NIH Microbicide Devices v4 030911

NIH-DAIDS/MRB/IPCP
Medical Device & Microbicide

Regulatory Training
Robert J. Russell
President - RJR Consulting
March 15-16 2011
Course Agenda
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 (Contd)
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

IVRs
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
43054
RJR Consulting, Inc.
rjrussell1280@msn.com
1717
154 E. Main St.

New Albany, OH
Ph. (614) 304-0110
Cell:(614) 551-
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.
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
Business Consulting
Solutions
Clinical Trial Set-Up
Strategy Development
CRO Management &
Project Management
Selection
Marketing Authorizations /
License Renewals
NDAs / Variations /
Amendment Filings
Manufacturing
Authorizations
International Regulatory
5
Surveillance Updating: NA,

EU, Japan, LAA
Government / Agency
Affairs
New Business
Development
Global Business
Expansion
Industry Training
Process Development &
Improvement
Distribution and
Global Reach
RJR Consulting, Inc. is headquartered in New Albany, Ohio
and has affiliate offices strategically located around the
world. These offices provide the in-country 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
FDA Regulatory Overview
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
What is regulated by FDA?

Regulated by FDA
Food
Alcohol
Tobacco
Drugs
Consumer Products
(shampoo, toothpaste, soap, etc.)
Medical Devices
Drugs of abuse
Biologics
Health Insurance
Veterinary products
Meat & Poultry
Cosmetics
Pesticides
Radiation-emitting
Products
Combination Products
(any combination of drug,
device or biologic)
Not Regulated by FDA
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
10
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
11
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
12
FDA Requirements for

Medical Devices &
13
Overall Regulatory Pathway

IVR/Microbicide Gel Combination
Products
Markets/countries
outside of EU
14
FDA Clinical Trial Evaluation Process
Device
15
Combination
Product
Ph I - Toxicity
Ph II - Efficacy
Ph III Statistical Efficacy & Adverse
Events
FDA Licensing Process
16
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 its safe
and effective?
What is the risk to the patient?

17
18
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
19
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
20
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
21
IND
NDA
Safety Concerns
Unknown interactions of combining two or more
approved products can lead to potential safety and

effectiveness concerns for patients
Combination
22
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
23
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)
24
Doesnt meet criteria above for Significant Risk
Different than minimal risk studies that qualify for

expedited review
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
25
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
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
*description in next slide
26
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
27
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
II
Class
III
Exem
pt
95%
3%
0%
NonExem
pt
5%
97%
100%
Class III
Class I
Class II
28
*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
29
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
30
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
31
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
32
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
33
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 firms 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

34
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
35
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
36
37
37
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
38
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
39
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
40
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
HDEs are exempt from effectiveness requirements
Must justify risk to FDA and demonstrate lack of predicate
41
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
42
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, Non-clinical 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, IRBs 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
44
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 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
45
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
46
Clinical Research Monitor (CRA)

Responsibilities
47
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 SOPs 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:
48
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)
49

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
50

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
51
EU/EMA Regulatory Overview
52
EU Member States & EEA
Austria
Belgium
Denmark
Finland
France
Germany
United Kingdom
Greece
Ireland
Italy
Luxembourg
The Netherlands
Portugal
Spain
EU Applicants
Croatia
Turkey
53
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 NBs 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 &
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 its 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
I (sterile
and/or
measuring)
II a
II b
III
Risk
Potential
Low
Low
Medium
Elevated
High
Product
Examples
Non-sterile
dressings,
bandages,
hospital
gowns, light
sources
Spirometers,
urine
drainage
bags, digital
thermometer
s
IV catheters,
tubing's for
anesthesia/v
entilation
Intraocular
lenses,
breast
implants,
endoprosthe
ses,
ventilators
Heart
valves,
reabsorbabl
e implants
Involveme
nt of
Notified
Body
Selfcertification
Declaration
of
Conformity
Selfcertification
Declaration
of Conformity
+ Notified
Body for
measuring
function/
sterility
Mandatory
Mandatory
Mandatory
61
Source: MEDDEV 2.4/1 Rev.8
62
63
64
65
Active Devices Continued
66
67
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,
68
electrical/thermal risks
Manufacturer Information
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 (Contd)

6. Product design and manufacturing specifications
76
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
Technical File Structure (Contd)
7. Product verification including:

7. Testing data and reports
8. Functionality studies
9. Wet lab or bench top testing
10.Materials certificates / reports on biological tests
11.EMC testing and certificates
12.Validation of the packaging / ageing studies
13.Compatibility studies (connection to other devices)
14.Risk analysis (ISO 14971)
15.List of requirements (Annex 1) indicating cross-
reference with documentation
16.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 Commissions classifications
A device intended to deliver a medicinal product is regulated as a

medicinal product (Ex: IVRs)
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 manufacturers 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 manufacturers 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 PreInitial
Notificatio Submissio
n
n Meeting
March 2011
June 2011
Sci. Advice Final

Work Party Advice
Meeting
July 2011
Sept/Oct
2011(dependin
g 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) Contd.

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) Contd.

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)

Contd
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 FDAs review is quicker to obtain than EMAs.

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)

Contd
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 (12-14 months)
100
FDA and EMA (Pharmaceuticals) Contd
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
Manufact
urer
Dimensions
(Diameter)
Composition
Indication
Active
Ingredie
nt
Cataly
st
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
Nuvarin
g
Organon
Outer: 54 mm
Cross-section: 4
mm
Ethylene
vinylacetate
copolymers &
magnesium stearate
Hormonal
Contraceptive
Etonoges
trel
& ethinyl
estradiol
N/A
Estring
Pfizer
Outer: 55 mm
Cross-section: 9
mm
Core: 2 mm
Silicone elastomers
Q7-4735 A&B, SFD
119 silicone fluid &
barium sulfate
Symptoms
related to
postmenopausal
atrophy of
vagina and
lower UT
Estradiol
Platinu
m
108
Minimal Regulatory
Requirements for
Testing & Standards
109
Coordination of FDA and EMA

Requirements
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 (CofAs), 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
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

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

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

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

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 (Contd)

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
120
X. Date of Revision of Text
Regulatory Challenges in
Developing IVRs
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

123
loss of physical properties (eg. flexibility)
Rationale for Selection of Materials
Compound XYZ is an excellent candidate for a topical
microbicide development due to its proven in-vitro and invivo 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

125
Quality data on gel drug substance
Specifications, testing, CofAs
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 (Contd)
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 virusspecific 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-bymolecule

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
Cell
Nanomedical robots
Nano robots are nanodevices that will be used for
Nanodevices
the purpose of maintaining andprotecting the
human body againstpathogens
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
Water
White
doneinthe
traditional
treatment
molecule
blood cell
132
Ultimately able to trackdownand destroy target

cells wherever they may be growing
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 21Food 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

Devices (Contd)
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

Devices (Contd)
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

Devices (Contd)
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
152
Development Process Concerns PreClinical->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
153
- Still advantageous to know opinion before you start or what

your later research commitments might be to support product
licensing

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
154
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:
155
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.
156

Post-Marketing
157
Determine products 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
158
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
159
Product Development Partnerships

Product Development Partnerships work with pharmaceutical
companies, research centers and other PDPs to prevent HIV

transmission through microbicide use in developing countries
PDPs 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 PDPs 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
160
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
APIs involved and complexity of the drug/device interactions
161
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
162
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 its a drug or device
Vast majority tend to be handled as drug registrations
163
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 its 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
166
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
Dont 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 carefullythey will be a Big
Part of the Programss success

167
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
168
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).
169
Questions?
170

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NIH-DAIDS/MRB/IPCP

Medical Device & Microbicide

8:30 8:45 - Biography/Company Overview

8:45 9:00 - FDA Overview

9:00 10:15 - FDA Requirements for Medical

10:15 10:30 Break

10:30 10:45 - EMA Overview

10:45 11:45 - EMA Requirements for Medical

11:45 12:00 - Differences between FDA and

12:00 1:00 Lunch

Course Agenda (Contd)

1:00 1:30 - Review of Medical Devices containing

1:30 2:00 - Minimal Regulatory Requirements for

2:00 2:45 - Regulatory Challenges in Developing

2:45 3:00 - Break

3:00 3:30 - Regulatory Challenges for Imaging

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

154 E. Main St.

28 years of industry experience as a CMC specialist, R&D Director

and Global Director of Regulatory Affairs for Merion Merrill Dow

Founded RJR Consulting, Inc. in 2002 to assist companies with

their Regulatory Affairs, Business Development, Distribution and

Bob has a BS / MS in Chemistry and regularly teaches classes on

a variety of regulatory topics within the Life Science industry.

RJR Consulting, Inc. - Company Profile

RJR Consulting, Inc. is a global consulting firm specializing in

Clinical Trial Set-Up

CRO Management &

Surveillance Updating: NA,

FDA Regulatory Overview

The U.S. Food and Drug

and Human Services

Responsible for protecting and promoting public health

through the regulation and supervision of food, tobacco

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,

Personnel are exchanged with EMA and PMDA for ICH

best practices and further harmonization

What is regulated by FDA?

Meat & Poultry

Not Regulated by FDA

FDA Organizational Structure

FDA made up of multiple

Each Center has multiple offices

Responsibilities become more

granular as you move down the

Main Centers of the FDA

Center for Tobacco Products

Center for Biologics Evaluation

Center for Drug Evaluation &

National Center for

Office of Combination Products

Specialty Office established in 1990 that

exists under the Office of the Commissioner

Acts as the gatekeeper for regulation of

Ensures proper direction and timely review

of combination product applications

Responsible for assigning an FDA Center to