Transcript US EU Japan GMP Requirements

NIH-DAIDS/MRB/IPCP
Medical Device & Microbicide
Regulatory Training
Robert J. Russell
President - RJR Consulting
March 15-16 2011
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Course Agenda
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
8:30 – 8:45 - Biography/Company Overview

8:45 – 9:00 - FDA Overview

9:00 – 10:15 - FDA Requirements for Medical Devices &
Combination Products

10:15 – 10:30 – Break

10:30 – 10:45 - EMA Overview

10:45 – 11:45 - EMA Requirements for Medical Devices &
Combination Products

11:45 – 12:00 - Differences between FDA and EU/EMA

12:00 – 1:00 – Lunch
Course Agenda (Cont’d)
3

1:00 – 1:30 - Review of Medical Devices containing Microbicides

1:30 – 2:00 - Minimal Regulatory Requirements for Testing &
Standards

2:00 – 2:45 - Regulatory Challenges in Developing IVR’s

2:45 – 3:00 - Break

3:00 – 3:30 - Regulatory Challenges for Imaging Devices

3:30 – 4:00 - Potential Development Process Concerns

4:00 – 4:30 - Emerging Global Requirements

4:30 – 5:00 - Conclusions/Questions/Final Discussion
Course Director - Biography
Bob Russell
President & CEO
RJR Consulting, Inc.
[email protected]
154 E. Main St.
New Albany, OH 43054
Ph. (614) 304-0110
Cell:(614) 551-1717
 28 years of industry experience as a CMC specialist, R&D Director and Global
Director of Regulatory Affairs for Merion Merrill Dow and Cordis-Dow.
 Founded RJR Consulting, Inc. in 2002 to assist companies with their Regulatory
Affairs, Business Development, Distribution and Manufacturing needs.
 Bob has a BS / MS in Chemistry and regularly teaches classes on a variety of
regulatory topics within the Life Science industry.
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RJR Consulting, Inc. - Company Profile
RJR Consulting, Inc. is a global consulting firm specializing in regulatory
compliance and business development solutions for companies, governments
and organizations within the Life Sciences and Consumer Products industries.
Global Regulatory Compliance
 Clinical Trial Set-Up
 Strategy Development
 CRO Management & Selection
 Project Management
 Marketing Authorizations / License
 Government / Agency Affairs
Renewals
 NDA’s / Variations / Amendment
Filings
 Manufacturing Authorizations
 International Regulatory Surveillance
Updating: NA, EU, Japan, LAA
 Labeling and Packaging Guidelines
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Business Consulting Solutions
 New Business Development
 Global Business Expansion
 Industry Training
 Process Development &
Improvement
 Distribution and Manufacturing
Solutions
Global Reach
RJR Consulting, Inc. is headquartered in New Albany, Ohio and has affiliate
offices strategically located around the world. These offices provide the incountry expertise needed to deliver successful projects to our clients
 North America
 New Albany, Ohio, US
 Vancouver, Canada
 Latin America
 Sao Paulo, Brazil
 Mexico City, Mexico
 Buenos Aires, Argentina
 European Union
 Brussels, Belgium
 Hamburg, Germany
 Asia Pacific
 Japan
 China
 Korea
 Taiwan
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FDA Regulatory Overview
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The U.S. Food and Drug Administration
 An agency of the United States Department of Health and Human Services
 Responsible for protecting and promoting public health through the
regulation and supervision of food, tobacco products, pharmaceuticals and
medical devices.
 Regulates more than $1 Trillion in consumer goods or 25% of all U.S
expenditures.
 Headquarters in Silver Spring, Maryland with hundreds of field offices
throughout the U.S.
 Offices abroad in China, India, Belgium, Costa Rica, Chile & UK
 Personnel are exchanged with EMA and PMDA for ICH best practices and
further harmonization
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What is regulated by FDA?
Regulated by FDA
 Food
 Alcohol
 Tobacco
 Consumer Products (shampoo,
 Drugs
 Medical Devices
 Biologics
 Veterinary products
 Cosmetics
 Radiation-emitting Products
 Combination Products (any
combination of drug, device or biologic)
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Not Regulated by FDA
toothpaste, soap, etc.)
 Drugs of abuse
 Health Insurance
 Meat & Poultry
 Pesticides
 Restaurants
 Water
FDA Organizational Structure
 FDA is headed by the Office of the
Commissioner
 FDA made up of multiple Centers
 All centers report into the Office
of the Commissioner
 Office of Regulatory Affairs is an
additional “Center” in charge of
field operations
 Each Center has multiple offices
 Ex: Office of Combination Products
 Each Office has multiple divisions
 Responsibilities become more
granular as you move down the chain
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Main Centers of the FDA
CTP
CBER
Center for Tobacco Products
Center for Biologics Evaluation
& Research
CDER
Center for Drug Evaluation &
Research
CFSAN
Center for Food Safety
& Applied Nutrition
CDRH
Center for Radiological
Devices & Health
NCTR
National Center for
Toxicological Research
CVM
Center for Veterinary
Medicine
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Source: www.fda.gov
Office of Combination Products
 Specialty Office established in 1990 that exists under the
Office of the Commissioner
 Small Office of 8 members
 Acts as the gatekeeper for regulation of combination
products
 Ensures proper direction and timely review of
combination product applications
 Responsible for assigning an FDA Center to have primary
jurisdiction based on primary mode of use
 Develops guidance on regulations having to do with
combination products
 Does not actually review marketing applications
 handled by CBER, CDER, CDRH
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FDA Requirements for
Medical Devices &
Combination Products
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Overall Regulatory Pathway
IVR/Microbicide Gel Combination Products
Markets/countries
outside of EU
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FDA Clinical Trial Evaluation Process
Device
Combination Product
Ph I - Toxicity
Ph II - Efficacy
Ph III – Statistical Efficacy & Adverse Events
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FDA Licensing Process
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Regulatory Requirements
 Many different factors are involved in obtaining regulatory approval for a
medical device or combination product:
 Questions to ask…
 Is it a combination product?
 What is the primary mode of action?
 Is it a device, drug or biologic?
 Is it exempt from classification?
 If not exempt, is it already classified by the FDA?
 Is there another device that is similar that has already been approved?
 Is it a new device that addresses an unmet need in the market?
 What is the level of control needed to make sure it’s safe and effective?
 What is the risk to the patient?
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Combination Products
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
Defined as a distinct combination of drug, device and biologic products
 Drug + Device
 Drug + Biologic
 Device + Biologic
 Drug + Device + Biologic

The combination of device and drug may fall under “combination” regulations, as
specified in Title 21 of the Code of Federal Regulations (CFR) Part 3.2, Subpart (e) (i.e.,
21 CFR 3.2(e)), which require both an investigational device exemption (IDE) and an
IND

The following are also considered under combination products:
 Two or more products that are packaged together or physically/chemically
combined
 An individually packaged product that is designed to be used with another
approved product to achieve the intended use
 An investigational product that is designed to be used with another approved
product to achieve the intended use
Request For Designation
 Request for Designation
 Request for guidance from FDA to determine necessary regulatory
submission
 Process & requirements outlined in 21 CFR Part 3 – no official “form”
 Submission must be limited to 15 pages
 Sponsor submits formal request to FDA to determine:
1. Primary mode of action
 Is it primarily a device, drug or biologic?
 IVR with microbicide is a drug (device used as delivery method)
 Stent is a device (drug is added for infection prevention)
 Vaccine filled syringe is a biologic (with a delivery device)
2. Lead Agency Center to be assigned for pre-market review
 Determination of jurisdiction usually takes 45-60 days
 Request can also be made informally by contacting Office of Combination
Products
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Intercenter Agreements
 Agreements entered into in 1991 by CDER, CBER and CDRH
 Provided guidance to determine how lead agency works with the other agencies
during review process
 Agreements identify specific combination products and how they are regulated
 Primary Mode of Action introduced in 2005 overrides most of previous
intercenter agreements
 Still provide helpful guidance in addition to jurisdictional determination
 Sets guidelines for how centers work together during review
 Each center is beginning to publish information on the determination and
approval of combination products through the OCP performance reports on
the Office of Combination Products homepage on http://www.fda.gov
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Regulatory Issues with Combination Products
 Organizational & process approval challenges exist when trying to obtain
regulatory approval for a Combination Product based on classification:
Product Type
Drug
Device
Biologic
Lead Agency
Center
CDER
CDRH
CBER
IDE
510(k)
PMA
IND
BLA
510K
PMA
NDA
Approval
Processes
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IND
NDA
Safety Concerns
 Unknown interactions of combining two or more approved products can
lead to potential safety and effectiveness concerns for patients
Combination
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Pre-IDE Process
 Contact FDA prior to submission of request for IDE
 FDA will provide one time pre-IDE feedback to sponsor at no cost
 Increases sponsor understanding of regulations and process
 Helps to minimize delay during actual submission process
 Typical 30-60 day response time
 FDA may have guidance meetings with sponsor about Pre-IDE submission
 Can be conference calls or face-to-face
 Meetings are usually formal but informal conversations can be had prior
to official meeting to ask questions
 Formal meetings are Determination meetings or Agreement meetings
 Determination meeting – request to discuss scientific information
needed in submission
 Agreement meeting – reach official agreement on parameters of
clinical protocol and investigational plan
 Will issue Notice of Disapproval or Withdrawal if Pre-IDE not approved
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Significant vs. Non-significant Risk
 Studies performed as part of pre-IDE process to determine riskiness of device
 Institutional Review Board (IRB) will review risk assessment from Sponsor

Review of prior investigational reports, investigational plan, subject selection criteria
 Significant Risk (SR)


Devices with potential for serious risk to health and safety of subject including
devices that are:

Implants

Supporting or sustaining human life

Treating or mitigating diseases
If SR is determined, both IRB and FDA need to approve before IDE process begins
 Non-Significant Risk (NSR)
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
Doesn’t meet criteria above for Significant Risk

Different than “minimal risk” studies that qualify for expedited review

If deemed to be NSR, sponsor does not have to submit an IDE to FDA
Investigational Device Exemption (IDE)
 Exemption granted to allow a device to be used in investigational clinical
studies (21 CFR 812)
 Allows for collection of safety and effectiveness data
 Data will eventually support the 510k or PMA submission
 Permits the device to be shipped for investigational study purposes’
 Listing/registering not required while device under investigation
 Requirements for an IDE include:
 Approval by institutional review board before clinical study initiated
 Significant risk device requires FDA approval along with IRB
 Informed consent for patients
 “Investigational use only” labeling
 On-going monitoring of clinical study
 Records and reports supporting the study
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Classification Types
 All devices will be classified as one of the following types:
 Class I
 Low risk, subject to general controls*
 Examples: gloves, scalpels, enema kits
 Class II
 Medium risk, subject to general and special controls*
 Examples: pregnancy tests, infusion pumps, powered wheelchairs
 Class III
 High risk, subject to general and special controls
 Devices that support/sustain human life or pose excess risk
 Examples: pacemakers, artificial hearts, implants
 Exempt (Class I or Class II)
 Very low risk, subject to general controls
 Some devices may be exempt from GMP as well
 Examples: Non-sterile surgical tools
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*description in next slide
General & Special Controls
 General Controls
 Basic rules that allow FDA the authority to regulate devices
 Required to be followed for all device classes
 Allows FDA to regulate many things including device registration,
product listing, labeling, quality measures (including misrepresentation)
& reporting
 Special Controls
 Additional controls applied to Class II and Class III devices to ensure
safety and effectiveness
 Includes such things as:
 Performance standards and specific guidelines
 Additional labeling requirements
 Post-market monitoring & surveillance
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Classification Statistics
 The majority of devices fall under the
Class I or Class II designation
 The majority of Class I devices are
exempt, while the majority of Class II
& III devices are non-exempt
Class I
Class III
Class I
Class II
Class
III
Exempt
95%
3%
0%
NonExempt
5%
97%
100%
Class II
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*source: www.fda.gov - 2009 data
Determining Classification
 Device class is determined by many different factors:
 Previous similar devices
 Intended use of the device
 Indications for use (specifics of intended use)
 Risk to the public
 You can use a number of methods to determine class of specific products
 CFR Search
 Search regulations on FDA website
 Determine the medical specialty (panel) of the device
 Each panel has list of products classified (16 panels)
 Located in 21 CFR 862-892
 Identify the classification regulation
 Search the product code classification database
 For combination products considered as “drugs”, the device component is
automatically classified as Class III
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Device Exemption
 A device is considered exempt if:
Category is included on the Class I & Class II Exempt Devices list
 List covers 21 CFR 862 – 892
 Grandfathered in from original amendment (May 28, 1976)

 Devices that qualify are exempt from:
 A pre-market notification application (510(k))
 FDA approval before marketing the product in the US
 Some product exemptions have limitations
 With an exempt product, Manufacturers are still required to:
 Register and list product with FDA
 Comply with any GMP or labeling requirements
 Some class I devices are exempt from GMP if not labeled as sterile
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Reclassification Process
 Classification is occasionally adjusted through a reclassification process
 FDA has power to reclass a device if necessary
 Reclassification can be up or down in product class
 Must convince FDA by providing data and reassuring safety
 Triggers to a reclassification of one or more products
 More experience and usage of a new device
 Receipt of new information on a device
 Petition from outside sources
 FDA will notify petitioners with a reclassification letter
 Federal register updated with any reclassification of devices
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Regulatory Submission
 With the device class and non-exempt status known, the type of regulatory
submission can be determined:
 Premarket Notification (510k)
 Required submission for all Class I & II non-exempt devices
 No actual FDA provided form for 510(k)
 Requirements for submission in 21 CFR 807 subpart E
 Product clear to be marketed in US when 510(k) is approved
 Premarket Approval (PMA)
 Required submission for Class III devices
 Very few pre-amendment devices grandfathered in
 Required due to higher risk of devices
 General & special controls insufficient in assuring safety
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Requirements for 510(k) submission
 Groups who are required to submit a 510(k) to FDA:
 Domestic manufacturers introducing device in US
 Specification developers introducing device in US
 Repackers/Labelers who make labeling changes
 Foreign manufacturers (or representatives) introducing device in US
 The following instances require that a 510(k) be submitted to FDA:
1. Introducing device for commercial use for first time
2. Proposing a different intended use for existing device
3. Modification to existing device that affects safety or effectiveness
 May require new 510(k) depending on what was changed
 Change to materials, sterilization or manufacturing process will
likely require new submission
 Burden is on Manufacturer
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When is a 510(k) Not Needed?
 Company is selling components or parts of devices to another
company for further processing
 Device is not being commercially marketed or distributed
 Distributing another firm’s domestically manufactured device
 Labeling of device has not significantly changed
 Device was commercially distributed before May 28, 1976
 Device is imported from foreign manufacturer who already has 510k
clearance
 Device is exempt through previous regulations
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Substantial Equivalence
 Key component to 510(k) submission is proving Substantial Equivalence (SE)
to another similar device (called a predicate)
 Substantially Equivalent criteria:
 Product has same intended use as predicate
 Product has same technological characteristics OR
 Product has different technological characteristics but does not introduce new
safety concerns
 Proof of SE should be provided with application
 FDA will respond with an order declaring SE (90 days)
 If Not Substantially Equivalent (NSE) is issued, De Novo petition or PMA required
 De Novo petition
 File petition with 30 days to justify why device should be Class I or II
 Meant for devices that do not have a predicate and are low risk
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Types of 510(k) Submissions
 Traditional

Most common – process as previously described
 Abbreviated
Used when guidance documents exist, special controls are in place and standards
are already in place
 Must prove conformity to the recognized standard
 Includes summary reports on use of guidance docs to expedite review

 Special
Done for device modification that does not affect intended use or technological
standards
 Contains a Declaration of Conformity to specific design controls
 Submission does not include data

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37
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Proposed Streamlining of 510(k) Process
 Plan released in January 2011 to streamline 501k review process
 Driven by CDRH to clarify timelines for submission of clinical data
 Create a Center Science Council of experts to speed up decision making
 Plan includes issuing draft guidance documents in 2011 on topics such as:
 Improving the quality and performance of clinical trials
 Process for appealing CDRH decisions
 Streamlining of the De Novo application process
 When to submit clinical data
 Identifying safety issues and concerns
 Characteristics included in the scope of “Intended Use”
 “Indication for Use” becomes part of “Intended Use”
 FDA ultimately decided against a CDRH proposal having another
classification category called Class IIb
Would have bridged gap between medium and high risk devices– similar to EMA
 Ex: No predicate exists but risk is in line with Class II device

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Premarket Authorization (PMA) Review
 Most stringent pre-marketing application
 Must be completed for all class III devices
 Often involves new concepts or ideas that have no precedent
 Four step review process
1. Completeness review – Is everything there?
2. Detailed scientific, regulatory and quality review
3. Review and recommendation by advisory committee
4. Final documentation and notification of approval
 FDA approval grants the owner license to market device in US
 Good science practices and scientific writing are key for approval
 Non-approval letter will contain application deficiencies or reasons for non-
approval
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PMA Application Methods
 Traditional PMA
 All volumes submitted to FDA at once
 For devices that have had clinical testing or have been approved elsewhere
 Modular PMA
 PMA broken into modules and each module submitted upon completion
 Meant for products in early stages of clinical study
 Streamlined PMA - (Pilot Program)
 For devices where the technology and use is well known by FDA
 Submitted as traditional PMA but review is interactive and streamlined
 Product Development Protocol (PDP)
 Early agreement with FDA regarding design/development details of device
 Work at own pace and keep FDA informed and involved
 Recommended for devices where the technology is well established
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PMA Amendments & Supplements
 PMA Amendment
 Submission during application process before FDA approval is obtained
 When additional data requested or modification to application is needed
 Restarts the submission process at beginning
 PMA Supplement
 For product changes after approval has been obtained
 Usually needed when changes impact safety, effectiveness or labeling
 Different timeframes for review (30-180 days) based on impact of change
 Humanitarian Device Exemption
 Incentive for developing devices that affect under 4000 people in U.S.
 Similar to orphan drug designation, except for devices
 HDE’s are exempt from effectiveness requirements
 Must justify risk to FDA and demonstrate lack of predicate
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PMA Requirements
 The following are required to be submitted within a traditional PMA:
 Name, address and table of contents
 Description of the device form and function
 Practices and procedures – what device is used for
 Foreign and domestic market history of the device, if any
 Details about manufacturing process in making the device
 Summary of clinical and non-clinical studies
 Conclusion of studies, include safety and effectiveness of device
 Reference to any performance standards followed
 Labeling and advertising literature (Ex: pamphlets)
 Results of non-clinical lab studies
 Results of clinical studies on human patients
 Financial certification and disclosure statement
 Bibliography of reports about safety/effectiveness of device
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Bioresearch Monitoring (BIMO) Program
43

Program consisting of on-site inspections and data auditing designed to monitor
research and data collection activities related to devices

Groups monitored include Sponsors, CROs, Clinical Investigators, Monitors, Nonclinical Labs and Institutional Review Boards
 Each group has an associated guidance document

Program designed to:
 Protect research subjects from unnecessary risk
 Ensure patient safety from potential hazards
 Uphold quality and integrity of data collected

BIMO program is coordinated by the Office of Regulatory Affairs
 Each Main Center (CDRH, CDER, CBER) supports BIMO effort
 CDER – Division of Scientific Investigations
 CBER – Bioresearch Monitoring Team
 CDRH – Division of Bioresearch Monitoring
BIMO Inspection Programs
 Two types of inspections under BIMO program:
1. Routine Inspections
 Random inspections of investigators, sponsors, IRB’s or labs
 Performed to monitor compliance with BIMO program
2. Directed Inspections (For-Cause)
 Inspection requested due to problem or issue
 Problem observed during 510k or PMA submission process
 Complaints from doctors/patients can also lead to inspection
 Inspector will assign a classification to the overall inspection based on
compliance:
 NAI – No Action Indicated
 VAI – Voluntary Action Indicated
 OAI – Official Action Indicated
 Warning letter may be issued based on severity of findings
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Sponsor Responsibilities
 Sponsors are responsible for the following when it comes to BIMO:
 Selecting a qualified investigator
 Ensuring proper monitoring of the investigation
 Verify investigator follows investigation plan and IND





45
protocols
Ensuring FDA and investigators stay informed of new risks or
adverse effects of drug/device
Obtaining proper information from the investigator prior to
inspection
Review and evaluate safety and effectiveness data
Discontinue investigations that pose significant risk
Maintain accurate records regarding financial interest and
receipt/shipment of the drug
Clinical Investigator Responsibilities
 When it comes to BIMO, Investigators are responsible for:
 Adhering to the Investigator Agreement
 Following the Clinical Investigation Plan
 Protecting the health, safety and well-being of patients/subjects
 This includes obtaining informed consent
 Obtaining IRB (and FDA) approvals
 Supervising and disposing of the devices
 Disclosing any financial interest that exists
 Documenting adverse effects or deviations from the plan
 Writing progress reports and delivering a final report
 Disqualification
 Will not continue to receive investigational devices if requirements are
repeatedly not followed
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Clinical Research Monitor (CRA) Responsibilities
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
Primary liaison between the sponsor and the investigator

Interviews & recommends investigators

Responsible for site selection and reporting progress of the clinical trial

Prepares clinical development plans

Ensures subject safety and verifies data integrity

Ensures the investigator:

Understands the regulations and need for accountability

Follows written SOP’s and provides timely reports to the Sponsor

Understands protocol and requirements to verify efficacy

Understands the need for prior & continuing IRB approval

Has documented procedures for reporting adverse events

Manages the trial to a successful conclusion

**IND regulations requiring sponsors to monitor clinical trial progress led to the
creation of the clinical research monitor role
Clinical Investigation Plan
 Comprehensive document or set of documents with detailed feasibility,
strategies, and administrative elements of clinical trial conduct
 Include input from all CRO to ensure process flow is accurate
 Establish timelines for finalization and sign off of all plans and adhere to the
timeframe
 The Clinical Investigation Plan is made up of several different plans
including:
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
Essential (Investigator) Document Plan

Monitoring Plan

Data Management Plan

Safety Plan

Statistical Analysis Plan

Communication Plan

Risk Assessment
Plans within the Clinical Investigation Plan
 Essential (Investigator) Document Plan
 Outlines format and acceptability of documents needed for release of
investigational product and continued Site participation in the study
 Monitoring Plan
 Outlines the monitoring guidelines and tasks not outlined in SOPs or the
Protocol
 Includes CRF retrieval plan
 Data Management Plan
 Outlines data collection, entry, review and completeness of the database
 Safety Plan
 Outlines SAE process and reconciliation
 Additionally can outline medical monitor review and oversight (Medical
Monitor Plan can be a separate plan)
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Plans within the Clinical Investigation Plan
 Statistical Analysis Plan
 Outlines the programming and analysis of the database
 Details the number of tables and listings and data analysis methods
 Communication Plan
 Outlines all the communication paths with internal and external team
members
 Risk Assessment
 Outlines all identified risks
 Risks are ranked by impact on the study
 Offers preventative and/or contingency actions
 Timelines – MS Project
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Plans within the Clinical Investigation Plan
 Issue Escalation Plan
 Can be part of Communication Plan
 Outlines path of communication for major issues that can adversely
 Affect the outcome of the study
 Have a major financial impact
 Details who is notified, timeframe for response and who is responsible
for actions
 All plans within the Clinical Investigation Plan should be ……
 Version controlled
 Signed by sponsor and CRO
 Reviewed and updated, as needed
 Become part of the Central Clinical Project Files
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EU/EMA Regulatory Overview
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EU Member States & EEA
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•
•
•
•
•
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Austria
Belgium
Denmark
Finland
France
Germany
United Kingdom
•
•
•
•
•
•
•
Greece
Ireland
Italy
Luxembourg
The Netherlands
Portugal
Spain
EU Applicants
•Croatia
•Turkey
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•
•
•
•
•
•
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Sweden
Cyprus
Czech Republic
Estonia
Hungary
Lithuania
Latvia
•
•
•
•
•
•
European Free Trade
Association Countries
•Iceland
•Liechtenstein
•Norway
•Switzerland
EU and EFTA countries (excluding Switzerland)
have a market of ~ 350 million customers
Malta
Poland
Slovakia
Slovenia
Bulgaria
Romania
EU Regulatory Bodies





54
European Commission (EC)

Ensures safety and public health of foods and consumer goods in EU

Responsible for proposing and upholding laws for EU related to drugs & devices
European Medicines Agency (EMA or EMEA)

Decentralized group in EU that evaluates medicines for human and veterinary use

Responsible for scientific evaluation and enforcing regulations for EU members
Committee for Medicinal Products for Human Use (CHMP)

Comprised of representatives from Member States along with medical experts

Part of EMA – conducts the drug review process
National Competent Authorities (NCA)

Responsible for local authorization and compliance within own country

Conducts research & development and determines available medicines in country
Notified Bodies (NB)

Designated by Competent Authorities – about 100 NB’s in Europe

Performs conformity assessments procedures to determine device class
EU Regulatory Structure
EC (Commission)
Project Manager
(Scientific/Medical
Advisors)
CHMP
Rapporteur/
Co-rapporteur
55
EMA (EMEA)
MRFG
(Medical
Devices)
NCAs
Notified Bodies
Inspectors
Ethics Committee
EU Requirements for
Medical Devices &
Combination Products
56
EU Path to Market for Devices
57
1.
Confirmation of Product Meeting - Medical Device Definition
2.
Which Directive is Referenced?
3.
Medical Device Classification (based on EU Rules)
4.
Selection of Lead Member State for CE Marking Device
5.
Selection of Notified Body (except for Class I devices)
6.
Confirmation of Device Classification
7.
Device Meets Essential Requirements
8.
Selection of Conformity Assessment Annexes / Procedures
9.
Audit / Non-Conformances / In-House Changes
10.
Conformity Assessment Certificate
11.
CE Marking Device
12.
Annual CE Mark Maintenance
EU Device Regulatory Flow
Which Directive applies?
Is it a Drug? Device? Combo?
If it’s a device….
58
EU Medical Device Definition
 The term ‘Medical Device' refers to any instrument, apparatus, appliance,
material or other article used alone or in combination, including the
software necessary for its proper application intended by the manufacturer,
to be used for human beings for the purpose of:
 diagnosis, prevention, monitoring, treatment or alleviation of disease
 diagnosis, monitoring, treatment, alleviation of or compensation for an
injury or handicap
 investigation, replacement or modification of the anatomy or of a
physiological process
 control of conception
 A Medical Device does not achieve its principal intended action in or on the
human body by pharmacological, immunological or metabolic means, but
may be assisted in its function by such means.
59
Classification of Medical Devices
 Rules for full classification of Class I, IIa, IIb and III are well defined in
Articles 9 & 11 of the Medical Device Directive (93/42/EEC)
 Device class is determined by the highest class rating of:

Characteristics or combination of characteristics

Intended purpose of the device
 Device classification may also be affected by the time period in which the
device performs its intended function.
 Three definitions for duration of use apply:

transient (normally intended for continuous use of less than 60 minutes)

short-term (normally intended for continuous use of 30 days or less)

long-term (normally intended for continuous use of more than 30 days)
 A graphical summary of classification of medical devices is in the slides to
follow and is for initial identification of probable device class

60
Always confirm definitive classification by reading all rules and examples in the
guidelines document
EU Classification Matrix
Device Class
Risk Potential
I
I (sterile and/or
measuring)
II a
II b
III
Low
Low
Medium
Elevated
High
Product
Examples
Non-sterile
dressings,
bandages,
hospital gowns,
light sources
Spirometers,
urine drainage
bags, digital
thermometers
IV catheters,
tubing's for
anesthesia/vent
ilation
Intraocular
lenses, breast
implants,
endoprostheses,
ventilators
Heart valves,
reabsorbable
implants
Involvement of
Notified Body
Self-certification
Declaration of
Conformity
Self-certification
Declaration of
Conformity +
Notified Body
for measuring
function/
sterility
procedures
Mandatory
Mandatory
Mandatory
61
Source: MEDDEV 2.4/1 Rev.8
62
Source: MEDDEV 2.4/1 Rev.8
63
64
Source: MEDDEV 2.4/1 Rev.8
Source: MEDDEV 2.4/1 Rev.8
65
Active Devices Continued
Source: MEDDEV 2.4/1 Rev.8
66
67
Source: MEDDEV 2.4/1 Rev.8
Device Essential Requirements
 Based on Annex I of MD Directive 93/42/EEC
 General Requirements
 Safety concerns, manufacturing, packaging, storage
 Chemical, Physical & Biological Properties
 Contaminant prevention, combination products
 Infection & Microbial Contamination
 Infection prevention, sterilization procedures
 Construction & Environmental Properties
 Devices with a Measuring Function
 Accuracy, stability, monitoring
 Radiation Protection
 Devices Connected to an Energy Source
 Performance concerns, power supply, electrical/thermal risks
 Manufacturer Information
68
Conformity Assessment Routes
 A manufacturer must follow a conformity assessment procedure in order to
place CE marked products on the market
 One of the more complex activities facing a medical device manufacturer
seeking to comply with the requirements of the MDD is the selection of a
conformity assessment route
 The class attributed to the product will determine the route that must be
followed by the manufacturer
 defined in Article 11 of the MDD for all classes
 The conformity procedures address two stages: design and manufacture
 For design, manufacturers must provide objective evidence of how the device
meets the essential requirements.
 This technical information should be held within a technical file or "design
dossier."
 For manufacturer, a documented quality system must be in place to ensure
that the devices continue to comply with the essential requirements and are
consistent with the information in the technical file.
69
Criteria for Conformity Assessment Route
 Manufacturer/Notified Body must decide on your conformity assessment
route to meet the essential requirements of the appropriate Directive
 MDD 93/42/EEC - Article 11
 Manufacturers can demonstrate conformity through:
 Testing result alone
 Testing results plus Quality system certification
 Quality system certification alone
 Most common methods are:
 Certification of full quality assurance
 EC Type Examination (product testing) plus certification of production
quality assurance
 For class I devices, there is a self-declaration procedure
70
71
The Technical File



72
What is a Technical File?

Contains all technical information about the device

Equivalent to the 501k or PMA filings for FDA
Parts of a Technical File

Part A: Summary of data relevant to conformity assessment procedures

Part B: Full report containing detailed data and test reports on the design,
manufacture and testing of the device

Class III devices required an extended Part A and a design dossier
Notified Body must review your Technical File based on product classification:

Class IIa: Brief overview to confirm all sections are present but no detailed
review

Class IIb: Desktop review for consistency and adequacy in fulfilling the essential
requirements of the Directive. This review can happen before or after the QMS
Certification

Class III: Full review (like IIb) but looks to substantiate the evidence presented
with primary clinical research in support of the clinical evidence section
Technical File Requirements
• Technical Documentation has to be updated whenever changes to the products
or processes are implemented or applicable requirements change (i.e.
standards, guidelines)
• For substantial changes to the quality system or changes of products the
Notified Body has to be informed
• Procedure has to be established for creation and maintenance of Technical
Documentation.
• Procedure should include links to:
- Design control process (new designs & design changes)
- Document control system (change of procedure, standards)
- Post Market Surveillance System (complaints, clinical data)
- Process for update of Notified Body (product line extension)
- Process for update of EU Representative (registration of
class I devices).
73
Technical File Contents
1.
Purpose, Objective, Revision History
2.
Device Descriptions and Variants

74
Including Functional Description, Performance, Intended Use
3.
Design Documentation and Design Control Procedures
4.
Demonstration of Compliance to Essential Requirements
5.
Statement regarding section 7.4 of Annex I (Medicinal Products)
6.
Description of Manufacturing Process, Quality Assurance
7.
Materials and Component Testing (i.e. Circuits, Packaging)
8.
Specific Product Testing (i.e. Safety, Sterility, Biocompatibility)
9.
User Information (Instructions, Labels, Service Manuals)
10.
Risk Analysis
11.
Clinical Data
Technical File Structure
75
1.
Cover Page (Company, Product/Product Group, Document ID)
2.
Index
3.
EC declaration of conformity and classification
4.
Name and address of the Manufacturer/European Representative and
Manufacturing Plants
5.
Product description including:

All variants

Intended clinical use

Indications / contraindications

Operating instructions / instructions for use warnings / precautions

Photographs highlighting the product photographs highlighting the
usage

Brochures, advertising, catalogue sheets, marketing claims
Technical File Structure (Cont’d)
6. Product design and manufacturing specifications including:
 Parts list
 Drawings, assembly drawings
 Sub-assembly drawings
 Drawings of components
 Specifications of materials used incl. data sheets
 List of standards applied
 Manufacturing specifications
 Sterilization specifications (if required)
 Packaging specifications
 QA specifications (QC specs., in-process controls etc.)
 Labeling
 Accompanying documents
 Packaging insert/Instructions for Use
 Service Manual
76
Technical File Structure (Cont’d)
7. Product verification including:
 Testing data and reports
 Functionality studies
 Wet lab or bench top testing
 Materials certificates / reports on biological tests
 EMC testing and certificates
 Validation of the packaging / ageing studies
 Compatibility studies (connection to other devices)
 Risk analysis (ISO 14971)
 List of requirements (Annex 1) indicating cross-reference with
documentation
 Clinical Data
77
EU Definition of Combination Product
 A combination product is composed of two or more constituent parts, if
viewed separately, would be regulated under more than one Directive
below:
 Medical Devices Directive (MDD)
 Medicines Directives (MD)
 Active Implantable Medical Devices Directive (AIMDD)
 Herbal Medicines Directives (HMD)
 Example: an antibiotic coated catheter is a combination product, but when
viewed separately:
 A catheter is regulated under the MDD
 The antibiotic is regulated under the MD
78
Device Types within Combination Products
 There are 3 different types of medicinal devices incorporated in
combination products:
1. For administration of medicines
 Ex: Empty single-use syringe, reusable spoons or droppers
 Regulated by medicinal device (MD) regulations
2. Combined with a medicinal product to form a single, integral product
designed to be used only in the combination
 Ex: Non-reusable products such as Pre-filled syringes
 Subject to assessment by drug regulatory authorities (DRA)
 Must meet requirements of the MDD (satisfied by use of CE mark)
3. Incorporated with a substance which, if used separately, may be
considered a medicinal product
 Ex: Heparin-coated catheter
 Notified Body will assess the product while drug info is sent to DRA
to verify safety, efficacy, and usefulness of drug
79
Regulation of Combination Products
 Combinations are almost solely regulated on the manufacturers intended
claims for the product

Ex: Wound care product containing an antimicrobial
 Regulated as a device if antimicrobial is to prevent excessive odor
 Regulated as a pharmaceutical if antimicrobial is to prevent infection
 Different combinations are regulated differently according to European
Commission’s classifications
A device intended to deliver a medicinal product is regulated as a medicinal
product (Ex: IVR’s)
 However, a kit containing an insulin pen and cartridge, the pen is subject to
device approval, but the cartridge is considered a medicinal product
 If a device and medicinal product form a single, integral product that is intended
exclusively for single use in the given combination, the single product is
regulated as a medicinal product
 Ex: Prefilled syringes, transdermal patches, various implants

 When in doubt, contact a Competent Authority to verify
80
Classification of Combination Products
 Certain groups of combination products fit easily into buckets and are
already classified
 Classification lists (mostly based on precedence) are available from some
Notified Bodies and are sometimes publicly available on the web
 If a device does not appear on one of the classification lists, then it needs to
be evaluated as both a medicine and a device (two-criteria) to determine
primary method of regulation
1. Criterion 1: the intended purpose of the product taking into account
the way it is presented (this is to establish if either the MDD or the MD
applies
2. Criterion 2: The method by which the principal intended action is
achieved
 Usually comes down to whether the principal intended action is achieved
by the mechanism of a device or the pharmaceutical.
81
Criteria for Combination Products
 Characteristics that usually lead to a device principal intended action are:

Mechanical, physical barrier, heat, light, non-ionizing radiation, sound/ultrasound

Radioactivity (unless deemed a radio-pharmaceutical)

Replacement of organ or support of body or function
 Characteristics that usually lead to a drug principal intended action are:

Pharmacological, immunological, metabolic
 Frequently the ‘method by which the principal intended action is achieved’
will be determined by:

Scientific evidence, method of use, labeling claims

Advice given to patients and clinicians
 Challenge: most new combination products achieve their principal intended
action through a “synergistic effect”

82
Neither the device nor the medicine alone would achieve desired effect
Decision on Principal Intended Action
 Manufacturer decides on the method by which the principal intended action
is achieved
 Decision is usually based on:
 Animal or clinical testing
 Argued scientific rationale
 Independent regulatory guidance
 Manufacturer may be able to adjust the labeling, the intended use or patient
population to strengthen its argument that a particular product fits into a
regulatory regime that it believes is to its best advantage
 Notified Body is normally the manufacturer’s prime point of contact and
‘kept in the loop’ if the manufacturer consults with a Competent Authority
 In Manufacturers’ own interest to have Notified Body or Competent
Authority to agree to the decision
83
Regulatory Regime
 Combination Product regulated as a Medicine
 Device information from the technical file is usually supplied in the
medicines application.
 Device will often be regarded as Medicinal Packaging
 Combination Product regulated as a Device
 Device will be treated as a Class III Medical Device
 Extensions to the Technical File, Design Dossier and Quality System are
required to cover the medicinal product content
 Full Quality Assurance route is almost always used but other
conformity assessment options are available for Class III products
84
Technical File Considerations
 Technical File Extension

For a combination product regulated as a device, information on the medicine
content of the product needs to be included in separate chapters of the technical
file.

This may necessitate some duplication-- the device section and the medicine section
each need to “stand alone”
 The medicine chapters of the device technical file should follow the same
methodology, structure and content as the appropriate authorization for the
medicinal product alone.
 The Notified Body is bound to “consult” with a Medicines Competent
Authority regarding the medicinal product during a Class III device review
 Post Marketing Considerations
85

Surveillance, reporting incidents and recalls are handled like a Class III device

Must meet any specific requirements applicable to the medicinal component
EC Certificate / Declaration of Conformity
 EC will issue a certificate demonstrating that all conditions of the Directive
have been met
 Not an official approval and does not diminish the responsibility of the
manufacturer in signing a Declaration of Conformity
 The manufacturer must draw up a written Declaration of Conformity prior to
affixing the CE mark
 This declaration must cover a given number of products manufactured and has
to be kept by the manufacturer
 Declaration of Conformity has been signed by a legal officer (a director) of the
company (manufacturer or EU Authorized Representative)
 Becomes both a corporate and a personal acknowledgement of responsibility
that the product meets the relevant applicable EU Directives
 If someone other than a director signs, then they need to understand the
personal liability they are accepting
 Should be added to the Quality Manual for GMP inspection purposes
86
Declaration of Conformity / CE Mark
 The Declaration of Conformity should contain the following information:

Title of Document (“Declaration of Conformity”)

Name and address of the manufacturer

Name and address of the Authorized Representative

Common name of device (i.e. RF Generator)

Description of device (i.e. model or type designation)

Annex used to verify conformity to the directive

Reference to Notified Body certificate (where applicable)

Identification of Notified Body (where applicable)

Signature of an authorized person
 After the DoC is created, the CE mark can be applied
87

CE Marking is the manufacturer’s declaration that the product meets all the
appropriate provisions of the relevant legislation

Once applied, the product can be freely marketed anywhere in the EU without
further control
Overview of Article 58
 Refers to Article 58 within EC Regulation 726/2004
 Allows for CHMP to give opinions on medicinal products exclusively
intended for markets outside of the EU
 Joint consulting venture with the World Health Organization (WHO)
 WHO cooperation allows for outreach to countries in need
 Goal is to provide medicines to countries where regulatory capacity is lacking
 Products may no longer be marketed in EU due to demand or other
commercial reasons
 Process is similar to getting a medicinal product approved in EU except no
decision from European Commission is necessary
 Roughly a 9-12 month process from Pre-submission to approval
 When approval opinion is positive, EMA publishes a European Public
Assessment Report (EPAR) to reflect the conclusions made
88
Scope of Article 58
 Medicines used to prevent/treat diseases of major public health interest

Reasoning behind WHO being involved in process
 Medicines in scope include:
89

Vaccines used in WHO expanded Programme on Immunization

Vaccines that protect against public health priority diseases

Vaccines involved in stock pile for emergency response

Medicines that treat the following WHO target diseases:

HIV/AIDS

Malaria

Tuberculosis

Leishmaniasis

Onchocerciasis

Dengue Fever

Leprosy
Innovation Task Force (ITF)
 Multi-disciplinary group to ensure scientific, regulatory and legal
coordination in areas of interest for EMA
 Provides forum of early dialogue for applicants with EMA
 ITF will work with the EC and CHMP to determine whether new products
for emerging therapies qualify for EMA procedures
 Considered the first step for regulatory advice when confirmation of
classification is needed
 Will setup briefing meetings to facilitate information exchange
 Meetings complement other formal procedures on scientific advice
 Applicant information kept confidential
 Services are provided free of charge
90
Pre-Article 58 Advice
 If a combination product is classified as a medicinal product, it is
recommended to request scientific advice from EMA
 Request for a pre-submission meeting with CHMP
 To obtain feedback on quality, clinical and non-clinical aspects of
combination product
 Entire Pre-submission process takes about 5-6 months to complete
Initial
Notification
March 2011
Pre-Submission Sci. Advice
Meeting
Work Party
Meeting
June 2011
July 2011
Final Advice
Sept/Oct
2011(depending on
additional meeting
requested)
91
Article 58 – Additional Details
 Impact on Devices with Microbicides

Devices (or combination products) with Microbicides are considered in scope of
Article 58 due to HIV/AIDS prevention

At least 3 different scientific opinions have been adopted in the area of HIV/AIDS
prevention

Article 58 applicants need to already be established in the EEA
 Additional Considerations
92

Paediatric Legislation requirements do not apply to Article 58 applications

Dossiers should be submitted electronically in CTD format

No EC incentives such as market exclusivity due to lack of EC decision

Process can be accelerated when justified during request of eligibility

No environmental risk assessment needed as part of Article 58

GMP & GCP inspections are still required – 18,900 euros/inspection
Combination Products – EMA vs. CA
 The EU CTD does apply to the “medicine” component of a combination
product and has significant impact on medical device development
The National Competent Authority in most countries regulate medicines and
medical devices (not EMA)
 Companies manufacture both medicines and devices and manage clinical trials for
both

 An increasing number of medicinal products are dealt with by the European
Medicines Agency (EMA) via a unified approval route (Centralized
Procedure)

Alternative to working through each National Competent Authority
 When the medicinal component of a combination product has been
approved through the Centralized European procedure, the same process is
followed
93

EMA should not always be substituted for National Competent Authority

Experience to date indicates that Centralized Procedure is likely to be a longer and
more expensive route.
Differences Between
FDA & EU/EMA
94
FDA vs. EU (Devices)
 Both the EU and US divide medical devices into different classes and provide
for somewhat different requirements for each class
 Therefore gaps between the US and EU requirements can vary by product
classification
 FDA offers one route to quality assurance for a medical device class
 EU has a modular approach to conformity assessment for quality assurance
with up to 4 different routes for a Class IIb device and 3 for a Class III device
 The EU manufacturer that closely follows the EU route that most closely
parallels FDA guidelines could save considerable time meeting regulatory
requirements
 Have same goal:
 To ensure that a medical device company produces a safe product and that
it is able to provide quality assurance that it can manufacture this safe
product consistently
95
FDA vs. EU (Devices) Cont’d.
 Both require the development of sufficient technical documentation for
regulators to determine whether the product as designed and conceived is safe
 FDA equivalents to technical file for Class I, IIa and IIb products and design
dossier for Class III devices is the premarket notification 510(k) evaluation and
premarket approval (PMA) review
 510(k) evaluation covers established devices and products that are largely
similar to devices already on the market
 PMA is generally required for Class III and high risk Class II devices
 For US companies it is difficult to close the gap between the 510(k) and the
technical file
 For European manufacturers, the technical file should more then satisfy the
FDA in most cases
96
FDA vs. EU (Devices) Cont’d.
 Any manufacturer no matter what country they are in if developing new
devices for international market is advised to use the essential requirements in
creating technical documentation
 By meeting CE marking requirements, FDA is largely satisfied which readily
accepts EU harmonized standards and European national standards to
demonstrate compliance with its requirements
 Quality assurance system in both EU and US must cover both production and
design control for Class II (a and b) and III products this is met by ISO 9001
and ISO 13485 they both have adopted to meet conformity assessment
requirements
 EU offers options to manufacturers as part of modular approach and are
described in Annexes III, IV, V, and VI of the MDD to give companies
separate design control from manufacturing or production control
 European manufacturers might benefit from the flexibly to these
alternative, but the FDA do not accept them
97
Comparing and Contrasting the FDA and EMA
(Pharmaceuticals)
 EMA allows greater flexibility to companies when designing their clinical
programs, including being able to choose the route of registration for most
products, while the FDA does not
 Both systems are deemed equivalent undergoing a scientific review to make
sure unsafe products are not granted a marketing authorization (License)
 The FDA allows ongoing scientific dialogue during the development of the
product and is more flexible with the applicant; EMA does not allow the
dialogue and is more strict especially with the centralized procedure (through
CHMP)
98
FDA and EMA (Pharmaceuticals) Cont’d
 The FDA does not charge a fee for providing a review and will comment on the
whole development plan for a new medicine, whereas with EMA it is necessary
to ask specific questions. Fees are dependent on scope and amount of
questions.
 The FDA’s review is quicker to obtain than EMA’s.
 The FDA application is submitted with continual dialogue, so the regulators
are familiar with the process; helps facilitation.
 EMA can have a product application enter their system with no previous
knowledge; slows review process.
99
FDA and EMA (Pharmaceuticals) Cont’d
 EMA is conservative when reviewing products on levels of specialty areas, such
as oncology. The FDA is seen as more willing to approve new therapies.
 The FDA is more willing to issue conditional and fast track authorizations
than the EMA. Process is relatively new (EMA) selectively used.
 The FDA grants authorizations based on scientific data only, while some are
concerned with the political aspect of EMA.
 Product review times are longer with EMA (18-24 months = 6 months advance
actions + 12-18 month dossier reviews ; Centralized procedure) than FDA (1214 months)
100
FDA and EMA (Pharmaceuticals) Cont’d
 Unlike the EMA, FDA does not issue renewal licenses; instead authorizations
are issued indefinitely and are constantly updated based on safety data,
efficacy and product modifications (amendments / variations)
 When introducing safety restrictions with EMA, it can take up to 9 months
to add a side effect to the SPC; 3 months typically with FDA
 Through FDA, companies have a wider range of product amendments they
are allowed to introduce as soon as variation applications are submitted than
through EMA. “Notifications” just recently introduced as a category in the
EU (inform only). Previously waited 30 days, even for Type IA variations.
101
Review of Implantable
Medical Devices
containing Microbicides
102
Medicated Intra-vaginal Rings
 Considered a Combination Product (device + drug) for regulatory review
 Requires an IDE for the Device and an IND for the Drug
 Requires a Technical File and performance against Essential Requirements
for the device (Ring)
 Requires Preclinical, Ph. I, Ph. II and Ph. III data for the drug component
or components
 Profile of impurities for both
 Extractable / leachable data - effect of drug on the polymeric ring
 Controlled release data - drug / polymer specific
103
Medicated Cervical Caps

The cervical cap is a contraceptive device that prevents sperm from entering the uterus

The cervical cap is a reusable, deep cup that fits tightly over the cervix

104
Smaller than the dome, measuring on average at around two to three centimeters
in diameter and shaped much like a small egg cup

The cervical cap is held in place by suction and has a strap to help with removal

It works by blocking the sperms route to the cervix thus preventing further entry to
the uterus

Only one cervical cap — FemCap — has Food and Drug Administration (FDA)
approval in the U.S.

FemCap is made of silicone rubber and must be fitted and prescribed by a doctor

The cervical cap is effective at preventing pregnancy only when used with
spermicide, which blocks or kills sperm

A medicated cervical cap would also be considered a combination product by FDA

Both the spermicide must be approved along with the device separately

The interaction of the two must also be evaluated
Medicated Condoms
 Sec. 884.5310 Condom with spermicidal lubricant
 A condom with spermicidal lubricant is a sheath which completely covers the
penis with a closely fitting membrane with a lubricant that contains a
spermicidal agent (ex: nonoxynol-9)
 This condom is used for contraceptive and prophylactic purposes (preventing
transmission of venereal disease)
 Classified as Class II (performance standards)
 Typically considered a SR device (for the condom alone)
 Would follow the evaluation pathway of the Medicinal Product + the device
performance standards / essential requirements evaluation
105
Medicated Films
 Polymeric drug delivery systems shaped as thin sheets usually ranging from
220-240 um in thickness
 Often square (5cm x 5cm), colorless and soft with a homogenous surface
 Produced with polymers such as polyacrylates, polyethylene glycol,
polyvinylalcohol and cellulose derivatives
 Traditionally intended for single use
 Considered a combination product (device + drug)
 Would follow the same path for Clinical Trials and device approval as the
Intra-vaginal ring
106
Application Devices (vaginal & rectal)
 First check with IRB for NSR classification (likely in agreement)
 An IDE might not be necessary
 A designed device trial (investigational new device) could be initiated
through FDA
 Trial objectives of efficacy and safety would be followed
 Design changes typically require iterations of studies
 Patient comfort
 Patient preferences
107
Current IVR Product Comparison
Product
Manufacturer
Dimensions
(Diameter)
Composition
Indication
Active
Ingredient
Catalyst
Femring®
Warner
Chilcott
Outer: 56 mm
Cross-section: 7.6 mm
Core: 2 mm
Cured silicone elastomer
composed of dimethyl
polysiloxane sinanol, silica,
propyl orthosilicate,
stannous octoate, barium
sulfate & estradiol acetate
Vulvar and vaginal
atrophy symptoms
related to
menopause
Estradiol
acetate
Tin
Nuvaring®
Organon
Outer: 54 mm
Cross-section: 4 mm
Ethylene vinylacetate
copolymers & magnesium
stearate
Hormonal
Contraceptive
Etonogestrel
& ethinyl
estradiol
N/A
Estring®
Pfizer
Outer: 55 mm
Cross-section: 9 mm
Core: 2 mm
Silicone elastomers Q74735 A&B, SFD 119
silicone fluid & barium
sulfate
Symptoms related
to postmenopausal
atrophy of vagina
and lower UT
Estradiol
Platinum
108
Minimal Regulatory
Requirements for
Testing & Standards
109
Coordination of FDA and EMA Requirements
 Combination Products
 Companies looking to register products in both the U.S. and EU should
follow ISO test methods where possible
 ISO-14155 Device Clinical Trials
 ISO-13485 Device Manufacturing
 ISO-10993 Biocompatibility (genotoxicity, carcinogenicity, reproductive
toxicity)
 Product specifications (CofA’s), impurities
 Release of by-products
 Mechanical safety issues (devices)
 Extractables & leachables (device) - chemical equivalence
 Toxicity: cytotoxicity, sub chronic toxicity
110
Minimal Regulatory Requirements for
Testing and Standards
 Combination Products
 Sensitization
 Irritation
 Antimicrobial effectiveness testing of gel
 Stability testing / product shelf-life (to extend for life of study)
 pH, viscosity, assays, microbial limits
 Labeling requirements
 Child-resistant packaging (?) - typically at commercialization
 Use of vendor data - obtain copies of original study reports
 Lab has strong GLP / GMP compliance
111
Minimal Regulatory Requirements for
Testing and Standards
 Device Physical Property Testing
 “Similar product” to one previously approved or clinically studied?
 Previously published and accepted Physical Properties of a Device
known to perform in the application?
 ASTM (American Society for Testing & Materials) Test Standards for
Physical Properties of Polymers:
 Tensile strength
 Flexural strength
 % Elongation
 Heat Distortion Temperature
 Mw, GPC profile
 HPLC or GC / Mass spec. impurity profile profile
 Medical-grade resins produced on Medical-grade manufacturing
lines
112
Minimal Regulatory Requirements for
Testing and Standards
 Pre-Clinical Safety Assessment (combination)
 Safety Pharmacology
 Cytotoxicity study using the elution method (ISO-10993-5)
 Sensitization….._____maximization study (ISO-10993-10)
 Irritation or intracutaneous reactivity…..vaginal irritation study in ______
(ISO-10993-10)
 Genotoxicity (ISO-10993-3)
 Bacterial reverse mutation study
 _____ lymphoma assay
 Subacute / subchronic toxicity
 XX day intravaginal toxicity study in _____
113
Minimal Regulatory Requirements for
Testing and Standards
 If data is available from a previous submission, you will need to perform
confirmatory testing if there are significant* changes in any of these areas:
 Materials selection
 Manufacturing processes
 Chemical composition of materials
 Nature of patient contact
 Sterilization methods
 Bridging studies are commonly requested to “bridge” available data on
prior published studies to the “current” products and study design being
considered
* Definition of Significant: Examples --- polymer change, new manufacturing
step, new additives, new intended use, new sterilization technique utilized.
Typically reviewed with and agreed to by Healthcare Authority.
114
Novel Microbicides
 Definition:
 New API, no Pre-clinical data, previous published CT reports, no
previously published global reports
 Requirements:
 Pre-clinical studies (full toxicity and biocompatibility assessment)
 Ph. I ,II, III Clinical Trials
 Full IND review
 CT Efficacy Data
 Pharmacovigilance profile
 Risk / Reward evaluation
115
Microbicide Combinations

Definition: Two or more microbicides combined together as the active

Possible Combinations:
1.
One known and one novel

2.
Both are novel



116
Requirements: Novel full-testing plus dual interaction data
Requirements: Full testing requirements
Requirements:

Definition on their interaction together

Chemical reaction together?

Positive synergistic efficacy

Combined unique toxicity effects

Reaction by-products
Remember Food, Drug & Cosmetic Act 505b2 licensing route
Microbicide APIs & Delivery Devices
 In EU, governed by Directive 65/65/EC
 Repeat dose toxicity study (90 day study; “permanent use of compound”)
 Clinical rates of gel delivery
 Controlled release (in vitro data); no dose dumping
 Over-riding review will be for the drug components
 Medical device will need to show that it brings “no deleterious effects” to
the drug product (eg. extractables, leachables)
117
Additional Requirements for
Testing and Standards
 Should I test device materials or only a composite of the finished device?
 Your responsibility is to gather safety data on every component and material
used in the device
 Long-term availability of Resin grade; Specification changes???
 Si
 EVA
 PVOH
 Best approach:
 Assemble vendor data on candidate materials
 Conduct analytical and vitro screening of materials
 Conduct confirmatory testing on a composite sample from the finished
device
118
Product Development Plan
Table of Contents for Product Development Plan
I. Name of the Medicinal Product
II. Qualitative & Quantitative Composition
III. Pharmaceutical Form
IV. Clinical Particular Information
119

Therapeutic indications

Posology and method of administration

Contraindications

Special warnings and precautions for use

Interaction with other medicinal products and other forms of interaction

Pregnancy and lactation

Effects on ability to drive and use machines

Undesirable effects (based on most recent clinical data)

Overdose
Product Development Plan (Cont’d)
V. Pharmacological Properties

Pharmacodynamic properties (Gel #1, Gel#2, combination)

Pharmacokinetic properties (Gel#1, Gel#2, combination)

Pre-clinical safety data
VI. Pharmaceutical Particulars

List of excipients

Incompatibilities

Shelf Life

Special precautions for storage

Nature and contents of container

Special precautions for disposal and other handling
VII. Marketing Authorization Holder
VIII. Marketing Authorization Number
IX. Date of First Authorization / Renewal Date
X. Date of Revision of Text
120
Regulatory Challenges in
Developing IVR’s
121
Manufacturing Considerations for Devices
 Compounding strategy and capability
 Equipment procurement & lead times
 Contract manufacturer identification
 Process scale-up
 Validation – analytical methods
 Polymer supply (silicone, EVA, etc), catalyst type used
 Resin grade consistency throughout Phases of study and ultimately to
commercialization (eg. impurity profile / extractables and leachables); resin
equivalency data
122
Batch Production & Campaign Strategy
 Efficiency determined by a number of factors
 Labor cost per batch
 Analytical testing cost
 In-processing testing strategy
 Down time
 Capacity to compound drug into polymer
 Compounding equipment requirements
 Stability Testing needed to define Expiration Date
 In a combination product, can be influenced by the most
susceptible component; the device or the drug
 Polymer product expirations- determined by loss of physical
properties (eg. flexibility)
123
Rationale for Selection of Materials
 Compound XYZ is an excellent candidate for a topical microbicide
development due to its proven in-vitro and in-vivo efficacy and safety
profiles
 ….also its physical and chemical properties
 Compound XYZ has demonstrated potent activity against wild-type HIV
strains and strains harboring different resistance inducing mutations
 Compound XYZ belongs to a class of drugs that has been used in first line
therapy in treatment of patients with HIV/AIDS
 Compound XYZ vaginal Ring is a ____-based drug delivery device
containing Compound XYZ
 These devices are a well-known, controlled release, drug delivery system,
with products already on the market
 Not mandatory, but simplest testing & regulatory pathway
124
Qualification of Materials and CMC for
Combination Products
125

Quality data on gel drug substance

Specifications, testing, CofA’s

Changes in materials used from one study to another

Changes in design (device) from one study to another

Concerns and demonstration of equivalency

Patient acceptance / “Ease of Use”

Irritation / Comfort / Discomfort

Manufacturing process changes: temperature processing / degradation

Processing: extrusion, injection molding, calendaring

Particular attention to additives such as colors (fading, partial fading after use,
toxicity effects)

Mixing, dispersion, UV sensitivity, body fluid / chemical attack, migration

Use of liquids, pellets, color concentrates

Effective container, closure system, packaging

Labeling, instructions for use, readability studies

What constitutes a Lot / Batch size?

Determining expiration dates on device alone
Nanotechnology
 The use of nanotechnology in the field of medicine could revolutionize the
way we detect and treat damage to the human body and disease
 One application of nanotechnology in medicine currently being developed
involves employing nanoparticles to deliver drugs, heat, light or other
substances to specific types of cells
 One of the earliest nanomedicine applications was the use of
nanocrystalline silver which is as an antimicrobial agent for the treatment
of wounds
 A nanoparticle cream has been shown to fight staph infections
 Ex: Burn dressing coated with nanocapsules containing antibotics
 If an infection starts the harmful bacteria in the wound causes the
nanocapsules to break open, releasing the antibotics
 This allows much quicker treatment of an infection and reduces the
number of times a dressing has to be changed
126
Nanotechnology in Medicine
127

BioDelivery Science --- Oral drug delivery of drugs encapuslated in a nanocrystalline
structure called a cochleate

CytImmune --- Gold nanoparticles for targeted delivery of drugs to tumors

Invitrogen --- Qdots for medical imaging

Smith and Nephew --- Antimicrobial wound dressings using silver nanocrystals

Luna Inovations --- Bucky balls to block inflammation by trapping free radicals

NanoBio --- Nanoemulsions for nasal delivery to fight viruses (such as the flu and
colds) or through the skin to fight bacteria

NanoBioMagnetics --- Magnetically responsive nanoparticles for targeted drug
delivery and other applications

Nanobiotix --- Nanoparticles that target tumor cells, when irradiated by xrays the
nanoparticles generate electrons which cause localized destruction of the tumor cells.

Nanospectra --- AuroShell particles (nanoshells) for thermal destruction of cancer
tissue

Nanosphere --- Diagnostic testing using gold nanoparticles to detect low levels of
proteins indicating particular diseases
Nanotechnology in Medicine (Cont’d)
128

Nanotherapeutics --- Nanoparticles for improving the performance of drug delivery by
oral or nasal methods

Oxonica --- Diagnostic testing using gold nanoparticles (biomarkers)

T2 Biosystems --- Diagnostic testing using magnetic nanoparticles

Z-Medica --- Medical gauze containing aluminosilicate nanoparticles which help blood
clot faster in open wounds.

Sirnaomics --- Nanoparticle enhanced techniques for delivery of siRNA

Makefield Therapeutics --- Nanoparticle cream for delivery of nitric oxide gas to treat
infection

DNA Medicine Institute --- Diagnostic testing system

NanoViricides --- Drugs called nanoviricides™ designed to attack virus particles

NanoMedia --- Targeted drug delivery

Taiwan Liposome --- Drug delivery using lipsomes

Traversa Therapeutics --- Delivery of siRNA molecules

Nano Science Diagnostics --- Diagnostic testing system
Nanoviricides


A “nanoviricide” is an agent designed to fool a virus into attaching to this agent

Works the same way that the virus normally attaches to receptors on a cell
surface

Once attached, the flexible nanoviricide glob wraps around the virus and traps it

Virus loses its coat proteins that it needs to bind to a cell and is thus neutralized
and effectively destroyed

Nanoviricides complete the task of dismantling the virus particle without
immune system assistance
A nanoviricide is created by chemically attaching a virus-binding ligand, derived from
the binding site of the virus located on cell surface receptor, to a nanomicelle flexible
polymer

129
This binding site does not change significantly when a virus mutates

Virus-specific nanoviricides have been created against important viruses such as HIV,
Influenza and Bird Flu by choosing highly virus-specific ligands

The National Institutes of Health (NIH) is funding research at eight Nanomedicine
Development Centers
Approaches for Creating Nanodevices
 There are two basic approaches for creating nanodevices
1. Top-down approach
 The top-down approach involves molding or etching materials into
smaller components
 This approach has traditionally been used in making parts for
computers and electronics
2. Bottom-up approach
 The bottom-up approach involves assembling structures atom-by-
atom or molecule-by-molecule
 May prove useful in manufacturing devices used in medicine
130
Nanodevices
Nanodevices are small enough to enter into cells
Cell
Nanodevices
Nanodevices
Water
molecule
131
White
blood cell
Nanodevices & Nanomedical Robots
 Classified as an advanced drug delivery system, the state-of-the art device has
numerous capabilities for destroying tumors, kidney stones and ulcers, and
treating cancer and HIV
 Nanomedical robots
Cell
 Nano robots are nanodevices that will be used for the
Nanodevicespurpose of maintaining and protecting the human body
against pathogens
 By having these Robots, we can refine the treatment
of diseases by using biomedical, nanotechnological engineering
 No difficulty in identifying the target site cells even at the very early
stages which cannot be done in the traditional treatment
 Ultimately able to track down and destroy target cells wherever they may
Waterbe growing
White
molecule
blood cell
132
Regulating Nanodevices
133

There is significant debate about who is responsible for the regulation of
nanotechnology

Calls for tighter regulation of nanotechnology have occurred alongside a growing
debate related to the human health and safety risks associated with nanotechnology

Stakeholders concerned by the lack of a regulatory framework to assess and control
risks associated with the release of nanoparticles and nanotubes
 Parallels have been drawn with bovine spongiform encephalopathy (‘mad cow’
disease), thalidomide, genetically modified food, nuclear energy, reproductive
technologies, biotechnology, and asbestosis

Academics have called for stricter application of the precautionary principle, with
delayed marketing approval, enhanced labeling and additional safety data
development requirements in relation to certain forms of nanotechnology

Institute for Food and Agricultural Standards has proposed that standards for
nanotechnology research and development should be integrated across consumer,
worker and environmental standards
Multiple Drugs in One Device
 Applies to both drugs being antiretroviral or both contraceptive
 Each drug considered for toxicity, efficacy and safety by itself or published
white papers from previous studies can be used to support an individual
drug (this can be for one or multiple drugs)
 The synergistic “hypothesis” is then prepared
 The interaction of two drugs together must be determined; toxicity, safety,
efficacy and synergy
 Chemical interaction
 Biological and physiological interaction
 Study Plan & testing regimen must be developed to “tell the above story”
134
Multiple Drugs in One Device

Applies to multiple antiretroviral drugs within one device

Ex: FDA approval of Atripla, 3-drug fixed dose combination antiretroviral


Combines the active ingredients of:

Sustiva (efavirenz), a Nonnucleoside Reverse Transcriptase Inhibitor
(NNRTI)

Emtriva (emtricitabine) and Viread (tenofovir disoproxil fumarate), two
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

The guidance encourages manufacturers to develop fixed dose combination and
co-packaged products consisting of previously approved antiretroviral therapies
for the treatment of HIV infection

The three components of Atripla have been in use for some time, their
characteristics and effects are well known

135
Atripla was approved in 3 months under FDA's fast track program
Safety and effectiveness of the combination of these three drugs were shown
in a 48 week-long clinical study with 244 HIV-1 infected adults receiving the
drugs
Multiple Drugs from Different Drug Classes
 Applies to an antiretroviral drug combined with a contraceptive drug
Typical Precautions: Warning Statements
 XXXXX may cause fetal harm when administered during the first trimester
to a pregnant woman.
 Women should not become pregnant or breastfeed while taking XXXXX
 Barrier contraception must always be used in combination with other
methods of contraception (e.g., oral or other hormonal contraceptives)
 If the patient becomes pregnant while taking XXXXX, she should be
apprised of the potential harm to the fetus
136
Multiple Drugs from Different Drug Classes
 Applies to an antiretroviral drug combined with a contraceptive drug


137
Another example warning………..Women taking oral contraceptives ("the pill") or
using the contraceptive patch to prevent pregnancy should use a different type of
contraception since XXXXX may reduce the effectiveness of oral or patch
contraceptives
FDA Warning / Alert: Counseling/Prevention
1.
Counsel all women of childbearing potential after diagnosis of human immunodeficiency
virus (HIV) and yearly thereafter
2.
Emphasize importance of barrier protection
3.
Emphasize importance of maintaining optimal health
4.
Consider possibility of pregnancy in all women of childbearing potential when prescribing
medications
5.
Educate patient about possible drug interactions
6.
Be aware of safe pregnancy termination services
7.
Be aware of reproductive options for HIV-infected women/couple
8.
Discuss the benefits of using combination antiretroviral therapy (ART) for prevention of
mother-to-child transmission (MTCT) with all pregnant women who are HIV infected
9.
Discuss possible guardianship issues with HIV-infected women desiring to have children
Regulatory Challenges
for Imaging Devices
138
Challenges - Light Emitting Devices
 TITLE 21—Food and Drugs CHAPTER I--Food and drug administration,
department of health and human services
 Subchapter J — Radiological Health
 Part 1040 -- Performance Standards For Light-emitting Products
 §1040.10 --- Laser products
 §1040.11 --- Specific purpose laser products
 §1040.20 --- Sunlamp products and ultraviolet lamps intended for use
in sunlamp products
 §1040.30 --- High-intensity mercury vapor discharge lamps
139
Regulatory Challenges for Radiation Emitting Devices
 TITLE 21 -- Food and Drugs – Chapter 1 – Food and Drug Administration,
Department of Health and Human Services - Subchapter J — Radiological
Health
 PART 1020 -- Performance Standards For Ionizing Radiation Emitting
Products
 §1020.10 --- Television receivers
 §1020.20 --- Cold-cathode gas discharge tubes
 §1020.30 --- Diagnostic x-ray systems and their major components
 §1020.31 --- Radiographic equipment
 §1020.32 --- Fluoroscopic equipment
 §1020.33 --- Computed tomography (CT) equipment
 §1020.40 --- Cabinet x-ray systems
140
Electronic Products Under FDA Jurisdiction
 FDA lists examples of electronic products regulated under the Radiation
Health Act in its regulations
 Any of the examples could be intended for a medical purpose and could
be regulated by FDA as medical devices
 Sampling of the electronic products regulated by FDA:
1. Television receivers
2. Computer monitors
3. Cell phones
4. X-ray machines (including medical, research, industrial, and educational)
5. Electron microscopes
6. Black light sources
7. Welding equipment
8. Alarm systems
9. Microwave ovens (devices that generate microwave power)
10. All lasers (including low power lasers such as DVD and CD
readers/writers/players) and other light emitting devices (Infrared and
Ultraviolet)
11. Ultrasonic instrument cleaner
12. Ultrasound machines
13. Ranging and detection equipment, such as laser levels
141
Classification of Light Emitting Devices
142

Classification of light emitting devices is based on:
 Type of light emitted
 Safety to clinician
 Safety to patient

FDA regulated electronic products include any manufactured or assembled products
(along with any component, part or accessory of such products) which contain or act
as a part of an electrical circuit and emit radiation of any kind

The law is drafted so FDA also regulates those electronic products that would emit
radiation if the source of radiation was not properly shielded
 Agency has jurisdiction if radiation is accessible or humans are exposed
 Jurisdiction also exists if the electronic product produces or generates radiation,
even if such radiation is inside some sort of shielding

Many radiation emitting electronic products are also medical devices
 Electronic product must comply with both the Radiation Health Act and the
Food Drug and Cosmetic Act (FDCA) governing medical devices
US Classification of Light Emitting Devices
The three classifications for medical devices at FDA apply to light emitting
devices as well:
 Class I -- Simple design and minimum potential for harm to user
 Class II -- General controls alone are insufficient to assure safety and
effectiveness, but existing methods are available to provide such
assurances
 Class III -- Devices where insufficient information exists to assure safety
and effectiveness solely through controls
 One device that causes some confusion as to its classification is the LED:
(light emitting diode)
 LED can be either a class I or II device depending on whether machines use
red or blue light, implement ultraviolet or infrared radiation, what the
range of the device's wavelengths are, and the device's intended use
 Given the variations in LED devices, it's important to verify their
classification with the FDA
143
EU Classification of Light Emitting Devices
EU Medical Device Classification Rules:
 Refer to EU Medical Device Directive 93/42/EC
 Rule 5: Device invasive in Body Orifice or Stoma (but not surgically)

Transient Use (<60 minutes)= Class I

Connected to an Active Medical Device of Class IIa or higher= IIa
 Rule 10: Active device for Diagnosis. May supply energy for “imaging
purpose”, monitor vital physiological processes= Iia
 Special Rule: All devices emitting ionizing radiation and related
monitors in medical procedures = IIb
144
Safety and Risk of Devices
Identified Risk
Recommended Mitigation
Ineffective treatment
Performance specifications
Thermal or optical injury
Performance specifications
Electrical injury
Electrical safety and Electromagnetic
compatibility
Electromagnetic interference
Electrical safety and Electromagnetic
compatibility
Cross-contamination
Infection control procedures
Improper use
Labeling
145
Requirements for Device Production
 The following FDA general controls apply to all devices classes (I, II, III):

510(k) exempt

Establishment registration

146

Requirement for organizations involved in the production and distribution
of medical devices marketed in the United States

Must provide the FDA with the location of medical-device manufacturing
facilities and importers.

Includes manufacturers, initial importers, foreign establishments, and
distributors
Good Manufacturing Practices (GMP)

Good manufacturing practices ensure manufacturers are using machine
parts and manufacturing practices that make safe devices

ISO-13485 is the international GMP standard for device manufacturers to be
audited against by certified /notified bodies

Medical device listing

Proper labeling
IDE Requirements for Imaging Devices
The following requirements apply to imaging devices used for research only:
 IRB would be approached for NSR vs. SR determination
 If NSR, no IDE would be required
 The device use would be described in the IND application
 If SR, an IDE would be required
 The IDE, considerations and process described under the following SR
slide would be followed
147
IDE Requirements for Imaging Devices (Cont’d)
Non-Significant Risk Devices (for research only):
 NSR devices need to be designed and built to an abbreviated subset of IDE
requirements as outlined in 21 CFR 812.2(b)
 Quality System Regulation Design Controls (21 CFR 820.30 [6]) and
Documentation (21 CFR 820.40 [6]) detailing how the system was built and tested
are essential, and should be completed as the clinical prototypes are being built
 Following construction, extensive testing is necessary
 Internal testing should be performed to ensure device safety
 Qualified consultants should conduct independent mechanical and electrical
safety testing and provide safety approval documentation
 A prototype identical to the clinical prototype should be used for final animal
testing and system validation
 Any new device intended for use in patient care must also be tested for safety by
the clinical engineering department of the hospital prior to its clinical use
 After these tests are completed, an IRB application can be submitted
148
IDE Requirements for Imaging Devices (Cont’d)
Significant Risk Devices (for research only):
 SR medical devices must be designed to meet all IDE requirements and will
be subject to extensive safety and failure mode analysis
 They must also be engineered to meet relevant subsections of the
Association for the Advancement of Medical Instrumentation
(AAMI)/International Electrotechnical Commission (IEC) standard
#60601[7]
 Similar to NSR devices, extensive testing is necessary to ensure device safety,
including internal and external testing by qualified consultants, as well as
clinical prototype testing with an equivalent system on animal models
 After completion of appropriate documentation and testing of the clinical
prototype, an IDE application must be submitted to the FDA
149
IDE Requirements for Imaging Devices (Cont’d)
The following requirements apply to imaging devices intended for future
commercial licensing & use:
 Same NSR vs. SR process is followed with the IRB
 However, must now add documentation and auditing of the Full Quality
Management system at the manufacturing location (eg. ISO-13485)
 Full Quality System Control documentation (21 CFR 820[6]), as specified
in the IDE instructions, is required prior to clinical translation
 Documentation should be written as clinical prototypes are built
150
Potential Development
Process Concerns
151
Development Process Concerns – Team Strategy
Pre-Clinical  Ph. I  Ph. II  Ph. III
 Resolve all issues associated with the product before proceeding with the
next Phase of study
 Build a tracking grid
 Pre-clinical, CMC, manufacturing, GMP
 Define gaps on issues requiring resolution before proceeding
 Assign specific team members for accountability on each issue
resolution
 Determine optimal processes and structures for implementing components
of study plan
 Conduct all planning with sub-teams*
* Examples: clinical/study, quality, product development, process development,
regulatory, legal
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Development Process Concerns – Pre-Clinical->Ph.I
 Defines the objectives of studies / testing (as previously described)
 Animal Species: availability, relevant, translatable, non-problematic species
 Consistency of species utilized in previous studies; translatable data
 Discuss pre-clinical plan with Healthcare Authority (U.S. FDA) prior to
initiation
 Discuss Pre-clinical data with Healthcare Authority (U.S. FDA) prior to
IND initiation
 Process globally known as “Scientific Advice” with HCA, EMA
- Saves “false starts” or sometimes difficult work to retrace and “add to”
- However, if you disagree with the answer, it has “become part of the official
record”
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- Still advantageous to know “opinion” before you start or what your later
research commitments might be to support product licensing
Development Process Concerns – Phase I-II-III
Ph. I  Ph. II  Ph. III
 Phase I : Determining safety, adverse reactions
 Phase II: Determining efficacy
 Phase III: Statistical adverse reactions, range of adverse events, statistical
efficacy data developed
 Strong monitoring efforts for detailed close-out of each Phase of Study
 Maintain consistency of drug and device utilized
 Long-term availability of device raw materials
 Data must hold up to regulatory scrutiny during “licensing phase”
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Parameters and Considerations
Define the parameters:

How many products?

How many trials?

Typical trial size (patient ranges):
- Phase I: 20-40 Phase II: 50-100 Phase III: 100-300

How many gels?

What is the ring (or device) manufacturing process?
Development process considerations:
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
Technical & Clinical Feasibility- all components for each product and each design
defined

Identify manpower - costs, staff, consultants, vendors

Associated Costs

Regulatory Risks – for various product and design options identified and quantified

Timeline requirements for all components of determining feasibility must be
determined for each trial scenario

Product Development Risks - knowledge gaps defined and resolution planning
established
Risk Relationship with Study Design
 Non-linear relationship between study design and time, effort, cost risk
 Number of Products
 Number of Arms
 Single product, 2-arm study is “X”
 3 Product, 6-arm study is a multiple of “X”
 The more people, the more management burden, the more risk, the more
set backs, the more it costs and the longer it takes
 However, the trial must be appropriately robust in order to evaluate the
endpoints
Development Process Conclusions:
 Timing differences between trials are not linear vs. the number of products
in trial
 The more complex, the more significant holes of knowledge will develop
 Costs, labor demands, technical feasibility, timing, etc.
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Development Process Concerns – Post-Marketing
157

Determine product’s long-term effectiveness on patient

Determine patient “Quality-of-Life”

Compare current “studied products” to traditional therapies

Cost effectiveness of New Licensed Therapy

Continuing to study range and statistics of adverse reactions (helps to build PSUR
[Periodic Safety Update Report] on Drug Component)

PSUR= every 6 months during first 2 years, then annually

Data assists in Product & License Renewal in those countries possessing that process
(typically every 5 years); no renewals currently in U.S. with FDA

It is a MA holder's responsibility to keep their product information up-to-date,
making variations to the Summary of Product Characteristics (SPC) as and when
data emerge:
 to introduce additional safeguards
 to reflect evolving therapeutic indications
 to take into account technical and scientific progress
Emerging Global Requirements
for Devices with Microbicides
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Global Challenges
 Regulatory pathways for combinations products need clarification in many
developing countries
 Parallel approval pathways are needed to speed up approval process
 Regulatory expectations are that combination products with multiple active
ingredients need to be superior to individual components
 Negative impact to cost and timeline to prove superiority
 Informed consent can be challenging due to language barriers and literacy
rates
 Ethics review committee recommended to help guide patients
 The following are some recommendations for improving the regulatory process
relating to microbicides and devices:
 Strengthen partnerships in worldwide organizations
 Better information sharing between organizations and countries of interest
 Promote quality & ICH standards
 Establish centers of excellence within impacted regions
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Product Development Partnerships
 Product Development Partnerships work with pharmaceutical companies,
research centers and other PDP’s to prevent HIV transmission through
microbicide use in developing countries
 PDP’s perform the following functions:
 Aid in product development process for microbicides and dual protection
products such as contraceptives combined with anti-STI products
 Conduct pre-clinical and clinical trials to evaluate compounds
 Helps establish manufacturing and distribution capacity
 Training of worldwide investigators
 Examples of PDP’s specializing in HIV/AIDS prevention include:
 IPM Global – http://www.ipmglobal.org
 CONRAD – http://www.conrad.org
 PATH – http://www.path.org
 Population Council – http://www.popcouncil.org
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WHO Considerations
 WHO has partnered with many organizations regarding HIV/AIDS
prevention
 Develops and drives global strategy on HIV prevention
 WHO is helping to get these combination products to areas of need by:
 Partnering with organizations such as EMEA on Article 58
 Helping to facilitate development and testing with other organizations
 Ensuring trials are conducted with high ethical standards
 Microbicide trials involving WHO in the last 2 years suggest:
 Microbicide gel alone did not change HIV infection rate
 Demand for devices with microbicides would be high
 Pre-qualification status for drugs for HIV prevention
 WHO can grant pre-qualification status for HIV/AIDS prevention
products if need is prevalent
 Status is not available for microbicides due to the number of API’s
involved and complexity of the drug/device interactions
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Considerations in Africa


Greatest need for devices with microbicides due to presence of HIV/AIDS

Microbicides of lower efficacy more likely to be accepted in Africa

Cannot be perceived as using developing nations as “Guinea Pigs”
Regulatory review requires expertise that developing countries in Africa typically do not
have

Most advanced tend to be South Africa, Algeria, Nigeria, Zimbabwe


Since risk of HIV is lower in US/EU, regulatory decisions will carry less significance
in developing countries

However, African HCAs and FDA both like to have patients from developed
countries included in the research

FDA or EMEA do not have specific knowledge of target market to make decisions
for other countries

However, some countries will approve based on prior US or EU approval

In some instances, conditional marketing authorizations are approved with incomplete
clinical data in market need is high

Some African regulatory authorities may not recognize outside opinions

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Regulatory capacity of these countries is limited but improving
Authority where product is licensed may not be as stringent
Considerations in Latin America
 Regulatory capabilities have vastly improved over the past decade
 Brazil, Mexico and Argentina are the leading authorities in Latin America
 No standardization amongst countries – each country has their own RA
 Regulatory approval is very complex due to differing requirements by
regulatory authorities
 Local authorities tend to be even more stringent than in the US
 70% of requirements are published, 30% is negotiated
(Examples: where API originates, where drug product is licensed, local
populations included in studies, how product is being brought to the
country; direct/distribution)
 Some areas require local manufacturing presence
 This leads to barrier to entry and longer drug/device approval times
 Combination products are handled similar to US & EU
 Determination made of whether it’s a drug or device
 Vast majority tend to be handled as drug registrations
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Considerations in Asia Pacific
 Most popular growth area for new drug marketing
 Large populations, willing CT participants, limited drug availability
 The PMDA in Japan is the clear leading authority in Asia Pacific
 Original ICH country with US & EU – very advanced
 Other growth markets are China, India, South Korea, Phillipines & Malaysia
 No standardization amongst countries – each country has their own RA
 Regulatory approval is the most complex due to differing requirements,
information availability and multiple languages
 Authorities tend to be mimic US or EU processes with slight alterations
 Approval times take longer than US/EU due to resource constraints
 Culture also has an impact on safety emphasis, regulatory approval process
& timing
 Combination products are handled similar to US & EU
 Determination made of whether it’s a drug or device
164
Conclusions &
Wrap-up
165
Conclusions & Wrap-up
 Clinical trials must be linked with the intended “Route to
Commercialization” and the “Regulatory Approval Pathway”
 Intended regions / countries of “use” should be identified
 NSR vs. SR review with IRBs define the initial steps to be taken
 Pre-IND meetings with FDA very valuable
 Scientific Advice meeting / discussion with EMA (CHMP) also very valuable
(Article 58 review intent)
 Combination product= Drug review + Class III Device registration pathway
 Device alone= likely Class II, IIa, IIb depending on region; In U.S.- mainly
Class II.
 Microbicide gel alone = Drug review
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Conclusions & Wrap-up
 Use as much published data on “Similar Products” as possible to gain an
“equivalency status”
 When in doubt…..dialogue with FDA / EMA
 Don’t underestimate the data needed….. For the device component review;
remember this will be a Class III review if combined
 Long term material availability (polymers) with vendors a MUST to avoid re-
testing
 Suggest you have team representation with experience in Material / Device
Development (including formulation), Regulatory and Change Control /
Auditing on your team for the changes that will undoubtedly occur
throughout product development, clinical studies, product qualification &
registration
 Pick your suppliers / partners carefully……they will be a Big Part of the
Programss success
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Thank you for your time and attentiveness! Best of Luck!
Web References
 U.S. Food & Drug Administration – www.fda.gov
 European Commission – http://ec.europa.eu
 European Medicines Agency - http://www.emea.europa.eu
 World Health Organization – http://www.who.int
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Material Copyright
This presentation was developed by RJR Consulting, Inc. for Advance
BioScience Laboratories, Inc. (ABL) and The Division of Acquired
Immunodeficiency Syndrome (DAIDS) a division of the National Institute of
Allergy and Infectious Diseases (NIAID).
All copyrights are reserved to Advance BioScience Laboratories, Inc. (ABL) and
The Division of Acquired Immunodeficiency Syndrome (DAIDS). It is unlawful
to reproduce, distribute, scan and post or use any developed materials without
the permission of Advance BioScience Laboratories, Inc. (ABL) or The Division
of Acquired Immunodeficiency Syndrome (DAIDS).
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Questions?
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