HIV/HSV Other STI with contraception not a priority Dosage Forms Major determining factor is PRODUCT ADHERENCE Highest development priority: Vaginal Rings Key Attributes and Parameters: Shelf life: 36 months Storage temperature: 40 o C Other attributes are all in the context of safety, efficacy, and each other!
Summary Findings from the TPP Survey for Drug-Drug and Drug-Device MPT Products Efficacy Targets: HIV: 40-80% Contraception: Current levels with recommended use STI: at least 40% Side Effects: No worse than individual indication products Needs evaluation in the context of acceptability and efficacy No significant input on cost of R&D, time to market, user costs, IP Results can vary depending on who is asked
Conclusions of the TPP Survey Exercise Defining broadly applicable attributes and parameters for all drug-drug or drug-device MPT products is challenging The interplay of different attributes is complex and unique per product concept and design It is possible to create general development priorities and fundamental design targets for such MPT products Useful to funders in terms of investment prioritization Useful to developers in terms of R&D focus
Outstanding Issues/Questions/Challenges Regarding Drug-Drug or Drug-Device MPT Products Expanded level of input Evaluate specific product concepts against key attributes and parameters of the (evolving) TPP Incite/manage collaborative funding and development efforts to achieve maximum efficiency Pursue the developed world potential of MPT products Build high impact MPT products and achieve the necessary access of such products to target populations