Download NIRI BioPharma Industry Roundtable January 10, 2007

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NIRI BioPharma Industry Roundtable
January 10, 2007
Daniel E. Troy
TOKYO
WASHINGTON, D.C.
The Situation at FDA Before 2004
2
•
Healthy appreciation for risk/benefit
•
All drugs have risks
•
FDA as a risk management agency
•
Lessons of the AIDS experience
•
Bayesian statistics discussion
•
Focus on post-marketing systems
•
Role of PDUFA
2004
• Preemption
• Importation
• Flu Vaccine
• SSRIs
• Vioxx
3
Consequences of Drug Safety Controversy
• Pendulum has swung
– bureaucratic incentives
• Slow-down in approvals
• Increased requests for pre-market studies
• Routine use of black box warnings
• Routine use of RiskMAPs
• Tysabri “pause”
• Palladone withdrawal
• Whistleblower culture
4
A (Scary) Vision of the Future
• RiskMAP Tools
– Targeted Education
– Reminder Systems
– Performance-Linked Access Systems
• Real-World Examples
– Forteo
– Humatrope
– Crestor
– Symalin
5
RiskMAP Tools
1. Targeted Education and Outreach
Healthcare practitioner letters
Training programs for healthcare practitioners or patients
Continuing education for healthcare practitioners
Prominent professional or product notifications
Patient labeling such as Medguides and PPIs
Promotional techniques such as DTC ads highlighting
appropriate use
Patient-sponsor interaction and education systems such
as disease management and patient access programs
6
RiskMAP Tools
2. Reminder systems
Consent forms
Training programs including testing or other
documentation
Enrollment of physicians, pharmacists, or patients in
registries
Limited number of doses in any prescription or refill limits
Specialized patient packaging
Stickers, attestations
7
RiskMAP Tools
3. Performance-Linked Access Systems
Sponsor’s use of compulsory access systems
Prescription only by specially certified healthcare
practitioners
Product dispensing limited to specially certified
pharmacies or practitioners
Product dispensing only with evidence or other
documentation of safe-use conditions (e.g., lab test
results)
8
Real-World Examples
• Forteo (12/02)
– Limited initial detailing as quantified by target
population and number of sales reps
– Physician education program
– Sampling – doctors must receive education on drug and
sign form acknowledging they have been informed
about drug’s risk and the approved patient population
– No DTC advertising
9
Real-World Examples
• Humatrope (8/03)
– Restricted labeling
– Physician education
– Marketing limited to pediatric endocrinologists
– Limited sales force
– No DTC
– Controlled distribution process
10
Real-World Examples
• Crestor (8/03)
– 5 mg professional samples to be made available
– Retailers must go through wholesalers to get 40 mg dose
• Symalin (3/05)
– No DTC
– No journal ads for 1 year
– Promotion limited to physicians specializing in diabetes
management
– Gradual introduction of Symalin into marketplace
– Education and outreach programs
• And all this is without explicit legal authority!
11
Further Raising the Ante:
Kennedy-Enzi Bill
• Train wreck ahead? -- Most of these language and
proposals will become a part of the PDUFA
reauthorization debate in the next Congress
• Would required Risk Evaluation & Mitigation Strategy
(REMS) for all NDAs, BLAs, ANDAs, and supplements
for a new indication
• Required elements
– professional labeling
– adverse event reporting
– pharmacovigilance statement & justification
– REMS assessments
12
Kennedy-Enzi Bill:
REMS: Additional Potential Elements
• MedGuide
• Patient package insert
• Communication plan to HCPs
• Post-approval study
• Post-approval clinical trial
• Preclearance of advertising
• Specific disclosures in advertising
• Ban on DTC advertising
13
Kennedy-Enzi Bill:
Restrictions on Distribution and Use
• The Secretary could impose restrictions on
distribution and use:
– specially trained HCPs
– special certifications for pharmacies, health care
centers, etc.
– evidence or documentation of safe-use conditions,
patient monitoring, registries
• Sponsor is responsible for enforcing compliance with
the restrictions, including limiting the participation of
HCPs who have failed to comply
• The Secretary has wide discretion in deciding whether
to impose a REMS requirement on a marketed drug
14
Kennedy-Enzi Bill:
Review, Action, and Dispute Resolution
• Secretary must review, approve, and describe the
REMS
• No earlier than 15 days and no later than 35 days
after “discussions” have begun, the applicant may
request “dispute resolution”
• Dispute resolution mechanism is DSB
• Secretary can meet action deadline by initiating
discussions and complying with timing deadlines of
the dispute resolution process
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Follow-On Proteins
• Two Different Regimes
• Pathways to approval
• 505(b)(2)
• PHS Act
• Omnitrope decision
• Waxman legislation
16
Two Different Regimes
• Food Drug and Cosmetic Act (section 505)
– mostly small molecules
– for historical reasons, some proteins, e.g.,
• insulin
• some hormones, including human growth hormone
• Public Health Service Act
– most biotechnology drugs
17
FDCA – Pathways to Approval
• Stand-alone NDA
• ANDA (a duplicate)
– showing of bioequivalence required
– generally, no clinical studies
– AB rated
• Petitioned ANDA
– differs in strength, dosage form, route of administration, or
active ingredient
– FDA decides, after petition, new clinical studies not needed
• 505(b)(2)
– used >80 times
– generally for new drugs, new indications, combo products
– generally not AB rated
18
FDA Reading of Section 505(b)(2)
• “An application [may be] submitted under [section 505(b)(1)] for
which [safety and effectiveness] investigations . . . relied upon by
the applicant [to support] approvals of the application were not
conducted by or for the applicant and for which the applicant has
not obtained a right of reference or use from the person by or for
whom the investigations were conducted [and] shall also include
[patent certifications for patents on the drug for which
investigations were conducted or a method of use statement].”
19
Different Interpretations of 505(b)(2)
• Paper NDA only (literature based)
• Parkman letter – bypass “phantom ANDA”
• FDA can rely on prior finding of safety and
effectiveness and require only “bridging” studies
• FDA can use material in NDAs
20
FDA View of (b)(2)
(from 10/14 Citizen Petition Response)
• Plain language of (b)(2) is broad, or at least ambiguous
• 1987 Parkman Letter announced broad view
• 1989 NPRM sought notice and comment
• 1994 Final Rule embodied this view in the regulation
• 1999 guidance articulated what FDA has been doing, with
industry knowledge and participation
21
Public Health Service Act
• Covers biologics – “virus, therapeutic serum, toxin,
antitoxin, vaccine, blood, blood component or derivative,
allergenic product, or analogous product . . . applicable to
prevention, treatment, or cure of a disease or condition in
human beings”
– Are also drugs
• No express abbreviated pathway
• Raw data made public
22
Differing views of FDA’s Authority to Create Abbreviated
Pathway Under PHS Act
• None
• Can do so prospectively, after notice and comment
rulemaking
• Can even affect existing product, but after notice-andcomment rulemaking
• Can make policy by approval by making ad hoc shortcuts
(with some use of guidance as well)
23
OmnitropeTM Decision
•
OmnitropeTM (somatropin [rDNA origin])
–
–
–
–
Recombinant human growth hormone
Relatively simple protein with a known mechanism of action
Well characterized single active ingredient
Regulated under the Federal Food, Drug, and Cosmetic Act (FDCA)
• Not the Public Health Service Act (PHSA) like most biologics
•
Sandoz submitted a 505(b)(2) application under the FDCA
– Included original clinical trials involving OmnitropeTM
– Referenced Pfizer’s somatropin product, Genotropin®
•
OmnitropeTM received FDA approval on May 30, 2006
– FDA determined that OmnitropeTM is “highly similar” to Genotropin®
• Relied on the finding that Genotropin® is safe and effective
• Did not rely on manufacturing or trade secret data related to Genotropin®
– To the extent the products differ, the clinical trials supported the
conclusion that OmnitropeTM is safe and effective
– Not rated therapeutically equivalent to Genotropin® (insufficient data)
24
OmnitropeTM Analysis
• Not a new pathway for follow-on proteins
– Previous approvals include GlucaGen®, HydaseTM, and Fortical®
• FDA confirmed its historical interpretation of 505(b)(2)
– May rely on FDA’s finding of safety and efficacy for a previously
approved drug product
• Not the data or trade secrets in the approved product’s application
– May rely on publications for which the 505(b)(2) applicant does not
have a right of reference
• Fact specific determination
– OmnitropeTM is a relatively simple protein (well characterized, single
active ingredient, known mechanism of action)
– Based on the specific facts, FDA concluded that OmnitropeTM is highly
similar to Genotropin® and approved OmnitropeTM under a 505(b)(2)
application that included new clinical data
• There is no abbreviated approval process under the PHSA
25
Access to Life-Saving Medicine Act
Background
• Introduced last year to establish an abbreviated approval
process for biologics under the Public Health Service Act
(PHSA) (H.R. 6257, S. 4016)
– Will likely be reintroduced this year
• Biologics are different than small molecule drugs
– Small molecule drugs are chemically synthesized and are easy
to duplicate
– Biologics are complex protein products made from living
organisms that are inherently variable
26
Access to Life-Saving Medicine Act
Abbreviated Approval
• A follow-on biologic that is “comparable” to a reference
product may rely on the reference product’s finding of
safety, purity, and potency
• Requirements for a comparable biological product
– No clinically meaningful differences from the reference product
– Comparable molecular structure to the reference product
• FDA is required to find that certain products have comparable
structures (e.g., minor differences in amino acid sequence)
– Same mechanism of action as the reference product
– Same conditions of use as the reference product
– Same route of administration, dosage form, and strength as
the reference product
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Access to Life-Saving Medicine Act
Abbreviated Approval (cont.)
• A comparable biologic may differ from the reference product if
there is sufficient data to establish safety, purity, and efficacy
– An application for a comparable biologic will likely require clinical data
• FDA must take final action on an application for a comparable
biological product within the earlier of 180 days from when FDA
accepts the application for filing or eight months from its
submission date, unless the applicant agrees to an extension
• Postmarketing studies may not be required for approval
• An applicant for a comparable biological product may request that
FDA make a determination about interchangeability
– Interchangeability means that the comparable product can be
expected to produce the same clinical result as the reference product
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Access to Life-Saving Medicine Act
Other Provisions
• Market Exclusivity
– Provides the first interchangeable comparable product with
180 days of exclusivity (even against authorized generics)
– No market exclusivity periods for brand name products
• Patents
– Applicant for a comparable biological product may request a
list of relevant patents from the brand name company
– Applicant may provide notice of the patents that are believed
to be invalid or not infringed and identify the jurisdiction
where the applicant agrees to be sued
– Brand name company has 45 days to bring suit on the patents
• Suits brought after 45 days are limited to a reasonable royalty
– No action may be brought on patents not timely disclosed
• No 30-month stay period
29
Access to Life-Saving Medicine Act
Other Provisions (cont.)
• Citizen Petitions Relating to Comparable Biologics
– May not delay approval of a comparable biologic
– Prohibits FDA from considering a citizen petition
submitted within 180 days of the comparable biologic’s
potential approval date without good cause
– Requires FDA to act on a petition within 180 days
• Tax credit for clinical testing regarding the
interchangeability of comparable biological products
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Access to Life-Saving Medicine Act
Summary of Issues
• Scientific Issues
– Comparable biological products may have different structures from
the reference product, which raises safety and efficacy issues
– Restricts FDA’s scientific judgment with respect to determining
whether compounds contain comparable molecular structures
– No clear path for interchangeability and substitution
• Patent and Exclusivity Issues
– Innovator companies received nothing in return for allowing
comparable biological products to rely on innovator data
– No market exclusivity periods for innovators
– No 30-month stay period
– Prohibits the enforcement of patents that are not timely disclosed
– Authorizes the defendant (generic) to select the litigation jurisdiction
• Miscellaneous Issues
– Restricts FDA’s ability to consider issues raised in citizen petitions
– Limits authorized generic products
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Thank you!
Daniel E. Troy
Sidley Austin LLP
202-736-8304
[email protected]
32
Institute of Medicine (IOM) Report
“The Future of Drug Safety: Action Steps for
Congress”
Recommends:
• Reducing FDA’s “dependence” upon PDUFA fees.
• Increasing FDA’s post-marketing safety surveillance
resources.
• Extending term of FDA Commissioner to six years
with for-cause removal.
• Requiring FDA to re-evaluate all new molecular
entities no later than five years after approval.
• Strengthening conflict-of-interest rules governing FDA
advisory committees.
33
Institute of Medicine (IOM) Report
“The Future of Drug Safety: Action Steps for
Congress”
Recommends:
• Giving FDA unambiguous post-marketing authority to
require companies to conduct risk assessment and
risk management programs.
• Requiring drug companies to affix new drugdesignation on newly approved drugs and indications.
• Amending PDUFA to include safety performance
goals.
• Requiring drug companies to publicize information
relating to clinical trials.
34
FDA Responses Thus Far (even pre-IOM)
• Enhanced Patient and Safety Information
– “Drug Watch” -- will be modified; will mention different
vehicles for communicating safety information (labeling,
PPIs\Med Guides, public health advisories, patient
information sheets, healthcare professional sheets,
alerts)
– Revise labeling format and new standardized electronic
drug labeling through NLM
• Restructured CDER -- elevating the Office of Drug Safety
• Enhancing the Culture of Safety in CDER -- formal
professional opinion dispute resolution process within CDER
for drug safety conflicts.
35
FDA Responses Thus Far (even pre-IOM)
Cont.
• Drug Safety Oversight Board (DSB) -- oversees CDER
drug safety work and manages communication of risk
information to patients and professionals.
• Enhancing Risk Communication
– clinicaltrials.gov
• Partnerships through the Critical Path
• Develop Electronic Health Information Architecture
• Dramatically Increased Use of RiskMaps
36
Additional Steps FDA is Likely to Take
• Task force to address IOM report
• Improve quality and effectiveness of information
– Gather better post-market data through contracts with
databases and working with CMS on using Part D claims
data
– Develop guidance on use of epidemiology data
– Re-launch MedWatch portal, regular reports like MMWR
– Collaborate with MIT on system to detect unanticipated
problems with prescription drugs
37
Additional Steps FDA is Likely to Take – Trying
to Refocus Attention on Benefits\Efficacy
• Improve analytical tools (Critical Path)
– collaboration with academy and private industry on
databases, developing assays
– Predictive Safety Testing Consortium (C-Path and
companies)
– five guidances on adaptive trials
– Bioinformatics board
– Guidance on preventative drugs
• secondary and primary prevention
• biomarkers
• optimal trial sizes and duration
38
Additional Steps FDA is Likely to Take
• Improve communication
– develop a social science base
– senior officer in charge of risk communication
– process for drug names
– collaborations with medical groups
39
Access to Life-Saving Medicine Act
Background (cont.)
• The Hatch-Waxman Act basically established an
abbreviated approval process for small molecule drugs
– It is a balance between generic and brand name interests
– A generic may rely on the finding of safety and efficacy for the
brand name drug
– In return, brand name products received 5 and 3-year market
exclusivity periods
– Additionally, the first generic to challenge a patent received a
180-day market exclusivity period
– There is also a 30-month stay to allow for resolution of patent
litigation before the generic receives final marketing approval
40