US and EU

Expedited Pathways
Agenda
• United States
– Defining “serious” and “unmet need”
– Fast Track designation
– Breakthrough therapy designation
– Accelerated Approval
– Accelerated Approval – the “Animal Rule”
– Priority Review
• Priority Review Vouchers
– 21st Century Cures Provisions
• Regenerative Medicine Advanced Therapy (RMAT)
• Limited Population Pathways for Antibiotics (LPAD)
– Exclusivity Provisions
Agenda
• Europe
– Accelerated Assessment
– Conditional Approval
– Exceptional Circumstances
– PRIME
– Adaptive Pathways
BACKGROUND:
FOUR FDA PROGRAMS FOR EXPEDITED REVIEW

• The intention is to directly attempt to meet unmet medical needs for treating serious/life threatening
conditions
• Four programs created by the FDA intended to improve speed to market and expedite drug
development and review of drugs
• We want to get the drug to the patient sooner
• FDA Refences: Section 506 with 3 subsections for detailed review 506(a), 506(b), 506(c)
 FDA 21 CFR 312.80
 establishes procedures to expedite the development, evaluation, and marketing of new therapies
intended to treat persons with life-threatening and severely-debilitating illnesses, especially where no
satisfactory alternative therapy exists

Breakthrough
Fast Track Accelerated Priority
Therapy
Designation Approval Review
Designation
 “Serious” defined

• . . . a disease or condition associated with morbidity that has substantial

impact on day-to-day functioning. Short-lived and self-limiting morbidity
will usually not be sufficient, but the morbidity need not be irreversible if
it is persistent or recurrent. Whether a disease or condition is serious is a
matter of clinical judgment, based on its impact on such factors as
survival, day-to-day functioning, or the likelihood that the disease, if left
untreated, will progress from a less severe condition to a more serious
one.

• All conditions meeting the definition of life-threatening as set forth at §

312.81(a) would also be serious conditions

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 “Serious” defined
• A drug must be intended to have an effect on a serious condition or a serious aspect of a
condition, such as a direct effect on a serious manifestation or symptom of a condition or
other intended effects, including the following:
– A diagnostic product intended to improve diagnosis or detection
of a serious condition in a way that would lead to improved
outcomes
– A product intended to mitigate or prevent a serious treatment-
related side effect (e.g., serious infections in patients receiving
immunosuppressive therapy)
– A product intended to avoid or diminish a serious adverse event
associated with available therapy for a serious condition (e.g.,
product that is less cardiotoxic than available cancer therapy)
– A product intended to prevent a serious condition or reduce the
likelihood that the condition will progress to a more serious
condition or a more advanced stage of disease

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 Unmet Medical Need

• If there is no available therapy for a serious condition, there is

clearly an unmet medical need.
• When an available therapy does exist for a condition, a new
treatment generally would be considered to address an unmet
medical need if the treatment:
– Has an effect on a serious outcome of the condition that is not known
to be influenced by available therapy (e.g., progressive disability or
disease progression when the available therapy has shown an effect
on symptoms, but has not shown an effect on progressive disability or
disease progression)
– Has an improved effect on a serious outcome(s) of the condition
compared with available therapy (e.g., superiority of the new drug to
available therapy when either used alone or in combination with
available therapy (i.e., as demonstrated in an add-on study))
– Has an effect on a serious outcome of the condition in patients who
are unable to tolerate or failed to respond to available therapy
 Unmet Medical Need

• When an available therapy does exist for a condition, a new

treatment generally would be considered to address an unmet
medical need if the treatment:
– Can be used effectively with other critical agents that cannot be
combined with available therapy
– Provides efficacy comparable to those of available therapy, while (1)
avoiding serious toxicity that occurs with available therapy, (2)
avoiding less serious toxicity that is common and causes
discontinuation of treatment of a serious condition, or (3) reducing
the potential for harmful drug interactions
– Provides safety and efficacy comparable to those of available therapy
but has a documented benefit, such as improved compliance, that is
expected to lead to an improvement in serious outcomes
– Addresses an emerging or anticipated public health need, such as a
drug shortage
 US Expedited Pathways
Program Fast Track BTD Accelerated Approval Priority Review
Name
Nature of Designation Designation Approval Pathway Designation
Program

Reference Section 506(b) of the FD&C Act, Section 506(a) of the 21 CFR 314, subpart H Prescription Drug User Fee
as added by section 112 of the FD&C Act, as added by 21 CFR part 601, subpart Act of 1992
Food and Drug Administration section 902 of FDASIA E
Modernization Act of 1997 Section 506(c) of the
(FDAMA) and amended by FD&C Act as amended by
section 901 of the Food and section 901 of FDASIA
Drug Administration Safety and
Innovation Act of 2012 (FDASIA
Qualifying A drug that is intended to treat a A drug that is intended to A drug that treats a An application (original or
Criteria serious condition AND treat a serious condition serious condition AND efficacy supplement) for a
nonclinical or clinical data AND preliminary clinical generally provides a drug that treats a serious
demonstrate the potential to evidence indicates that meaningful advantage condition AND, if approved,
address unmet medical need OR the drug may demonstrate over available therapies would provide a significant
A drug that has been designated substantial improvement AND demonstrates an improvement in safety or
as a qualified infectious disease on a clinically significant effect on a surrogate effectiveness OR
product. endpoint(s) over available endpoint that is Any supplement that
therapy reasonably likely to proposes a labeling change
predict clinical benefit or pursuant to a report on a
on a clinical endpoint that pediatric study under 505Ab
can be measured earlier OR
than irreversible morbidity An application for a drug that
These designations and pathways or mortality (IMM) that is has been designated as a
are independent of each other. reasonably likely to qualified infectious disease
predict an effect on IMM product OR
or other clinical benefit Any application or
(i.e., an intermediate supplement for a drug
clinical endpoint). submitted with a priority
review voucher.
 US Expedited Pathways - Continued
Program Name Fast Track BTD Accelerated Priority Review
Approval
When to Submit With IND or After With IND of after The sponsor should With original BLA, NDA
Request Ideally, no later than the pre- Ideally no later than the ordinarily discuss the or efficacy supplement.
BLA or pre-NDA meeting end of phase 2 meeting possibility of
accelerated approval
with the review division
during development,
supporting, for
example, the use of the
planned endpoint as a
basis for approval and
discussing the
confirmatory trials,
which should usually be
already underway at the
time of approval.
Timeline to Within 60 calendar days of Within 60 days of Not specified Within 60 calendar days
Agency Response receipt of the request receipt of the request of receipt of original
BLA, NDA or efficacy
supplement.
Features Actions to expedite Intensive guidance on Approval based on an Shorter clock for review
development and review efficient drug effect on a surrogate of marketing
Rolling review development endpoint or an applications (6 months
Organizational intermediate clinical compared to 10-month
commitment endpoint that is standard review).
Rolling review reasonably likely to
Other actions to predict a drug’s clinical
expedite review benefit.
US Expedited Pathways - Continued
Program Name Fast Track BTD Accelerated Fast Track
Approval Designation
Additional Designation may be Designation may be Promotional materials Designation will be
Considerations rescinded if it no longer rescinded if it no longer Confirmatory trials to assigned at the time of
meets the qualifying meets the qualifying verify and describe the original BLA, NDA or
criteria for fast tract. criteria for BTD anticipated effect on efficacy supplement
IMM or other clinical filling.
benefit
Subject to expedited
withdrawal
Fast Track Designation
Breakthrough Therapy Designation
Accelerated Approval
 Animal Rule
• Accelerated Approval – Animal Efficacy Rule:
21 CFR Part 314 Subpart I (NDA) / 21 CFR Part
601 Subpart H (BLA) - Approval of new drugs
when human efficacy studies are not ethical or
feasible. Products have been studied for their
safety and efficacy in ameliorating or preventing
serious or life-threatening conditions caused by
exposure to lethal or permanently disabling toxic
biological, chemical, radiological, or nuclear
substances.
Priority Review
What is a Priority Review Voucher (PRV)?
• PRV program is a regulatory incentive program
administered by the FDA to promote drug
development for certain unmet medical needs.

• A voucher is issued by the FDA to the sponsor

of a drug for a tropical disease, rare pediatric
disease or product developed for a medical
countermeasure at the time of marketing
application approval.

• Sponsors can redeem a PRV to gain priority

review of one New Drug Application (NDA) or
Biological License Application (BLA) or
supplement—regardless of indication.

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 Priority Review Vouchers
Tropical Disease Priority Pediatric Rare Disease Medical Countermeasures
Review Voucher Priority Review Voucher
Date established 2007 (FDAAA) 2012 (FDASIA) 2016 21st Century Cures

Criteria Section 1102 of FDAAA Specifically targets the need Encouraging Treatments for
authorizes FDA to award for additional therapies for Agents that Present a
priority review vouchers to rare pediatric subsets of National Security Threat
sponsors of certain tropical other diseases. [Section 3086].
disease product applications
that meet the criteria Section 908 of FDASIA The Act creates a new
specified by the Act. A defines a "rare pediatric priority review voucher
priority review voucher may disease" as one which program for “material threat
be used by the sponsor who "primarily affects individuals medical countermeasures.”
obtains it or another aged from birth to 18 years, The Act defines the term to
sponsor to obtain a priority including age groups often be drugs or vaccines
review for a different called neonates, infants, intended to treat biological,
application. A priority review children and adolescents," chemical, radiological, or
voucher may be transferred and is a rare disease nuclear agents that present
from the sponsor who according to federal statute a national security threat, or
obtains it to another (200,000 persons in the US to treat harm from a
sponsor. or fewer). condition that may be
caused by administering a
drug or biological product
against such an agent.
 Priority Review Vouchers
Tropical Disease Priority Pediatric Rare Disease Medical Countermeasures
Review Voucher Priority Review Voucher
Outcomes Upon marketing approval of Upon marketing approval of The Secretary shall award a
a NDA, BLA or supplement, a NDA, BLA or supplement, priority review voucher to
the FDA grants a voucher for the FDA grants a voucher the sponsor of a material
priority review to be used for priority review to be threat medical
with a product of its choice used with a product of its countermeasure application
or sold to another developer choice or sold to another upon approval by FDA
developer
Permanent Will sunset (expire) in 2020 The program is scheduled to
and will need to be sunset (expire) on October
reauthorized by Congress 1, 2023.
 21st Century Cures - Incentives
Signed in to law December 2016. Legislative package
which promotes biomedical innovation.

• Sec. 3033 Accelerated Approval for Regenerative

Advanced Therapies
– Allows FDA to grant accelerated approval for regenerative
therapeutic products. This section does not change the
standards of evidence or limit any other of the authorities
of FDA.
• Sec. 3042 Limited Population Pathway
– Provides FDA with more flexibility to approve
antimicrobial and antifungal drugs based on a limited
population if the drug treats a life-threatening infection.
 RMAT

As described in Section 3033 of the 21st Century

Cures Act and in FDA’s guidance, “Expedited
Programs for Regenerative Therapies for Serious
Conditions,” sponsors developing regenerative
medicine therapies (cell therapies, therapeutic
tissue engineering products, human cell and
tissue products) can apply for a RMAT
designation for their product.
RMAT versus Breakthrough
 LPAD
Section 506(h) of the FD&C Act provides that FDA may
approve an antibacterial or antifungal drug, alone or in
combination with one or more other drugs, under the LPAD
pathway, if:
• The drug is intended to treat a serious or life-threatening
infection in a limited population of patients with unmet
needs;
• The standards for approval under section 505(c) and (d) of
the FD&C Act (21 U.S.C. 355) or the standards for licensure
under section 351 of the Public Health Service Act (PHS Act)
(42 U.S.C. 262), as applicable, are met; and
• FDA receives a written request from the sponsor to approve
the drug as a limited population drug
 LPAD

• The LPAD approval mechanism is not feasible for antibacterial

drugs that treat serious infections due to highly resistant
bacterial pathogens to be developed using traditional, large
scale clinical trials due to the limited numbers of patients in
which these serious infections occur.
• LPAD products would be narrowly indicated for use in small,
well-defined populations of patients for whom the drugs’
benefits have been shown to outweigh their risks.
• Under the LPAD mechanism, a drug’s safety and effectiveness
could be studied in substantially smaller, more rapid, and less
expensive clinical trials.
Incentives to spur innovation - Exclusivity
Type of Exclusivity Exclusivity granted Notes

New Chemical Entity 5 years • Granted to a drug that contains no active moiety
that has been approved by FDA under section 505(b)
• Runs from time of NDA approval
• Bars FDA from accepting for review any ANDA or
505(b)(2) application for a drug containing the same
active moiety for: - five years if an ANDA or 505(b)(2)
does not contain a paragraph IV certification to a
listed patent - four years if an ANDA or 505(b)(2) is
submitted containing a paragraph IV certification to
a listed patent
Drug - New Indication/ new population/ new dosage 3 years • New clinical studies in humans, conducted by
form/Rx-to-OTC switches sponsor and essential for approval

Orphan drug 7 years marketing exclusivity • Blocks competitors from obtaining FDA approval
even if they have generated their own data
• Applies only to the indication for which the product
is approved

First generic 180 days • Provides an incentive of 180 days of market

exclusivity to the "first" generic applicant who
challenges a listed patent by filing a paragraph IV
certification and running the risk of having to defend
a patent infringement suit
Qualified Infectious Disease Products (QIDP) 5 years • Adds five years to already granted exclusivity
Pediatric Exclusivity (BPCA) 6 months • Grants an additional 6 months of market protection
at the end of listed patents and/or exclusivity for
sponsor’s drug products containing the active
moiety, when the sponsor has conducted and
submitted pediatric studies on the active moiety in
response to a Written Request from FDA
Incentives to spur innovation - Exclusivity
Type of Exclusivity Exclusivity granted Notes

Biologic 12 years (4 years data and 12 • 12 year marketing exclusivity for new biological
year marketing) structures – but if application is filed by same
sponsor or manufacturer of the Pioneer product (or
a licensor, predecessor in interest or a related party),
the changed biological structure must also result in a
(1) change in indications, route of administration,
dosing schedule, dosing form, delivery system,
delivery device or strength or (2) change in safety,
purity or potency
First interchangeable biosimilar 12 months • First follow-on product that is deemed by FDA to be
interchangeable

First biosimilar No exclusivity provided • No follow on exclusivity for same biological structure

New indication for an approved biologic No exclusivity provided • “Evergreening” not in scope
 EU Expedited Pathways
Program Accelerated Conditional Exceptional PRIME Adaptive
Name Assessment Approval Circumstances Pathways
Nature of Designation Designation Designation Designation Designation
Program
Reference Recital 33 of Regulation (EC) (EC) No 507/2006 Article 14 (8) of Recital 33 and Article Recital 33 and Article
No 726/20041 Regulation (EC) No 14(9) of Regulation 14(9) of Regulation
726/2004 (EC) No 726/2004 (EC) No 726/2004,
Qualifying A justification including the Limited to products to The applicant can show The scheme aims to Based on 3 principles:
Criteria major benefits expected should treat: that he is unable to support medicinal 1. Iterative
be submitted. The following list 1. seriously debilitating provide comprehensive products of major public development. This is
of key items would normally be diseases of life- data on the efficacy and health interest and in either:
addressed in a justification for a threatening diseases safety under normal particular from the - a. staggered approval
request for accelerated 2. to be used in conditions of use, viewpoint of therapeutic from an initial restricted
assessment: emergency situations because: innovation (i.e. those patient population in
- The unmet needs and the 3. Orphan Medicinal - The indications for which fulfil the which the benefit
available methods of prevention, Products which the product in accelerated outweighs the risk, to
diagnosis or treatment. Must demonstrate: question is intended are assessment criteria). increasingly wider
- The extent to which the The risk-benefit balance encountered so rarely Criteria: populations (expansion
medicinal product is expected to of the product is that the applicant Addresses an unmet of the indication); or
have major impact on medical positive cannot reasonably be medical need - b. confirmation of the
practice, its major added value, It is likely that the expected to provide potential to address to a benefit/risk balance of a
and/or how it addresses the applicant will be able to comprehensive significant extent the product authorized
greater unmet needs. provide comprehensive evidence, or unmet medical need for under Conditional
- A brief outline of the main data - In the present state of maintaining and Marketing Authorization
available evidence (e.g., number Fulfilment of unmet scientific knowledge, improving the health of with early or surrogate
of clinical trials, key results) on medical need comprehensive the Community, endpoint
which the applicant bases its The benefits to public information cannot be 2. Gathering of
claim of major public health health of the immediate provided, or evidence thorough real-
interest. availability outweigh the - It would be contrary to life data to supplement
risks inherent in the fact generally accepted clinical trial date
that additional data are principles of medical 3. Involvement of
still required ethics to collect such patients and health
information, a technology assessment
marketing authorization (HTA) bodies in the
may be granted subject discussion of the
to certain obligations product development
design
EU Expedited Pathways - Continued
Accelerated Conditional Exceptional PRIME Adaptive
Assessment Approval Circumstances Pathways

When to submit As early as possible but Submitted as a Recommended that Can be submitted at At a point in
Request prior to the submission component of the appropriateness is the time of proof of development when
of the MAA but at least Letter of Intent to discussed at the pre- concept (Phase III) the principles can be
10 days before the start Submit (4 – 6 submission meeting. for larger pharma or applied to the
of the procedure. months) prior to the Justification should proof of principle for development
submission of the be included as part of SMEs. program.
MAA. Module 1.

Timeline to Up to 20 days with a Determination of Determination of Assessed by the At least 4 weeks

Agency Response decision taken by the acceptability will be acceptability will be Scientific Advice
start of the review part of the normal part of the normal Working Party
procedure. scientific review scientific review (SAWP) with a
process.. process.. timetable of 40 days.
 EU Expedited Pathways - Continued
Accelerated Conditional Exceptional PRIME Adaptive
Assessment Approval Circumstances Pathways
Features Review time Approval with less Approval with less Guaranteed access The approach builds
decreased from 210 than complete data than complete data to accelerated on regulatory
to 180 days. and conditions with a and is expected to be access, early processes already in
set timetable for converted to a full appointment of place within the
fulfillment. approval if sufficient CHMP/CAT existing EU legal
data is eventually rapporteur and framework. These
generated. increased access to include: scientific
scientific advice. advice;
compassionate use;
the conditional
approval mechanism
(for medicines
addressing life-
threatening
conditions); patient
registries and other
pharmacovigilance
tools that allow
collection of real-life
data and
development of the
risk-management
plan for each
medicine.
 EU Expedited Pathways - Continued

Accelerated Conditional Exceptional PRIME Adaptive

Assessment Approval Circumstances Pathways
Additional Can revert back to Pre-submission N/A It is currently a pilot
Considerations a standard advice is program; Shire a
timetable recommended. part of it
depending on the Guideline under
review of the data. revision to be
Pre-submission released in
advice is upcoming months
recommended.