1 nih-daids/mrb/ipcp medical device & microbicide regulatory training robert j. russell...

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NIH-DAIDS/MRB/IPCP

Medical Device & MicrobicideRegulatory Training

Robert J. RussellPresident - RJR Consulting

March 15-16 2011

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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

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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

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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-

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28 years of industry experience as a CMC specialist, R&D Director and Global Director of Regulatory Affairs for Merion Merrill Dow and Cordis-Dow.

Founded RJR Consulting, Inc. in 2002 to assist companies with their Regulatory Affairs, Business Development, Distribution and Manufacturing needs.

Bob has a BS / MS in Chemistry and regularly teaches classes on a variety of regulatory topics within the Life Science industry.

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RJR Consulting, Inc. - Company Profile

RJR Consulting, Inc. is a global consulting firm specializing in regulatory compliance and business development solutions for companies, governments and organizations within the Life Sciences and Consumer Products industries.Global Regulatory Compliance

Clinical Trial Set-Up

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

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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

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FDA Regulatory Overview

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The U.S. Food and Drug Administration

An agency of the United States Department of Health and Human Services

Responsible for protecting and promoting public health through the regulation and supervision of food, tobacco products, pharmaceuticals and medical devices.

Regulates more than $1 Trillion in consumer goods or 25% of all U.S expenditures.

Headquarters in Silver Spring, Maryland with hundreds of field offices throughout the U.S.

Offices abroad in China, India, Belgium, Costa Rica, Chile & UK

Personnel are exchanged with EMA and PMDA for ICH best practices and further harmonization

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What is regulated by FDA?

Regulated by FDA

Food

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

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FDA Organizational Structure

FDA is headed by the Office of the Commissioner

FDA made up of multiple Centers All centers report into the

Office of the Commissioner Office of Regulatory Affairs is

an additional “Center” in charge of field operations

Each Center has multiple offices Ex: Office of Combination

Products

Each Office has multiple divisions

Responsibilities become more granular as you move down the chain

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Main Centers of the FDA

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

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Office of Combination Products

Specialty Office established in 1990 that exists under the Office of the Commissioner Small Office of 8 members

Acts as the gatekeeper for regulation of combination products

Ensures proper direction and timely review of combination product applications

Responsible for assigning an FDA Center to have primary jurisdiction based on primary mode of use

Develops guidance on regulations having to do with combination products

Does not actually review marketing applications handled by CBER, CDER, CDRH

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FDA Requirements for Medical Devices &

Combination Products

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Overall Regulatory Pathway

Markets/countriesoutside of EU

IVR/Microbicide Gel Combination Products

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FDA Clinical Trial Evaluation Process

Device Combination Product

Ph I - ToxicityPh II - EfficacyPh III – Statistical Efficacy & Adverse Events

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FDA Licensing Process

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Regulatory Requirements

Many different factors are involved in obtaining regulatory approval for a medical device or combination product:

Questions to ask…

Is it a combination product?

What is the primary mode of action?

Is it a device, drug or biologic?

Is it exempt from classification?

If not exempt, is it already classified by the FDA?

Is there another device that is similar that has already been approved?

Is it a new device that addresses an unmet need in the market?

What is the level of control needed to make sure it’s safe and effective?

What is the risk to the patient?

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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

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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


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Intercenter Agreements

Agreements entered into in 1991 by CDER, CBER and CDRH

Provided guidance to determine how lead agency works with the other agencies during review process

Agreements identify specific combination products and how they are regulated

Primary Mode of Action introduced in 2005 overrides most of previous intercenter agreements

Still provide helpful guidance in addition to jurisdictional determination Sets guidelines for how centers work together during

review

Each center is beginning to publish information on the determination and approval of combination products through the OCP performance reports on the Office of Combination Products homepage on http://www.fda.gov

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Regulatory Issues with Combination Products

Organizational & process approval challenges exist when trying to obtain regulatory approval for a Combination Product based on classification:

Product Type

Drug Device Biologic

Lead Agency Center

CDER CDRH CBER

Approval Processes

INDNDA

IDE510(k)PMA

INDBLA510KPMANDA

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Safety Concerns

Unknown interactions of combining two or more approved products can lead to potential safety and effectiveness concerns for patients

Combination

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Pre-IDE Process

Contact FDA prior to submission of request for IDE FDA will provide one time pre-IDE feedback to sponsor at no

cost Increases sponsor understanding of regulations and process Helps to minimize delay during actual submission process Typical 30-60 day response time

FDA may have guidance meetings with sponsor about Pre-IDE submission Can be conference calls or face-to-face Meetings are usually formal but informal conversations can be

had prior to official meeting to ask questions Formal meetings are Determination meetings or Agreement

meetings Determination meeting – request to discuss scientific

information needed in submission Agreement meeting – reach official agreement on

parameters of clinical protocol and investigational plan

Will issue Notice of Disapproval or Withdrawal if Pre-IDE not approved

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Significant vs. Non-significant Risk

Studies performed as part of pre-IDE process to determine riskiness of device

Institutional Review Board (IRB) will review risk assessment from Sponsor Review of prior investigational reports, investigational plan,

subject selection criteria

Significant Risk (SR) Devices with potential for serious risk to health and safety

of subject including devices that are: Implants Supporting or sustaining human life Treating or mitigating diseases

If SR is determined, both IRB and FDA need to approve before IDE process begins

Non-Significant Risk (NSR) 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

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Investigational Device Exemption (IDE)

Exemption granted to allow a device to be used in investigational clinical studies (21 CFR 812) Allows for collection of safety and effectiveness data

Data will eventually support the 510k or PMA submission

Permits the device to be shipped for investigational study purposes’

Listing/registering not required while device under investigation

Requirements for an IDE include: Approval by institutional review board before clinical

study initiated Significant risk device requires FDA approval along with

IRB Informed consent for patients “Investigational use only” labeling On-going monitoring of clinical study Records and reports supporting the study

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Classification Types

All devices will be classified as one of the following types: Class I

Low risk, subject to general controls* Examples: gloves, scalpels, enema kits

Class II Medium risk, subject to general and special controls* Examples: pregnancy tests, infusion pumps, powered

wheelchairs Class III

High risk, subject to general and special controls Devices that support/sustain human life or pose excess

risk Examples: pacemakers, artificial hearts, implants

Exempt (Class I or Class II) Very low risk, subject to general controls Some devices may be exempt from GMP as well Examples: Non-sterile surgical tools

*description in next slide

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General & Special Controls

General Controls Basic rules that allow FDA the authority to regulate

devices Required to be followed for all device classes Allows FDA to regulate many things including

device registration, product listing, labeling, quality measures (including misrepresentation) & reporting

Special Controls Additional controls applied to Class II and Class III

devices to ensure safety and effectiveness Includes such things as:

Performance standards and specific guidelines Additional labeling requirements Post-market monitoring & surveillance

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Classification Statistics

The majority of devices fall under the Class I or Class II designation

The majority of Class I devices are exempt, while the majority of Class II & III devices are non-exempt

*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%

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Determining Classification

Device class is determined by many different factors: Previous similar devices Intended use of the device Indications for use (specifics of intended use) Risk to the public

You can use a number of methods to determine class of specific products CFR Search

Search regulations on FDA website Determine the medical specialty (panel) of the device

Each panel has list of products classified (16 panels) Located in 21 CFR 862-892

Identify the classification regulation Search the product code classification database

For combination products considered as “drugs”, the device component is automatically classified as Class III

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Device Exemption

A device is considered exempt if: Category is included on the Class I & Class II Exempt

Devices list List covers 21 CFR 862 – 892

Grandfathered in from original amendment (May 28, 1976)

Devices that qualify are exempt from: A pre-market notification application (510(k)) FDA approval before marketing the product in the US

Some product exemptions have limitations

With an exempt product, Manufacturers are still required to: Register and list product with FDA Comply with any GMP or labeling requirements Some class I devices are exempt from GMP if not

labeled as sterile

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Reclassification Process

Classification is occasionally adjusted through a reclassification process

FDA has power to reclass a device if necessary

Reclassification can be up or down in product class Must convince FDA by providing data and reassuring

safety

Triggers to a reclassification of one or more products More experience and usage of a new device Receipt of new information on a device Petition from outside sources

FDA will notify petitioners with a reclassification letter

Federal register updated with any reclassification of devices

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Regulatory Submission

With the device class and non-exempt status known, the type of regulatory submission can be determined:

Premarket Notification (510k) Required submission for all Class I & II non-exempt

devices No actual FDA provided form for 510(k)

Requirements for submission in 21 CFR 807 subpart E

Product clear to be marketed in US when 510(k) is approved

Premarket Approval (PMA) Required submission for Class III devices

Very few pre-amendment devices grandfathered in Required due to higher risk of devices

General & special controls insufficient in assuring safety

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Requirements for 510(k) submission

Groups who are required to submit a 510(k) to FDA: Domestic manufacturers introducing device in US Specification developers introducing device in US Repackers/Labelers who make labeling changes Foreign manufacturers (or representatives) introducing

device in US

The following instances require that a 510(k) be submitted to FDA:1. Introducing device for commercial use for first 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

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When is a 510(k) Not Needed?

Company is selling components or parts of devices to another company for further processing

Device is not being commercially marketed or distributed

Distributing another firm’s domestically manufactured device

Labeling of device has not significantly changed

Device was commercially distributed before May 28, 1976

Device is imported from foreign manufacturer who already has 510k clearance

Device is exempt through previous regulations

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Substantial Equivalence

Key component to 510(k) submission is proving Substantial Equivalence (SE) to another similar device (called a predicate)

Substantially Equivalent criteria: Product has same intended use as predicate Product has same technological characteristics OR Product has different technological characteristics but does not

introduce new safety concerns

Proof of SE should be provided with application

FDA will respond with an order declaring SE (90 days) If Not Substantially Equivalent (NSE) is issued, De Novo petition

or PMA required

De Novo petition File petition with 30 days to justify why device should be Class I

or II Meant for devices that do not have a predicate and are low risk

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Types of 510(k) Submissions

Traditional Most common – process as previously described

Abbreviated Used when guidance documents exist, special controls

are in place and standards are already in place Must prove conformity to the recognized standard Includes summary reports on use of guidance docs to

expedite review

Special Done for device modification that does not affect

intended use or technological standards Contains a Declaration of Conformity to specific design

controls Submission does not include data

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Proposed Streamlining of 510(k) Process

Plan released in January 2011 to streamline 501k review process Driven by CDRH to clarify timelines for submission of clinical data Create a Center Science Council of experts to speed up decision

making

Plan includes issuing draft guidance documents in 2011 on topics such as: Improving the quality and performance of clinical trials Process for appealing CDRH decisions Streamlining of the De Novo application process When to submit clinical data Identifying safety issues and concerns Characteristics included in the scope of “Intended Use”

“Indication for Use” becomes part of “Intended Use”

FDA ultimately decided against a CDRH proposal having another classification category called Class IIb Would have bridged gap between medium and high risk devices–

similar to EMA Ex: No predicate exists but risk is in line with Class II device

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Premarket Authorization (PMA) Review

Most stringent pre-marketing application Must be completed for all class III devices Often involves new concepts or ideas that have no

precedent

Four step review 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

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PMA Application Methods

Traditional PMA All volumes submitted to FDA at once For devices that have had clinical testing or have been approved

elsewhere

Modular PMA PMA broken into modules and each module submitted upon

completion Meant for products in early stages of clinical study

Streamlined PMA - (Pilot Program) For devices where the technology and use is well known by FDA Submitted as traditional PMA but review is interactive and

streamlined

Product Development Protocol (PDP) Early agreement with FDA regarding design/development details

of device Work at own pace and keep FDA informed and involved Recommended for devices where the technology is well

established

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PMA Amendments & Supplements

PMA Amendment Submission during application process before FDA approval is

obtained When additional data requested or modification to application

is needed Restarts the submission process at beginning

PMA Supplement For product changes after approval has been obtained Usually needed when changes impact safety, effectiveness or

labeling Different timeframes for review (30-180 days) based on impact

of change

Humanitarian Device Exemption Incentive for developing devices that affect under 4000 people

in U.S. Similar to orphan drug designation, except for devices

HDE’s are exempt from effectiveness requirements Must justify risk to FDA and demonstrate lack of predicate

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PMA Requirements

The following are required to be submitted within a traditional PMA: Name, address and table of contents Description of the device form and function Practices and procedures – what device is used for Foreign and domestic market history of the device, if any Details about manufacturing process in making the

device Summary of clinical and non-clinical studies Conclusion of studies, include safety and effectiveness of

device Reference to any performance standards followed Labeling and advertising literature (Ex: pamphlets) Results of non-clinical lab studies Results of clinical studies on human patients Financial certification and disclosure statement Bibliography of reports about safety/effectiveness of

device

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Bioresearch Monitoring (BIMO) Program

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

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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

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Sponsor Responsibilities

Sponsors are responsible for the following when it comes to BIMO: Selecting a qualified investigator Ensuring proper monitoring of the investigation

Verify investigator follows investigation plan and IND 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

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Clinical Investigator Responsibilities

When it comes to BIMO, Investigators are responsible for: Adhering to the Investigator Agreement Following the Clinical Investigation Plan Protecting the health, safety and well-being of

patients/subjects This includes obtaining informed consent

Obtaining IRB (and FDA) approvals Supervising and disposing of the devices Disclosing any financial interest that exists Documenting adverse effects or deviations from the

plan Writing progress reports and delivering a final report

Disqualification Will not continue to receive investigational devices if

requirements are repeatedly not followed

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Clinical Research Monitor (CRA) Responsibilities

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

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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

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Plans within the Clinical Investigation Plan

Essential (Investigator) Document Plan

Outlines format and acceptability of documents needed for release of investigational product and continued Site participation in the study

Monitoring Plan

Outlines the monitoring guidelines and tasks not outlined in SOPs or the Protocol

Includes CRF retrieval plan

Data Management Plan

Outlines data collection, entry, review and completeness of the database

Safety Plan

Outlines SAE process and reconciliation

Additionally can outline medical monitor review and oversight (Medical Monitor Plan can be a separate plan)

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Statistical Analysis Plan

Outlines the programming and analysis of the database

Details the number of tables and listings and data analysis methods

Communication Plan

Outlines all the communication paths with internal and external team members

Risk Assessment

Outlines all identified risks

Risks are ranked by impact on the study

Offers preventative and/or contingency actions

Timelines – MS Project


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Issue Escalation Plan

Can be part of Communication Plan

Outlines path of communication for major issues that can adversely

Affect the outcome of the study

Have a major financial impact

Details who is notified, timeframe for response and who is responsible for actions

All plans within the Clinical Investigation Plan should be ……

Version controlled

Signed by sponsor and CRO

Reviewed and updated, as needed

Become part of the Central Clinical Project Files


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EU/EMA Regulatory Overview

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EU Member States & EEA

• 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

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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

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EC (Commission)

EMA (EMEA)

MRFG InspectorsNotified Bodies

Ethics Committee

NCAs

CHMP

Rapporteur/Co-rapporteur

Project Manager(Scientific/Medical

Advisors)

(Medical Devices)

EU Regulatory Structure

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EU Requirements for Medical Devices &


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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

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EU Device Regulatory Flow

Which Directive applies?Is it a Drug? Device? Combo?

If it’s a device….

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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.

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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

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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

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Source: MEDDEV 2.4/1 Rev.8

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64 Source: MEDDEV 2.4/1 Rev.8

65


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Active Devices Continued


67 Source: MEDDEV 2.4/1 Rev.8

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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

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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.

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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

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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

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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).

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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

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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

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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

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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)

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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

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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

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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

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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)

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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

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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.

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Differences BetweenFDA & EU/EMA

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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

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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

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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

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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)

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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.

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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)

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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.

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Review of Implantable Medical Devices

containing Microbicides

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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

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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

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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

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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

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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

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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

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Minimal Regulatory Requirements for

Testing & Standards

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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

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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

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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

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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 _____

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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.

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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

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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

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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)

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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

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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

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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)

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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

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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

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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

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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

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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

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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

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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

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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

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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”

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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

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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

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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

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Regulatory Challengesfor Imaging Devices

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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)

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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


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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


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Potential Development Process Concerns

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Development Process Concerns – Team Strategy

Pre-Clinical Ph. I Ph. II Ph. III

Resolve all issues associated with the product before proceeding with the next Phase of study

Build a tracking grid Pre-clinical, CMC, manufacturing, GMP

Define gaps on issues requiring resolution before proceeding Assign specific team members for accountability on

each issue resolution

Determine optimal processes and structures for implementing components of study plan

Conduct all planning with sub-teams*

* Examples: clinical/study, quality, product development, process development, regulatory, legal

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Development Process Concerns – Pre-Clinical->Ph.I

Defines the objectives of studies / testing (as previously described)

Animal Species: availability, relevant, translatable, non-problematic species

Consistency of species utilized in previous studies; translatable data

Discuss pre-clinical plan with Healthcare Authority (U.S. FDA) prior to initiation

Discuss Pre-clinical data with Healthcare Authority (U.S. FDA) prior to IND initiation

Process globally known as “Scientific Advice” with HCA, EMA

- Saves “false starts” or sometimes difficult work to retrace and “add to”

- However, if you disagree with the answer, it has “become part of the official record”

- Still advantageous to know “opinion” before you start or what your later research commitments might be to support product licensing

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Development Process Concerns – Phase I-II-III

Ph. I Ph. II Ph. III

Phase I : Determining safety, adverse reactions

Phase II: Determining efficacy

Phase III: Statistical adverse reactions, range of adverse events, statistical efficacy data developed

Strong monitoring efforts for detailed close-out of each Phase of Study

Maintain consistency of drug and device utilized

Long-term availability of device raw materials

Data must hold up to regulatory scrutiny during “licensing phase”

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Parameters and Considerations

Define the parameters: How many products?

How many trials?

Typical trial size (patient ranges):

- Phase I: 20-40 Phase II: 50-100 Phase III: 100-300

How many gels?

What is the ring (or device) manufacturing process?

Development process considerations: 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

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Risk Relationship with Study Design

Non-linear relationship between study design and time, effort, cost risk

Number of Products

Number of Arms

Single product, 2-arm study is “X”

3 Product, 6-arm study is a multiple of “X”

The more people, the more management burden, the more risk, the more set backs, the more it costs and the longer it takes

However, the trial must be appropriately robust in order to evaluate the endpoints

Development Process Conclusions:

Timing differences between trials are not linear vs. the number of products in trial

The more complex, the more significant holes of knowledge will develop

Costs, labor demands, technical feasibility, timing, etc.

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Development Process Concerns – Post-Marketing

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

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Emerging Global Requirements

for Devices with Microbicides

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Global Challenges

Regulatory pathways for combinations products need clarification in many developing countries Parallel approval pathways are needed to speed up approval

process Regulatory expectations are that combination products with

multiple active ingredients need to be superior to individual components Negative impact to cost and timeline to prove superiority

Informed consent can be challenging due to language barriers and literacy rates Ethics review committee recommended to help guide patients

The following are some recommendations for improving the regulatory process relating to microbicides and devices: Strengthen partnerships in worldwide organizations Better information sharing between organizations and

countries of interest Promote quality & ICH standards Establish centers of excellence within impacted regions

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Product Development Partnerships

Product Development Partnerships work with pharmaceutical companies, research centers and other PDP’s to prevent HIV transmission through microbicide use in developing countries

PDP’s perform the following functions: Aid in product development process for microbicides and

dual protection products such as contraceptives combined with anti-STI products

Conduct pre-clinical and clinical trials to evaluate compounds

Helps establish manufacturing and distribution capacity Training of worldwide investigators

Examples of PDP’s specializing in HIV/AIDS prevention include: IPM Global – http://www.ipmglobal.org CONRAD – http://www.conrad.org PATH – http://www.path.org Population Council – http://www.popcouncil.org

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WHO Considerations

WHO has partnered with many organizations regarding HIV/AIDS prevention Develops and drives global strategy on HIV prevention

WHO is helping to get these combination products to areas of need by: Partnering with organizations such as EMEA on Article 58 Helping to facilitate development and testing with other

organizations Ensuring trials are conducted with high ethical standards

Microbicide trials involving WHO in the last 2 years suggest: Microbicide gel alone did not change HIV infection rate Demand for devices with microbicides would be high

Pre-qualification status for drugs for HIV prevention WHO can grant pre-qualification status for HIV/AIDS

prevention products if need is prevalent Status is not available for microbicides due to the number of

API’s involved and complexity of the drug/device interactions

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Considerations in Africa

Greatest need for devices with microbicides due to presence of HIV/AIDS Microbicides of lower efficacy more likely to be accepted in Africa Cannot be perceived as using developing nations as “Guinea Pigs”

Regulatory review requires expertise that developing countries in Africa typically do not have Most advanced tend to be South Africa, Algeria, Nigeria, Zimbabwe

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

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Considerations in Latin America

Regulatory capabilities have vastly improved over the past decade

Brazil, Mexico and Argentina are the leading authorities in Latin America

No standardization amongst countries – each country has their own RA Regulatory approval is very complex due to differing

requirements by regulatory authorities Local authorities tend to be even more stringent than in the US 70% of requirements are published, 30% is negotiated

(Examples: where API originates, where drug product is licensed, local populations included in studies, how product is being brought to the country; direct/distribution)

Some areas require local manufacturing presence This leads to barrier to entry and longer drug/device approval

times Combination products are handled similar to US & EU

Determination made of whether it’s a drug or device Vast majority tend to be handled as drug registrations

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Considerations in Asia Pacific

Most popular growth area for new drug marketing Large populations, willing CT participants, limited drug

availability The PMDA in Japan is the clear leading authority in Asia Pacific

Original ICH country with US & EU – very advanced Other growth markets are China, India, South Korea, Phillipines &

Malaysia No standardization amongst countries – each country has their own

RA Regulatory approval is the most complex due to differing

requirements, information availability and multiple languages Authorities tend to be mimic US or EU processes with slight

alterations Approval times take longer than US/EU due to resource

constraints Culture also has an impact on safety emphasis, regulatory

approval process & timing Combination products are handled similar to US & EU

Determination made of whether it’s a drug or device

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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

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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

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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

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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

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