Download FDA Update: FDA`s increasing expectations, Ways to address and

FDA Update:
FDA’s increasing expectations, Ways to address and capitalize on
them, and Alternate ways to survive in the current environment
Mike Druckman, Partner, Pharmaceutical and Biotechnology Practice
November 11, 2010
Food and Drug Group / Washington, D.C. Office
Overview
• FDA’s Increasing Expectations
– Comparative Effectiveness Data
– Biomarkers, including genomic biomarkers
• Ways to Address and Capitalize on Them
– Anticipate new expectations; avoid surprises; listen carefully; keep
updated; build credibility with FDA
– Capitalize on opportunities, and consider creative approaches
• Alternate Ways to Survive in the Current Environment
– Federal grants and cooperative agreements
– Partnerships and licensing deals
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FDA’s Increasing Expectations:
Comparative Effectiveness Data
• Comparative effectiveness data are not statutorily required
for drug approval
• C. Estes Kefauver, co-sponsor of the 1962 Drug
Amendments, stated:
– It was “only intended that the manufacturer satisfy the Food ad Drug
Administration that it (a drug) was efficacious for the use intended and
claimed by the manufacturer, not [that] it is better than some other
drug or poorer than some other drug.”
• The preamble to the prescription drug labeling rule, 44 Fed.
Reg. 37446 (June 26, 1979), stated:
– “The Commissioner advises that [section] 201.57(c)(3)(v) does not
require that comparative safety or efficacy data be developed for a
drug; rather, it requires that comparative statements of safety or
effectiveness in prescription drug labeling be supported by substantial
evidence or other adequate scientific evidence.”
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FDA’s Increasing Expectations:
Comparative Effectiveness Data
• But for years, doctors have been calling for more
comparative data, to help inform their prescribing
decisions
• FDA desires more comparative effectiveness data
developed during drug development, and that
expectation has increased over the years
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FDA’s Increasing Expectations:
Comparative Effectiveness Data
• FDA created a requirement for comparative
effectiveness in drugs intended to treat lifethreatening and contagious diseases, and those
with irreversible morbidity (e.g., heart attack), where
approved therapies already exist, on safety grounds
• Articulated in 60 Fed. Reg. 29180 (Aug. 1, 1995)
– Acknowledged that superiority to placebo is the norm, but:
– “In certain circumstances, however, it may be important to
consider whether a new product is less effective than
available alternative therapies, when less effectiveness
could present a danger to the patient or to the public.”
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FDA’s Increasing Expectations:
Comparative Effectiveness Data
• FDA has been expanding that concept to cover
more categories of drugs, particularly late entrants
into crowded therapeutic classes
– E.g. Fanapt (iloperidone) – atypical antipsychotic for
schizophrenia
•
•
•
July 25, 2008 Not Approvable Letter: Even though the sponsor
showed superiority to placebo, FDA rejected the application based
on concerns that iloperidone demonstrated inferior effectiveness
compared to active comparators in the same drug class
FDA stated that for schizophrenia, inferior efficacy is a safety risk
Ultimately, FDA approved the application because the sponsor
showed that apparent difference in effectiveness was skewed, that
any difference did not equate to safety risks, and that iloperidone
has safety advantages over other drugs in its class
– Ultimately, complex comparative analysis was required
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FDA’s Increasing Expectations:
Comparative Effectiveness Data
• The American Recovery and Reinvestment Act of
2009 (the stimulus bill) provided $1.1 billion for
Comparative Effectiveness Research (CER), all of
which had to be appropriated by September 2010
• The Patient Protection and Affordable Care Act of
2010 (the Healthcare bill) provides sustained federal
funding for CER through 2019
– It also created the Patient-Centered Outcomes Research
Institute (PCORI), a non-profit corporation designed to set
priorities and help channel CER funding (with sources for
at least $650 million through 2019)
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FDA’s Increasing Expectations:
Comparative Effectiveness Data
• Result of federally funded CER will be that more
comparative effectiveness data on drugs will
ultimately be available
• Doctors, patients, and the public will come to expect
more comparative effectiveness data for all drugs
• Companies will face increased pressure to include
such information in labeling, and FDA will face
increased pressure to require comparative
effectiveness information in labeling and for
approval
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FDA’s Increasing Expectations:
Biomarkers
• Definition: A characteristic that is objectively
measured and evaluated as an indicator of normal
biological processes, pathogenic processes, or
pathological responses to a therapeutic intervention
• Examples:
–
–
–
–
–
Cholesterol
Blood pressure
QT/QTc interval prolongation
Titer levels (suggesting protection against infection)
Certain DNA sequences (that cause disease or indicate
susceptibility to disease)
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FDA’s Increasing Expectations:
Biomarkers
• FDA has initiated many efforts to develop and validate
biomarkers to improve drug safety and efficacy
– The Biomarker Consortium, a public-private research
partnership launched by FDA, the Foundation of the National
Institutes of Health (FNIH), and PhRMA, has funded multiple
biomarker projects
– The Critical Path Institute (C-Path), an independent nonprofit institute, created in 2005 by FDA and the University of
Arizona, has helped develop drug-induced organ toxicity
biomarkers
– Oct. 2010，FDA issued a draft Guidance: Qualification
Process for Drug Development Tools, to encourage industry
to qualify drug development tools like biomarkers
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FDA’s Increasing Expectations:
Biomarkers
• 7 biomarkers that signal kidney injury were
accepted by FDA in May 2008 (and by EMA) for use
in preclinical tests
– Qualified based on a data package developed by the
Predictive Safety Testing Consortium
•
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a group of 16 companies formed by C-Path to allow firms to pool
the resources to develop biomarkers for preclinical safety testing
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FDA’s Increasing Expectations:
Biomarkers
• Biomarkers for drug-drug interactions based on effect on
transporter proteins
– Drugs are actively transported into and out of cells by a variety of
transporter proteins
– Certain drugs are substrates of those transporter proteins
•
•
•
interfere with transporter proteins’ activity
affect the body’s ability to metabolize them
cause drug-drug interactions
– This past March (2010), FDA’s Advisory Committee for
Pharmaceutical Science and Clinical Pharmacology voted that all new
molecular entities should be routinely evaluated during drug
development for whether they are substrates of five critical transporter
proteins
• Pre-clinical expectations are constantly evolving
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FDA’s Increasing Expectations:
Genomic Biomarkers
• One class of biomarker of particular interest to FDA is the
genomic biomarker
– Defined as: “A measurable DNA and/or RNA characteristic that is an
indicator of normal biological processes, pathogenic processes,
and/or response to therapeutic or other interventions.”
– Pharmacogenomics (PGx): “The study of variations of DNA and RNA
characteristics as related to drug response.”
•
Explores ways to predict whether a patient will have a good or bad
response to a drug, or no response at all
• PGx is a category of personalized medicine - the concept
that people’s differences in genetic makeup, environment,
and lifestyle are critical factors in the diseases to which they
are susceptible and the therapies to which they will respond
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FDA’s Increasing Expectations:
Genomic Biomarkers
• Pharmacogenomic information is contained in about
10% of approved drug labels
– List of validated genomic biomarkers in drug labeling:
http://www.fda.gov/Drugs/ScienceResearch/ResearchAre
as/Pharmacogenetics/ucm083378.htm
– Can play an important role in:
•
•
•
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Identifying responders and non-responders
Avoiding toxicity
Adjusting drug dosages to optimize their safety and efficacy
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FDA’s Increasing Expectations:
Genomic Biomarkers
• Most labels, to date, do not provide an immediate
recommendation for a specific action (like genetic
testing)
• Some labels recommend or require genetic testing
to be used for reaching a therapeutic decision, e.g.,
– Erbitux (cetuximab): indicated for patients with Epidermal
Growth Factor Receptor (EGFR)-expressing metastatic
colorectal cancer
– Herceptin (trastuzumab) is indicated for patients whose
tumors have been evaluated with an assay validated to
predict overexpression of the protein known as human
epidermal growth factor receptor 2 (HER2)
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FDA’s Increasing Expectations:
Genomic Biomarkers
• FDA encourages all sponsors conducting pharmacogenomic
tests to submit the results to FDA, but only require the
submission in certain circumstances:
– For INDs:
•
•
•
Where the test results relate to a valid biomarker
Where the results are used to inform clinical trial decisionmaking
Where the results are used to inform drug use decisions (like dose
selection and schedule)
– For NDAs / BLAs:
•
•
Where the test results relate to a valid or probable valid biomarker
When the results will be included in the drug’s labeling or will be submitted
to support approval
• All other exploratory or observational PGx data may be
submitted to FDA on a voluntary basis, as a Voluntary
Exploratory Data Submission (VXDS)
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FDA’s Increasing Expectations:
Genomic Biomarkers
• A VXDS will not be used for regulatory decision
making and will not impact FDA’s review
• FDA encourages VXDS because it can benefit both
the industry and FDA in a general way by providing
a means for sponsors to ensure that regulatory
scientists are familiar with and prepared to
appropriately evaluate future genomic submissions.
• FDA issued the October 2010 draft guidance on the
qualification process for drug development tools in
part to encourage sponsors to collaborate in
qualifying genomic biomarkers
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FDA’s Increasing Expectations:
Genomic Biomarkers
• Required pharmacogenomic data will be evaluated
by FDA as part of the standard review process
• Based on its assessment, FDA may include
pharmacogenomic data in the drug label, either in
an informational manner (that can be considered by
the physician) or to identify appropriate dosages or
patients
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FDA’s Increasing Expectations:
Genomic Biomarkers
• FDA has issued significant other guidance on genomic data,
e.g.:
– Guidance for Industry: Pharmacogenomic Data Submissions (March
2005),
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM
126957.pdf
– Attachment to Guidance on Pharmacogenomic Data Submissions:
Examples of Voluntary Submissions or Submissions Required Under
21 CFR 312, 314, or 601 (March 2005),
http://www.fda.gov/OHRMS/DOCKETS/98fr/2003d-0497-gdl000201.pdf
– E15 Definitions for Genomic Biomarkers, Pharmacogenomics,
Genomic Data and Sample Coding Categories (April 2008)(ICH),
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory
Information/Guidances/ucm073162.pdf
– Genomics: Frequently Asked Questions,
http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmac
ogenetics/ucm083893.htm
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Ways to Address and Capitalize on
FDA’s Increasing Expectations
• Anticipate new expectations
– Where at all unclear, ask explicitly whether comparative effectiveness
data and biomarker data (including genomic biomarker data) will be
required
– Ask on the record in a setting where FDA must produce official
minutes, such as during a formal pre-IND meeting
– Ask details about the nature and extent of the data, and about the
requirements for designing the trial and qualifying the biomarkers
– Having FDA responses in writing helps avoid miscommunications,
and forces FDA personnel to focus as a group on the key issues
– Although FDA can change its mind based on developments in science
or on new facts, sometimes having a strong record can provide a
basis for changing FDA’s view (e.g., iloperidone example), for
obtaining concessions from FDA, or for a formal appeal if necessary
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Ways to Address and Capitalize on
FDA’s Increasing Expectations
• Avoid surprises to the extent possible
– Seek bad news early, in full detail
•
Although FDA will occasionally issue a complete response based on
something totally new and not previously discussed, often they involve
issues FDA or the sponsor raised, which the sponsor incorrectly believed
were resolved
– Keep in mind that FDA personnel do not know your product or your
submission as well as you do
•
•
•
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They sometimes base their advice, at least in part, on what you tell them
during meetings – be transparent and direct; do not assume they have
read everything (example of separate BLA issue)
Particularly during early development, they do not have time to review
everything in your IND files in depth
Although FDA personnel have a lot of experience, they are not clairvoyant
and cannot predict everything that might go wrong with your drug
development program or whether a certain trial design will be optimal
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Ways to Address and Capitalize on
FDA’s Increasing Expectations
• On the other hand, FDA personnel are privy to nonpublic information about drug development
programs that failed
• If they ask for particular tests or data that appear
out of the blue, it often is because they have seen a
problem with a related investigational drug that they
need to rule out
– listen carefully
– read between the lines for clues
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Ways to Address and Capitalize on
FDA’s Increasing Expectations
• Keep updated
– Science and regulatory expectations are evolving quickly
– FDA will expect you to incorporate regulatory changes
(e.g., the requirement imposed this past March that all
new molecular entities be tested for whether they are
substrates of 5 specific transporter proteins that influence
drug metabolism) into your development program, even if
the change occurred after your pre-IND meeting
• Think proactively
– Design trials strategically
•
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E.g., consider implications of active controls (like iloperidone)
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Ways to Address and Capitalize on
FDA’s Increasing Expectations
• Build credibility with FDA
– Demonstrate your familiarity with evolving science and
regulatory requirements by asking about whether they
apply, citing specific guidance documents
– To the extent a new guidance or regulatory expectation
applies, acknowledge it and demonstrate your
understanding and plan to comply (unless you have a
basis to object or seek an exception, in which case do so
directly)
– The relationship you establish early on with FDA is critical
•
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Don’t be the company that FDA brands as the one that “just does
not get it”
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Ways to Address and Capitalize on
FDA’s Increasing Expectations
• Capitalize on Opportunities
– Opportunities for earlier and more frequent conversations
with FDA
•
E.g., to discuss qualification of biomarkers and design of
comparative effectiveness trials
– Use or build on already-qualified biomarkers
•
•
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Under the Drug Development Tool (DDT) Qualification guidance,
“Once a DDT is qualified for a specific context of use, industry can
use the DDT for the qualified purpose during drug development,
and CDER reviewers can be confident in applying the DDT for the
qualified use without the need to reconfirm the DDT’s utility.”
CDER intends to make DDTs available to the public, such as by
issuing new qualification determinations as draft guidance
appendices to the DDT Qualification guidance
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Ways to Address and Capitalize on
FDA’s Increasing Expectations
• Capitalize on Opportunities
– Join or partner with consortia or other organizations to defray costs of
developing biomarkers
– Qualifying a biomarker or implementing a clinical trial arm with an active
comparator may give FDA more assurance in the drug’s safety and
efficacy
•
Ultimately may speed the review process and eliminate multiple review
cycles
– Possibly qualify for accelerated approval (21 CFR Part 314 Subpart H)
– On the other hand, early detection of a safety signal might help a
sponsor cut its losses early, or alternatively, to come up with an
alternate strategy, like focused warnings or a REMS, early in the
development process, making it easier to implement
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Ways to Address and Capitalize on
FDA’s Increasing Expectations
• Capitalize on Opportunities
– Narrow indicated population to those for whom drug will
be effective with a favorable safety profile
•
•
Increase chances of approval
Increase likelihood of showing equal or superior efficacy compared
to an existing therapy (synergy between biomarkers and
comparative effectiveness)
– With a favorable head-to-head trial, obtain data to use in
comparative advertising and promotion
•
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But: proceed cautiously – under 21 CFR 201.6, a false or
misleading representation in the labeling of one drug with respect
to a second drug or device renders the first drug misbranded
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Ways to Address and Capitalize on
FDA’s Increasing Expectations
• Capitalize on benefits
– Use creative strategies to capitalize on benefits
– E.g., if using PGx testing narrows the indicated population
to satisfy the criteria for an Orphan Drug (under 200,000
patients in the U.S.), seek Orphan Drug Designation and
obtain the benefits of an Orphan Drug Approval, including:
•
•
•
•
•
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7 years of exclusivity for that use
Annual grant funding to defray the cost of clinical testing
Tax credits for the cost of clinical research
Assistance with clinical research designs
Waiver of PDUFA filing fees
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Alternate ways to survive in the current environment
• Government Grants and Cooperative Agreements
– As discussed above, comparative effectiveness research
will be funded through 2019
– Although most CER grants issued so far went to
Universities, non-profit organizations, and some private
consulting companies, for-profit companies, including
pharmaceutical, biotech, and medical device companies,
are eligible if their proposals meet the criteria
•
At least one CER grant was issued to a biotech company
– Was a continuation of a prior Small Business Innovative Research
(SBIR) grant
– To develop an angiotensin peptide for treating chronic diabetic ulcers
– In collaboration with scientists at the USC KECK School of Medicine
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Alternate ways to survive in the current environment
• Government Grants and Cooperative Agreements
– Possible strategy: partner with academic researchers or
non-profits on a CER grant
– Another possible strategy: if your product has any
biodefense or medical countermeasure use, seek a
government grant or cooperative agreement, through the
Department of Health and Human Service’s Biomedical
Advanced Research and Development Authority (BARDA)
•
•
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HHS announced a new initiative in August to improve the nation’s
medical countermeasure enterprise
BARDA issues RFPs in this area, including one in August seeking
the development of animal models for testing medical
countermeasures
30
Alternate ways to survive in the current environment
• Partnership strategies
– Common for companies to license out their inventions to
marketing partners
– Also common to use CROs and CMOs to reduce costs
– Medical device companies with novel delivery systems,
like autoinjectors and patches, can partner with
drug/biotech companies to produce combination products
•
FDA has indicated that standards for generics to obtain approval
will be fairly strict
– See FDA Response to Citizen Petition by King Pharmaceuticals on
ANDAs referencing products with autoinjector delivery systems, July
29, 2009, Docket Nos. FDA-2007-P-0128 and FDA-2009-P-0040.
– See also FDA draft guidance, Technical Considerations for Pen, Jet,
and Related Injectors Intended for Use with Drugs and Biological
Products (April 2009)
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Alternate ways to survive in the current environment
• In due diligence, potential partners and buyers
usually assess potential generic competition
– Thus, having a lifecycle management plan is critical
• Medical device companies with genomic biomarkers
or expertise may be able to partner with drug and
biotech companies to pursue a personalized
medicine labeling strategy that lengthens the drug’s
lifecycle
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