Global Regulatory Strategy for Medical Devices Supplementary Materials

Table of Contents Tips and Best Practices ................................................................................................................................... 1 Acronyms Guide .............................................................................................................................................. 2 References and Resources .............................................................................................................................. 3 Course Workbook ........................................................................................................................................... 8 Appendix ....................................................................................................................................................... 51

RAPS Online University | Global Regulatory Strategy for Medical Devices 1

TIPS AND BEST PRACTICES SYSTEM REQUIREMENTS

• Web Version o Internet Explorer 8 is the preferred browser; participants can also use a current version of Firefox or Safari o Google Chrome is not a supported browser o Flash 9 is a common plug-in used in the courses and can be downloaded for free at www.adobe.com o Participants may need to disable their browser’s pop-up blocker; instructions are provided on the course launch page

• iPad Version o Download the free Articulate Mobile Player App from the App Store o Content in this format can be made available for offline viewing; before attempting to download the course to your iPad, ensure that

you have enough available storage space on your device. This information is provided on the course launch page.

USING ONLINE UNIVERSITY There are three orientation videos accessible from the Welcome screen, which review the features and functions of the course players and online system to help maximize and simplify your learning experience. It is also a good idea to read the Online University FAQs accessible in the “HELP” section. MAXIMIZE YOUR LEARNING Courses are organized into lessons to let you to fit in learning as your schedule permits. For optimal comprehension and retention, however, try to complete at least 15–30 minutes of content at a time. Lesson title pages offer a convenient point to put down the course and the bookmarking feature automatically saves your progress. To ensure bookmarks save properly, exit the course player and let the SCORM Controller window close by itself (Web version) or close the Articulate App (iPad version). Bookmarks do not transfer between Web and iPad versions. It is also helpful to have this packet of supplementary materials handy when going through the content. The course Storyboard is intended to be an organizational tool for your own note-taking and not the full course text; printable full text is not available. Some of the Storyboard images may appear blank or incomplete because the multimedia used cannot be exported to other formats. TAKING THE FINAL ASSESSMENT

• 30 questions— a mix of true/false, multiple choice and/or numeric test items • 80% passing score • Untimed completion • An answer key is not provided • Cannot “save and return” • No limit on the number of attempts allowed • Each time the assessment is taken some of the questions will change

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ACRONYMS GUIDE 510(k) Premarket Notification AHWP Asian Harmonization Working Party ANVISA Agência Nacional de Vigilância Sanitária (Brazil) BRIC Brazil, Russia, India and China CAB Conformity Assessment Body CAPA Corrective and Preventive Action CFR Code of federal Regulations CI Competitive Intelligence DHF Design History File DMR Device Master Record EP Essential Principles EU European Union FD&C Act Food Drug & Cosmetic Act FDA US Food and Drug Administration FOIA Freedom of Information Act GAAT General Agreement on Tariffs and Trade GHTF Global Harmonization Task Force GLP Good Laboratory Practice GMP Good Manufacturing Practice GVP Good Vigilance Practice HBD Harmonization By Doing ICH International Conference on Harmonization

INMETRO National Institute of Metrology, Standardization and Industrial Quality

IP Intellectual Property ISO International Organization for Standardization IVD In vitro diagnostic IVDD In Vitro Diagnostics Directive MAH Marketing Approval Holder MDD Medical Devices Directive

MHLW Ministry of Health, Labor and Welfare (Japan) OCP Office of Combination Products (FDA) OIVD Office of In Vitro Diagnostics (FDA) PAL Pharmaceutical Affairs Law PMA Premarket Approval PMDA Pharmaceuticals and Medical Devices Agency QOL Quality of life QSR Quality System Regulation SBAC Brazilian Conformity Assessment System SCIP Society of Competitive Intelligence Professionals

SFDA Central State Food and Drug Administration (China)

STED Summary Technical Documentation TGA Therapeutics Goods Act WHO World Health Organization

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REFERENCES AND RESOURCES Lesson 1 • 21 CFR 862 • 21 CFR 864 • 21 CFR 866. • GHTF, SG1/N29R16:2005. Information Document Concerning the Definition of the Term “Medical Device.” GHTF Study Group 1. 20 May 2005. • Therapeutic Goods Administration. Australian Medical Devices Guidance Document Number 25: Classification of Medical Devices. Published January 2005. • Health Canada. Section (1), Medical Devices Regulations • Medical Devices Directive 93/42/EEC, Article 1. • English Regulatory Information Task Force, Japan Pharmaceutical Manufacturers Association. Pharmaceutical Administration and Regulations in Japan. IDRAC review. March 2006. • Federal Food Drug & Cosmetic Act Section 201(h). • FDA. Overview of IVD Regulation • Global Harmonization Task Force Study Group 1. Principles of Medical Device Classification (GHTF/SG1/N15:2006). Published June 2006. • Health Canada. Draft guidance for risk based classification system [25 April 2010]. • European Commission DG Enterprise. Guidelines for the classification of medical devices. MEDDEV 2.4/1 Rev.8. Published July 2001. [Accessed 25 April 2010]. • Global Harmonization Task Force Study Group 1. Principles of In Vitro Diagnostic (IVD) Medical Devices Classification (GHTF/SG1/N45:2008). Published June 2008. • Canadian Food and Drug Act: http://laws-lois.justice.gc.ca/eng/acts/F-27/index.html • Department of Justice Canada. Medical Devices Regulations (SOR/98-282) • Health Canada. Drug and Health Products, Guidance Documents • Health Canada. Medical Device Active License Listing(MDALL) • Health Canada. Drug and Health Products, Establishment Licences • Health Canada. Guidance Document for Risk Based Classification System for In Vitro Diagnostic Devices • Australian Government, Regulations of IVDs in Australia Lesson 2 • Essential Principles of Safety and Performance of Medical Devices (SG1/N020R5), • Safe Medical Devices Act of 1990. • Filmore D. “East to Meet West on Cardiovascular Clinical Trial Design.” The Gray Sheet. 2006; 32(49). • Novales-Li P. “A regulatory manager’s best practices for integrating regulatory matters in seminal business decisions.” Regulatory Affairs Focus.

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2006; Volume 11, Issue 4. • Kennel NJ. “Trials and tribulations of conducting clinical studies and tips on how to avoid them from a small medical device company perspective.” Regulatory Affairs Focus. 2005; Volume 10, Issue 8. • ANVISA. Resolution RDC 206/2006 (Chinese language only) • The Diretoria Colegiada [Collegiate Directorate] of the Agência Nacional de Vigilância Sanitária [National Health Surveillance Agency], in the use of the attribution conferred by paragraph IV of art. 11 of the Regulation • Amann. M. “Developing a Regulatory Strategy” Applied Clinical Trials, Volume 17, No. 10, October 2008. • Central Drugs Standard Control Organization, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India Lesson 3 • Giroud D. “Ethics in Medical Device Clinical Assessments” Regulatory Focus. 2007; Volume 12, Issue 1. • ISO 13485:2003: Medical Devices-Quality Management Systems-Requirements for Regulatory Purposes. • Global Harmonization Task Force. Essential principles of safety and performance of medical devices (GHTF-SG1-N41R9:2005). • Global Harmonization Task Force. Role of Standards in the Assessment of Medical Devices (SG1-N012R10). • Global Harmonization Task Force. Final Document Summary: Technical Documentation (STED) for Demonstrating Conformity to the Essential Principles of Safety and Performance (SG1/N011:2008). • Kennel NJ. “Trials and tribulations of conducting clinical studies and tips on how to avoid them from a small medical device company perspective.” Regulatory Affairs Focus. 2005; Volume 10, Issue 8. • Robinson R. “Nonclinical Development Activities for Medical Devices.” Regulatory Affairs Focus. 2004; Volume 9, Issue 7. • Hauptmann S. “The best practices and common pitfalls of drug lifecycle management.” Regulatory Focus. 2007; Volume 12, Issue 5. • Steneberg HJ. “Considerations for EU approvals of new technology devices.” Regulatory Affairs Focus. 2003; Volume 8, Issue 12. • Hickey J. “Considering reimbursement issues during the regulatory planning process for product success.” Regulatory Affairs Focus. 2006; Volume 11, Issue 6. Lesson 4 • Brown-Tuttle, M. “RA strategy 101: How to present regulatory strategy.” Regulatory Affairs Focus. 2005; Volume 10, Issue 7. • Brown-Tuttle M. “Regulatory intelligence 101. Regulatory Affairs Focus. 2004; Volume 9, Issue 12. • General Agreement on Tariffs and Trade (GAAT). • Tolomeo D. “FDA 510(k) applications as evidence in patent litigation.” Regulatory Affairs Focus. 2004; Volume 9, Issue 7. • Society for Competitive Intelligence Professionals. “SCIP Code of Ethics for CI Professionals” • International Clinical Trials Registry Platform (ICTRP). • Brown-Tuttle, M. “Regulatory Intelligence Tools Update.” Regulatory Affairs Focus. 2007; Volume 12, Issue 5. • Lingamaneni, R. and Sarnelli, T. “The role of regulatory affairs professionals.” Regulatory Affairs Focus. 2006; Volume 11, Issue 8.

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• Brittle M. “Negotiating skills for regulatory professionals.” Regulatory Affairs Focus. 2005; Volume 10, Issue 8. • RAPS. “Reflections on the Regulatory Profession.” Regulatory Affairs Focus. 2009; Volume 14, Issue 4. [Accessed 4-25-10]. • International Committee of Medical Journal Editors. “Uniform Requirements for Manuscripts Submitted to Biomedical Journals.” Selected Sources of Competitive Intelligence Blogs www.healthbusinessblog.com www.biotech-weblog.com Links to Global Regulatory Agencies www.fda.gov/oia/agencies.htm www.drw-research.com/resources.html http://www.ghtf.org/information/international.htm#Europe Professional Journals and Newsletters Gray/Silver Sheets www.fdcreports.com International Medical Device Regulatory Monitor www.fdanews.com Medical Device & Diagnostic Industry www.mddionline.com IVD technology www.ivdtechnology.com Medical Device Daily www.medicaldevicedaily.com Regulatory Focus Magazine(RAPS) www.raps.org Regulatory Affairs Journal (Device) http://www.rajpharma.com/home/ Specialized Regulatory Intelligence Software (paid subscription) Compliance Control www.compliance-control.com IDRAC www.idrac.com Tarius www.tarius.com MediRegs www.mediregs.com Regulatory Alerts/Updates/Newsletters/Subscriptions and Services Dickinson’s FDA WebView www.fdaweb.com Discovery Dossier www.bioportfolio.com DRW Research & Information Services www.drw-research.com FDA News www.fdanews.com Health News Daily www.healthnewsdaily.com Tarius Interactive www.tarius.com

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RAPS (Weekly Update email) www.raps.org Educational Resources RAPS www.raps.org AdvaMed’s Medical Technology Learning Institute www.advamed.org American Conference Institute www.americanconference.com Association for the Advancement of Medical Instrumentation www.aami.org Barnett/Parexel www.barnettinternational.com Cato Research www.cato.com/events.shtml Center for Professional Advancement www.cfpa.com Center for Professional Innovation & Education www.cfpie.com FOI Services www.foiservices.com Global Harmonization Task Force www.ghtf.org/meetings Institute of Validation Technology www.ivthome.com International Quality and Productivity Center www.iqpc.com Management Forum www.management-forum.co.uk Noblitt & Rueland www.fdaconsulting.com Ovid www.ovid.com TOPRA www.topra.org Regulatory Information/Research Providers Clinivation www.clinivation.com Datamonitor www.datamonitor.com DRW Research & Information Services www.drw-research.com Food and Drug Administration www.fda.gov Graematter Inc. www.graematter.com Lorenz www.reg123.com RegIntel Ltd. www.regintel.com RegSource www.regsource.com Business Intelligence Biospace www.biospace.com Bureau of National Affairs Inc. www.bna.com Centerwatch www.centerwatch.com Datamonitor www.datamonitor.com IFPMA Clinical Trials Portal www.ifpma.org/clinicaltrials.html Mediregs www.mediregs.com

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SCIP www.scip.org Industry Associations (Regulatory) AdvaMed www.advamed.org EUCOMED www.eucomed.org International Conference on Harmonization www.ich.org International Organization for Standardization www.iso.ch Medical Device Manufacturer Association www.medicaldevices.org MEDEC-- Canada's Medical Device Technology Companies www.medec.org RAPS www.raps.org Advisory Committee Updates AdComm Bulletin www.idrac.com Advisory Committee Updates www.FDAAdvisoryCommittee.com FDA Advisory Committee Website www.fda.gov/ohrms/dockets/ac/acmenu.htm Patents USPTO www.uspto.gov World Intellectual Property Organization www.wipo.int European Patent Office www.european-patent-office.org Canadian Intellectual Property Office www.cipo.ic.gc.ca Reimbursement Centers for Medicare &Medicaid Services (CMS) http://www.cms.gov Global Integrated Reimbursement Services Inc. http://girsinc.com/ Emergo Group http://www.emergogroup.com/services/europe/germany-medical-device-reimbursement Pacific Bridge http://www.pacificbridgemedical.com/publications/japan/2007_medical_device_reimbursement

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COURSE STORYBOARD

Global Regulatory Strategy for Medical Devices

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Global Regulatory Strategy for Medical Devices Course Overview The medical device market changes frequently in terms of technology, risk potential, marketing and reimbursement. Therefore, it is imperative for regulatory professionals to be aware of existing requirements and new developments in the global market. This course is intended to teach participants to ask the right questions and adapt the course concepts within their own organizations. This course provides a basic description of global regulatory strategy for medical devices and explains the relationships between regulatory strategy and product development. It offers guidelines for developing successful global strategies for medical devices, including definitions and classifications worldwide, elements of regulatory strategy, sources of competitive and regulatory intelligence, selection of development and product approval pathways and suggestions for professional development. Learning Objectives Upon completion of this course, participants will be able to:

• Describe the elements impacting the definition and classification of medical devices globally • Determine the points to consider in the development of a global regulatory strategy • Define the tools for global regulatory strategy development • Recognize sources of regulatory and competitive intelligence • Identify the elements of a regulatory plan • Apply global regulatory principles to develop a regulatory plan, including STED documents for global registrations

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Lesson 1: Medical Device Rules in Different Regions Introduction Medical devices are classified differently based on intended use, safety risks and the jurisdiction in which they fall. Many countries have adopted the Medical Devices Directive (MDD) and International Conference on Harmonization (ICH) guidelines. However, each country reserves the right to enforce specific rules and regulations within its jurisdiction. Therefore, the accurate labeling and intended use of a device can make the difference between a successful or delayed market launch. Regulatory agencies primarily regulate products according to their intended use. The agencies generally take into account technology risks, patient populations and conditions intended to be mitigated. Typically the accuracy, support for, and the risk of the information provided are the main areas of concern. Submissions made to the regulatory agencies should support the intended use and the labeling claims made. Lesson Objectives Upon completion of this course, participants will be able to:

• define medical devices and in vitro diagnostics (IVDs) from a global perspective • describe regional differences in regulation • classify medical devices

\

GHTF (until 2012, when it was replaced by the International Medical Device Regulators Forum) was composed of regulatory authorities and industry from five countries/regions:

1. ___________________________________________ 2. ___________________________________________ 3. ___________________________________________ 4. ___________________________________________ 5. ___________________________________________

GHTF’s goal was to enhance ____________________ and increase ____________________________________. In 2006, GHTF accepted applications from __________________ and __________________ to become GHTF Liaison Bodies.

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TERM DEFINITION Medical devices Accessories Components Software

Exception products that are considered medical devices in some jurisdictions, but have no harmonized approach:

• ___________________________________________________________________________

• ___________________________________________________________________________

• ___________________________________________________________________________

• ___________________________________________________________________________

• ___________________________________________________________________________

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COUNTRY/REGION IVD DEFINITION REFERENCE United States European Union Brazil Russia China India Japan Canada

A device for in vitro examination includes: • ___________________________________________ • ___________________________________________ • ___________________________________________ • ___________________________________________ • ___________________________________________

Brazil’s new IVD regulations establish nine rules for determining risk class, based on these five main criteria:

1. ___________________________________________________________________________

2. ___________________________________________________________________________

3. ___________________________________________________________________________

4. ___________________________________________________________________________

5. ___________________________________________________________________________

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RULE CLASS(ES) DESCRIPTION SUMMARY Rule 1 Rule 2 Rule 3 Rule 4 Rule 5 Rule 6

The classification of an IVD is based on the following GHTF criteria: • ___________________________________________ • ___________________________________________ • ___________________________________________ • ___________________________________________

Home brew reagents are: Based on their risk potential, they may be classified according to:

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TRUE or FALSE In the US a combination product must be either a drug/device or a biologic/device.

TRUE or FALSE A “Part 3 Designation” can be requested by a US sponsor of a device from the FDA Office of Combination Products.

TRUE or FALSE In Canada, a drug/device combination product is classified as a drug or device based on the principal mechanism of action.

TRUE or FALSE For combination products in Australia, the rules for the lower-risk component will determine its regulation.

TRUE or FALSE Brazil and Japan have specific regulatory requirements for combination products, but Russia and China do not.

MEDICAL DEVICE

MEDICINAL PRODUCT

Drug delivery or administration devices (e.g.,

syringes)

Single-use medicinal product-device combinations (e.g., pre-

filled syringes)

Devices incorporating medicinal substances (e.g., antibiotic-coated catheters)

For each statement concerning EU combination products, identify the correct classification for the product:

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Stand-alone software is classified as a device by the GHTF according to:

The GHTF has adopted ____________ for Medical Device Software. The classification for combination products and stand-alone software has been adopted by:

• __________________________________________

• __________________________________________

• __________________________________________

COUNTRY/REGION

REFERENCE DIFFERENCES FROM GHTF DEFINITION

Australia

Brazil

Canada

China

EU

India

Japan

Russia

US

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CLASS US Requirements Class I

Class II

Class III

The GHTF system consists of four risk classes: 1. ___________________________________________ 2. ___________________________________________ 3. ___________________________________________ 4. ___________________________________________

Medical devices are assigned to regulatory classes based on:

Risk depends in part on __________________________, __________________________ and/or whether the device __________________________.

TRUE or FALSE Australia, Brazil, Canada, China and the EU use a rules-based classification system similar to that of the GHTF.

In 2005, Japan replaced the 4 GHTF-like classes with 3 new medical device classes:

1. ___________________________________________ 2. ___________________________________________ 3. ___________________________________________

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Identify the Classification Scheme for Non-IVD Medical Devices for Each Country/Region

US CANADA EU GHTF I, IIa, IIb, III X A, B, C, D X I, II, III, IV X I, II, III X

Identify the Classification Scheme for IVD Medical Devices for Each Country/Region

BRAZIL CHINA INDIA GHTF Non-critical, Critical A, B, C, D I, II, III, IV I, II, III

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Thought Questions 1. Why do countries/regions have different classification schemes for medical devices? _______________________________________. _________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________ 2. Compare and contrast general medical devices and in vitro diagnostic medical devices. _________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________ Practice Exercises 1. Your company is developing a drug/device combination product that you plan to market in the US, EU, Brazil, Japan, Canada, and Australia. What specific documents will you research, to learn the requirements for combination products in each country? _________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________ 2. You have a Class I medical device, according to the US FDA. What class would you expect that product to be for Brazil, Canada, and China? ___________________________. What class would it be, according to the GHTF classification? __________________________________. Key Take-aways

• Medical devices have similar definitions in each GHTF country, with minor variations. • Medical devices are described as not achieving their primary intended action in or on the human body by pharmacological, immunological or

metabolic means. • Devices are classified based on the risk with their intended use; higher-risk devices undergo greater scrutiny by regulatory agencies. Risk-based

classification differs within each region depending upon device type and intended use. • For IVD classification, criteria involve intended use and indications, user expertise, impact of the result on the individual, and importance of the

information to diagnosis.

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Lesson 2: Regulatory Strategy Elements Introduction One of the most challenging and critical aspects of the regulatory profession is the development of effective, sound and competitive strategies for products. This process includes assessment of regulatory risk, decisions about types of filings, marketing and labeling strategy, content and timing of submissions, meetings with regulatory authorities, approval metrics, issue identification and development of target marketing claims. A strategy must be developed at the beginning of the program and modified as new data become available and industry trends and business objectives change. A winning strategy for device development is to “begin with the end in mind.” This approach is especially appropriate for US companies developing medical devices under Quality System Regulation (QSR) design controls (21 CFR 820.30). In the US, design inputs and outputs must be considered before product development begins to show traceability of design, conformity assessment routes and compliance with design control standards. Elements of the regulatory strategy form the basis of the regulatory plan. Planning involves development of a map or pathway to reach the big-picture regulatory goal (e.g., marketing approval), taking into account all relevant information on the product. Regulatory strategy incorporates the device development plan, unresolved issues on previous versions of the device, background information, regulations and/or guidance documents, strategic advice and recommendations on implementation. Lesson Objectives Upon completion of this course, participants will be able to:

• identify the elements of regulatory strategy for medical devices • discuss how these elements fit together to create a global regulatory strategy

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The product description includes: • ___________________________________________

• ___________________________________________

• ___________________________________________

• ___________________________________________

• ___________________________________________

• ___________________________________________

What is a claim?

Claims can be either direct (_______________________) or indirect (_______________________) and are conveyed through _______________________, _______________________, or _______________________.

Claims definition requires knowledge of the product’s _________________, _________________, and ________________.

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What is the Difference in Intended Use and Indications for Use? INTENDED USE INDICATIONS FOR USE

In developing claims, questions to answer should include: • ______________________________________

• ______________________________________

• ______________________________________

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Describe the Type of Claim

SAFETY AND EFFECTIVENESS PERFORMANCE QUALITY OF LIFE COMPARATIVE AND SUPERIORITY

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In strategic planning for claims, _________________________ and _________________________ should be taken into consideration.

What is typically needed for “reaching” claims, intended to exceed the competitor’s stated claims?

Identification of applicable laws, regulations, standards and guidance depends on ___________________, ___________________, ____________________, and access to _____________________.

To identify applicable laws and regulations, it is essential to have a clear vision of _________________________________ and _________________________________ from the sponsor.

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Describe the Harmonization By Doing (HBD) pilot project between the US and Japan:

TRUE or FALSE Assumptions may change due to new information, but a regulatory plan should not be changed.

Assumptions to support regulatory strategy include: • ______________________________________

• ______________________________________

• ______________________________________

• ______________________________________

• ______________________________________

• ______________________________________

• ______________________________________

• ______________________________________

A regulatory risk assessment details key regulatory and project risks, including:

• ______________________________________

• ______________________________________

• ______________________________________

A risk assessment team is typically composed of _______________, _______________, _______________, and _______________ professionals.

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Regulatory risk questions include: • _________________________________________________________________________________________________

• _________________________________________________________________________________________________

• _________________________________________________________________________________________________

• _________________________________________________________________________________________________

• _________________________________________________________________________________________________

Questions to consider when conducting a gap analysis:

• _________________________________________________________________________________________________

• _________________________________________________________________________________________________

• _________________________________________________________________________________________________

• _________________________________________________________________________________________________

• _________________________________________________________________________________________________

• _________________________________________________________________________________________________

• _________________________________________________________________________________________________

• _________________________________________________________________________________________________

• _________________________________________________________________________________________________

• _________________________________________________________________________________________________

What is a gap analysis?

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TRUE or FALSE Assumptions may change due to new information, but a regulatory plan should not be changed.

TRUE or FALSE All regulatory bodies encourage pre-meetings with the sponsor.

TRUE or FALSE Any written or verbal agreements from meetings with regulatory agencies are generally not binding.

TRUE or FALSE Common mistakes in meetings with regulatory agency include withholding important information and trying to cover too much ground.

The objective of agency meetings is to facilitate _______________ from the agency to the sponsor.

Dialogue during the development process keeps the review division of the regulatory agency _________________________ and provides an opportunity to ____________________________.

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What are the time-consuming elements of a meeting with a regulatory agency?

• ______________________________________

• ______________________________________

• ______________________________________

• ______________________________________

Match the Global Strategy Section to its Contents:

Regulatory Strategy

Reference Number

If new product, list of countries to

market product

Classification of product

New, existing or discontinued product

Reason for Regulatory

Strategy

Classification in US, EU and major markets

Countries Impacted

Unique identifier to manage requests within company

Details of Associated

Testing/Validation

Statement that the RA strategy would change if there are changes

to regulations, guidance, or standards

Documents Impacted

Timeline for completion of initial RA strategy

RA strategy Timeline

List procedures, protocols and reports impacted by this change

Disclaimer Summarize the testing planned to support the changes described

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Thought Questions 1. In what ways can early definition of the claims for a medical device guide the entire product development process? _________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________ 2. A product’s risk/benefit analysis and regulatory pathway reply on assumptions, often based on incomplete information. As the product is developed, how would you proceed in filling in the information gaps? _________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________ Practice Exercises 1. Your company is developing a medical device and has requested a meeting with a regulatory agency. Describe some of the situations and questions that could arise in the meeting, and how should you prepare for them? _________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________

Input from individual countries that informs the global regulatory strategy includes:

1. ________________________________________________

2. ________________________________________________

3. ________________________________________________

4. ________________________________________________

5. ________________________________________________

6. ________________________________________________

To develop approval timelines and country priorities, the regulatory professional should determine how long _____________________, the types of _____________________, and the _____________________.

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2. Your company is developing a medical device, and you are asked to develop a claim for each of the four types of claims (performance, safety/effectiveness, quality-of-life, and comparative claims). List the four claims for your specific product _________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________ Key Take-aways

• Medical device regulatory strategy is based on marketing/performance claims, regulatory statutes and submission requirements. Product claims require documentation in order to substantiate those claims.

• Device classification and market positioning is based on how a product fits into the rules for each region and the documentation required to demonstrate compliance with regional requirements.

• Regulatory strategy varies, depending on the device type, its risks and intended use. In most regions, product and design documentation is required as part of an overall quality system that governs the development and manufacturing of a device.

• A combination of claim substantiation, quality system compliance and risk management are required elements for device product submissions in most regions.

• Regulatory meetings provide insight into agency thinking and clarify requirements. • Each country has unique regulatory requirements that need to be kept in mind when preparing timelines for the global regulatory strategy.

Some examples include: o Certificate to Foreign Government or Certificate of Export o ISO 13485 certificate required by non-EU countries o Certificate of Free Sale if product not regulated in the US o Legalization of documents o Declaration letters specific to each country which may prolong the lead time

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Lesson 3: Regulatory Documentation Introduction Regulatory documentation is required of manufacturers of medical devices to demonstrate safety and effectiveness of a product. Documentation must be developed and presented under the agency requirements of the region in which a manufacturer wishes to market a product. The creation and development of the Design History File (DHF) and the final Device Master Record (DMR) as a deliverable of the design and development process should provide the documentation required for country-specific registrations. As a design and development team member, the regulatory professional should document the deliverables required during the design process to meet the specific country requirements for the planned distribution as defined by marketing. This planning can reduce the time required to compile information from various design documents if the design team understands the specific data required for each section of the submission and/or technical document file. Consideration should also be given to any possible future or secondary marketing plans. This will help to prevent repeating verification/validation testing that may have country specific-requirements beyond the original testing, which may save time and resources for future submissions. In this lesson we will cover the key elements of documentation, regulatory submission requirements and general considerations for product development and specific requirements as they apply to indicated regions. Lesson Objectives Upon completion of this course, participants will be able to: discuss general considerations for documentation during device development define registration requirements based on the device classification define key elements for documentation of STED and non-STED submissions based on country-specific interpretation

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The quality management system is influenced by:

• ________________________________________________

• ________________________________________________

• ________________________________________________

• ________________________________________________

For the US, medical device manufacturers must comply with the Quality System Regulation, found in 21 CFR _______.

What standard is used by founding GHTF members to establish a quality management system?

The BRIC countries (Brazil, Russia, India and China) and Canada accept either _________________and/or _________________.

Medical devices that are based on existing, well-established technologies may not require clinical trials. What do they rely on to prove intended performance?

What are the three primary considerations for clinical evaluations? • ________________________________________________

• ________________________________________________

• ________________________________________________

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Standards Characteristics Alternate Name Description Of Standard Example Basic Safety Standards

Group Safety Standards

Product Safety Standards

For high-risk medical devices, describe the extremes in clinical evaluation requirements among countries.

Conformity assessment routes include: • ________________________________________________

• ________________________________________________

• ________________________________________________

• ________________________________________________

Compliance with standards recognized by the regulatory authority may demonstrate compliance with ________________ and/or ________________________.

A declaration of conformity to a recognized standard may be documented in a _______________________ and submitted, where appropriate, in place of _______________________.

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Identify the major sections of the STED format: • ________________________________________________

• ________________________________________________

• ________________________________________________

• ________________________________________________

• ________________________________________________

• ________________________________________________

In what GHTF document are submission requirements (STED) outlined? Only what kind of documents should be incorporated in the STED?

In what document are US Premarket Notification Submission [510(k)] requirements outlined?

What is the advantage of a Special 510(k)?

TRUE or FALSE A 510(k) submission can be formatted in the globally harmonized format of the STED.

TRUE or FALSE The premarket approval (PMA) is only used to evaluate safety and effectiveness of Class II medical devices.

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Match the Date of the Draft Guidances to Their Titles:

Draft Guidance issued 27 December 2011

Medical Device Classification Product

Codes

Draft Guidance issued 27 July 2011 (withdrawn

17 July 2012)

Draft Guidance issued 3 January 2012

The 510(k) Program: Evaluating Substantial

Equivalence in Premarket Notifications [510(k)]

510(k) Device Modifications; Deciding When to Submit a 510(k) for a change to an

Existing Device

Health Canada defines requirements for medical devices in which four guidances?

1. ________________________________________________

2. ________________________________________________

3. ________________________________________________

4. ________________________________________________

Health Canada strongly encourages use of STED for premarket license applications for Class ______ and Class _______ devices.

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Define the Following Terms and Acronyms: ACRONYM/TERM DEFINITION Annex II of RDC-185

ANVISA

INMETRO

SBAC

Check all required documentation for registration in Brazil: Free sales certificate or an INMETRO certificate Projected sales figures Certificate of Good Manufacturing Practice (GMP) Instructions manual translated into Portuguese Labeling and packaging Instructions manual translated into Spanish

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Match the Requirements for Registration in Japan with its Device Class

The New Pharmaceutical Affairs Law (PAL) is harmonized with international requirements, with what exception?

In Japan, a Marketing Authorization Holder (MAH) license is required in order to:

Who publishes guidance documents for medical devices in Japan? a. ____________________________________________

b. ____________________________________________

Class I

Certification (ninsho) Class II

Class III and IV

Market Approval (shonin)

Notification (todokede)

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Check all required documentation for registration in China: Business license Quality guarantee letter Projected sales figures Manufacturing authorization document in the country of

origin Product operation manual

Name the regulatory agency for medical devices in China:

All three classes of medical devices in China require: _____________________, ____________________ and ____________________. Classes II and III also require _____________________.

TRUE or FALSE Emerging and regulated markets may follow GHTF recommendations, but there are many nuances to their requirements.

TRUE or FALSE Typically, the device user manual and labeling must be translated into the country’s language, but not the submission.

TRUE or FALSE The requirement for “product description” has been harmonized across all countries to be a short text description only.

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Thought Questions 1. Requirements for demonstrating clinical evaluation vary among countries: some may require only literature searches; others may require clinical trials. What are some advantages and disadvantages of conducting human clinical trials versus literature searches only? _________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________ 2. What are the advantages to having some of the submission requirements for medical devices harmonized through the STED? _________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________ Practice Exercises 1. You are developing a medical device that you want to market in the US and other countries. How would you ensure that you are in compliance with US 21 CFR 820 and ISO 13485 standard? _________________________________________________________________________. _________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________ 2. You are developing a medical device that may need clinical evaluation in some or all of the countries where you plan to market the device. Describe the potential different approaches to demonstrating the clinical evaluation _________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________ Key Take-aways

• Regulatory submission documentation is a complex process representing the product, its classification, intended use and target markets. • Documentation for devices includes how the design process was developed, agreed upon, and documented; what risks were identified and

mitigated; what clinical evaluations were selected; and the conformity assessment route taken to demonstrate regulatory compliance. • The documentation must also demonstrate that due diligence is taken to control manufacturing methods to ensure the manufacture of a safe

and effective device. • Submission requirements outlined in the GHTF document Summary Technical Documentation (STED) describes the same major elements

generally required in different countries and regions. However, all submission requirements are not harmonized across jurisdictions, so research should be done to determine the specific country requirements beyond the STED.

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Lesson 4: General Regulatory Strategy Introduction We’ve discussed regulatory requirements and development strategy. Regulatory professionals also need to develop business, collaboration, communication and negotiation skills to achieve success. A regulatory professional may be technically proficient, but must employ a teamwork approach to achieve the goal of marketing authorization for a device. The key is the ability to work within the sponsor’s or client’s structure with existing resources and within the business culture of the organization. In this section we discuss strategies you can use to define a business and regulatory strategy and present it to key players in a way that wins early buy-in to the project. Lesson Objectives Upon completion of this course, participants will be able to:

• identify key questions to consider in the development of regulatory strategy • discuss regulatory strategy planning • cite benefits of a well-developed and executed plan • explain the interaction of strategy and device development • identify tools for regulatory strategy development including regulatory and competitive intelligence • describe the personal development goals for a successful global regulatory professional • define the benefits of a global regulatory strategy

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Describe Each Skill Needed by Strategic Regulatory Professionals

SKILL DESCRPTION

Scientific and technical skills

Business development skills

Communication skills

Regulatory ethics

Regulatory and governmental affairs skills

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• Development of a written development plan (regulatory plan) is essential in __________________ as well as __________________ from regulatory agencies.

• A well-developed and executed regulatory plan identifies regulatory issues and their impact on __________________ and __________________.

• When developing the regulatory plan, you should build the __________________ for each step into the overall regulatory plan, presenting the __________________ available for each step, the __________________ of each option and the __________________ option.

Place the steps of developing a regulatory plan for a new product into the correct order:

Collect background information

Formulate strategic advice

Make recommendations on practical implementation steps

Collect references

Form assumptions

Collect, reevaluate and distill data on an ongoing basis

Define the questions to be asked

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The project schedule should include:

• ________________________________________________

• ________________________________________________

• ________________________________________________

Periodic meetings should be held to:

A critical path analysis consists of those items that:

Cost analysis activities should include:

• ________________________________________________

• ________________________________________________

• ________________________________________________

• ________________________________________________

• ________________________________________________

• ________________________________________________

Who would you contact to confirm the accuracy of the review timelines posted by regulatory agencies?

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How does lifecycle management aid with compliance integrity?

The best way for medical device companies to ensure compliance is by integrating product information with:

• ________________________________________________

• ________________________________________________

• ________________________________________________

TRUE or FALSE Agency clearance guarantees that there will be insurance coverage.

TRUE or FALSE Insurance coverage is directly related to the relevance and quality of clinical evidence for the product.

TRUE or FALSE Without insurance coverage, devices will not be used by clinicians despite regulatory approval.

TRUE or FALSE

If there are no internal (company) resources knowledgeable in reimbursement, the regulatory professional should consult the FDA or other regulatory agency.

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Patents can be obtained not only on a device itself but also on: Patent protection extends for 20 years from the date of patent filing, according to:

Under patent infringement law, what can happen to the manufacturer of a new medical device?

In strategy development for new medical devices, why is regulatory intelligence needed?

Why is competitive intelligence needed?

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Define regulatory intelligence:

How does regulatory intelligence help to support regulatory strategy?

• ________________________________________________

• ________________________________________________

• ________________________________________________

• ________________________________________________

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TYPE OF REGULATORY INTELLIGENCE DESCRIPTION EXAMPLES

Direct sources

Indirect sources

Literature and Journal research

Define competitive intelligence:

Check all likely sources of competitive intelligence: Central Intelligence Agency Regulatory environment Typical timing and cost of milestones Medical environment Competitor products

Variables in sources of competitive intelligence include:

• ________________________________________________

• ________________________________________________

• ________________________________________________

• ________________________________________________

Place the steps of conducting competitive intelligence for a new product into the correct order: Report intelligence-gathering results to company project teams Assess impact of gathered intelligence on chosen strategy Assemble data into broad categories Refine the competitive intelligence-gathering process for

future products Examine the data for trends

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In product development, the regulatory department provides input on:

• ________________________________________________

• ________________________________________________

• ________________________________________________

• ________________________________________________

• ________________________________________________

The regulatory strategy development process ideally should start in which phase? Regulatory professionals can add value to projects by ________________________ and by ________________________.

TRUE or FALSE Strategic marketing of a product depends on its regulatory classification, risk potential and specific documentation requirements for each region.

TRUE or FALSE A cross-regional strategy should not consider reimbursement, because regions vary too much in their requirements.

TRUE or FALSE

Alternative strategies for global device marketing, such as repackaging of devices with partners, and outsourcing OEM manufacturing are not allowed in most countries.

TRUE or FALSE Programs that incorporate cross-regional intelligence will reduce losses from delayed launches due to unanticipated regulatory burdens.

TRUE or FALSE Rewards for a global strategy include long-term market coverage, establishment of credibility and brand loyalty.

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Thought Questions 1. How is a written development plan (regulatory plan) essential to the following areas?

Project approval

Regulatory approval/clearance

Intellectual property documentation

Patent enforcement

Substantial equivalence determinations

Future new products

2. Of the skills needed for a successful strategic regulatory professional (scientific/technical, business development, ethics, communication, regulatory/government affairs), which one is most important, and why? ______________________________________________________ _________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________

A final review before sending a submission to target market countries should include:

• All ___________________________ required by the agencies have been completed

• A clear device ___________________________ has been provided

• No discrepancies in the document regarding ________________________, _______________________ or _______________________.

• Submitted performance data that is supportive of the _______________________.

• Clinical data that supports the _______________________.

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Practice Exercises 1. Your company plans to submit marketing applications for a medical device product in several countries. You have found the countries’ regulatory agency review timelines on their websites. What factors should you keep in mind when using these timelines? _________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________ 2. Your company is developing a medical device and you have been asked to gather regulatory intelligence, in order to develop the strategic regulatory plan. What sources of regulatory intelligence will you use and why? _________________________________________________________________________________________________________________

_________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________ _________________________________________________________________________________________________________________ Key Take-aways

• To be successful, a strategic regulatory professional needs skills in science and technology, business development, ethics, communication, and regulatory/government affairs.

• Regulatory strategy and effective planning is based on device classification, its benefit/risk potential, and the regional regulatory requirements of the target markets.

• Proper product definition, market placement and properly documented design development history are essential elements for a global regulatory strategy.

• A strategy plan may start out with a brief description and basic regulatory information. Elements of regulatory planning include intended use and key claims, possible predicates, intended market, reimbursement, labeling requirements, pertinent guidances and standards, and regulatory risks and contingency plans. This plan can be updated and revised as company and regulatory requirements are discovered.

• In a regulatory strategy plan, regulatory and competitive intelligence programs are needed to provide information in a timely manner. • Regulatory strategy plans can be successful if they define global regulatory and product definitions early. The strategic regulatory professional

can play a major role in product development to provide the best safe and effective device products to patients.

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RAPS Online University | Global Regulatory Strategy for Medical Devices

APPENDIX 1 Comparison of Medical Device Definitions Across Regions Country/Region Highlighted Differences Australia

— Includes devices used for diagnosis, monitoring, treatment, alleviation of or compensation for a handicap

— Includes accessories Australian Medical Devices Guidance Document Number 25: Classification of Medical Devices

Brazil — Includes appliances, materials or accessories whose use or application is related to diagnostic and analytical purposes, to cosmetics and perfumes, as well as to dietetic, optical, medical acoustic, odontology and veterinary products

http://www.anvisa.gov.br/eng/medical_devices/index.htm Canada

— Includes devices used to restore, correct or modify body functions in humans — Includes component parts and/or accessories — Details devices for diagnosis of pregnancy as well as those used at or after human

childbirth, including the care of a child Section (1), Medical Devices Regulations

China — Includes passive and active device for temporary, short term and long term use that includes:

- skin, cavity and tract - trauma tissue - blood circulation and central circulation

http://www.sfdachina.com/infosort/12_1.htm EU — Includes devices intended to diagnose, monitor, treat, alleviate or compensate for

a handicap — Includes accessories

Medical Device Directive 93/42/EEC, Article 1 India — Medical devices are classified as life-saving and non-life-saving devices

— Implantable devices, diagnostic kits and sterile products are registered under the drug regulations in India under the Drug and Cosmetics Act of 1940 and 1945; the rest of the devices are not regulated

http://dst.gov.in/whats_new/whats_new07/MDRA-Act.pdf Japan — Includes devices and equipment intended for diagnosis, treatment or prevention

of animal diseases, or affecting the structure or function of an animal body (English Regulatory Information Task Force, Japan Pharmaceutical Manufacturers Association. Pharmaceutical Administration and Regulations in Japan. Mar 2006 IDRAC review p2)

Russia — Includes devices intended to diagnose, monitor, treat, alleviate or compensate for a handicap (similar to EU classification)

— Includes accessories (Roszdravnadzor Order No 3731; dated 9 November 2007 and GOST-R 51609-2000) http://www.emergogroup.com/resources/articles/russia-medical-device-approval-process

US — Includes devices used to treat/diagnose/mitigate/prevent an animal disease — Includes devices intended to affect the structure or any function of a human or

animal body — Includes components and accessories

Section 201(h) of the Federal Food Drug & Cosmetic (FD&C) Act

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APPENDIX 2

Non-IVD Medical Device Risk Classes for Major Markets

Risk Level Low Low-Moderate Moderate-High High GHTF A B C D Australia I IIa IIb III Brazil I II III IV Canada I II III IV China I II III India only certain classes of medical devices are regulated under the Drugs & Cosmetics Act Russia I IIa IIb III EU I IIa IIb III Japan I general II controlled III highly controlled,

IV highly controlled, high

US I II III

IVD Risk Classes for Major Markets Risk Level Low Low-Moderate Moderate-High High GHTF A B C D Australia I II III IV Brazil I II III IV Canada I II III IV China I II III

EU Non-Annex II Annex II-B Annex II-A

India Non-critical (non-notified) Critical (notified) classified under the Drugs &

Japan I general II controlled III highly controlled,

IV highly controlled, high Russia Regulated as medical device supply or medical device equipment

US I II III

RAPS Online University | Global Regulatory Strategy for Medical Devices

APPENDIX 3 Guidance in Preparing a Global Regulatory Strategy

SECTION GUIDANCE Regulatory Strategy Reference Number A unique identifier would be useful to manage a

large number of requests within the company Product Name and codes, or if new Project Name Provide product name and codes if currently

marketed product; if new product, provide project name and, if applicable, the internal Change Order Number

Classification of product (if legacy product) Classification in US, EU and major markets If New Product Provide claims or indications for use desired Name of Individual Initiating Strategy Request Name, title, dept. and contact information of the

initiator Reason for Change or New Product Provide cost savings to business or reason for

criticality to business or if new project, provide timeline

Reason for the Regulatory Strategy New, existing or discontinued product. Changes to process, product, equipment, facility, labeling, packaging, raw material, supplier, line extension, other

Countries Impacted If legacy product, provide countries; if new product, provide list of possible countries where product will be marketed

Predicate Device

Product name and product codes if predicate device is known.

Description of the change/new product Enough details to be provided if legacy product, and state if changes to process, finished goods, IFU, etc. Provide the differences of current vs. future. Enough detail should be provided for RA to clearly identify the differences.

Why is the Change Necessary? Describe the reason for the change and what the desired outcome/known outcome is after the change has taken place. For new product, detail the product, process, legal manufacturer, etc.

Details of Associated Testing/Validation Summarize the testing planned or already carried out to support the changes described. Also provide timeline for planned testing

Documents Impacted List procedures, protocols, reports, etc. impacted by this change. Is there an existing RA strategy for this change? Is this an amendment to an existing request?

Timeline for RA strategy Estimated timeline to be provided for completion of the initial RA strategy

Disclaimer Statement to be included that the RA strategy would be subject to change if changes to regulations, guidance, standards or change in the description of the original RA strategy

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APPENDIX 4 Sample Spreadsheet of Worldwide Regulatory Assessment Information

Country RA Impact Y/N

If yes, submission with approval or without approval

If approval required, estimated timeline

List of documents required for submission

If change to product or label, can the old and

new products be imported after approval

Additional comments

China Yes Submission with approval

12-24 months upon submission

• PoA • CFG • Declaration Letters • Raw Material

Specifications • Stability Study Report • Manufacturing

Process Flow

Once approval received for modified label, can

no longer import original labeled product

• 3 dozen samples required for type testing;

• signed original English IFU,

• Chinese language labeling and IFU required