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© NAMSA 2017 Regulatory Pathways: Reducing Time and Cost | 1

MEDICAL RESEARCH ORGANIZATION

Regulatory Pathways: Reducing Time and CostCarla M. Wiese5/25/2017


Carla M. WiesePrincipal Medical Research Scientist

• 18 years in medical device industry- NAMSA: 3 months as a regulatory consultant and

strategist- FDA: 5 years as Lead Reviewer, engineering consultant

in the Division of Cardiovascular Devices and program lead for the Early Feasibility Studies Program

- Research and Development Engineer (large company and startup)


Agenda

• Key factors that impact timeline and cost

• Starting point

• Understanding the regulatory pathways

• Predict regulatory/test requirements

• Develop least burdensome test strategy

• Summary


• Regulatory pathway• Expensive/time consuming testing needs to be re-done (animal

study, MR compatibility etc…) • Clinical study optimized? Leveragability across global regions?• Payers may want different information• Cost to make the product• Problematic data (materials fail biocompatible tests), data that is

difficult to interpret• Will product changes resulting in repeat testing?• Is technology novel? No standards? New to regulators?• Preparedness of the development team

Some Key Factors that Effect Timeline and Cost


Understanding the Competitive Landscape

Indications/claims

Benefits and risks associated with using the device/therapy

Will help you to…

• Anticipate regulatory requirements

• Potentially leverage information

• Understand what will be required to ascertain a competitive advantage


• Define your ideal final product

• Label claims (can be found in the device’s labeling, but may also be conveyed orally during sale of the product!)

Will significantly contribute to data requirements and provide for competitive advantage

• Dosage form (therapeutics)

• Treatment duration

• Target price

• Etc…

START WITH THE END IN MIND

Use this vision to have conversations with regulatory agencies, patients, prescribers, payers

Are your initial thoughts realistic scientifically, socially, culturally, economically?


Understanding Regulatory Pathways


Will your product be regulated by FDA?

• Is your product or product idea intended to cure, treat, mitigate, diagnose, or prevent disease in humans, or is your product (other than food)intended to affect the structure or function of the human body?

- If yes, then your product will likely be regulated by FDA


Center for Biologics

Evaluation and Research (CBER)

Center for Drug Evaluation and

Research (CDER)

Center for Devices and Radiological

Health (CDRH)

Office of In Vitro Diagnostics and

Radiologic Health (OIR)

Office of Device Evaluation

(ODE)


Review Divisions in ODEO

DE

Anesthesiology, General Hospital, Respiratory, Infection Control, Dental

Cardiovascular

Ophthalmic and ENT

Neurological and Physical Medicine

Orthopedic

Surgical, Reproductive, Gastro-renal, Urological


CDER Review Offices O

ffice

of N

ew D

rugs

Office of Drug Evaluation I (ODE I)Cardiovascular and Renal Products, Neurology Products, Psychiatry Products

Office of Drug Evaluation II (ODE II)Anesthesia, Analgesia, and Addiction Products, Metabolism and Endocrinology Products, Pulmonary, Allergy, and

Rheumatology Products

Office of Drug Evaluation III (ODE III)Gastroenterology and Inborn Errors Products, Dermatology and Dental Products, Bone, Reproductive, and Urologic

Products

Office of Drug Evaluation IV (ODE IV)Medical Imaging Products, Non-prescription Clinical Evaluation (OTC), Non-prescription Regulation Development (OTC)

Office of Antimicrobial ProductsAnti-Infective Products, Antivirals, Transplant and Ophthalmology Products

Office of Hematology and Oncology Products


Which Center will Regulate Your Product?

1. Does your product achieve its primary intended purposes through chemical action and is your product metabolized by the human body?

a. If yes, go to 2

b. If no, go to 4

2. Is your product chemically synthesized

a. If yes, you will likely be regulated as a drug by CDER

b. If no, continue to 3

3. Is your product composed of sugars, proteins, nucleic acids or complex combinations of these substances, or other living entities such as cells and tissues.

a. If yes, you will likely be regulated as a biologic by CBER

b. If no, continue to 4

4. Is your product an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory?

a. If yes – then you will likely be regulated as a medical device

If you answered yes to more than one of questions 2, 3, or 4 you may be regulated and reviewed as a combination product.


Regulatory Pathways

Medical Device


Classification Depends on Intended Use, Indication for Use and the Risk

Regulatory Pathway Depends on Device Classification

Example (intended use versus indication): a scalpel’s intended use is to cut tissue. A subset of intended use arises when a more specialized indication is added in the device’s labeling such as, “for making incisions in the cornea”.

Example (different Class for different indications):Measurement of BhCG for pregnancy detection (Class II/510k)Measurement of BhCG for cancer detection (Class III/PMA)

Indications for use can be found in the device’s labeling, but may also be conveyed orally during sale of the product.


US FDA Device Classification

Note: Different global regions may classify your device differently

and may have somewhat different test requirements.


FDA Pathways to US Market

Class I

Class II

Class III

510(k) Exempt

510(k) not required, must meet…

- Registration and listing- Labeling

- GMP

Premarket Approval (PMA)

Market a new device, or a device designed to support or sustain life

Humanitarian Device Exemption

(HDE)

Treating conditions that affect <4,000

people/year in the US

Premarket Notification 510(k)

De Novo

Substantial equivalence to an existing device (predicate)

No predicate


Clinical Data May Require an IDE

Required if the intent of the study is to determine safety and effectiveness for a significant risk device/procedure or in cases where S/E can not be determined without clinical evidence.

Required for PMA productsInfrequently required for 510(k) products.

Ex #1: The Paxman Scalp Cooler is indicated to reduce the likelihood of chemotherapy-induced alopecia (CIA) in women with breast cancer.

Ex #2: …The COOLIEF* Cooled Radiofrequency Probe is to be used in conjunction with a radiofrequency generator to create lesions in nervous tissue…

An IDE approval may be sought for investigations without the intent to market a product.


Other CDRH Programs of Interest

• Early Feasibility Studies (EFS)

- Early stage clinical studies – may be First In Man

- Establish proof of concept

- Level of testing could be less than a larger clinical trial

• Expedited Access Pathway (EAP) program

- A “faster” PMA/De Novo

- For devices treating/diagnosing life threatening/debilitating disease, fulfilling an unmet need, is a breakthrough technology, or offers significant advantages over existing alternatives

• Breakthrough program

- To be defined in the future


Regulatory Pathways

Drugs & Biologics


CDER & CBER Applications

• New Drug Application (NDA)

• Abbreviated New Drug Application (ANDA) - Generics

• Over-the-Counter Drugs (OTC)

• Biologic License Application (BLA)

• Biologic 510(k) (BK)

• Investigational New Drug (IND)


New Drug Application (NDA) and Biologic License Application (BLA)

• Module 1 - Administrative and Prescribing Information: FDA Application form, Labeling, Patent information and certification, financial certification/disclosure

• Module 2 – Common Technical Document Summaries

• Module 3 – Quality: Also referred to as the CMC section –manufacturing & QC, container closure, etc.

• Module 4 - Nonclinical Study Reports: nonclinical pharmtox

• Module 5 - Clinical Study Reports: human pharmacokinetics (NDA), microbiology, clinical data, statistics


Abbreviated New Drug Application (ANDA) – Generic Drug Application

• Generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.

• Must scientifically demonstrate that the product is bioequivalent (i.e., performs in the same manner as the innovator drug). - One way scientists demonstrate bioequivalence is to measure

the time it takes the generic drug to reach the bloodstream in 24 to 36 healthy, volunteers.


Investigational New Drug (IND)

IND Contents

• Animal Pharmacology and Toxicology Studies

• Manufacturing Information

• Clinical Protocols and Investigator Information


Other CDER/CBER Programs of Interest

Must address an unmet medical need in the treatment of a serious condition

1) Fast track designation

2) Breakthrough therapy designation

3) Accelerated approval

4) Priority review designation

Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics

https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf


Average time to Decision (days) – FY 2015

0

50

100

150

200

250

300

350

400

510(k) De Novo PMA (no panel) PMA (panel) IDE

Note: projected estimateshttp://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/UserFeeReports/PerformanceReports/ucm497747.htm

Pre-sub meeting: 90 days

http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/UserFeeReports/PerformanceReports/ucm497747.htm


Average time to Decision (days) – FY 2015

0

50

100

150

200

250

300

350

NDA/BLA (standard) NDA/BLA (priority)

Pre-IND meeting: 60 days

Note: projected estimateshttp://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/UserFeeReports/PerformanceReports/ucm497747.htm

http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/UserFeeReports/PerformanceReports/ucm497747.htm


Predicting Regulatory Requirements


Public Information from FDA

• 510(k): 510(k) Summary- Indications for predicate

- Testing required

• De Novo: Decision Summary- Indications

- Identified risks and mitigations

- Special controls (testing required)

• PMA: Summary of Safety and Effectiveness Data- Indications and key labeling information

- Details on testing required including acceptance criteria. Detailed results of preclinical & clinical studies.

https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Databases/default.htm


Product Information

510(k) summary


CleanCisionTM Wound Retraction and Protection System…is intended for use by a surgeon during abdominal surgery to: retract the surgical incision, provide access to the abdominal cavity, and irrigate the surgical wound edge.

510(k) summary


Public Information

https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm

Drug Approval Package


Public Information

• Additional public information can be found on– Company information (website, label …)– News coverage / scientific articles and abstracts– Clinical trial information (https://clinicaltrials.gov/ ;

https://eudract.ema.europa.eu/) – Redacted product approval information from FDA website

https://clinicaltrials.gov/

https://eudract.ema.europa.eu/


Know What Standards are Relevant for Your Product Type

• International / USISO 10993-1:2009 Biological evaluation of medical devices -- Part 1: Evaluation and testing within a risk management process

IEC 60601-1 - Medical electrical equipment - Part 1: General requirements for basic safety and essential performance

ASTM

Clinical and Laboratory Standards Institute (for IVDs)

• Regulatory body guidance - “FDA Guidance on the Content of Premarket Notification [510(K)] Submissions for

Hypodermic Single Lumen Needles”

Using standards shortens the conversation!!!!


Developing a Test Plan


General principles

• Reg: Patient benefit/risk profile derived from the indication is the cornerstone for decision making

• You know your device best and are responsible for the performance

• Be prepared to offer scientific explanations and high quality documentation- Why test plan sufficiently mitigates risks to the patient

- Why sample sizes are appropriate

- Why acceptance criteria are appropriate

- How your clinical trial design will provide statistically valid data that will be informative

- Protocols include objectives, methodology, information on samples used etc…


General principles continued…

• Develop a test strategy based on patient risk/benefit, what stage of product development you are in and leverage information where possible

• Understand the tradeoffs and risks associated with key decisions

• Present test plan to the regulators as early as possible if the appropriate test plan is not clear

• Pre-submission (CDRH) or pre-IND (CBER & CDER)

• Intent: come to agreement on a test plan


Test Plan for a Known Device (i.e. 510(k))

Reference to predicate and appropriate standards


Test Plan for a Novel Device/Therapy

High level, used as a communication tool with FDA

Reference FDA guidance on Early Feasibility Studies


Opportunity to Reduce Test Burden/Plan for the Future: Example

Device: Brain Implant made of electrodes

Biocompatibility/animal testing is super expensive!!!Is there an opportunity for leverage information and reduce costs?

YES!


Reduce Burden Associated with Biocompatibility Testing

• Use of facsimile devices: For high cost devices such as electrodes there is an option to manufacture a larger facsimile device for testing.- Reduces cost associated with producing lots of devices for testing

• An animal study is a regulatory requirement for this brain implant. Some biocompatibility endpoints can be leveraged from the animal study (i.e. systemic toxicity).- Cost saving > $100,000

• Decision point: Should we do chemical characterization testing? It’s optional and a little pricey…- Recommendation: This may information can be used in lieu of a couple

of ISO 10993 tests (cost off-set) and may replace expensive systemic toxicity testing later. In this case, do it!


Don’t Be Too Cheap!

Collecting more data early may reduce problems later- Consider using control arms for animal studies

• Especially important for novel or complex technology

• This can help you decipher whether the results are attributable to the device/therapy

- Collect more data in an early stage small clinical study than you would in a pivotal study

• Can reduce data collection later but you may benefit from a very thorough look at the first few patients

• May be especially useful if the data interpretation will be a challenge (i.e. severely compromised patient population)


Reducing Burden Associated with Clinical Studies

- Do I need a study?

- What type of study(ies) do I need to do and how many studies may be required?

• EFS? Feasibility? Pivotal? Confirmatory? Control Arm or Single Arm?

- How can I minimize burden for a given study?

Let’s say we are planning for the pivotal study to support a market application….

Note: A clinical study may be required for a 510(k) device

Note: It is possible to go from EFS

straight to pivotal

Note: If significant historical information is available, this could be

use for a performance goal for a single arm study.


Reduce Clinical Study Burden

Sample size is a function of 4 things

Can I control this?

Significance level (α) Probability of incorrectly showing your device is better

No Regulator risk = regulator controlledUsually .05 is required, .1 may be ok for pilot/feasibility study

Power Probability of correctly showing your device is better

SomewhatCompany risk90% is best, 80% most common (changes the sample size significantly)

Variability (standard deviation) in the data Broad patient population = more variabilityLack of measurement precision = more variability

Yes! Limit inclusion/exclusion and target a narrow indication

Difference in treatment effect Not muchYou need to estimate, and justify, the differenceDepends on clinical significance, may anticipate based on smaller study


Size of Clinical Study

Control Test Device Standarddeviation

Total patients(80%/90%

power)3(mmHg) 2(mmHg) 5(mmHg) 788/1052

4(mmHg) 2(mmHg) 5(mmHg) 200/266

3(mmHg) 2(mmHg) 3(mmHg) 286/382

Suppose we design a trial to show a superiority in means at the 0.05 significance level


Example of How an Indication Will be Narrowed (variability reduced)

Indication the inventor wants…

My awesome stent can improve peripheral blood flow in anyone that has a narrowed artery.

https://www.google.com/search?q=peripheral+stent+images&source=lnms&tbm=isch&sa=X&ved=0ahUKEwiGsvGyxfzTAhVrllQKHQcaCO8Q_AUICigB&biw=1804&bih=870#imgrc=MVxDQzABlAnXFM:


Example of how an indication will be narrowed continued…

Indication that is practical to obtain….

The Misago® RX Self-expanding Peripheral Stent is indicated to improve luminal diameter in symptomatic patients with de novo or restenotic native lesions or occlusions of the superficial femoral artery (SFA) and/or proximal popliteal arterywith reference vessel diameters ranging from 4mm to 7mm and lesion length up to 150mm.

Clinical Trial261 patients US + OUS In the US, this was a multi-center, single-arm, non-randomized, prospective clinical trial

Historical information leveraged –

performance goal


Note: Other Important Factors to Consider…

• Available patient population to be treated (based on indication), ability to enroll and technologies that address a clinical unmet need for serious conditions.- HDEs (devices): 4,000 are less patients, will change to 8,000 or less

- Orphan products (drugs/biologics): 200,000 or less patients

- Pediatrics: FDA guidance on extrapolation available

- Breakthrough technology

Look for Opportunities…


Summary



Key Factors MitigationsRegulatory pathway Research pathways/competition

Expensive/time consuming testing needs to be re-done (animal study, MR compatibility etc…)

Early FDA input on test plan and protocols

Clinical study optimized? Leveragability across global regions?

Research least burdensome study design. Consider indications, reducing variability. Early input from regulators in various global regions.

Payers may want different information

Talk to payers early (before pivotal study)



Key Factors MitigationsCost to make the product Research options to reduce # test samples/leverage

information

Problematic data Biocomp.: Know your materials, use medical grade, control manufacturing environment. Know that never-used-before materials require more scrutiny (especially for implants).Know that product changes result in a re-assessment of biocompatibility.Consider using a control arm (i.e. animal studies)

Is technology novel? No standards? New to regulators?

Engage with regulators very early to come to agreement on how to test the product.

Will product changes resulting in repeat testing?

Plan for this in advance. (i.e. chemical characterization to reduce testing down the road)


What’s Your Strategy?

• Define your product

• Complete due diligence: competitors, regulatory requirements, standards

• Come up with a plan

• Review this plan with the regulators as needed

INFORMATION ABOUT NAMSA

Appendix B

NAMSA MRO Services| Confidential | 53

We are driven to make a scientific contribution to every medical device in the world


The Only Medical Research Organization

• NAMSA accelerates time to market and reduces costs for medical device product development.

• We do this by providing global expertise in Consulting, Laboratory Services, and Clinical Research.

It’s Called the MRO® Approach


Complete Medical Device Development Services

• Regulatory Strategy & Quality Systems

• Biostatistics• Biological Safety

and Validation

CONSULTING TESTING CLINICAL• Preclinical Studies• Analytical Services• Microbiology• In Vivo & In Vitro

Biocompatibility

• Clinical Study Management

• Data Management• Site Monitoring

& Safety


NAMSA is on the Cutting Edge of Thought Leadership…

Key contributor to the development of the test methods that govern the medical device industry

Our scientists actively participate in domestic and international standard setting committees to help shape the future of test methods

Subject matter experts consult on current regulatory and clinical data requirements to reduce product development cycles

NAMSA MRO Services | Confidential | 56


Global Reach Provides in Market Expertise…

Global Headquarters

Clinical & Consulting

Laboratory Services

Northwood, OH, USA

Minneapolis, MN, USA

Irvine, CA, USA

Sunnyvale, CA, USA

Selby, UK

Frankfurt, Germany

Tel Aviv, Israel

Lyon, France

Seoul, South Korea

Tokyo, Japan

Beijing, China

Shanghai, China

Taipei, Taiwan

Sao Paulo, Brazil


MEDICAL RESEARCH ORGANIZATION

Therapeutic Areas of Expertise and Focus

Neurosurgery/Spinal Surgery

Urology / Renal

Ophthalmology / Ophthalmic

DiabeticCare

IVD / Companion Diagnostics

General Surgery

Ear / Nose / Throat

Oncology

OBGYN

Dental

Anesthesia / Respiratory

Diagnostic Imaging

Transplantation

Regenerative Medicine

SleepDisorders

Orthopedics Cardiology

Dermatology & Wound Healing

PeripheralVascular Endocrinology

Gastroenterology & Bariatrics


Breadth and Depth of Experience

Regulatory Submissions > 1,000s

Laboratory Test Services > 85,000+ / year

• Biocompatibility tests

• Microbiology tests

• Chemistry tests

• Functional & efficacy studies

• PMA

• 510(k)

• De Novo

• IDE

• CE Mark

• CFDA

• PMDA

• MHLW


Partnering with NAMSA

The MRO Approach integrates consulting, laboratory services, and clinical disciplines for our clients:

NAMSA MRO Services | Confidential | 60

NAMSA IS A TRUSTED AND EXPANDING BRAND

ASSOCIATES FROM THE DEVICE INDUSTRY, ACADEMIA, & REGULATORY AGENCIES; WITH BROAD & DEEP EXPERIENCE

MILESTONE DRIVEN, DISCIPLINED, ACCURATE AND TIMELY DELIVERABLES

ONE POINT OF CONTACT FOR ALL PRODUCT DEVELOPMENT NEEDS

WILL ACCELERATE TIME TO MARKET AND REDUCE COSTS

GLOBAL MEDICAL RESEARCH ORGANIZATION (DEVICE FOCUSED)


Thank you

NAMSAHeadquarters6750 Wales RoadNorthwood, OH 43619 USA

Telephone: 866.666.9455 (toll free)+1 419.666.9455 (outside of USA)+1 419.662.4386 (fax)[email protected]

For more information, please contact your NAMSA representative:

Carla [email protected]

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MEDICAL RESEARCH ORGANIZATION - ncai-cc.ccf.orgncai-cc.ccf.org/skills/documents/I-Corps@Ohio 2017 - Regulatory... · MEDICAL RESEARCH ORGANIZATION. ... (Class II/510k) ... – Redacted