The Trials and Tribulations of Combination Product Development

Steve Rabin, Ph.D.SBR ConsultingBio2Device Group

September 7, 2010

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

mailto:[email protected]

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)

Drug patches

Pre-loaded Injector Pens

Collagen Sponge with Human Protein

Drug-eluting Stents

4© 2010 Steve Rabin

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


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

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


Drugs and Devices are regulated differently, by different parts of the FDA

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



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


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


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

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


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


But something is missing here—What is it?

No regulatory authority! Still subject to guidances and rules of each

reviewing center, PLUS any guidances and rules from OCP


Filing company

OCP

CDERCBER

CDRH

Why is this a potential problem?

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

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


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


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)


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)


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


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


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

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

Europe◦ Newer regulations◦ More ‘holistic’◦ Not easier, just different

Elsewhere, very varied, still developing


THANKS FOR YOUR ATTENTION !

ANY QUESTIONS?

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The Trials and Tribulations of Combination Product Development