Latest Developments in and the Future of the Regulatory Landscape for Approving Treatments for Orphan and Rare Diseases.

Solving FDA Legal Challenges for the Life of a Life Sciences Company -1- www.fdacounsel.com
LAW OFFICES OF MICHAEL A. SWIT
Latest Developments and the Future of
the Regulatory Landscape for
Approving Treatments
for Orphan/Rare Diseases
Orphan Drugs & Rare Diseases 2018 Americas - West Coast
San Diego • June 25, 2018
Michael A. Swit, Esq.
Managing Principal

Standard Disclaimers
• Views expressed here are solely mine and do not
reflect those of my firm or any of its clients.
• This presentation supports an oral briefing and
should not be relied upon solely on its own to
support any conclusion of law or fact.
• These slides are intended to provide general
educational information and are not intended to
convey legal advice.

Topics
• Overview
– Basics of Orphan Products
– Recent Performance at FDA
• Legal/Regulatory Issues
• Regulatory Challenges
• Time to market

Overview of Basics

➢ Four key incentives to facilitate drug development for
rare diseases:
– Seven years marketing exclusivity -- during which time no
other company can secure approval for the same drug for the
orphan indication
– Protocol assistance*
– Tax credits*
– Research Grants*
* Don’t have to secure approval for these benefits; designation confers access to benefits
➢ User Fees – waived
– not a direct benefit under ODA
Basics of Orphan Drug Act (ODA)

➢ To qualify for benefits under the Orphan Drug Act, a
drug must serve a patient population:
– < 200,000 people in the United States or
– if > 200,000, orphan drug applicant must show it cannot
reasonably recoup its commercial investment in the research and
development of the product –
• rarely used
➢ Key question for orphan drug status is patient
population --
– the indication sought must be “medically plausible”
– not just a "salami sliced" indication of a greater patient
population that might be otherwise over 200,000.
How Does a Drug Become an
Adoptable Orphan?

FDA -- The Statistical Record
7

8
Source: “Insights into Rare Disease Drug Approval: Trends and Recent Developments.” Lanthier, Mike (Operations Research Analyst, FDA
Office of Commissioner). NORD Rare Diseases & Orphan Products Breakthrough Summit. October 17, 2017. at Slide 4.

Source: Lanthier, at Slide 7.

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2017 O.D. Approvals – Therapeutic Areas

2017/2018
➢ 2017 -- of 46 “novel” drugs approved – where active
ingredient never approved before -- 18 were for
orphan diseases
– Aliqopa, Alunbrig, Austedo, Bavencio, benznidazole, Besponsa,
Brineura, Calquence, Emflaza, Hemlibra, Idhifa, Macrilen,
Mepsevii, Prevymis, Radicava, Rydapt, Xermelo, and Zejula.
• Source:
– CDER Report – “ADVANCING HEALTH THROUGH INNOVATION --
2017 NEW DRUG THERAPY APPROVALS.” January 2018, at page 10.
➢ Approvals (novel + previously approved ingredients) –
77/34 (through 6/24/2018)
➢ Designations – 477/172 (through 6/24/2018)
Source: FDA Orphan Drug Designations and Approvals Database

FDA Planning for the Future
15

➢ Commissioner Blog -- June 29, 2017 – Announced --
Goals & Features
– Eliminate backlog within 90 days
– 100% of new O.D. Designation requests to get response in 90 days
– Webinar Tutorial on Designation Requests
• access at:
https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanP
roductDesignation/ucm597126.htm
– Plan – access at:
• https://www.fda.gov/downloads/ForIndustry/DevelopingProductsforRareDiseasesConditions/Howtoapply
forOrphanProductDesignation/UCM565068.pdf
➢ Draft Guidance – Dec. 2017 -- Designation for Pediatric
Subpopulations of Common Diseases
FDA O.D. Modernization Plan
16

➢ O.D. Designation Pilot Plan – fillable designation form
➢ Public workshop – held on May 9, 2018 -- to address
changing landscape of O.D. development posed by
targeted therapies and molecularly defined diseases.
– https://www.fda.gov/NewsEvents/MeetingsConferencesWorkshops/ucm592778.htm
➢ MOU with NORD -- for collaboration to enhance
patient involvement in regulatory discussions
➢ More at:
https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/Events/u
cm593077.htm
FDA – 2018 Rare Disease Day Announcements
17

Legal/Regulatory Issues
18

Designation Issues – or Can Identical Drugs
Be Adopted by Two Different Families – or
does one Drug have to be Superior?
➢ Clinical Superiority – FDA may regard – for Orphan Drug
Act purposes, including exclusivity -- as different, drugs that
are chemically the same and for same indication if the second
drug is clinically superior to the first drug
– prior to 2017’s Food & Drug Administration Reauthorization Act
(FDARA), FDA had construed the ODA that you had to show
superiority
– BUT, a 2014 court case – Depomed (re Gralise®) had found that
superiority was not required – in effect, you could have two drugs with
O.D. exclusivity
• FDA – after Depomed, said it would ignore the court’s decision
– FDARA resolved this for drugs subject to the ODA after the
enactment date of FDARA (August 18, 2017)

➢ 3 Types of Clinical Superiority – each must show that
it presents a “significant therapeutic advantage” as to
either:
– Greater Efficacy; or
– Greater Safety; or
– Providing a Major Contribution to Patient Care (“MC-PC”)
➢ How to Prove Superiority – 21 CFR 316
– Effectiveness – “as assessed by effect on a clinically meaningful
endpoint in adequate and well controlled trials”
• typically – direct, head-to-head, clinical trials (as per a comparative claim)
– Safety – “in a substantial portion of the target population”
Clinical Superiority
20

➢ Very subjective; some factors FDA will consider (from
2013 revised regulations);
– Convenient treatment location (e.g., home vs. clinic)
– Reduced treatment burden
– Increased patient comfort
– Improved administration
– Potential for self-administration
➢ Not MC-PC:
– Increased quality of life
– Improved patient compliance
How to Prove MC-PC Superiority

➢ Efficacy
– Serono’s Rebif >to Avonex for relapsing-remitting MS based on a
head-to-head clinical study (2002)
➢ Safety
– Biogen’s Avonex > Berlex’s Betaseron due to a reduced risk of an
adverse event – injection site necrosis
➢ MC-PC
– Academic’s Sotalol HCl > Betapace due to change in dosage form
from oral to injectable allowed use with patients that could not use oral
dosage
– Eagle’s Ryanodex > Dantrium IV because anesthesiologist could
prepare in 1 minute vs. 1 hour for Dantrium, allowing anesthesiologist
to concentrate on treating the patient
Clinical Superiority (“>”) – Examples
22

➢ FDA Final Rule – July 2013 – situations where a viable
orphan subset may exist in a “non-rare” disease
– Toxicity of the drug – e.g., a small subset are refractory to normal
treatment, but would respond to a more toxic drug
– Mechanism of action – e.g., breast cancer is not rare, but those
where the drug mechanism impacts a specific biomarker where
the population is orphan
➢ Illegitimate slicing
– Disease grade – e.g., all breast cancer stages are seen as same
disease; but contrast – FDA says pneumonia in CF patients is
different disease than community-acquired pneumonia
– Clinical trial – inclusion/exclusion criteria – can’t pick only “left-
handed lawyers”
Subsets – Legitimate “Salami Slicing”

➢ “Molecular differentiation” (my term) -- in other cases,
FDA has gone to some length to differentiate a product on
the basis of how its molecular structure differs from an
approved orphan drug.
– “Silly Little Amino Acid” Case – 91 vs. 92 amino acid chains
“Same” Drug?
24

Orphan Drug Development Challenges
25

➢ Clinical study hurdles …
– Often chronic, progressive, serious, life-limiting and life-
threatening with unmet medical needs
– Endpoints, outcome measures, tools, instruments, biomarkers
usually lacking
– “Natural history” of diseases simply not as well documented
➢ Clinical study differences – examples:
– Carglumic acid – for NAGS deficiency – approved with just one
study – an open label, historically controlled, retrospective cases
series of 23 subjects
– Dalfampiridine – to improve walking in patients with multiple
sclerosis – two randomized, placebo controlled studies with 540
subjects
Orphan Drug Development Challenges
2
6

➢ No difference in standards for approval – still must
prove “substantial evidence” of safety and
effectiveness using adequate and well-controlled
investigations and clinical benefit
➢ Clinical study hurdles
– Small patient populations
• Hard to recruit
• Clinical investigators – more likely to be “naïve” as to Good Clinical
Practices (GCP)
– Poorly understood disease processes – hard to diagnose
– Many orphan diseases are genetically based – estimated as high as
70% -- thus, can be very heterogeneous populations –
confounding study predictability
O.D. Challenges …
2
7

➢ Tougher to recruit for many reasons
– Fewer patients
– Ethical considerations
• Informed consent/assent
• Willingness of parent or guardian
– Organ development differences – not just proportionally smaller
adults
– Frequently genetically based conditions
O.D. Challenges – Rare Pediatric Diseases

Time to Market
29

30
Source: https://csdd.tufts.edu/csddnews/

Questions?
➢ Call, e-mail or write:
Michael A. Swit, Esq.
San Diego, California 92130
m: 760-815-4762
e: mswit@fdacounsel.com
web: www.fdacounsel.com
➢ Follow me on:
– LinkedIn: http://www.linkedin.com/in/michaelswit
– Twitter: https://twitter.com/FDACounsel

About Your Speaker
Michael A. Swit, Esq., has been addressing critical FDA legal and regulatory issues for over 30
years. Before returning to his private law practice in late 2017, he served for 3 years as the chief
regulatory counsel at Illumina, Inc., the world’s leading developer of gene sequencing technologies.
Prior to that, Swit was a special counsel in the FDA Law Practice at the global law firm of
Duane Morris LLP, in its San Diego office. Before joining Duane Morris in March 2012, Swit served
for seven years as a vice president at The Weinberg Group Inc., a preeminent scientific and
regulatory consulting firm in the Life Sciences.
His expertise includes product development, compliance and enforcement, recalls and crisis
management, submissions and related traditional FDA regulatory activities, labeling and advertising,
and clinical research efforts for all types of life sciences companies, with a particular emphasis on
drugs, biologics, therapeutic biotech products, medical devices, and IVDs.
His FDA legal and regulatory work also has included tenures in private practice with McKenna &
Cuneo and Heller Ehrman, and as vice president, general counsel and secretary of Par
Pharmaceutical, a top public generic and specialty drug firm, where he helped spearhead the
company’s emergence from the Generic Drug Scandal. He also was, from 1994 to 1998, CEO of
FDANews.com, a premier publisher of regulatory newsletters and other specialty information
products for FDA-regulated firms.
He has taught and written on many topics relating to FDA regulation and associated commercial
activities and is a past member of the Food & Drug Law Journal Editorial Board. He earned his
A.B., magna cum laude, with high honors in history, at Bowdoin College, and his law degree at
Emory University.

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