the trials and tribulations of combination product development
TRANSCRIPT
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Steve Rabin, Ph.D.SBR ConsultingBio2Device Group
September 7, 2010
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Lots of combo product development experience
Well-versed in pharma, med device regulations
Passion is for developing products that enhance people’s lives
Recovering New Yorker Contact info: SBR Consulting [email protected] 650-799-8441
© 2010 Steve Rabin 2
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Any combination of two types of therapeutic products, both of which are necessary to achieve intended use◦ Drug/Medical Device◦ Biologic/Medical Device◦ Biologic/Drug
Becoming more prevalent as companies:◦ Push the technological envelope◦ Expand patent protection◦ Work with other companies (partnerships, alliances)
3© 2010 Steve Rabin
FDA Combination Product Definition: 21 CFR § 3.2(e)
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Drug patches
Pre-loaded Injector Pens
Collagen Sponge with Human Protein
Drug-eluting Stents
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Drug Delivery◦ Enhance bioavailability, reduce side effects,
continuous delivery, targeted delivery Convenience◦ Epi-pen
Business reasons◦ New life for old drugs and devices Possibly reduced regulatory requirements◦ Add-ons and enhancements for existing devices◦ Patent extensions◦ Possibility of competitive advantage
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Fully integrated◦ Comes as one unit, operation can’t be separated◦ Examples: patches, single-use injectors, drug-
coated stents Partially integrated◦ Comes separated, often reusable◦ Example: Asthma inhalers, reusable injectors
Non-integrated◦ Two unique parts that don’t really work together Example: surgical kits containing drug (lidocaine, for
example) © 2010 Steve Rabin 6
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Non-integrated◦ Straightforward—two independent products, one
drug, one device◦ Generally, FDA centers only review parts that are
under their jurisdictions Partially integrated◦ Can be done as independent products (or not…)
Fully integrated◦ Can be much more difficult◦ Real intent of the combination products guidances
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Drugs and Devices are regulated differently, by different parts of the FDA
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Must adhere to rules and ‘guidances’ of both disciplines
Always use good science and engineering Quite a bit of overlap◦ Opportunity for streamlining
Some things may not make sense E.g. accelerated drug stability protocol for devices Must do what does make sense; address the
‘requirements’ by documenting decisions
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Drugs DevicesRegulated by: CDER CDRHRelevant sections Drug cGMPs (21CFR
210-211)Device cGMPs (21CFR 820)
Emphasis •Quality systems•Corrective and preventive action•Individual outputs•Large clinical trials•Risk assessment (but not really…)
•Quality systems•Design controls•Quality by design•Risk assessment•Process as a continuum•Small, focused clinical trials (maybe)
Timeframes Long (6-10 years) Short-medium (1-5 years)CDER = FDA Center for Drug Evaluation and ResearchCDRH = FDA Center for Device and Radiological HealthCFR = Code of Federal RegulationscGMPs = Current good manufacturing practices
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IND submissionPre-IND
Animal
Phase I
FDA Approval SmallSafety Study
Phase II
Mid-sizedTest efficacy
Phase III
LargeEfficacy
Adverse reactions
NDAsubmission
FDA Approval
(hopefully)
Honkin’ big E-document
John Q. Public
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Class I – No approvals needed Class II – No clinicals neededClass III – Full approval needed with clinicals
Source: http://www.emergogroup.com/files/uploads/brochures/Medical-Device-Regulatory-Process-Chart-USA.pdf
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Pre-2003◦ No official policy; regulated by whichever office
they thought appropriate Since 2003◦ The Medical Device User Fee and Modernization Act
(MDUFMA) created the Office of Combination Products (OCP)◦ Mission of the OCP: act as a focal point for
combination product issues for agency reviewers and industry
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Duties have been evolving over the years◦ Developing guidances for industry◦ Act as project manager for products reviewed by
multiple centers◦ Act as ‘referee’ between centers and filing company◦ Assign an FDA center primary jurisdiction for review
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But something is missing here—What is it?
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No regulatory authority! Still subject to guidances and rules of each
reviewing center, PLUS any guidances and rules from OCP
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Filing company
OCP
CDERCBER
CDRH
Why is this a potential problem?
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The industry doesn’t sell therapies, it sells risk◦ ANY procedure, drug, device use incurs risk◦ May not work as intended◦ May have adverse effects (or worse…)
The industry tries its best to mitigate risk◦ Clinical trials◦ Information to patients and HCPs◦ Idiot-proofing
Informed decision between patients and HCPs Risk is also what the FDA sells© 2010 Steve Rabin 15
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FDA’s primary role: Protecting the American people◦ They take this very seriously, and do a good job at
it! FDA oversight by Congress◦ “Why did you let this drug out?”◦ “Why did you not require a review of this device?”◦ “This isn’t safe!”
As a result, FDA is somewhat gun-shy Look at risk/benefits
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No concept of ‘failure’◦ All individual units considered the ‘same’◦ Variability in dosage level taken into account in
labeling Understood in terms of adverse effects or
lack of efficacy Mitigated by clinical studies and labeling◦ Test on large number of people to show safety and
efficacy (‘a numbers game’)◦ Risk assessment
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Everything will fail◦ The questions are how, when, and what happens
The idea is to push failure point way out of the operating domain◦ Time◦ Environmental conditions◦ Training
Mitigated by Design, Risk Assessment, Training, Clinicals (if applicable)
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Each center defines and understands risk differently
Each center honestly wants to protect the public
Each weighs in on their area of expertise◦ Sometimes, they weigh in on things they aren’t in
their areas of expertise as well Reviews are not done jointly (meetings are)
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Filings are complex Often get long list of “requests” upon review◦ Sometimes these are conflicting
The ‘f’ word (failure)◦ Understood for medical devices, but not drugs◦ Must be mentioned and addressed, but be careful—
not always understood
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Lots of recent turnover◦ Many of the experienced people have left◦ People VERY dedicated, but some are still learning
CBER, CDRH have collaborative reputations◦ CBER in particular likes to meet with companies and
maintain lines of communication; act as a sounding board◦ CDRH also will do this
CDER is very overworked◦ Difficult to get an audience with Only will meet if absolutely necessary◦ Prefer things in writing, with answers in writing
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Often come from an expansion of existing capabilities of one class (e.g. a device company expanding into drugs)
Starting from scratch Rule of thumb:◦ Companies do a good job developing product
within their expertise, but not such a good job outside◦ Device regs sufficiently different than drug regs and
biologic regs© 2010 Steve Rabin 22
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Get the right personnel◦ Hire people who have the right expertise in the area where you’re
weakest◦ Don’t depend on developing the right people internally without
getting the expertise up front The regs are sufficiently complex and different
Design the product from the start as a combination product, not an ‘add-on’
Adhere to all of the regs as best as possible—don’t skimp Communicate internally Partner with the FDA◦ OCP and both centers◦ Get as much discussion and guidance as possible◦ Don’t be afraid of the FDA—they’re good scientists, engineers and
doctors, and very professional◦ Let your SME’s do the talking—build a rapport with the Agency© 2010 Steve Rabin 23
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Europe◦ Newer regulations◦ More ‘holistic’◦ Not easier, just different
Elsewhere, very varied, still developing
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THANKS FOR YOUR ATTENTION !
ANY QUESTIONS?