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COMING SOON:GENERIC ARVs
Tim HornTreatment Action Group
Federal AIDS Policy Partnership MeetingDecember 2014
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PATENTS AND EXCLUSIVITY 101
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Myriad Policies
• Patents issued >1996 have term of 20 years• Only certain patents are eligible for extensions:
– Delays caused by USPTO processes– Some 17-year patents issued before June 1995
• Uruguay Rounds Agreements Act/Trade-Related Aspects of Intellectual Property Rights (1994)
– Patent term restoration to account for time lost satisfying regulatory requirements
• Hatch-Waxman Act (1984)• Cannot exceed 5 years; cannot extend patent life beyond
14 years post approval
– Pediatric exclusivity (additional six months)
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Patent and Exclusivity Timeline: The Simple Version
5 1510 20 25
Original Patent Term20 years
Hatch-Waxman Extension
Ex: ~24 months
Pediatric Exclusivity6 months
Patent Filed
IND Filed
Clinical Testing Phase
NDA Filed
NDA Approved
NCE Exclusivity
ANDA can be filed with FDA at start of extension period, with tentative approval during period, and marketing started at end of extension and exclusivity period
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Patent and Exclusivity Timeline: A Bit More Detail
5 1510 20 25
Original Patent Term20 years
Patent Filed
IND Filed
Clinical Testing Phase
NDA Filed
NDA Approved
NCE Exclusivity
ANDA (Para IV)
Filed Patent Infringement
Lawsuit
30 mo. stay
If no infringement:Hatch-Waxman Amendment permits 6-month Exclusivity to generic challenger/manufacturer
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THE GENERIC ARV “PIPELINE”
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Best Guess Patent Expirations: HHS-Recommended ARVs
Drug Patent Expiration Drug Patent Expiration
Lamivudine 2010 Tenofovir alafenamide fumarate (TAF)
2021
Abacavir 2012 Raltegravir 2022
Efavirenz 2013 (Actual: 12/2017) Rilpivirine 2022
Darunavir 2015 Elvitegravir 2023
Ritonavir (gel caps) 2016 Ritonavir (tablets) 2024
Atazanavir 2017 Dolutegravir 2026
Tenofovir disoproxil fumarate (TDF)
2017 Cobicistat 2027
Emtrictabine 2021
Combination patents: TDF/emtricitabine (2021), abacavir/lamivudine (2016), elvitegravir/cobicistat/tenofovir/emtricitabine, and TAF-inclusive formulations.
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Best Guess Patent Expirations: HHS-Recommended ARVs
Drug Patent Expiration Drug Patent Expiration
Lamivudine 2010 Tenofovir alafenamide fumarate (TAF)
2021
Abacavir 2012 Raltegravir 2022
Efavirenz 2013 (Actual: 12/2017) Rilpivirine 2022
Darunavir 2015 Elvitegravir 2023
Ritonavir (gel caps) 2016 Ritonavir (tablets) 2024
Atazanavir 2017 Dolutegravir 2026
Tenofovir disoproxil fumarate (TDF)
2017 Cobicistat 2027
Emtrictabine 2021
Combination patents: TDF/emtricitabine (2021), abacavir/lamivudine (2016), elvitegravir/cobicistat/tenofovir/emtricitabine, and TAF-inclusive formulations.
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Generic Regimens of the Near Future
DarunavirAtazanavirEfavirenz
Abacavir + LamivudineTenofovir + Lamivudine
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The Big Questions
• Will these agents remain recommended by HHS guidelines?
• Single-tablet regimens (STRs) vs. multi-tablet regimens (MTRs)– Virtually no datasets indicating MTRs inferior
to STRs– However… STRs preferred among PLWHIH and
providers – All-generic STRs likely to be produced in time
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Generic Regimens of the Near Future
Merck STR:Doravirine (MK-1439) plus
generic tenofovir and lamivudine
Tobira FDC:Cenicriviroc and generic lamivudine
For use with third agent
OTHERS???
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REGULATORY REQUIREMENTS
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Regulatory RequirementsOriginator/Innovator Drugs -- NDA* Generic Drugs – ANDA**
Chemistry Chemistry
Manufacturing Manufacturing
Controls Controls
Labeling Labeling
Testing Testing
Animal Studies Bioequivalence
Clinical Studies
Bioavailability
* New drug application** Abbreviated new drug application
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Generic Equivalence
• Must contain the same active pharmaceutical ingredient (API)
• Must involve the same route of administration, formulation, and dosing
• Must also meet stringent criteria for bioequivalence– Extent (and, often, the rate) of absorption must not
differ significantly from that of the originator drug• Generic drug that meets these standards should
not behave any differently, either in terms of efficacy or safety outcomes
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Establishing Bioequivalence
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Bioequivalent, Not Identical
• Despite API bioequivalence:– Generic may be different size, shape or color– May contain different inactive
ingredients/excipients:• Binding materials• Flavoring agents• Dyes• Preservatives
– Rarely a source of serious problems
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Therapeutic Windows
• Narrow windows: warfarin, levothyroxine, digoxin– Care required when generics are used
• Wide windows: modern-day ARVs– Even with variation, Cmax is below max.
tolerated dose (MTC)– Problem with older drugs (e.g., stavudine,
first-generation PIs)
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YES… BUT WILL THEY SAVE MONEY?
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Mathematical Modeling
• Quality-adjusted life expectancy, costs, and incremental cost-effectiveness ratio comparisons:– Efavirenz + Lamivudine + Viread®– Efavirenz + Truvada®– Atripla®
Walensky, et al. Ann Intern Med. 2013;158(2):84-92
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$1 Billion in Savings! … ?
• Assuming 75% price drop for generics:– 40% reduction in the total regimen cost
($15,300 > $9,200; $6,100 saved per year)– $42,500 in healthcare system savings in
lifetime costs per person– If all U.S. patients start/switch to
efavirenz/lamivudine/Viread: $920 million saved in first year alone
– Efavirenz + Truvada®: $560 million saved
Walensky, et al. Ann Intern Med. 2013;158(2):84-92
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Assumptions
• Efavirenz/lamivudine/Viread 7% less virologically effective vs. Atripla– Overly pessimistic?
• 75% price reduction– Similar to that seen when generic competition
ensued for other diseases:• simvastatin for hypercholesterolemia (↓66%)• methylphenidate for ADHD (↓72%)• warfarin (↓85%)
Walensky, et al. Ann Intern Med. 2013;158(2):84-92
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Will there be sufficient competition?
• HIV technically a rare disease• Will ARVs remain HHS recommended?• Will patients or providers help increase
demand, despite tradeoffs? – Efficacy concerns (e.g., 3TC vs. FTC)– STR vs. MTR (even if QD)– Loss of pharma co-pay assistance programs
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What Will Insurers Do?
• ADAP– Brand-name ARVs already deeply discounted (~50%).
Will generics be able to compete? – Will scale-back of RW appropriations require greater
cost mgmt. by ADAPs? – However, major shift to Medicaid and Qualified
Health Plans• Medicaid
– Medicaid drug rebate program: 23% for brand-name drugs; 13% for generics – is this enough?
– Given important differences, will generic ARVs be mandatory?
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What Will Insurers Do?
• Private Plans– Most likely to benefit from lower-cost generics– Interpretations of cost-effectiveness data
• Formulary practices vs. HHS recommendations• STRs vs MTRs
– Risk pushback from patients, providers, and activists?
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The (Even Bigger) Questions
• Will generics create a two-class HIV care system in U.S.? – The haves and have-nots– Can we afford another structural barrier?
• Will cost savings actually be reinvested into cash-strapped programs needed to improve prevention, care, and treatment outcomes?
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Talking Points
• Competition is good– Key to price reductions
• Beware of anti-generics rhetoric• Leverage generic prices in new brand-
name drug pricing advocacy• Push for brand-name/generic FDCs, STRs
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Talking Points
• Be cognizant (and critical) of policy landscape– Generic Drug User Fee Amendment (GDUFA)
• Work to ensure cost savings are reinvested in HIV care and prevention programs
• Be mindful of formulary changes based solely on cost– Evidence-based prescribing practices a must