1 NIH-DAIDS/MRB/IPCP Medical Device & Microbicide Regulatory Training Robert J. Russell President -...
-
Upload
aron-henderson -
Category
Documents
-
view
221 -
download
5
Transcript of 1 NIH-DAIDS/MRB/IPCP Medical Device & Microbicide Regulatory Training Robert J. Russell President -...
1
NIH-DAIDS/MRB/IPCP
Medical Device & MicrobicideRegulatory Training
Robert J. RussellPresident - RJR Consulting
March 15-16 2011
2
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
3
Course Agenda (Cont’d)
1:00 – 1:30 - Review of Medical Devices containing Microbicides
1:30 – 2:00 - Minimal Regulatory Requirements for Testing & Standards
2:00 – 2:45 - Regulatory Challenges in Developing IVR’s
2:45 – 3:00 - Break
3:00 – 3:30 - Regulatory Challenges for Imaging Devices
3:30 – 4:00 - Potential Development Process Concerns
4:00 – 4:30 - Emerging Global Requirements
4:30 – 5:00 - Conclusions/Questions/Final Discussion
4
Course Director - Biography
Bob Russell 154 E. Main St. President & CEO New Albany, OH
43054 RJR Consulting, Inc. Ph. (614) 304-0110 [email protected] Cell:(614) 551-
1717
28 years of industry experience as a CMC specialist, R&D Director and Global Director of Regulatory Affairs for Merion Merrill Dow and Cordis-Dow.
Founded RJR Consulting, Inc. in 2002 to assist companies with their Regulatory Affairs, Business Development, Distribution and Manufacturing needs.
Bob has a BS / MS in Chemistry and regularly teaches classes on a variety of regulatory topics within the Life Science industry.
5
RJR Consulting, Inc. - Company Profile
RJR Consulting, Inc. is a global consulting firm specializing in regulatory compliance and business development solutions for companies, governments and organizations within the Life Sciences and Consumer Products industries.Global Regulatory Compliance
Clinical Trial Set-Up
CRO Management & Selection
Marketing Authorizations / License Renewals
NDA’s / Variations / Amendment Filings
Manufacturing Authorizations
International Regulatory Surveillance Updating: NA, EU, Japan, LAA
Labeling and Packaging Guidelines
Business Consulting Solutions
Strategy Development Project Management Government / Agency
Affairs New Business
Development Global Business
Expansion Industry Training Process Development &
Improvement Distribution and
Manufacturing Solutions
6
Global Reach
North America New Albany,
Ohio, US Vancouver,
Canada
European Union Brussels,
Belgium Hamburg,
Germany
Latin America Sao Paulo, Brazil Mexico City,
Mexico Buenos Aires,
Argentina
Asia Pacific Japan China Korea Taiwan
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
7
FDA Regulatory Overview
8
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
9
What is regulated by FDA?
Regulated by FDA
Food
Tobacco
Drugs
Medical Devices
Biologics
Veterinary products
Cosmetics
Radiation-emitting Products
Combination Products (any combination of drug, device or biologic)
Not Regulated by FDA
Alcohol
Consumer Products (shampoo, toothpaste, soap, etc.)
Drugs of abuse
Health Insurance
Meat & Poultry
Pesticides
Restaurants
Water
10
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
11
Main Centers of the FDA
Center for Biologics Evaluation & Research
CBER
CDERCenter for Drug Evaluation &
Research
CFSANCenter for Food Safety
& Applied Nutrition
CDRHCenter for Radiological
Devices & Health
NCTRNational Center for
Toxicological Research
CVMCenter for Veterinary
MedicineSource: www.fda.gov
CTPCenter for Tobacco Products
12
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
13
FDA Requirements for Medical Devices &
Combination Products
14
Overall Regulatory Pathway
Markets/countriesoutside of EU
IVR/Microbicide Gel Combination Products
15
FDA Clinical Trial Evaluation Process
Device Combination Product
Ph I - ToxicityPh II - EfficacyPh III – Statistical Efficacy & Adverse Events
16
FDA Licensing Process
17
Regulatory Requirements
Many different factors are involved in obtaining regulatory approval for a medical device or combination product:
Questions to ask…
Is it a combination product?
What is the primary mode of action?
Is it a device, drug or biologic?
Is it exempt from classification?
If not exempt, is it already classified by the FDA?
Is there another device that is similar that has already been approved?
Is it a new device that addresses an unmet need in the market?
What is the level of control needed to make sure it’s safe and effective?
What is the risk to the patient?
18
Combination Products
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
19
Request For Designation
Request for Designation Request for guidance from FDA to determine necessary
regulatory submission Process & requirements outlined in 21 CFR Part 3 – no official
“form” Submission must be limited to 15 pages
Sponsor submits formal request to FDA to determine:1. Primary mode of action
Is it primarily a device, drug or biologic? IVR with microbicide is a drug (device used as delivery
method) Stent is a device (drug is added for infection
prevention) Vaccine filled syringe is a biologic (with a delivery
device)2. Lead Agency Center to be assigned for pre-market review
Determination of jurisdiction usually takes 45-60 days Request can also be made informally by contacting Office of
Combination Products
20
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
21
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
Approval Processes
INDNDA
IDE510(k)PMA
INDBLA510KPMANDA
22
Safety Concerns
Unknown interactions of combining two or more approved products can lead to potential safety and effectiveness concerns for patients
Combination
23
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
24
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) Doesn’t meet criteria above for Significant Risk Different than “minimal risk” studies that qualify for
expedited review If deemed to be NSR, sponsor does not have to submit an
IDE to FDA
25
Investigational Device Exemption (IDE)
Exemption granted to allow a device to be used in investigational clinical studies (21 CFR 812) Allows for collection of safety and effectiveness data
Data will eventually support the 510k or PMA submission
Permits the device to be shipped for investigational study purposes’
Listing/registering not required while device under investigation
Requirements for an IDE include: Approval by institutional review board before clinical
study initiated Significant risk device requires FDA approval along with
IRB Informed consent for patients “Investigational use only” labeling On-going monitoring of clinical study Records and reports supporting the study
26
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
27
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
28
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
*source: www.fda.gov - 2009 data
Class I
Class II
Class III Class I
Class II
Class III
Exempt
95% 3% 0%
Non-Exempt
5% 97% 100%
29
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
30
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
31
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
32
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
33
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 time2. Proposing a different intended use for existing device3. 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
34
When is a 510(k) Not Needed?
Company is selling components or parts of devices to another company for further processing
Device is not being commercially marketed or distributed
Distributing another firm’s domestically manufactured device
Labeling of device has not significantly changed
Device was commercially distributed before May 28, 1976
Device is imported from foreign manufacturer who already has 510k clearance
Device is exempt through previous regulations
35
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
36
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
3737
38
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
39
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 process1. Completeness review – Is everything there?2. Detailed scientific, regulatory and quality review3. Review and recommendation by advisory committee4. 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
40
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
41
PMA Amendments & Supplements
PMA Amendment Submission during application process before FDA approval is
obtained When additional data requested or modification to application
is needed Restarts the submission process at beginning
PMA Supplement For product changes after approval has been obtained Usually needed when changes impact safety, effectiveness or
labeling Different timeframes for review (30-180 days) based on impact
of change
Humanitarian Device Exemption Incentive for developing devices that affect under 4000 people
in U.S. Similar to orphan drug designation, except for devices
HDE’s are exempt from effectiveness requirements Must justify risk to FDA and demonstrate lack of predicate
42
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
43
Bioresearch Monitoring (BIMO) Program
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
44
BIMO Inspection Programs
Two types of inspections under BIMO program:1. Routine Inspections
Random inspections of investigators, sponsors, IRB’s or labs
Performed to monitor compliance with BIMO program2. 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
45
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
46
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
47
Clinical Research Monitor (CRA) Responsibilities
Primary liaison between the sponsor and the investigator Interviews & recommends investigators Responsible for site selection and reporting progress of the
clinical trial Prepares clinical development plans Ensures subject safety and verifies data integrity Ensures the investigator:
Understands the regulations and need for accountability Follows written SOP’s and provides timely reports to the
Sponsor Understands protocol and requirements to verify efficacy Understands the need for prior & continuing IRB approval Has documented procedures for reporting adverse events
Manages the trial to a successful conclusion
**IND regulations requiring sponsors to monitor clinical trial progress led to the creation of the clinical research monitor role
48
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: Essential (Investigator) Document Plan
Monitoring Plan
Data Management Plan
Safety Plan
Statistical Analysis Plan
Communication Plan
Risk Assessment
49
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)
50
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
Plans within the Clinical Investigation Plan
51
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
Plans within the Clinical Investigation Plan
52
EU/EMA Regulatory Overview
53
EU Member States & EEA
• Austria • Belgium• Denmark • Finland • France• Germany• United Kingdom
• Greece• Ireland• Italy• Luxembourg• The Netherlands• Portugal• Spain
• Sweden• Cyprus• Czech Republic • Estonia• Hungary• Lithuania• Latvia
• Malta• Poland• Slovakia• Slovenia• Bulgaria• Romania
EU Applicants•Croatia•Turkey
European Free Trade Association Countries•Iceland•Liechtenstein•Norway•Switzerland
EU and EFTA countries (excluding Switzerland) have a market of ~ 350 million customers
54
EU Regulatory Bodies
European Commission (EC) Ensures safety and public health of foods and consumer goods in EU Responsible for proposing and upholding laws for EU related to drugs & devices
European Medicines Agency (EMA or EMEA) Decentralized group in EU that evaluates medicines for human and veterinary
use Responsible for scientific evaluation and enforcing regulations for EU members
Committee for Medicinal Products for Human Use (CHMP) Comprised of representatives from Member States along with medical experts Part of EMA – conducts the drug review process
National Competent Authorities (NCA) Responsible for local authorization and compliance within own country Conducts research & development and determines available medicines in
country Notified Bodies (NB)
Designated by Competent Authorities – about 100 NB’s in Europe Performs conformity assessments procedures to determine device class
55
EC (Commission)
EMA (EMEA)
MRFG InspectorsNotified Bodies
Ethics Committee
NCAs
CHMP
Rapporteur/Co-rapporteur
Project Manager(Scientific/Medical
Advisors)
(Medical Devices)
EU Regulatory Structure
56
EU Requirements for Medical Devices &
Combination Products
57
EU Path to Market for Devices
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
58
EU Device Regulatory Flow
Which Directive applies?Is it a Drug? Device? Combo?
If it’s a device….
59
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.
60
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 Always confirm definitive classification by reading all rules and
examples in the guidelines document
61
EU Classification Matrix
Device Class
I 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 thermometers
IV catheters, tubing's for anesthesia/ventilation
Intraocular lenses, breast implants, endoprostheses, ventilators
Heart valves, reabsorbable implants
Involvement of Notified Body
Self-certification Declaration of Conformity
Self-certification Declaration of Conformity + Notified Body for measuring function/ sterility procedures
Mandatory Mandatory Mandatory
62
Source: MEDDEV 2.4/1 Rev.8
63
Source: MEDDEV 2.4/1 Rev.8
64 Source: MEDDEV 2.4/1 Rev.8
65
Source: MEDDEV 2.4/1 Rev.8
66
Active Devices Continued
Source: MEDDEV 2.4/1 Rev.8
67 Source: MEDDEV 2.4/1 Rev.8
68
Device Essential Requirements
Based on Annex I of MD Directive 93/42/EEC General Requirements
Safety concerns, manufacturing, packaging, storage
Chemical, Physical & Biological Properties Contaminant prevention, combination products
Infection & Microbial Contamination Infection prevention, sterilization procedures
Construction & Environmental Properties Devices with a Measuring Function
Accuracy, stability, monitoring Radiation Protection Devices Connected to an Energy Source
Performance concerns, power supply, electrical/thermal risks
Manufacturer Information
69
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.
70
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
71
72
The Technical File
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
73
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).
74
Technical File Contents
1. Purpose, Objective, Revision History
2. Device Descriptions and Variants 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
75
Technical File Structure
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
76
Technical File Structure (Cont’d)
6. Product design and manufacturing specifications including: Parts list Drawings, assembly drawings Sub-assembly drawings Drawings of components Specifications of materials used incl. data sheets List of standards applied Manufacturing specifications Sterilization specifications (if required) Packaging specifications QA specifications (QC specs., in-process controls etc.) Labeling Accompanying documents Packaging insert/Instructions for Use Service Manual
77
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
Technical File Structure (Cont’d)
78
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
79
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) regulations2. 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
80
Regulation of Combination Products
Combinations are almost solely regulated on the manufacturers intended claims for the product Ex: Wound care product containing an antimicrobial
Regulated as a device if antimicrobial is to prevent excessive odor
Regulated as a pharmaceutical if antimicrobial is to prevent infection
Different combinations are regulated differently according to European Commission’s classifications A device intended to deliver a medicinal product is regulated as
a medicinal product (Ex: IVR’s) However, a kit containing an insulin pen and cartridge, the
pen is subject to device approval, but the cartridge is considered a medicinal product
If a device and medicinal product form a single, integral product that is intended exclusively for single use in the given combination, the single product is regulated as a medicinal product Ex: Prefilled syringes, transdermal patches, various implants
When in doubt, contact a Competent Authority to verify
81
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.
82
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” Neither the device nor the medicine alone would achieve desired
effect
83
Decision on Principal Intended Action
Manufacturer decides on the method by which the principal intended action is achieved
Decision is usually based on: Animal or clinical testing Argued scientific rationale Independent regulatory guidance
Manufacturer may be able to adjust the labeling, the intended use or patient population to strengthen its argument that a particular product fits into a regulatory regime that it believes is to its best advantage
Notified Body is normally the manufacturer’s prime point of contact and ‘kept in the loop’ if the manufacturer consults with a Competent Authority
In Manufacturers’ own interest to have Notified Body or Competent Authority to agree to the decision
84
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
85
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 Surveillance, reporting incidents and recalls are handled like a
Class III device Must meet any specific requirements applicable to the medicinal
component
86
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
87
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 CE Marking is the manufacturer’s declaration that the product
meets all the appropriate provisions of the relevant legislation
Once applied, the product can be freely marketed anywhere in the EU without further control
88
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
89
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: 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
90
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
91
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 completeInitial Notification
Pre-Submission Meeting
Sci. Advice Work Party Meeting
Final Advice
March 2011 June 2011 July 2011 Sept/Oct 2011(depending on additional meeting requested)
92
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 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
93
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 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.
94
Differences BetweenFDA & EU/EMA
95
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
96
FDA vs. EU (Devices) Cont’d.
Both require the development of sufficient technical documentation for regulators to determine whether the product as designed and conceived is safe
FDA equivalents to technical file for Class I, IIa and IIb products and design dossier for Class III devices is the premarket notification 510(k) evaluation and premarket approval (PMA) review 510(k) evaluation covers established devices and
products that are largely similar to devices already on the market
PMA is generally required for Class III and high risk Class II devices
For US companies it is difficult to close the gap between the 510(k) and the technical file
For European manufacturers, the technical file should more then satisfy the FDA in most cases
97
FDA vs. EU (Devices) Cont’d.
Any manufacturer no matter what country they are in if developing new devices for international market is advised to use the essential requirements in creating technical documentation
By meeting CE marking requirements, FDA is largely satisfied which readily accepts EU harmonized standards and European national standards to demonstrate compliance with its requirements
Quality assurance system in both EU and US must cover both production and design control for Class II (a and b) and III products this is met by ISO 9001 and ISO 13485 they both have adopted to meet conformity assessment requirements EU offers options to manufacturers as part of modular
approach and are described in Annexes III, IV, V, and VI of the MDD to give companies separate design control from manufacturing or production control European manufacturers might benefit from the flexibly
to these alternative, but the FDA do not accept them
98
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)
99
FDA and EMA (Pharmaceuticals) Cont’d
The FDA does not charge a fee for providing a review and will comment on the whole development plan for a new medicine, whereas with EMA it is necessary to ask specific questions. Fees are dependent on scope and amount of questions.
The FDA’s review is quicker to obtain than EMA’s.
The FDA application is submitted with continual dialogue, so the regulators are familiar with the process; helps facilitation.
EMA can have a product application enter their system with no previous knowledge; slows review process.
100
FDA and EMA (Pharmaceuticals) Cont’d
EMA is conservative when reviewing products on levels of specialty areas, such as oncology. The FDA is seen as more willing to approve new therapies.
The FDA is more willing to issue conditional and fast track authorizations than the EMA. Process is relatively new (EMA) selectively used.
The FDA grants authorizations based on scientific data only, while some are concerned with the political aspect of EMA.
Product review times are longer with EMA (18-24 months = 6 months advance actions + 12-18 month dossier reviews ; Centralized procedure) than FDA (12-14 months)
101
FDA and EMA (Pharmaceuticals) Cont’d
Unlike the EMA, FDA does not issue renewal licenses; instead authorizations are issued indefinitely and are constantly updated based on safety data, efficacy and product modifications (amendments / variations)
When introducing safety restrictions with EMA, it can take up to 9 months to add a side effect to the SPC; 3 months typically with FDA
Through FDA, companies have a wider range of product amendments they are allowed to introduce as soon as variation applications are submitted than through EMA. “Notifications” just recently introduced as a category in the EU (inform only). Previously waited 30 days, even for Type IA variations.
102
Review of Implantable Medical Devices
containing Microbicides
103
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
104
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
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
105
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
106
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
107
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
108
Current IVR Product Comparison
Product Manufacturer
Dimensions (Diameter)
Composition Indication Active Ingredient
Catalyst
Femring®
WarnerChilcott
Outer: 56 mmCross-section: 7.6 mmCore: 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
Estradiolacetate
Tin
Nuvaring®
Organon Outer: 54 mmCross-section: 4 mm
Ethylene vinylacetate copolymers & magnesium stearate
Hormonal Contraceptive
Etonogestrel& ethinyl estradiol
N/A
Estring® Pfizer Outer: 55 mmCross-section: 9 mmCore: 2 mm
Silicone elastomers Q7-4735 A&B, SFD 119 silicone fluid & barium sulfate
Symptoms related to post-menopausal atrophy of vagina and lower UT
Estradiol Platinum
109
Minimal Regulatory Requirements for
Testing & Standards
110
Coordination of FDA and EMA Requirements
Combination Products Companies looking to register products in both the
U.S. and EU should follow ISO test methods where possible
ISO-14155 Device Clinical Trials ISO-13485 Device Manufacturing ISO-10993 Biocompatibility (genotoxicity,
carcinogenicity, reproductive toxicity) Product specifications (CofA’s), impurities Release of by-products Mechanical safety issues (devices) Extractables & leachables (device) - chemical
equivalence Toxicity: cytotoxicity, sub chronic toxicity
111
Minimal Regulatory Requirements for
Testing and Standards
Combination Products Sensitization Irritation Antimicrobial effectiveness testing of gel Stability testing / product shelf-life (to extend for
life of study) pH, viscosity, assays, microbial limits
Labeling requirements Child-resistant packaging (?) - typically at
commercialization Use of vendor data - obtain copies of original study
reports Lab has strong GLP / GMP compliance
112
Minimal Regulatory Requirements for
Testing and Standards
Device Physical Property Testing “Similar product” to one previously approved or
clinically studied? Previously published and accepted Physical Properties
of a Device known to perform in the application? ASTM (American Society for Testing & Materials) Test
Standards for Physical Properties of Polymers: Tensile strength Flexural strength % Elongation Heat Distortion Temperature Mw, GPC profile HPLC or GC / Mass spec. impurity profile profile Medical-grade resins produced on Medical-grade
manufacturing lines
113
Minimal Regulatory Requirements for
Testing and Standards
Pre-Clinical Safety Assessment (combination)
Safety Pharmacology
Cytotoxicity study using the elution method (ISO-10993-5)
Sensitization….._____maximization study (ISO-10993-10)
Irritation or intracutaneous reactivity…..vaginal irritation study in ______ (ISO-10993-10)
Genotoxicity (ISO-10993-3)
Bacterial reverse mutation study
_____ lymphoma assay
Subacute / subchronic toxicity
XX day intravaginal toxicity study in _____
114
Minimal Regulatory Requirements for
Testing and Standards
If data is available from a previous submission, you will need to perform confirmatory testing if there are significant* changes in any of these areas:
Materials selection
Manufacturing processes
Chemical composition of materials
Nature of patient contact
Sterilization methods
Bridging studies are commonly requested to “bridge” available data on prior published studies to the “current” products and study design being considered
* Definition of Significant: Examples --- polymer change, new manufacturing step, new additives, new intended use, new sterilization technique utilized. Typically reviewed with and agreed to by Healthcare Authority.
115
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
116
Microbicide Combinations
Definition: Two or more microbicides combined together as the active
Possible Combinations:
1. One known and one novel Requirements: Novel full-testing plus dual interaction
data
2. Both are novel 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
117
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)
118
Additional Requirements for Testing and Standards
Should I test device materials or only a composite of the finished device?
Your responsibility is to gather safety data on every component and material used in the device
Long-term availability of Resin grade; Specification changes??? Si EVA PVOH
Best approach:
Assemble vendor data on candidate materials
Conduct analytical and vitro screening of materials
Conduct confirmatory testing on a composite sample from the finished device
119
Product Development Plan
Table of Contents for Product Development PlanI. Name of the Medicinal Product
II. Qualitative & Quantitative Composition
III. Pharmaceutical Form
IV. Clinical Particular Information 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
120
Product Development Plan (Cont’d)
V. Pharmacological Properties Pharmacodynamic properties (Gel #1, Gel#2,
combination) Pharmacokinetic properties (Gel#1, Gel#2,
combination) Pre-clinical safety data
VI. Pharmaceutical Particulars List of excipients Incompatibilities Shelf Life Special precautions for storage Nature and contents of container Special precautions for disposal and other handling
VII. Marketing Authorization Holder
VIII. Marketing Authorization Number
IX. Date of First Authorization / Renewal Date
X. Date of Revision of Text
121
Regulatory Challenges in Developing IVR’s
122
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
123
Batch Production & Campaign Strategy
Efficiency determined by a number of factors
Labor cost per batch
Analytical testing cost
In-processing testing strategy
Down time
Capacity to compound drug into polymer
Compounding equipment requirements
Stability Testing needed to define Expiration Date
In a combination product, can be influenced by the most susceptible component; the device or the drug
Polymer product expirations- determined by loss of physical properties (eg. flexibility)
124
Rationale for Selection of Materials
Compound XYZ is an excellent candidate for a topical microbicide development due to its proven in-vitro and in-vivo efficacy and safety profiles ….also its physical and chemical properties
Compound XYZ has demonstrated potent activity against wild-type HIV strains and strains harboring different resistance inducing mutations
Compound XYZ belongs to a class of drugs that has been used in first line therapy in treatment of patients with HIV/AIDS
Compound XYZ vaginal Ring is a ____-based drug delivery device containing Compound XYZ These devices are a well-known, controlled release,
drug delivery system, with products already on the market
Not mandatory, but simplest testing & regulatory pathway
125
Qualification of Materials and CMC for Combination Products
Quality data on gel drug substance Specifications, testing, CofA’s Changes in materials used from one study to another Changes in design (device) from one study to another Concerns and demonstration of equivalency Patient acceptance / “Ease of Use” Irritation / Comfort / Discomfort Manufacturing process changes: temperature processing /
degradation Processing: extrusion, injection molding, calendaring Particular attention to additives such as colors (fading,
partial fading after use, toxicity effects) Mixing, dispersion, UV sensitivity, body fluid / chemical
attack, migration Use of liquids, pellets, color concentrates Effective container, closure system, packaging Labeling, instructions for use, readability studies What constitutes a Lot / Batch size? Determining expiration dates on device alone
126
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
127
Nanotechnology in Medicine
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
128
Nanotechnology in Medicine (Cont’d)
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
129
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
This binding site does not change significantly when a virus mutates
Virus-specific nanoviricides have been created against important viruses such as HIV, Influenza and Bird Flu by choosing highly virus-specific ligands
The National Institutes of Health (NIH) is funding research at eight Nanomedicine Development Centers
130
Approaches for Creating Nanodevices
There are two basic approaches for creating nanodevices 1. Top-down approach
The top-down approach involves molding or etching materials into smaller components
This approach has traditionally been used in making parts for computers and electronics
2. Bottom-up approach The bottom-up approach involves assembling
structures atom-by-atom or molecule-by-molecule
May prove useful in manufacturing devices used in medicine
131
Nanodevices
Cell
White blood cell
Water molecule
Nanodevices
Nanodevices
Nanodevices are small enough to enter into cells
132
Nanodevices & Nanomedical Robots
Cell
White blood cell
Water molecule
Nanodevices
Classified as an advanced drug delivery system, the state-of-the art device has numerous capabilities for destroying tumors, kidney stones and ulcers, and treating cancer and HIV
Nanomedical robots
Nano robots are nanodevices that will be used for the purpose of maintaining and protecting the human body against pathogens
By having these Robots, we can refine the treatment of diseases by using biomedical, nanotechnological engineering
No difficulty in identifying the target site cells even at the very early stages which cannot be done in the traditional treatment
Ultimately able to track down and destroy target cells wherever they may be growing
133
Regulating Nanodevices
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
134
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”
135
Multiple Drugs in One Device
Applies to multiple antiretroviral drugs within one device
Ex: FDA approval of Atripla, 3-drug fixed dose combination antiretroviral
Atripla was approved in 3 months under FDA's fast track program
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
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
136
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
137
Multiple Drugs from Different Drug Classes
Applies to an antiretroviral drug combined with a contraceptive drug 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
138
Regulatory Challengesfor Imaging Devices
139
Challenges - Light Emitting Devices
TITLE 21—Food and Drugs CHAPTER I--Food and drug administration, department of health and human services
Subchapter J — Radiological Health
Part 1040 -- Performance Standards For Light-emitting Products §1040.10 --- Laser products §1040.11 --- Specific purpose laser products §1040.20 --- Sunlamp products and ultraviolet
lamps intended for use in sunlamp products §1040.30 --- High-intensity mercury vapor
discharge lamps
140
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
141
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 monitors3. Cell phones4. X-ray machines (including medical, research, industrial, and
educational)5. Electron microscopes6. Black light sources7. Welding equipment 8. Alarm systems9. 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 cleaner12.Ultrasound machines13.Ranging and detection equipment, such as laser levels
142
Classification of Light Emitting Devices
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
143
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
144
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
145
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
146
Requirements for Device Production
The following FDA general controls apply to all devices classes (I, II, III): 510(k) exempt Establishment registration
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
147
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
148
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
IDE Requirements for Imaging Devices (Cont’d)
149
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
IDE Requirements for Imaging Devices (Cont’d)
150
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
IDE Requirements for Imaging Devices (Cont’d)
151
Potential Development Process Concerns
152
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
153
Development Process Concerns – Pre-Clinical->Ph.I
Defines the objectives of studies / testing (as previously described)
Animal Species: availability, relevant, translatable, non-problematic species
Consistency of species utilized in previous studies; translatable data
Discuss pre-clinical plan with Healthcare Authority (U.S. FDA) prior to initiation
Discuss Pre-clinical data with Healthcare Authority (U.S. FDA) prior to IND initiation
Process globally known as “Scientific Advice” with HCA, EMA
- Saves “false starts” or sometimes difficult work to retrace and “add to”
- However, if you disagree with the answer, it has “become part of the official record”
- Still advantageous to know “opinion” before you start or what your later research commitments might be to support product licensing
154
Development Process Concerns – Phase I-II-III
Ph. I Ph. II Ph. III
Phase I : Determining safety, adverse reactions
Phase II: Determining efficacy
Phase III: Statistical adverse reactions, range of adverse events, statistical efficacy data developed
Strong monitoring efforts for detailed close-out of each Phase of Study
Maintain consistency of drug and device utilized
Long-term availability of device raw materials
Data must hold up to regulatory scrutiny during “licensing phase”
155
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: 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
156
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.
157
Development Process Concerns – Post-Marketing
Determine product’s long-term effectiveness on patient
Determine patient “Quality-of-Life”
Compare current “studied products” to traditional therapies
Cost effectiveness of New Licensed Therapy
Continuing to study range and statistics of adverse reactions (helps to build PSUR [Periodic Safety Update Report] on Drug Component)
PSUR= every 6 months during first 2 years, then annually
Data assists in Product & License Renewal in those countries possessing that process (typically every 5 years); no renewals currently in U.S. with FDA
It is a MA holder's responsibility to keep their product information up-to-date, making variations to the Summary of Product Characteristics (SPC) as and when data emerge: to introduce additional safeguards to reflect evolving therapeutic indications to take into account technical and scientific progress
158
Emerging Global Requirements
for Devices with Microbicides
159
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
160
Product Development Partnerships
Product Development Partnerships work with pharmaceutical companies, research centers and other PDP’s to prevent HIV transmission through microbicide use in developing countries
PDP’s perform the following functions: Aid in product development process for microbicides and
dual protection products such as contraceptives combined with anti-STI products
Conduct pre-clinical and clinical trials to evaluate compounds
Helps establish manufacturing and distribution capacity Training of worldwide investigators
Examples of PDP’s specializing in HIV/AIDS prevention include: IPM Global – http://www.ipmglobal.org CONRAD – http://www.conrad.org PATH – http://www.path.org Population Council – http://www.popcouncil.org
161
WHO Considerations
WHO has partnered with many organizations regarding HIV/AIDS prevention Develops and drives global strategy on HIV prevention
WHO is helping to get these combination products to areas of need by: Partnering with organizations such as EMEA on Article 58 Helping to facilitate development and testing with other
organizations Ensuring trials are conducted with high ethical standards
Microbicide trials involving WHO in the last 2 years suggest: Microbicide gel alone did not change HIV infection rate Demand for devices with microbicides would be high
Pre-qualification status for drugs for HIV prevention WHO can grant pre-qualification status for HIV/AIDS
prevention products if need is prevalent Status is not available for microbicides due to the number of
API’s involved and complexity of the drug/device interactions
162
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
Regulatory capacity of these countries is limited but improving 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 Authority where product is licensed may not be as stringent
163
Considerations in Latin America
Regulatory capabilities have vastly improved over the past decade
Brazil, Mexico and Argentina are the leading authorities in Latin America
No standardization amongst countries – each country has their own RA Regulatory approval is very complex due to differing
requirements by regulatory authorities Local authorities tend to be even more stringent than in the US 70% of requirements are published, 30% is negotiated
(Examples: where API originates, where drug product is licensed, local populations included in studies, how product is being brought to the country; direct/distribution)
Some areas require local manufacturing presence This leads to barrier to entry and longer drug/device approval
times Combination products are handled similar to US & EU
Determination made of whether it’s a drug or device Vast majority tend to be handled as drug registrations
164
Considerations in Asia Pacific
Most popular growth area for new drug marketing Large populations, willing CT participants, limited drug
availability The PMDA in Japan is the clear leading authority in Asia Pacific
Original ICH country with US & EU – very advanced Other growth markets are China, India, South Korea, Phillipines &
Malaysia No standardization amongst countries – each country has their own
RA Regulatory approval is the most complex due to differing
requirements, information availability and multiple languages Authorities tend to be mimic US or EU processes with slight
alterations Approval times take longer than US/EU due to resource
constraints Culture also has an impact on safety emphasis, regulatory
approval process & timing Combination products are handled similar to US & EU
Determination made of whether it’s a drug or device
165
Conclusions &Wrap-up
166
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
Conclusions & Wrap-up
167
Use as much published data on “Similar Products” as possible to gain an “equivalency status”
When in doubt…..dialogue with FDA / EMA
Don’t underestimate the data needed….. For the device component review; remember this will be a Class III review if combined
Long term material availability (polymers) with vendors a MUST to avoid re-testing
Suggest you have team representation with experience in Material / Device Development (including formulation), Regulatory and Change Control / Auditing on your team for the changes that will undoubtedly occur throughout product development, clinical studies, product qualification & registration
Pick your suppliers / partners carefully……they will be a Big Part of the Programss success
Thank you for your time and attentiveness! Best of Luck!
Conclusions & Wrap-up
168
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
Web References
169
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).
Material Copyright
170
Questions?