Delayed Access to Generic Medicine: A Comment on the Hatch-Waxman
Orphan Drugs: overview of current issues · Orphan Drug . Orphan Drug Act, 1983 : 7 years . New...
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Orphan Drugs: overview of current issues 2.5.18 Michael S. Broder, MD, MSHS
Transcript of Orphan Drugs: overview of current issues · Orphan Drug . Orphan Drug Act, 1983 : 7 years . New...
Orphan Drugs: overview of current issues
2.5.18 Michael S. Broder, MD, MSHS
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What TV series was instrumental in the passage of
the Orphan Drug Act?
For extra credit, what was the main character’s first
name?
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Orphan Drug Act of 1983
Covered drugs
that had “no reasonable expectation that…cost…will be recovered
from…sales” (commercially non-viable) and are not patentable.
Amended in 1984 to
allow drugs for diseases affecting “less than 200,000 persons”
(prevalence-based definition*) and remove non-patentability
requirement.
US has no “ultra rare” vs “rare” distinction.
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* roughly 65/100,000 in the US
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1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
US led the way in orphan drug legislation
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1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997
USA
Japan
Canada
Australia
China
EU
Columbia
Argentina
Mexico
Source: Arnold, et. al., F1000Research, 2015
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Most countries use a prevalence threshold around 40 cases per 100,000 population
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Source: Richter, et. al., Value in Health, 2015
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Most countries use a prevalence threshold of about 40 cases per 100,000 population
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Source: Richter, et. al., Value in Health, 2015
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Benefits of orphan status have expanded
• As of 1985 o 7 year exclusivity period
o 50% tax credit for clinical R&D
o Protocol development assistance
o Various research grants/subsidies
• 2010 ACA added o Exemption from user fees ($2 million/submission in 2017)
o Exemption from 340B drug discounting
o Exemption from annual market-share fee ($4 billion for the whole market in 2017)
o Dedicated FDA resources (frequently faster approval)
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…but orphan exclusivity is less important
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Exclusivity category/legislation Exclusivity period
Orphan Drug Orphan Drug Act, 1983 7 years
New molecular entity Hatch-Waxman Act, 1984 5 years
New formulation Hatch-Waxman Act, 1984 3 years
Innovator biologic Affordable Care Act, 2010 12 years
Pediatric exclusivity FDA Modernization Act, 1997 6 months
Qualified infectious disease product FDA Safety and Innovation Act, 2012 5 years
Single-enantiomer products FDA Amendments Act, 2007 5 years
Source: Healthy Policy Brief: Pricing Orphan Drugs, Health Affairs, 2017
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*novel drugs, new indications for orphan drugs, and new orphan indications for non-orphan drugs Source: US Food and Drug Administration (FDA) website
Orphan designations and approvals 2000-2016
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71 81 66
98
135 125 145
121
167 169
199 202 197
266
293
358 333
5 4 8 8 11 9 6 7 10 12 6 15 15 14 22 27 11
0
50
100
150
200
250
300
350
400
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Designations Novel Drug Approvals New Indications*
Presenter
Presentation Notes
9 of 22 novel drugs approved in 2016 were orphan (41%)
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Concern about (un)intended consequences
• Growth in numbers of orphan drugs/indications
• Growth in cost to the system
• High prices
• Face validity/gaming
• Lower evidentiary standards
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US pharmaceutical spending on orphan and other drugs
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Source: Divino, et. al., Health Affairs, 2016
Presenter
Presentation Notes
2016 orphan indications accounted for $35bn in spending in the US out of $450bn (8%) about 1% is orphan indications for non-orphan drugs.
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Median cost per patient per year (2012-2016)
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$64,099 $69,203
$88,503
$80,124 $83,883
$6,543 $8,017 $9,065 $13,402 $15,239
$0
$10,000
$20,000
$30,000
$40,000
$50,000
$60,000
$70,000
$80,000
$90,000
$100,000
2012 2013 2014 2015 2016
Med
ian
Cos
t per
Pat
ient
Orphan Non-OrphanSource: EvaluatePharma® Orphan Drug Report February 2017
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[VALUE]
2000s
41%
2010s
12%
1980s
[VALUE]
1990s
Biologics and oncology therapies have become a bigger proportion of orphan drugs
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[VALUE]
1980s
[VALUE]
2000s
[VALUE]
2010s
Source: US Food and Drug Administration (FDA) website
Biologics
Cancer 23%
1990s
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Monthly cost of oncology drugs 2009-2015 does not differ substantially by orphan status
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median $9,897 ($6,170-13,672) median $12,764 ($9,240-64,260) median $8,701 ($5,535-77,554)
Source: Kesselheim, et. al., PLOS Medicine, 2017
Presenter
Presentation Notes
Biomarker derived includes: e.g., Zelboraf (BRAFT+ melanoma), Kalydeco (CF with specific mutation) and make up 16% of orphan sample non-biomarker: Repatha (FHL), Kyprolis (multiple myeloma) Biomarkers can be used to define a subset if “properties of the drug…preclude its use in the remaining persons.”— FDA Final Rule 2012 21 CFR Part 316
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What is an orphan?
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What is an orphan?
356 branded orphan drugs (1983-2013), and 64 had ≥1 non-orphan
indication.
• Epogen is orphan for anemia in ESRD (n=80,000) but $2bn sales
mostly off label
• Humira is orphan in JRA (n=50,000) but $8bn in sales mostly for
non-orphan indications
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Presenter
Presentation Notes
80% of orphans approved since 1983 are for drugs with 1 approval (an orphan)
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Most orphan drugs are innovative
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Presenter
Presentation Notes
first-in-class NME = first to be approved in its pharmacologic class, advance-in-class = priority review based on potential to be a significant improvement over existing therapies. addition-to-class = standard review by the FDA.
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Evidence standards probably lower for orphans
"orphan designation does not alter…regulatory requirements”--FDA
Neurology: 32% with an orphan indication had ≥ 2 placebo-controlled
RCTs vs 100% with no orphan indication (Mitsumoto)
Oncology: orphan pivotal trials less often blinded (4% vs 33%), fewer
patients (96 vs 290), less likely to be randomized (30% vs 80%)
(Kesselheim)
All approvals 1983-2010: “flexibility” by FDA in 2/3 (90/135)
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Source: Mitsumoto, et. al., Ann Neurol, 2009; Kesselheim, JAMA, 2011; NORD 2015
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Summary • ODA stimulated the development of certain types of drug
• Rare diseases now have more treatments
• More money (too much?) is made treating those diseases
• Conditions treated might differ from original conception o is cancer what Is this what Quincy (and Congress) had in mind?
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Presenter
Presentation Notes
Whether the rarity or seriousness of a condition should affect standards for approval and payment, and what diseases are truly “orphan” are ultimately political decisions, not readily amenable to economic analysis.
