Learn about FDA's priorities for implementing The 21st Century Cures Act and how they will impact clinical research from PAREXEL Consulting experts.

1. CONFIDENTIAL © 2018 PAREXEL INTERNATIONAL CORP.
FDA INITIATIVES
UNDER 21ST
CENTURY
CURES ACT
Washington Life Science Innovation Conference
March 27, 2018
Mamata Gokhale, Ph.D., RAC

2. © 2018 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL2
THE 21ST CENTURY CURES ACT
• A landmark bipartisan US congress legislation signed into law on the 13th of
December 2016 with the promise to help every American family
• This “bill of the year” brings breathtaking advances and innovations in
biomedical research to doctors’ offices and patients’ medicine cabinets
• Cures Act contains three primary titles that address acceleration of medical
product: discovery, development, and delivery
• Provides $500 million to FDA (development & regulation), $4.8 billion to NIH
(discovery) and $1 billion in grants to states (opioid crisis); also addresses
mental health crisis and e-health records
• Title III of the Cures Act is specifically focused on activities regulated by FDA
• Over the next 10 years, provisions related to development will allow FDA to:
o Help modernize drug, biologics, and device product development & review
o Create greater efficiencies and predictability in product development & review
o Improve ability to hire, retain scientific and technical professionals

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FDA PRIORITIES UNDER 21ST CENTURY CURES ACT
• To implement the Cures Act Title III (Development & Regulation), FDA created
an implementation plan for the fiscal years 2017 - 2025
• Subtitles under Title III, prioritized for FDA Innovation Fund and endorsed by
FDA’s Science Advisory Board include:
o Patient-Focused Drug Development
o Advancing New Drug Therapies
o Modern Trial Design And Evidence Development
o Patient Access To Therapies And Information
o Antimicrobial Innovation And Stewardship
o Improving Scientific Expertise And Outreach At FDA
o Medical Countermeasures Innovation
o Vaccine Access, Certainty, And Innovation

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• Collection, review & use of
meaningful patient experience data
(what is most important to patient -
burden of the disease, burden of the
treatment)
• Data collected by patients, family &
caregivers, patient advocacy
organizations, disease research
foundations, researchers &
manufacturers
• Dedicated patient engagement staff in
the Office of Medical Products &
Tobacco
• Public workshop in December 2017,
titled “Patient-Focused Drug
Development: Guidance 1- Collecting
Comprehensive and Representative
Input.”
• A new subsection called “Patient
Experience Data” now included in drug
and biologic review documents
• Announcement of Patient Engagement
Advisory Committee (PEAC) by CDRH
• 5 year plan to issue guidance
documents on collection, submission of
patient experience data to FDA; review
of it for the benefit/risk evaluation
• Integration of patient perspectives into
FDA’s decision making process
KEY FEATURES
PATIENT-FOCUSED DRUG DEVELOPMENT
CURRENT STATUS
IMPACT

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• Qualification of drug development tools
(biomarkers, clinical outcome
assessments, animal models)
• Incentive for targeted drugs
(gene/protein modifiers) for rare
diseases (allow data from approved
applications using the same technology)
• Reauthorization of program to
encourage treatments for rare pediatric
diseases
• Orphan Drug grants amended for
interventional & observational studies
(natural history), New Pilot Program and
on-line tutorial
• Grants to support & improve the
process of automated manufacturing of
drugs & biologics (continuous
manufacturing)
• Involvement of external experts &
biomedical research consortia; INDs,
NDAs & BLAs supported by surrogate
markers
• Data incentives for targeted therapies
for rare diseases reduce financial
burden yet maintain the safety and
efficacy standards
• Increase in pediatric rare disease
designations and priority review
vouchers
• Better understanding of rare diseases
(variability in genotype, phenotype &
subpopulations)
• Faster, reliable and cost effective
manufacture of pharmaceuticals
reduces drug shortages and recalls
due to product or facility quality
KEY FEATURES
ADVANCING NEW DRUG THERAPIES (1/2)
IMPACT

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• Roadmaps for qualification of biomarkers, animal models and clinical outcome
assessment provided in 2017
• Qualification programs in August 2017 to collaborate with external stakeholders, e.g.
Major Depressive Disorder Scale captures symptoms that matter most to patients
• Guidance document published in 2017 for targeted therapies to support the
treatments that address underlying genetic mutations
• Guidance document published in 2017 to determine if an in vitro diagnostic (IVD)
device used in a study must undergo its own review distinct from a drug study
• The pediatric rare disease (PRD) priority review voucher (PRV) program was
extended until 2020; 14 PRVs awarded since 2014, 5 PRVs awarded in 2017
• Award of 15 grants for interventional clinical trials & 6 grants for observational natural
history studies to stimulate product development for rare diseases
• Emerging Technology Program to promote the adoption of innovative approaches to
pharmaceutical product design and manufacturing; Guidance in Sept. 2017 to
advance novel technology & lower the manufacturing costs
• Award to U of Connecticut for a continuous manufacturing platform with modular
components for complex dosage forms and a graphical user interface library
ADVANCING NEW DRUG THERAPIES (2/2)
CURRENT STATUS

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• Novel clinical trial designs incorporating modeling,
simulations, adaptive designs
• Real world evidence outside of randomized
clinical trials, e.g. e-health records, billings, claims
& registries
• Protection of human research subjects by
reducing regulatory duplication, shared IRB
review & harmonizing with Common Rule
• Informed consent waiver or alteration, flexibility
when the risk is minimal
• Engagement in PBPK
modeling, placebo behavior,
creation of natural history
data bases for rare diseases,
device models for design &
testing virtual patients
• June-Sept. 2017 - approval of
Sapien 3, Guidance on use of
RWE for device approvals
• Flatiron & CancerLinQ
partnership for data analytics
(big data)
• Public workshop with
stakeholders (Duke Margolis)
on RWE
• Guidance in July 2017 on
“IRB Waiver or Alteration of
Informed Consent”
• Use of in silico tools for clinical trials, external
technology collaborations
• Acceptance of RWE (healthcare status & delivery)
• Streamlined IRB process & meaningful informed
consent
KEY FEATURES
MODERN TRIAL DESIGN & EVIDENCE DEVELOPMENT
CURRENT STATUS
IMPACT

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• Approval of a new indication for an approved drug based
on qualified summaries
• Transparent & efficient process and data base for
Expanded access to therapies outside of clinical trials
• Accelerated approval pathway (RMAT designation) for
regenerative advanced therapies (cell & tissue products)
for serious conditions with unmet medical need
• Breakthrough devices pathway for PMA, 510K & De Novo
submissions, expanded expedited access program,
human device exemption limit raised to 8000
• Exemption for 510(k) requirement to > 70 Class I & 1,000
Class II device types
• Tailored, risk based approach towards digital health
technologies & developers
• Web based Expanded
access navigator tool
available since Nov. 2017
• 1632/1637 INDs &
protocols approved for
eligible patients as of
Sept. 2017
• Guidance documents in
2017 on RMAT,
Breakthrough devices and
software modifications, list
of reusable devices
requiring use & validation
instructions for sterility
• 12 RMATs granted as of
Jan. 2018
• 54/94 breakthrough
device requests granted
since 2017• Access to compassionate use; encouragement &
acceptance of innovation
KEY FEATURES
PATIENT ACCESS TO THERAPIES AND INFORMATION
CURRENT STATUS
IMPACT

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• Limited Population Pathway for Antibacterial and Antifungal Drugs
(LPAD), at an applicant’s request, to approve an antibacterial or
antifungal drug, alone or in combination with other drugs
• Intended to treat a serious or life-threatening infection in a limited
population of patients with unmet needs
• Safety & effectiveness reflect the benefit-risk profile in limited
population though lack of evidence in a broader patient population
• Labeling & advertising must contain the statement “Limited
Population” in a prominent manner
• Updated susceptibility test interpretive criteria to determine how
much of a drug to use to treat which infections
• Guidance
document in
2017 on
susceptibility test
interpretive
criteria (STIC) for
labeling
• Guidance
document in
2017 on
Antibacterial
therapies for
patients with
unmet medical
need
• Online postings
and updates to
antibacterial and
antifungal STIC
KEY FEATURES
ANTIMICROBIAL INNOVATION AND STEWARDSHIP
CURRENT
STATUS
• Builds on GAIN Act for qualified infectious disease product
designation (QIDP)
• Flexibility to rely on traditional and/or non-traditional endpoints in a
limited population & preclinical data
• Addresses rising antibiotic resistance
IMPACT

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• Scientific, technical professional appointments for the
development, review, and regulation of medical products
• Maximum salary not exceeding that of the President
(currently $400,000 per year) allowed
• Establishment of inter-center institutes
• Best practices for post marketing pharmacovigilance &
criteria for public posting of adverse event signals
• Modernized independent, non profit organization to advance
regulatory science
• Plan to meet critical
staffing needs,
strategy for hiring,
training & retaining
• Oncology Center for
Excellence established
in 2017, similar
centers for
neuroscience &
immunology under
consideration
• Sentinel system
launch in 2017, public
workshop in Feb. 2018
• Reagan-Udall
Foundation for the
FDA with expanded
mission
KEY FEATURES
IMPROVING SCIENTIFIC EXPERTISE AND OUTREACH @
FDA
CURRENT STATUS
IMPACT
• Recruitment & retention of qualified candidates including
those from industry
• Synergy between drug, device and biologics centers
based on therapeutic area
• Improved scientific engagement
• Safety surveillance focused on post marketing risks

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• Continued commitment to facilitate development and availability of
medical countermeasures (MCM)
• Vaccines, therapies, and diagnostic tests to counter chemical,
biological, radiological, nuclear and emerging threats, e.g.
pandemic flu, Zika virus
• Emergency use authorization applicable to approved/unapproved
animal drugs
• Priority review voucher (PRV) program until 2023 to help
incentivize the development of material threat medical
countermeasures
• Funding of MCM related regulatory science through intramural and
extramural research grants
• Federal register
announcement of
PRV program in
2017, fee of
$2,830,579
• Guidance in 2017
on Emergency
Use Authorization
of Medical
Products
• Guidances
planned for MCM
specific issues &
animal models
• Broad agency
announcement
for extramural
funding open till
end of March
2018
• Modern tools to assess MCM safety, efficacy, quality & performance
• Collaborations with BARDA, HHS ASPR, CDC
• Emergency preparedness
KEY FEATURES
MEDICAL COUNTERMEASURES INNOVATION
CURRENT
STATUS
IMPACT

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• Vaccine innovation promoted through collaborations with
NIH, CDC, BARDA, and consultations with DoD and VA
• Ties into provisions covered under
1. Novel clinical trial designs
2. Real world evidence
3. Protection of human research subjects
4. Informed consent waiver or alteration for clinical
investigation
• All guidance
documents
covering the
provisions above
are applicable
• All incentives
covering the
provisions above
are applicable
• Framework for
vaccine
development and
access to be
defined through
Interagency
collaborations in
near future
• Use of adaptive trial designs, modeling tools, streamlined
IRB process and acceptance of RWE
• Harmonize differences between HHS and FDA regulations
KEY FEATURES
VACCINE ACCESS, CERTAINTY, AND INNOVATION
CURRENT STATUS
IMPACT

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KEY MESSAGES FROM
CURES ACT
• Provides an unprecedented discretion to
regulators over the type of evidence they
require to approve new drugs and devices
• Expands acceptance of biomarkers and
surrogate endpoints to accelerate
development significantly
• Shifts regulatory landscape with
o Opportunities (streamlined development,
more regulatory advice, faster times to
market)
o Risks (smaller clinical data sets, rapidly
changing science, reimbursement hurdles)
• Requires agility and flexibility on the part of
developers to reap the benefits while avoiding
the pitfalls
• Impacts Accelerated Pathways - no longer an
exception but rather a rule
• Provides tactics, e.g., meeting with regulators
to pressure test the ideas and seeking
tailored agreements

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STRATEGIC DEVELOPMENT OPTIONS UNDER CURES ACT
Patient Centric
Approach
Adaptive Trial Designs
& Modeling
Breakthrough Device
Program
Therapies for Rare
Diseases
Real World Evidence
Medical
Countermeasures
Strategy
Limited Population
Pathway for
Antibacterial Drugs
Regenerative
Advanced Therapies

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REFERENCES
• https://www.congress.gov/114/plaws/publ255/PLAW-114publ255.pdf
• https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstot
heFDCAct/21stCenturyCuresAct/default.htm
• https://www.fda.gov/NewsEvents/Testimony/ucm587804.htm
• http://www.fdalawblog.net/2016/12/the-president-signs-21st-century-cures-into-law-
highlights-of-drug-and-biologic-related-provisions-p/
• http://www.fdalawblog.net/2016/12/highlights-of-drug-and-biologic-related-provisions-of-
21st-century-cures-part-two/
• https://www.raps.org/regulatory-focus%e2%84%a2/news-articles/2016/11/regulatory-
explainer-21st-century-cures-redux-and-what-it-will-mean-for-fda
• https://www.fda.gov/downloads/ForIndustry/DevelopingProductsforRareDiseasesCondition
s/HowtoapplyforOrphanProductDesignation/UCM565068.pdf
• https://blogs.fda.gov/fdavoice/index.php/2017/06/fostering-medical-innovation-a-plan-for-
digital-health-devices/
• https://www.fda.gov/downloads/drugs/developmentapprovalprocess/smallbusinessassistan
ce/ucm572939.pdf
• https://www.raps.org/news-articles/news-articles/2017/8/fda-finalizes-guidance-on-
antibacterial-therapies-for-unmet-needs
• https://www.fda.gov/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/
AboutMCMi/ucm262925.htm?utm_campaign=20180228%20MCMi&utm_medium=email&ut
m_source=Eloqua
• https://globalforum.diaglobal.org/issue/march-2018/

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THANK YOU
© 2018 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL16
Mamata.Gokhale@PAREXEL.com