Overview of strategic options for expediting new drug development

1. Expedited Development & Review of New Drugs
Jason E. Moore, M.S., M.B.A.
Regulatory Affairs Roundtable

2. Presentation Overview
Strategic Options for Accelerating New Drug Approval
Expedited Review:
Subparts E and H
Expedited
Review p
Subpart E
Life‐threatening or severely debilitating diseases where no satisfactory alternative
therapies exist
Review
Subpart E
Fast Track Designation
Subpart H
Expedited ReviewSubpart H
Fast Track
For “serious or life‐threatening conditions”
Priority Review
Directs attention and resources to the evaluation of
applications that have the potential for significant advances
Designation
Priority
Review applications that have the potential for significant advances
Special Protocol Assessment
Protocol review and agreement for pivotal trials, registration
stability, pivotal carcinogenicity studies
SPA
Orphan Drug
Designation
Orphan Drug Designation
Exclusivity and other benefits for drugs to treat diseases
or conditions that are considered rare in the United States

3. Introduction
Strategic Regulatory Options for Accelerating Drug
Development & Approval

4. Marketing of Drug Products
• Life science companies exist to get new drugs
through regulatory hurdles to the marketthrough regulatory hurdles to the market
• To get to market
$ illi ( f )• $802 million; 10‐15 years (Tufts CSDD)
• $1.7 billion (Bain)
• Much attention to speeding
development and lowering costs
• FDAMA, PDUFA, AA & FT regulations
• Corporate/regulatory strategy

5. New Drug Development
2 4 6 8 1
0
12 14 160

6. Requirements for Drug Approval
• Safety (FDCA, 1933)
• Efficacy demonstrated in adequate and well controlled studies
(1962)(1962)
• Ability to generate product labeling that
• Defines an appropriate patient population
• Provides adequate information to enable safe and effective use• Provides adequate information to enable safe and effective use
• Approval for an indication, not drug
• Basis for efficacy:
• Regular approvalg pp
• Clinical benefit
• Established surrogate for clinical benefit
• Accelerated approval (Subpart H)
Surrogate (reasonably likely to predict CB)• Surrogate (reasonably likely to predict CB)
• Benefits vs risks
• A note about regulatory risk in
new drug developmentnew drug development

7. How Many Trials?
• 505(d) of the FDCA: Substantial evidence: “Adequate and well‐
controlled investigations”
• FDA's position: Congress generally intended to require at least two
d t d ll t ll d t di h i i it tadequate and well‐controlled studies, each convincing on its own, to
establish effectiveness.1
• Single trial (plus supportive evidence):
FDAMA (§115(a)): Agency may consider “data from one adequate and• FDAMA (§115(a)): Agency may consider data from one adequate and
well controlled clinical investigation and confirmatory evidence” to
constitute substantial evidence if FDA determines that such data and
evidence are sufficient to establish effectiveness.
Effi G id “ ll l i i• Efficacy Guidance: “generally only in cases in
which a single multicenter study of excellent
design provided highly reliable and
statistically strong evidence of an important
li i l b fit d fi t t dclinical benefit… and a confirmatory study
would have been difficult to conduct on
ethical grounds.”2
1 See e g Final Decision on Benylin 44 FR 51512 518 (August 31 1979); Warner Lambert Co V Heckler 787 F 2d 147 (3d Cir 1986))1 See e.g., Final Decision on Benylin, 44 FR 51512, 518 (August 31, 1979); Warner‐Lambert Co. V. Heckler, 787 F. 2d 147 (3d Cir. 1986)).
FDA’s position is based on the language in the statute and the legislative history of the 1962 amendments. Language in a Senate report
suggested that the phrase "adequate and well‐controlled investigations" was designed not only to describe the quality of the required
data but the "quantum" of required evidence. (S. Rep. No. 1744, Part 2, 87th Cong. 2d Sess. 6 (1962))
2 Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drugs and Biological Products, 1998.

8. Expedited Review
Subpart E

9. Subpart E
• In 1988, FDA formalized procedure to expedite the
development, evaluation, and marketing of products
intended to treat life‐threatening or severely
debilitating diseases where no satisfactory
alternative therapies existp
• Largely superceded by Subpart H, but remains viable
• One of few instances in which FDA has been receptive
to less substantial datato less substantial data
• Supports broad patient access
• Allows a compressed clinical trial p
procedure
• No formal application procedures
or guidance docsor guidance docs

10. Applicable Definitions
• “Life Threatening”: Diseases or conditions where the
likelihood of death is high or likely (ie, 6 months to 1
year) unless the course of the disease is interruptedyear) unless the course of the disease is interrupted,
and diseases or conditions with potentially fatal
outcomes where the endpoint of clinical trial analysis
is survival
• Eg, metastatic breast cancer, amyotrohic lateral sclerosis
“S l D bilit ti ” Di diti th t• “Severely Debilitating”: Diseases or conditions that
cause major irreversible morbidity.
• Alzheimer’s disease or Huntington’s diseaseAlzheimer s disease or Huntington s disease
[21 CFR 312.81]

11. Subpart E Elements
• Four key elements
• Early consultation between FDA and sponsor y p
[21 CFR 312.82]
• Phase 2 controlled clinical studies designed to
provide sufficient data to support an approval
decision
Ri k b fi l i i FDA’ f S/E• Risk‐benefit analysis in FDA’s assessment of S/E [21
CFR 312.84]
• Post‐approval studies requiredPost approval studies required
[21 CFR 312.85]

12. Early Consultation
• FDA will consult earlier and more fully on design
of preclinical and clinical studies
• Essentially, Agency itself makes an investment in
the development process

13. Phase 2 Controlled Clinical Studies
• FDA will consider using data derived from
phase 2 trials as basis for approval
• Phase 3 studies not eliminated, but instead
“compressed” into the phase 2 studies.
• Phase 1 and 2 studies generally larger and more
complex—thus more expensive—than
t diti l h 2 t ditraditional phase 2 studies
• Traditional assessment of
b fit/ i k i b tbenefit/risk remains, but
Agency can be more flexible

14. Phase 2 Controlled Clinical Studies (cont)
• Sponsors should plan in advance a strategy for
replicating key findings through a second well‐
t ll d t dcontrolled study
• But, in rare cases, a single multi‐center study
demonstrating a consistently dramatic increase indemonstrating a consistently dramatic increase in
survival among independently evaluable study
sites could be the basis of an approvalpp
• FDA may ask sponsor to submit a
Treatment IND protocol while
application is under review if
preliminary results appear promising
[21 CFR 312 83][21 CFR 312.83]

15. FDA Benefit‐Risk Analysis
• FDA reviews marketing application for adequacy of
substantial evidence of safety and efficacy
FDA i l id f f d ffi• FDA requires no less evidence of safety and efficacy,
but have greater flexibility on where hurdle is set
• Subpart E codifies a review procedure to consider• Subpart E codifies a review procedure to consider
disease severity, and whether a satisfactory
alternative therapy exists, in determining whether
benefits > risks
• All normal safeguards to ensure
patient safety still applypatient safety still apply

16. Post‐Approval Studies
• Upon approval, FDA will almost certainly require the
sponsor to conduct post approval studies whichsponsor to conduct post‐approval studies, which
could include:
• Different doses or schedules
• Variations of approved use
• Different patient populations or stages of disease
• Longer treatment times• Longer treatment times
• Two‐fold purpose:
• Extend knowledge about drug’s safety
and efficacy
• Allow physicians to optimize
product useproduct use

17. Strategic Issues/Risks of Subpart E
• Increased Agency participation could result in loss of
control of R&D process
• “Condensed” study approach leads to “condensed”
study costs
• Requirement for post‐approval studies offsets some
advantages of condensed studies
• Treatment protocol brings with it…
• Product liability exposure
L ll d d• Less controlled study

18. Expedited Review
Subpart H

19. Subpart H ‐‐ “Accelerated Approval”
• Intended to expedite approval for patients with
“serious or life threatening illnesses” when the drugserious or life threatening illnesses when the drug
provides “meaningful therapeutic benefit” to
patients over existing treatments [21 CFR 314.500]
• Elements:
• Use of surrogate endpoints
P t l t di• Post‐approval studies
• Pre‐review of promotional materials
• Provisions for restricted distribution or use
• Again, no guidance document on
Subpart H/AA, but…

20. Accelerated Approval Discussed
Extensively in FRExtensively in FR
57 FR 58942-5896057 FR 58942 58960

21. “Serious and Life‐Threatening”
• “Serious”:
• A matter of judgment, but based on its impact on
factors such as survival day‐to‐day functioning or thefactors such 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 (HIV/AIDS IBD Alzheimer’s)one (HIV/AIDS, IBD, Alzheimer s)
• “Life‐threatening”:
• Diseases or conditions where the likelihood of
death is high or likely unless the
course of the diseases is interrupted,
and
• Diseases or conditions with
potentially fatal outcomes where
the endpoint of clinical trial p
analysis is survival

22. “Meaningful Therapeutic Benefit”
• “Benefit”
• is clinically meaningful y g
• Depends almost completely on clinical setting
• FDA cites use of “available internal and external• FDA cites use of available internal and external
expertise” to define
Benefit risk context• Benefit‐risk context

23. Surrogate Endpoints
• Accelerated approval of new drugs and biologics
based on product’s effects on an objective surrogatebased on product s effects on an objective surrogate
(non‐ultimate) clinical endpoint [21 CFR 314.510]
• Surrogate Endpoint: “A laboratory or physical sign• Surrogate Endpoint: A laboratory or physical sign
that is used in the therapeutic trials as a substitute
for a clinically meaningful endpoint that is a direct f y gf p
measure of how a patient feels,
functions, or survives and that
is expected to predict the
effect of the therapy.” [57 FR 13234]
bl h d bl h d• Established vs un‐established surrogates

24. Motivation for Using Surrogates
• Replace a distal endpoint with a more proximal
one that can be measured
• earlier
• more easily or frequently
• with higher precision
• Less subject to competing risks
• Less affected by other treatment
modalities
• Reduced sample size requirements
• Faster decision making

25. Biomarkers and Surrogate Endpoints
• Surrogate endpoints are a subset of biomarkers
• Surrogate Endpoint: Laboratory effect or other direct measurement that
itself does not directly measure clinical benefit, but is thought to
correspond to clinical outcome
• Biomarker: Characteristic that is objectively measured and evaluated as
indicator of normal biologic or pathogenic processes or pharmacological
responses to a therapeutic interventionresponses to a therapeutic intervention
• Physiologic function (blood pressure; total lipids, lipid fractions; CD4 count)
• Effects on activity of an intrinsically or externally induced molecule (enzyme,
hormone, or cytokine), y )
• Effect on etiologic agents or anatomical features (RNA viral load; tumor size;
coronary artery occlusion; hallmarks of neurologic disease)
• A biomarker is a candidate for surrogate
endpoint if the biomarker is expected
to predict clinical benefit based on
epidemiologic, therapeutic,
pathophysiologic, or other scientific evidence

26. Post‐Marketing Data
• Required to…
• “verify and describe the drug’s clinical benefit and to resolveverify and describe the drug s clinical benefit and to resolve
remaining uncertainty as to the relation of the surrogate
endpoint upon which approval was based to clinical benefit, or
the observed clinical benefit to ultimate outcomes.”
[21 CFR 314 510][21 CFR 314.510]
• If data are not confirmatory,
or the applicant fails to
d h d i hconduct the study with
due diligence, the regulations
describe a procedure for p
withdrawing the product
from the market
[21 CFR 314 530][21 CFR 314.530]

27. Strategic Issues/Risks of Subpart H
• Surrogate‐Related Evidence for Accelerated Approval
• Substantial evidence from well controlled clinical trialsSubstantial evidence from well controlled clinical trials
regarding a surrogate endpoint
• NOT: Borderline evidence regarding a clinical benefit endpoint
• ODAC Meeting on Accelerated Approvals (March 2003)• ODAC Meeting on Accelerated Approvals (March 2003)
• Confirmatory studies should be part of drug development plan
• Early discussion of confirmatory studies with Agency
• ODAC wants to be consulted on confirmatory study plans• ODAC wants to be consulted on confirmatory study plans
• Other Issues
• Statistical issues
i l di hi h d b l• Requires post‐approval studies, which tend to be larger

28. Strategic Issues/Risks of Subpart H (cont)
• Vast majority of post‐approval studies conducted (in
cancer indications) were controlled trials comparing
the Subpart H product with one or more alternativethe Subpart H product with one or more alternative
treatments
• So, sponsors that choose this option must beSo, sponsors that choose this option must be
confidents that their drug will be comparable
(ie, non‐inferior) to alternative treatments
• This is especially important because of
expedited withdrawal procedures

29. “E” Versus “H”
Subpart E
• Procedure to expedite the
development evaluation and
Subpart H
• “Accelerated approval” of new
drugs and biologics based ondevelopment, evaluation, and
marketing of products intended
to treat “life‐threatening or
severely debilitating diseases
h i f
drugs and biologics based on
product’s effects on an objective
surrogate endpoint
• Intended to expedite approval
where no satisfactory
alternative therapies exist”
• Less substantial data
Supports broad patient access
for patients with “serious or life
threatening illnesses” when the
drug provides “meaningful
therapeutic benefit” to patients• Supports broad patient access
• Allows a compressed clinical
trial procedure
therapeutic benefit to patients
over existing treatments

30. Fast Track Designation

31. Fast Track Designation
• Fast Track refers to a process for interacting with FDA
during drug development
• 1997: Sec. 112 of FDAMA created Sec. 506 of FDCA
• Codifies and expands Subpart H regulations
• Under Sec. 506, FDA must, at the request of a sponsor,
facilitate development and expedite review of drugs that
demonstrate the potential to address unmet medical
needs for “serious or life‐threatening conditions”
• “Fast Track Product”: drugs that
demonstrate the potential todemonstrate the potential to
address unmet medical needs
for serious or life‐threatening
conditions

32. Fast Track Algorithm
Is some aspect of the condition
serious or life‐threatening?serious or life threatening?
No Not FTYes; possibly FT
Does the drug show potential to treatDoes the drug show potential to treat
a serious aspect of the condition?
Yes, possible FT No Not FT
Is the drug development program designed
to determine whether the drug will affect
f h d
p
a serious aspect of the condition?
Yes, possible FT No Not FT

33. Fast Track Algorithm (cont)
Is there any approved treatment for the
serious or life‐threatening aspect of theg p
condition being studied?
Yes, possibly FT No FTes, poss b y
Is a medical need unmet by
available treatments
No FT
available treatments
Yes, possibly FT
Is that unmet medical need being
No Not FT
Is that unmet medical need being
studied with this product? No Not FT
Yes FT

34. Fast Track Components
• FDA may approve application based on
li i l d i t t d i tclinical endpoints or surrogate endpoints,
and impose
R i t f t l t di ( d• Requirement for post‐approval studies (and
provision for expedited withdrawal)
• Pre‐review of promotional materialsPre review of promotional materials
• Permits “rolling” marketing
applicationsapplications
• FDA awareness efforts

35. Qualifying for Fast‐Track Designation
• Sponsor may request designation if met
conditions of algorithmconditions of algorithm
• Request generally required to state and
support:pp
• That the therapy is intended to treat a serious or
life‐threatening condition, and
Th t th th h th t ti l• That the therapy has the potential
to address an unmet medical need
that is being evaluated
• Note: FT Designation applies to
combination of therapy and
indication (and not to theindication (and not to the
product alone)

36. “Serious and Life‐Threatening” ‐‐ Same as
in Subpart Hin Subpart H
• “Serious”:
• A matter of judgment but based on its impact on factors• A matter of judgment, but based on its impact on factors
such as survival, day‐to‐day functioning, or the likelihood
that the disease, if left treated, will progress from a less
( /severe condition to a more serious one (HIV/AIDS, IBD,
Alzheimer’s)
• “Life‐threatening”:• Life‐threatening :
• Diseases or conditions where the likelihood
of death is high or likely unless the
course of the diseases is interrupted, and
• Disease or conditions with potentially
fatal outcomes where the endpointfatal outcomes where the endpoint
of clinical trial analysis is survival.

37. Selected Fast Track Indications
• CDER
• Coronary syndrome
• CBER
• Advanced RA
• CVA
• ALS
• Malignancies
• Malignancies
• Fabry’s Disease
• Critical limb ischemiag
• Acute pancreatitis
• Platelet adhesion
• HIV
• Muscular dystrophy
• Hepatic failure
• Crohn’s disease• HIV
• SLE
• ARDS
• Crohn s disease
• HIV
• SLE
• Acromegaly • Multiple Sclerosis

38. Discusses…
• Criteria for qualification
• Process for designation
of drug for FT program
• Programs for expediting
development and
review

39. Fast Track Programs for Expediting
Development ‐‐ MeetingsDevelopment ‐‐ Meetings
• Pre‐IND consultation
• Design of preclinical studies to demonstrate potential toDesign of preclinical studies to demonstrate potential to
address UMN
• Overall development strategy
• Other possible issues regarding FT designation• Other possible issues regarding FT designation
• End‐of‐P1 meeting
• Potential for data from P2 controlled clinical
t i l f lif th t i ltrials for life‐threatening or severely
debilitating illnesses to be basis for approval
(21 CFR 312.82)
E d f P2 ti• End‐of‐ P2 meeting
• Agreement on design of pivotal trials
(note substantial evidence standard
(21 CFR 314 126) i li bl )(21 CFR 314.126) remains applicable)

40. Fast Track Programs for Expediting
Development ‐‐ Meetings (cont)Development ‐‐ Meetings (cont)
• Pre BLA/NDA meeting, to achieve agreement on:
P li i id f ff ti i i i l WCT• Preliminary evidence of effectiveness seen in principal WCTs
• Structure, content, and timing of BLA/NDA, including in rolling
submission
• Structure and content of any electronic submissions
• Readiness for, and proposed timing of, PAIs
• Potential for, and proposed timing of, advisory committee , p p g , y
presentation
• Meeting to discuss labeling issues
In addition to meeting minutes the• In addition to meeting minutes, the
FDA will provide (commitment)
letters at EOP1 and EOP2
commenting on adeq ac ofcommenting on adequacy of
P2/3 development plans

41. FT Programs for Expediting Review
• Rolling Submission
• Only entire sections eligible (eg CMC Tox Clinical;Only entire sections eligible (eg, CMC, Tox, Clinical;
some exceptions, at Agency discretion)
• No draft reports
• Official filing awaits complete application; review
clock starts with complete NDA/BLA
• Expectation that submission schedule
is adhered to by sponsor
Scheduling of review TBD by• Scheduling of review TBD by
division
• User fee must be paid withUser fee must be paid with
first portion

42. Other Programs/Standards
Applicable with FTApplicable with FT
• Priority Review of BLAs/NDAs – FT products
normally eligible (see below)
• Eligibility for Priority Review and Accelerated
Approval (unlinked)
• Efficacy standard in 505(d) (unlinked)y ( ) ( )

43. Priority Review
• All marketing applications designated as “priority” or
“standard”
• Depends on estimate of therapeutic, preventive, or
diagnostic value
• Directs attention and resources to the evaluation ofDirects attention and resources to the evaluation of
applications that have the potential for significant
advances, particularly for patients with serious or life‐
threatening illnessesthreatening illnesses
• FDA, under its PDUFA requirements,
is committed to review “standard”
NDA BLA i hi 10 hNDA or BLA within 10 months
of submission
• Reviews “priority” NDA or BLAReviews priority NDA or BLA
within 6 months

44. Priority Review (cont)
• Drug or biologic product may receive priority review, for
example, if
• There is documented improvement in patient compliance• There is documented improvement in patient compliance
• There is a significant reduction or elimination of a treatment‐
limiting drug reaction
• There is adequate safety ad effectiveness data to justify theThere is adequate safety ad effectiveness data to justify the
use of the product in a new subpopulation of patients with the
disease [CDER MAPP 6020.3]
• While biologic products must be intended for the g p
treatment, diagnosis, or prevention of a
serious or life‐threatening disease to
receive a priority review…p y
• Drug products can attain a priority
designation if they offer a significant
improvement compared to marketed p p
products for serious or
non‐serious disease

45. Special Protocol Assessment

46. Special Protocol Assessment
• Provided for in section 505(b) of the Act by Section
119(a) of FDAMA
FDA i t t ith t h t th• FDA is to meet with sponsors to reach agreement on the
design and size of pivotal clinical trials
• If agreement reached, Agency will reduce agreement to
writing and make it part of administrative record
• An agreement may not be changed by the sponsor or
FDA after the trial begins, except g , p
• with the written agreement of the
sponsor and FDA, or
• if "a substantial scientific issue essentialif a substantial scientific issue essential
to determining the safety or
effectiveness of the drug" is
identified later

47. Special Protocol Assessment
• Upon request, FDA will evaluate within 45 days
certain protocols to assess whether they meet
i ifi d l i id ifi d bscientific and regulatory requirements identified by
the sponsor (eg, design, conduct, analysis)
• Animal carcinogenicity protocolsg y p
• Final product stability protocols
• Certain clinical protocols for phase 3 trials
Trials whose data will form the primary basis for• Trials whose data will form the primary basis for
an efficacy claim (pivotal clinical trials)
and have been subject of discussion at
an end‐of‐phase 2/pre‐phase 3 meeting
with the review divisionwith the review division
• Trials for which the division agrees
to such a review because the division
is aware of the developmental context
h h h l b din which the protocol is being reviewed
and the questions are being answered

48. Discusses…
• Background
• Requests
– Timing
– Format
• Agency Process• Agency Process
• Meetings
• Documentation

49. Orphan Drug Designation

50. Orphan Drug Designation
• Orphan Drugs treat diseases or conditions that are
considered rare in the United States
• "...the term rare disease or condition means any
disease or condition which
( )• (a) affects less than 200,000 persons in the U.S.
[prevalence], or
• (b) affects more than 200,000 persons ( ) , p
in the U.S. but for which there is
no reasonable expectation that the cost
of developing and making available p g g
in the U.S. a drug for such disease
or condition will be recovered from
sales in the U.S. of such drug." g
• See 21 CFR 316

51. Incentives under the ODA
• A seven‐year period of exclusive marketing to the first
sponsor who obtains marketing approval for a designated
orphan drug or biological product for a particular indicationorphan drug or biological product for a particular indication
• Tax credits for clinical research undertaken by a sponsor to
generate required data for marketing approval
• Human drug application not subject to a User Fee unless it• Human drug application not subject to a User Fee unless it
includes an indication for other than a rare disease or
condition
• Protocol Assistance• Protocol Assistance
• The ODA provides for formal protocol assistance
when requested by the sponsors of drugs
for rare diseases or conditions
• A sponsor need not have obtained
orphan drug designation to receive
protocol assistance

52. OOPD Grants Program
• Requires separate application; not synonymous
with orphan drug designation
• Provides funds for clinical development of orphan
products
• All studies must be conducted under an IND/IDE
• Clinical trials are awarded grantsClinical trials are awarded grants
from $200,000 (Phase 1) to
$350,000 (Phase 2 and 3) $ , ( )
per year in total costs for
up to 3 years

53. New Drug Development
2 4 6 8 1
0
12 14 160

54. Thank you!!
Jason E. Moore, M.S., M.B.A.
j @ l h | 713 842 1249 207jason.moore@plxpharma.com | 713‐842‐1249 x207
http://www.linkedin.com/pub/jason‐moore/9/1b6/b0b

55. Questions?