NIH-DAIDS/MRB/IPCPMedical Device & Microbicide Regulatory Training Robert J. Russell President - RJR Consulting March 15-16 2011 1 Course Agenda 2 8:30 – 8:45 - Biography/Company Overview 8:45 – 9:00 - FDA Overview 9:00 – 10:15 - FDA Requirements for Medical Devices & Combination Products 10:15 – 10:30 – Break 10:30 – 10:45 - EMA Overview 10:45 – 11:45 - EMA Requirements for Medical Devices & Combination Products 11:45 – 12:00 - Differences between FDA and EU/EMA 12:00 – 1:00 – Lunch Course Agenda (Cont’d) 3 1:00 – 1:30 - Review of Medical Devices containing Microbicides 1:30 – 2:00 - Minimal Regulatory Requirements for Testing & Standards 2:00 – 2:45 - Regulatory Challenges in Developing IVR’s 2:45 – 3:00 - Break 3:00 – 3:30 - Regulatory Challenges for Imaging Devices 3:30 – 4:00 - Potential Development Process Concerns 4:00 – 4:30 - Emerging Global Requirements 4:30 – 5:00 - Conclusions/Questions/Final Discussion OH Ph.Biography Bob Russell President & CEO 43054 RJR Consulting. Bob has a BS / MS in Chemistry and regularly teaches classes on a variety of regulatory topics within the Life Science industry. R&D Director and Global Director of Regulatory Affairs for Merion Merrill Dow and Cordis-Dow. Founded RJR Consulting. New Albany. in 2002 to assist companies with their Regulatory Affairs. Distribution and Manufacturing needs.com 1717 154 E. (614) 304-0110 Cell:(614) 551- 28 years of industry experience as a CMC specialist. Business Development. rjrussell1280@msn. Main St.Course Director . 4 . Inc. Inc. Inc. governments and organizations within the Life Sciences and Consumer Products industries. EU.Company Profile RJR Consulting. Global Regulatory Compliance Business Consulting Solutions Clinical Trial Set-Up Strategy Development CRO Management & Project Management Selection Marketing Authorizations / License Renewals NDA’s / Variations / Amendment Filings Manufacturing Authorizations International Regulatory 5 Surveillance Updating: NA. is a global consulting firm specializing in regulatory compliance and business development solutions for companies. Inc.RJR Consulting. . Japan. LAA Government / Agency Affairs New Business Development Global Business Expansion Industry Training Process Development & Improvement Distribution and . Inc. Argentina European Union Brussels. is headquartered in New Albany. Brazil Mexico City.Global Reach RJR Consulting. Ohio. Germany 6 Asia Pacific Japan China Korea Taiwan . US Vancouver. Canada Latin America Sao Paulo. These offices provide the in-country expertise needed to deliver successful projects to our clients North America New Albany. Ohio and has affiliate offices strategically located around the world. Mexico Buenos Aires. Belgium Hamburg. FDA Regulatory Overview 7 . Maryland with hundreds of field offices throughout the U. India. Offices abroad in China. Headquarters in Silver Spring. 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.S.S. Belgium. Regulates more than $1 Trillion in consumer goods or 25% of all U.S expenditures.The U. Chile & UK Personnel are exchanged with EMA and PMDA for ICH best practices and further harmonization 8 . Costa Rica. pharmaceuticals and medical devices. tobacco products. etc. soap.) Medical Devices Drugs of abuse Biologics Health Insurance Veterinary products Meat & Poultry Cosmetics Pesticides Radiation-emitting Products Combination Products (any combination of drug.What is regulated by FDA? Regulated by FDA Food Alcohol Tobacco Drugs Consumer Products (shampoo. device or biologic) 9 Not Regulated by FDA Restaurants Water . toothpaste. FDA Organizational Structure FDA is headed by the Office of the Commissioner FDA made up of multiple Centers All centers report into the Office of the Commissioner Office of Regulatory Affairs is an additional “Center” in charge of field operations Each Center has multiple offices Ex: Office of Combination Products Each Office has multiple divisions Responsibilities become more granular as you move down the chain 10 . gov .Main Centers of the FDA CTP CBER Center for Tobacco Products Center for Biologics Evaluation & Research CDER Center for Drug Evaluation & Research CFSAN Center for Food Safety & Applied Nutrition CDRH Center for Radiological Devices & Health NCTR National Center for Toxicological Research CVM Center for Veterinary Medicine 11 Source: www.fda. CDER. CDRH 12 .Office of Combination Products Specialty Office established in 1990 that exists under the Office of the Commissioner Small Office of 8 members Acts as the gatekeeper for regulation of combination products Ensures proper direction and timely review of combination product applications Responsible for assigning an FDA Center to have primary jurisdiction based on primary mode of use Develops guidance on regulations having to do with combination products Does not actually review marketing applications handled by CBER. FDA Requirements for Medical Devices & Combination Products 13 . Overall Regulatory Pathway IVR/Microbicide Gel Combination Products Markets/countries outside of EU 14 . FDA Clinical Trial Evaluation Process Device 15 Combination Product Ph I .Toxicity Ph II .Efficacy Ph III – Statistical Efficacy & Adverse Events . FDA Licensing Process 16 Regulatory Requirements Many different factors are involved in obtaining regulatory approval for a medical device or combination product: Questions to ask… Is it a combination product? What is the primary mode of action? Is it a device, drug or biologic? Is it exempt from classification? If not exempt, is it already classified by the FDA? Is there another device that is similar that has already been approved? Is it a new device that addresses an unmet need in the market? What is the level of control needed to make sure it’s safe and effective? What is the risk to the patient? 17 Combination Products 18 Defined as a distinct combination of drug, device and biologic products Drug + Device Drug + Biologic Device + Biologic Drug + Device + Biologic The combination of device and drug may fall under “combination” regulations, as specified in Title 21 of the Code of Federal Regulations (CFR) Part 3.2, Subpart (e) (i.e., 21 CFR 3.2(e)), which require both an investigational device exemption (IDE) and an IND The following are also considered under combination products: Two or more products that are packaged together or physically/chemically combined An individually packaged product that is designed to be used with another approved product to achieve the intended use An investigational product that is designed to be used with another approved product to achieve the intended use Lead Agency Center to be assigned for pre-market review Determination of jurisdiction usually takes 45-60 days Request can also be made informally by contacting Office of Combination Products 19 . 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.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. CBER and CDRH Provided guidance to determine how lead agency works with the other agencies during review process Agreements identify specific combination products and how they are regulated Primary Mode of Action introduced in 2005 overrides most of previous intercenter agreements Still provide helpful guidance in addition to jurisdictional determination Sets guidelines for how centers work together during review Each center is beginning to publish information on the determination and approval of combination products through the OCP performance reports on the Office of Combination Products homepage on http://www.fda.gov 20 .Intercenter Agreements Agreements entered into in 1991 by CDER. Regulatory Issues with Combination Products Organizational & process approval challenges exist when trying to obtain regulatory approval for a Combination Product based on classification: Product Type Drug Device Biologic Lead Agency Center CDER CDRH CBER IDE 510(k) PMA IND BLA 510K PMA NDA Approval Processes 21 IND NDA . Safety Concerns Unknown interactions of combining two or more approved products can lead to potential safety and effectiveness concerns for patients Combination 22 . Pre-IDE Process Contact FDA prior to submission of request for IDE FDA will provide one time pre-IDE feedback to sponsor at no cost Increases sponsor understanding of regulations and process Helps to minimize delay during actual submission process Typical 30-60 day response time FDA may have guidance meetings with sponsor about Pre-IDE submission Can be conference calls or face-to-face Meetings are usually formal but informal conversations can be had prior to official meeting to ask questions Formal meetings are Determination meetings or Agreement meetings Determination meeting – request to discuss scientific information needed in submission Agreement meeting – reach official agreement on parameters of clinical protocol and investigational plan Will issue Notice of Disapproval or Withdrawal if Pre-IDE not approved 23 . both IRB and FDA need to approve before IDE process begins Non-Significant Risk (NSR) 24 Doesn’t meet criteria above for Significant Risk Different than “minimal risk” studies that qualify for expedited review . 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.Significant vs. investigational plan. 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 Device Exemption (IDE) Exemption granted to allow a device to be used in investigational clinical studies (21 CFR 812) Allows for collection of safety and effectiveness data Data will eventually support the 510k or PMA submission Permits the device to be shipped for investigational study purposes’ Listing/registering not required while device under investigation Requirements for an IDE include: Approval by institutional review board before clinical study 25 initiated Significant risk device requires FDA approval along with IRB Informed consent for patients “Investigational use only” labeling On-going monitoring of clinical study Records and reports supporting the study . scalpels. implants Exempt (Class I or Class II) Very low risk. subject to general and special controls Devices that support/sustain human life or pose excess risk Examples: pacemakers.Classification Types All devices will be classified as one of the following types: Class I Low risk. subject to general controls Some devices may be exempt from GMP as well Examples: Non-sterile surgical tools *description in next slide 26 . subject to general and special controls* Examples: pregnancy tests. subject to general controls* Examples: gloves. enema kits Class II Medium risk. powered wheelchairs Class III High risk. artificial hearts. infusion pumps. product listing.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. quality measures (including misrepresentation) & reporting Special Controls Additional controls applied to Class II and Class III devices to ensure safety and effectiveness Includes such things as: Performance standards and specific guidelines Additional labeling requirements Post-market monitoring & surveillance 27 . labeling. while the majority of Class II & III devices are non-exempt Class I Class II Class III Exem pt 95% 3% 0% NonExem pt 5% 97% 100% Class III Class I Class II 28 *source: www.fda.2009 data .Classification Statistics The majority of devices fall under the Class I or Class II designation The majority of Class I devices are exempt.gov . the device component is automatically classified as Class III 29 .Determining Classification Device class is determined by many different factors: Previous similar devices Intended use of the device Indications for use (specifics of intended use) Risk to the public You can use a number of methods to determine class of specific products CFR Search Search regulations on FDA website Determine the medical specialty (panel) of the device Each panel has list of products classified (16 panels) Located in 21 CFR 862-892 Identify the classification regulation Search the product code classification database For combination products considered as “drugs”. Manufacturers are still required to: Register and list product with FDA Comply with any GMP or labeling requirements Some class I devices are exempt from GMP if not labeled as sterile 30 . 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.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. Reclassification Process Classification is occasionally adjusted through a reclassification process FDA has power to reclass a device if necessary Reclassification can be up or down in product class Must convince FDA by providing data and reassuring safety Triggers to a reclassification of one or more products More experience and usage of a new device Receipt of new information on a device Petition from outside sources FDA will notify petitioners with a reclassification letter Federal register updated with any reclassification of devices 31 . the type of regulatory submission can be determined: Premarket Notification (510k) Required submission for all Class I & II non-exempt devices No actual FDA provided form for 510(k) Requirements for submission in 21 CFR 807 subpart E Product clear to be marketed in US when 510(k) is approved Premarket Approval (PMA) Required submission for Class III devices Very few pre-amendment devices grandfathered in Required due to higher risk of devices General & special controls insufficient in assuring safety 32 .Regulatory Submission With the device class and non-exempt status known. sterilization or manufacturing process will likely require new submission Burden is on Manufacturer 33 .Requirements for 510(k) submission Groups who are required to submit a 510(k) to FDA: Domestic manufacturers introducing device in US Specification developers introducing device in US Repackers/Labelers who make labeling changes Foreign manufacturers (or representatives) introducing device in US The following instances require that a 510(k) be submitted to FDA: 1. Introducing device for commercial use for first time 2. Modification to existing device that affects safety or effectiveness May require new 510(k) depending on what was changed Change to materials. Proposing a different intended use for existing device 3. 1976 Device is imported from foreign manufacturer who already has 510k clearance Device is exempt through previous regulations 34 .When is a 510(k) Not Needed? Company is selling components or parts of devices to another company for further processing Device is not being commercially marketed or distributed Distributing another firm’s domestically manufactured device Labeling of device has not significantly changed Device was commercially distributed before May 28. De Novo petition or PMA required De Novo petition File petition with 30 days to justify why device should be Class I or II Meant for devices that do not have a predicate and are low risk 35 .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. special controls are in place and standards are already in place Must prove conformity to the recognized standard Includes summary reports on use of guidance docs to expedite review Special Done for device modification that does not affect intended use or technological standards Contains a Declaration of Conformity to specific design controls Submission does not include data 36 .Types of 510(k) Submissions Traditional Most common – process as previously described Abbreviated Used when guidance documents exist. 37 37 . Proposed Streamlining of 510(k) Process Plan released in January 2011 to streamline 501k review process Driven by CDRH to clarify timelines for submission of clinical data Create a Center Science Council of experts to speed up decision making Plan includes issuing draft guidance documents in 2011 on topics such as: Improving the quality and performance of clinical trials Process for appealing CDRH decisions Streamlining of the De Novo application process When to submit clinical data Identifying safety issues and concerns Characteristics included in the scope of “Intended Use” “Indication for Use” becomes part of “Intended Use” FDA ultimately decided against a CDRH proposal having another classification category called Class IIb Would have bridged gap between medium and high risk devices– similar to EMA Ex: No predicate exists but risk is in line with Class II device 38 . Premarket Authorization (PMA) Review Most stringent pre-marketing application Must be completed for all class III devices Often involves new concepts or ideas that have no precedent Four step review process 1. Completeness review – Is everything there? 2. Detailed scientific. Final documentation and notification of approval FDA approval grants the owner license to market device in US Good science practices and scientific writing are key for approval Non-approval letter will contain application deficiencies or reasons for non-approval 39 . Review and recommendation by advisory committee 4. regulatory and quality review 3. PMA Application Methods Traditional PMA All volumes submitted to FDA at once For devices that have had clinical testing or have been approved elsewhere Modular PMA PMA broken into modules and each module submitted upon completion Meant for products in early stages of clinical study Streamlined PMA - (Pilot Program) For devices where the technology and use is well known by FDA Submitted as traditional PMA but review is interactive and streamlined Product Development Protocol (PDP) Early agreement with FDA regarding design/development details of device Work at own pace and keep FDA informed and involved Recommended for devices where the technology is well established 40 PMA Amendments & Supplements PMA Amendment Submission during application process before FDA approval is obtained When additional data requested or modification to application is needed Restarts the submission process at beginning PMA Supplement For product changes after approval has been obtained Usually needed when changes impact safety, effectiveness or labeling Different timeframes for review (30-180 days) based on impact of change Humanitarian Device Exemption Incentive for developing devices that affect under 4000 people in U.S. Similar to orphan drug designation, except for devices HDE’s are exempt from effectiveness requirements Must justify risk to FDA and demonstrate lack of predicate 41 PMA Requirements The following are required to be submitted within a traditional PMA: Name, address and table of contents Description of the device form and function Practices and procedures – what device is used for Foreign and domestic market history of the device, if any Details about manufacturing process in making the device Summary of clinical and non-clinical studies Conclusion of studies, include safety and effectiveness of device Reference to any performance standards followed Labeling and advertising literature (Ex: pamphlets) Results of non-clinical lab studies Results of clinical studies on human patients Financial certification and disclosure statement Bibliography of reports about safety/effectiveness of device 42 Bioresearch Monitoring (BIMO) Program 43 Program consisting of on-site inspections and data auditing designed to monitor research and data collection activities related to devices Groups monitored include Sponsors, CROs, Clinical Investigators, Monitors, Non-clinical Labs and Institutional Review Boards Each group has an associated guidance document Program designed to: Protect research subjects from unnecessary risk Ensure patient safety from potential hazards Uphold quality and integrity of data collected BIMO program is coordinated by the Office of Regulatory Affairs Each Main Center (CDRH, CDER, CBER) supports BIMO effort CDER – Division of Scientific Investigations CBER – Bioresearch Monitoring Team CDRH – Division of Bioresearch Monitoring BIMO Inspection Programs Two types of inspections under BIMO program: 1. Routine Inspections Random inspections of investigators, sponsors, IRB’s or labs Performed to monitor compliance with BIMO program 2. Directed Inspections (For-Cause) Inspection requested due to problem or issue Problem observed during 510k or PMA submission process Complaints from doctors/patients can also lead to inspection Inspector will assign a classification to the overall inspection based on compliance: NAI – No Action Indicated VAI – Voluntary Action Indicated OAI – Official Action Indicated Warning letter may be issued based on severity of findings 44 Sponsor Responsibilities Sponsors are responsible for the following when it comes to BIMO: Selecting a qualified investigator Ensuring proper monitoring of the investigation Verify investigator follows investigation plan and IND protocols Ensuring FDA and investigators stay informed of new risks or adverse effects of drug/device Obtaining proper information from the investigator prior to inspection Review and evaluate safety and effectiveness data Discontinue investigations that pose significant risk Maintain accurate records regarding financial interest and receipt/shipment of the drug 45 Clinical Investigator Responsibilities When it comes to BIMO. Investigators are responsible for: Adhering to the Investigator Agreement Following the Clinical Investigation Plan Protecting the health. safety and well-being of patients/subjects This includes obtaining informed consent Obtaining IRB (and FDA) approvals Supervising and disposing of the devices Disclosing any financial interest that exists Documenting adverse effects or deviations from the plan Writing progress reports and delivering a final report Disqualification Will not continue to receive investigational devices if requirements are repeatedly not followed 46 . Clinical Research Monitor (CRA) Responsibilities 47 Primary liaison between the sponsor and the investigator Interviews & recommends investigators Responsible for site selection and reporting progress of the clinical trial Prepares clinical development plans Ensures subject safety and verifies data integrity Ensures the investigator: Understands the regulations and need for accountability Follows written 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 . strategies.Clinical Investigation Plan Comprehensive document or set of documents with detailed feasibility. and administrative elements of clinical trial conduct Include input from all CRO to ensure process flow is accurate Establish timelines for finalization and sign off of all plans and adhere to the timeframe The Clinical Investigation Plan is made up of several different plans including: 48 Essential (Investigator) Document Plan Monitoring Plan Data Management Plan Safety Plan Statistical Analysis Plan Communication Plan Risk Assessment . entry. review and completeness of the database Safety Plan Outlines SAE process and reconciliation Additionally can outline medical monitor review and oversight (Medical Monitor Plan can be a separate plan) 49 .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. Plans within the Clinical Investigation Plan Statistical Analysis Plan Outlines the programming and analysis of the database Details the number of tables and listings and data analysis methods Communication Plan Outlines all the communication paths with internal and external team members Risk Assessment Outlines all identified risks Risks are ranked by impact on the study Offers preventative and/or contingency actions Timelines – MS Project 50 . Plans within the Clinical Investigation Plan Issue Escalation Plan Can be part of Communication Plan Outlines path of communication for major issues that can adversely Affect the outcome of the study Have a major financial impact Details who is notified. as needed Become part of the Central Clinical Project Files 51 . 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. EU/EMA Regulatory Overview 52 . EU Member States & EEA • • • • • • • Austria Belgium Denmark Finland France Germany United Kingdom • • • • • • • Greece Ireland Italy Luxembourg The Netherlands Portugal Spain EU Applicants •Croatia •Turkey 53 • • • • • • • Sweden Cyprus Czech Republic Estonia Hungary Lithuania Latvia • • • • • • European Free Trade Association Countries •Iceland •Liechtenstein •Norway •Switzerland EU and EFTA countries (excluding Switzerland) have a market of ~ 350 million customers Malta Poland Slovakia Slovenia Bulgaria Romania . EU Regulatory Bodies 54 European Commission (EC) Ensures safety and public health of foods and consumer goods in EU Responsible for proposing and upholding laws for EU related to drugs & devices European Medicines Agency (EMA or EMEA) Decentralized group in EU that evaluates medicines for human and veterinary use Responsible for scientific evaluation and enforcing regulations for EU members Committee for Medicinal Products for Human Use (CHMP) Comprised of representatives from Member States along with medical experts Part of EMA – conducts the drug review process National Competent Authorities (NCA) Responsible for local authorization and compliance within own country Conducts research & development and determines available medicines in country Notified Bodies (NB) Designated by Competent Authorities – about 100 NB’s in Europe Performs conformity assessments procedures to determine device class . EU Regulatory Structure EC (Commission) Project Manager (Scientific/Medical Advisors) CHMP Rapporteur/ Co-rapporteur 55 EMA (EMEA) MRFG (Medical Devices) NCAs Notified Bodies Inspectors Ethics Committee . EU Requirements for Medical Devices & Combination Products 56 . Confirmation of Product Meeting . Selection of Conformity Assessment Annexes / Procedures 9. Annual CE Mark Maintenance .EU Path to Market for Devices 57 1. CE Marking Device 12. Which Directive is Referenced? 3. Selection of Notified Body (except for Class I devices) 6. Selection of Lead Member State for CE Marking Device 5. Conformity Assessment Certificate 11.Medical Device Definition 2. Confirmation of Device Classification 7. Device Meets Essential Requirements 8. Medical Device Classification (based on EU Rules) 4. Audit / Non-Conformances / In-House Changes 10. 58 .EU Device Regulatory Flow Which Directive applies? Is it a Drug? Device? Combo? If it’s a device…. material or other article used alone or in combination. to be used for human beings for the purpose of: diagnosis. 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.EU Medical Device Definition The term ‘Medical Device' refers to any instrument. prevention. 59 . treatment or alleviation of disease diagnosis. monitoring. alleviation of or compensation for an injury or handicap investigation. appliance. apparatus. treatment. monitoring. including the software necessary for its proper application intended by the manufacturer. immunological or metabolic means. but may be assisted in its function by such means. Classification of Medical Devices Rules for full classification of Class I. Three definitions for duration of use apply: transient (normally intended for continuous use of less than 60 minutes) short-term (normally intended for continuous use of 30 days or less) long-term (normally intended for continuous use of more than 30 days) A graphical summary of classification of medical devices is in the slides to follow and is for initial identification of probable device class 60 Always confirm definitive classification by reading all rules and examples in the guidelines document . 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. IIa. urine drainage bags. bandages. light sources Spirometers. digital thermometer s IV catheters. reabsorbabl e implants Involveme nt of Notified Body Selfcertification Declaration of Conformity Selfcertification Declaration of Conformity + Notified Body for measuring function/ sterility Mandatory Mandatory Mandatory 61 .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. tubing's for anesthesia/v entilation Intraocular lenses. endoprosthe ses. breast implants. hospital gowns. ventilators Heart valves. 8 62 .Source: MEDDEV 2.4/1 Rev. 4/1 Rev.8 63 .Source: MEDDEV 2. 8 .64 Source: MEDDEV 2.4/1 Rev. 8 65 .4/1 Rev.Source: MEDDEV 2. 4/1 Rev.8 66 .Active Devices Continued Source: MEDDEV 2. 67 Source: MEDDEV 2.4/1 Rev.8 . 68 electrical/thermal risks Manufacturer Information . stability. storage Chemical. sterilization procedures Construction & Environmental Properties Devices with a Measuring Function Accuracy. Physical & Biological Properties Contaminant prevention. monitoring Radiation Protection Devices Connected to an Energy Source Performance concerns. power supply.Device Essential Requirements Based on Annex I of MD Directive 93/42/EEC General Requirements Safety concerns. manufacturing. combination products Infection & Microbial Contamination Infection prevention. packaging. " For manufacturer. This technical information should be held within a technical file or "design dossier.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. 69 . manufacturers must provide objective evidence of how the device meets the essential requirements. 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. there is a self-declaration procedure 70 .Criteria for Conformity Assessment Route Manufacturer/Notified Body must decide on your conformity assessment route to meet the essential requirements of the appropriate Directive MDD 93/42/EEC - Article 11 Manufacturers can demonstrate conformity through: Testing result alone Testing results plus Quality system certification Quality system certification alone Most common methods are: Certification of full quality assurance EC Type Examination (product testing) plus certification of production quality assurance For class I devices. 71 . 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 .The Technical File 72 What is a Technical File? Contains all technical information about the device Equivalent to the 501k or PMA filings for FDA Parts of a Technical File Part A: Summary of data relevant to conformity assessment procedures Part B: Full report containing detailed data and test reports on the design. Process for update of EU Representative (registration of class I devices). 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. 73 .Post Market Surveillance System (complaints.Technical File Requirements • Technical Documentation has to be updated whenever changes to the products or processes are implemented or applicable requirements change (i.Design control process (new designs & design changes) . standards) . • Procedure should include links to: . standards. clinical data) .Document control system (change of procedure.e.Process for update of Notified Body (product line extension) . User Information (Instructions. Quality Assurance 7. Risk Analysis 11. Demonstration of Compliance to Essential Requirements 5. Circuits. Purpose. Performance. Clinical Data . Statement regarding section 7. Service Manuals) 10. Device Descriptions and Variants 74 Including Functional Description. Description of Manufacturing Process. Packaging) 8.Technical File Contents 1.e. Design Documentation and Design Control Procedures 4. Materials and Component Testing (i. Biocompatibility) 9. Labels. Revision History 2. Specific Product Testing (i. Objective. Safety.4 of Annex I (Medicinal Products) 6. Sterility.e. Intended Use 3. Technical File Structure 75 1. Index 3. advertising. Name and address of the Manufacturer/European Representative and Manufacturing Plants 5. Cover Page (Company. catalogue sheets. Document ID) 2. marketing claims . Product/Product Group. EC declaration of conformity and classification 4. 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. Product design and manufacturing specifications 76 including: Parts list Drawings. 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 . assembly drawings Sub-assembly drawings Drawings of components Specifications of materials used incl.Technical File Structure (Cont’d) 6. Risk analysis (ISO 14971) 15.EMC testing and certificates 12.List of requirements (Annex 1) indicating cross- reference with documentation 16.Validation of the packaging / ageing studies 13. Testing data and reports 8. Product verification including: 7.Materials certificates / reports on biological tests 11. Wet lab or bench top testing 10.Clinical Data 77 .Technical File Structure (Cont’d) 7. Functionality studies 9.Compatibility studies (connection to other devices) 14. if viewed separately.EU Definition of Combination Product A combination product is composed of two or more constituent parts. would be regulated under more than one Directive below: Medical Devices Directive (MDD) Medicines Directives (MD) Active Implantable Medical Devices Directive (AIMDD) Herbal Medicines Directives (HMD) Example: an antibiotic coated catheter is a combination product. but when viewed separately: A catheter is regulated under the MDD The antibiotic is regulated under the MD 78 . and usefulness of drug 79 . For administration of medicines Ex: Empty single-use syringe. if used separately. Incorporated with a substance which. efficacy.Device Types within Combination Products There are 3 different types of medicinal devices incorporated in combination products: 1. 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. Combined with a medicinal product to form a single. 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. reusable spoons or droppers Regulated by medicinal device (MD) regulations 2. a kit containing an insulin pen and cartridge. the single product is regulated as a medicinal product Ex: Prefilled syringes. the pen is subject to device approval.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. various implants When in doubt. but the cartridge is considered a medicinal product If a device and medicinal product form a single. transdermal patches. contact a Competent Authority to verify 80 . integral product that is intended exclusively for single use in the given combination. 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.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. 81 . physical barrier. non-ionizing radiation. method of use. light. heat.Criteria for Combination Products Characteristics that usually lead to a device principal intended action are: Mechanical. 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. metabolic Frequently the ‘method by which the principal intended action is achieved’ will be determined by: Scientific evidence. labeling claims Advice given to patients and clinicians Challenge: most new combination products achieve their principal intended action through a “synergistic effect” 82 Neither the device nor the medicine alone would achieve desired effect . immunological. the intended use or patient population to strengthen its argument that a particular product fits into a regulatory regime that it believes is to its best advantage Notified Body is normally the manufacturer’s prime point of contact and ‘kept in the loop’ if the manufacturer consults with a Competent Authority In Manufacturers’ own interest to have Notified Body or Competent Authority to agree to the decision 83 .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. Regulatory Regime Combination Product regulated as a Medicine Device information from the technical file is usually supplied in the medicines application. Design Dossier and Quality System are required to cover the medicinal product content Full Quality Assurance route is almost always used but other conformity assessment options are available for Class III products 84 . 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. This may necessitate some duplication-.Technical File Considerations Technical File Extension For a combination product regulated as a device. The Notified Body is bound to “consult” with a Medicines Competent Authority regarding the medicinal product during a Class III device review Post Marketing Considerations 85 Surveillance.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. reporting incidents and recalls are handled like a Class III device Must meet any specific requirements applicable to the medicinal component . information on the medicine content of the product needs to be included in separate chapters of the technical file. structure and content as the appropriate authorization for the medicinal product alone. then they need to understand the personal liability they are accepting Should be added to the Quality Manual for GMP inspection purposes 86 .EC Certificate / Declaration of Conformity EC will issue a certificate demonstrating that all conditions of the Directive have been met Not an official approval and does not diminish the responsibility of the manufacturer in signing a Declaration of Conformity The manufacturer must draw up a written Declaration of Conformity prior to affixing the CE mark This declaration must cover a given number of products manufactured and has to be kept by the manufacturer Declaration of Conformity has been signed by a legal officer (a director) of the company (manufacturer or EU Authorized Representative) Becomes both a corporate and a personal acknowledgement of responsibility that the product meets the relevant applicable EU Directives If someone other than a director signs. 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. model or type designation) Annex used to verify conformity to the directive Reference to Notified Body certificate (where applicable) Identification of Notified Body (where applicable) Signature of an authorized person After the DoC is created. the CE mark can be applied 87 CE Marking is the manufacturer’s declaration that the product meets all the appropriate provisions of the relevant legislation Once applied. RF Generator) Description of device (i. the product can be freely marketed anywhere in the EU without further control .e. Overview of Article 58 Refers to Article 58 within EC Regulation 726/2004 Allows for CHMP to give opinions on medicinal products exclusively intended for markets outside of the EU Joint consulting venture with the World Health Organization (WHO) WHO cooperation allows for outreach to countries in need Goal is to provide medicines to countries where regulatory capacity is lacking Products may no longer be marketed in EU due to demand or other commercial reasons Process is similar to getting a medicinal product approved in EU except no decision from European Commission is necessary Roughly a 9-12 month process from Pre-submission to approval When approval opinion is positive. EMA publishes a European Public Assessment Report (EPAR) to reflect the conclusions made 88 . Scope of Article 58 Medicines used to prevent/treat diseases of major public health interest Reasoning behind WHO being involved in process Medicines in scope include: 89 Vaccines used in WHO expanded Programme on Immunization Vaccines that protect against public health priority diseases Vaccines involved in stock pile for emergency response Medicines that treat the following WHO target diseases: HIV/AIDS Malaria Tuberculosis Leishmaniasis Onchocerciasis Dengue Fever Leprosy . regulatory and legal coordination in areas of interest for EMA Provides forum of early dialogue for applicants with EMA ITF will work with the EC and CHMP to determine whether new products for emerging therapies qualify for EMA procedures Considered the first step for regulatory advice when confirmation of classification is needed Will setup briefing meetings to facilitate information exchange Meetings complement other formal procedures on scientific advice Applicant information kept confidential Services are provided free of charge 90 .Innovation Task Force (ITF) Multi-disciplinary group to ensure scientific. it is recommended to request scientific advice from EMA Request for a pre-submission meeting with CHMP To obtain feedback on quality. Advice Final Work Party Advice Meeting July 2011 Sept/Oct 2011(dependin g on additional meeting requested) 91 .Pre-Article 58 Advice If a combination product is classified as a medicinal product. clinical and non- clinical aspects of combination product Entire Pre-submission process takes about 5-6 months to complete PreInitial Notificatio Submissio n n Meeting March 2011 June 2011 Sci. Article 58 – Additional Details Impact on Devices with Microbicides Devices (or combination products) with Microbicides are considered in scope of Article 58 due to HIV/AIDS prevention At least 3 different scientific opinions have been adopted in the area of HIV/AIDS prevention Article 58 applicants need to already be established in the EEA Additional Considerations 92 Paediatric Legislation requirements do not apply to Article 58 applications Dossiers should be submitted electronically in CTD format No EC incentives such as market exclusivity due to lack of EC decision Process can be accelerated when justified during request of eligibility No environmental risk assessment needed as part of Article 58 GMP & GCP inspections are still required – 18.900 euros/inspection . CA The EU CTD does apply to the “medicine” component of a combination product and has significant impact on medical device development The National Competent Authority in most countries regulate medicines and medical devices (not EMA) Companies manufacture both medicines and devices and manage clinical trials for both An increasing number of medicinal products are dealt with by the European Medicines Agency (EMA) via a unified approval route (Centralized Procedure) Alternative to working through each National Competent Authority When the medicinal component of a combination product has been approved through the Centralized European procedure. . the same process is followed 93 EMA should not always be substituted for National Competent Authority Experience to date indicates that Centralized Procedure is likely to be a longer and more expensive route.Combination Products – EMA vs. Differences Between FDA & EU/EMA 94 . FDA vs. EU (Devices) Both the EU and US divide medical devices into different classes and provide for somewhat different requirements for each class Therefore gaps between the US and EU requirements can vary by product classification FDA offers one route to quality assurance for a medical device class EU has a modular approach to conformity assessment for quality assurance with up to 4 different routes for a Class IIb device and 3 for a Class III device The EU manufacturer that closely follows the EU route that most closely parallels FDA guidelines could save considerable time meeting regulatory requirements Have same goal: To ensure that a medical device company produces a safe product and that it is able to provide quality assurance that it can manufacture this safe product consistently 95 . 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. the technical file should more then satisfy the FDA in most cases 96 .FDA vs. 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. EU (Devices) Cont’d. but the FDA do not accept them 97 . 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.FDA vs. EU (Devices) Cont’d. IV. 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. V. while the FDA does not Both systems are deemed equivalent undergoing a scientific review to make sure unsafe products are not granted a marketing authorization (License) The FDA allows ongoing scientific dialogue during the development of the product and is more flexible with the applicant. EMA does not allow the dialogue and is more strict especially with the centralized procedure (through CHMP) 98 .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. 99 . helps facilitation. so the regulators are familiar with the process. whereas with EMA it is necessary to ask specific questions. The FDA application is submitted with continual dialogue.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. The FDA’s review is quicker to obtain than EMA’s. EMA can have a product application enter their system with no previous knowledge. slows review process. Fees are dependent on scope and amount of questions. FDA and EMA (Pharmaceuticals) Cont’d EMA is conservative when reviewing products on levels of specialty areas. Product review times are longer with EMA (18-24 months = 6 months advance actions + 12-18 month dossier reviews . Centralized procedure) than FDA (12-14 months) 100 . The FDA is more willing to issue conditional and fast track authorizations than the EMA. The FDA is seen as more willing to approve new therapies. Process is relatively new (EMA) selectively used. while some are concerned with the political aspect of EMA. The FDA grants authorizations based on scientific data only. such as oncology. it can take up to 9 months to add a side effect to the SPC. instead authorizations are issued indefinitely and are constantly updated based on safety data. 101 . Previously waited 30 days. companies have a wider range of product amendments they are allowed to introduce as soon as variation applications are submitted than through EMA. even for Type IA variations. FDA does not issue renewal licenses. 3 months typically with FDA Through FDA. efficacy and product modifications (amendments / variations) When introducing safety restrictions with EMA.FDA and EMA (Pharmaceuticals) Cont’d Unlike the EMA. “Notifications” just recently introduced as a category in the EU (inform only). Review of Implantable Medical Devices containing Microbicides 102 . Ph.drug / polymer specific 103 . III data for the drug component or components Profile of impurities for both Extractable / leachable data .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. II and Ph.effect of drug on the polymeric ring Controlled release data . 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.Medicated Cervical Caps The cervical cap is a contraceptive device that prevents sperm from entering the uterus The cervical cap is a reusable. 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 . deep cup that fits tightly over the cervix 104 Smaller than the dome. 5310 Condom with spermicidal lubricant A condom with spermicidal lubricant is a sheath which completely covers the penis with a closely fitting membrane with a lubricant that contains a spermicidal agent (ex: nonoxynol-9) This condom is used for contraceptive and prophylactic purposes (preventing transmission of venereal disease) Classified as Class II (performance standards) Typically considered a SR device (for the condom alone) Would follow the evaluation pathway of the Medicinal Product + the device performance standards / essential requirements evaluation 105 .Medicated Condoms Sec. 884. colorless and soft with a homogenous surface Produced with polymers such as polyacrylates. polyethylene glycol.Medicated Films Polymeric drug delivery systems shaped as thin sheets usually ranging from 220-240 um in thickness Often square (5cm x 5cm). polyvinylalcohol and cellulose derivatives Traditionally intended for single use Considered a combination product (device + drug) Would follow the same path for Clinical Trials and device approval as the Intra-vaginal ring 106 . Application Devices (vaginal & rectal) First check with IRB for NSR classification (likely in agreement) An IDE might not be necessary A designed device trial (investigational new device) could be initiated through FDA Trial objectives of efficacy and safety would be followed Design changes typically require iterations of studies Patient comfort Patient preferences 107 . barium sulfate & estradiol acetate Vulvar and vaginal atrophy symptoms related to menopause Estradiol acetate Tin Nuvarin g® Organon Outer: 54 mm Cross-section: 4 mm Ethylene vinylacetate copolymers & magnesium stearate Hormonal Contraceptive Etonoges trel & ethinyl estradiol N/A Estring® Pfizer Outer: 55 mm Cross-section: 9 mm Core: 2 mm Silicone elastomers Q7-4735 A&B. silica.6 mm Core: 2 mm Cured silicone elastomer composed of dimethyl polysiloxane sinanol. SFD 119 silicone fluid & barium sulfate Symptoms related to postmenopausal atrophy of vagina and lower UT Estradiol Platinu m 108 . propyl orthosilicate.Current IVR Product Comparison Product Manufact urer Dimensions (Diameter) Composition Indication Active Ingredie nt Cataly st Femring ® Warner Chilcott Outer: 56 mm Cross-section: 7. stannous octoate. Minimal Regulatory Requirements for Testing & Standards 109 . chemical equivalence Toxicity: cytotoxicity. reproductive toxicity) Product specifications (CofA’s). carcinogenicity. and EU should follow ISO test methods where possible ISO-14155 Device Clinical Trials ISO-13485 Device Manufacturing ISO-10993 Biocompatibility (genotoxicity. sub chronic toxicity 110 .S.Coordination of FDA and EMA Requirements Combination Products Companies looking to register products in both the U. impurities Release of by-products Mechanical safety issues (devices) Extractables & leachables (device) . obtain copies of original study reports Lab has strong GLP / GMP compliance 111 . microbial limits Labeling requirements Child-resistant packaging (?) . viscosity.typically at commercialization Use of vendor data . assays.Minimal Regulatory Requirements for Testing and Standards Combination Products Sensitization Irritation Antimicrobial effectiveness testing of gel Stability testing / product shelf-life (to extend for life of study) pH. GPC profile HPLC or GC / Mass spec.Minimal Regulatory Requirements for Testing and Standards Device Physical Property Testing “Similar product” to one previously approved or clinically studied? Previously published and accepted Physical Properties of a Device known to perform in the application? ASTM (American Society for Testing & Materials) Test Standards for Physical Properties of Polymers: Tensile strength Flexural strength % Elongation Heat Distortion Temperature Mw. impurity profile profile Medical-grade resins produced on Medical-grade manufacturing lines 112 . vaginal irritation study in ______ (ISO-10993-10) Genotoxicity (ISO-10993-3) Bacterial reverse mutation study _____ lymphoma assay Subacute / subchronic toxicity XX day intravaginal toxicity study in _____ 113 .Minimal Regulatory Requirements for Testing and Standards 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…. Minimal Regulatory Requirements for Testing and Standards If data is available from a previous submission. new intended use.polymer change. 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 --. new manufacturing step. new sterilization technique utilized. Typically reviewed with and agreed to by Healthcare Authority. new additives. 114 . no previously published global reports Requirements: Pre-clinical studies (full toxicity and biocompatibility assessment) Ph.Novel Microbicides Definition: New API. I . previous published CT reports. III Clinical Trials Full IND review CT Efficacy Data Pharmacovigilance profile Risk / Reward evaluation 115 . no Pre-clinical data.II. Both are novel 116 Requirements: Novel full-testing plus dual interaction data Requirements: Full testing requirements Requirements: Definition on their interaction together Chemical reaction together? Positive synergistic efficacy Combined unique toxicity effects Reaction by-products Remember Food. Drug & Cosmetic Act 505b2 licensing route . One known and one novel 2.Microbicide Combinations Definition: Two or more microbicides combined together as the active Possible Combinations: 1. governed by Directive 65/65/EC Repeat dose toxicity study (90 day study. leachables) 117 . “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.Microbicide APIs & Delivery Devices In EU. Specification changes??? Si EVA PVOH Best approach: Assemble vendor data on candidate materials Conduct analytical and vitro screening of materials Conduct confirmatory testing on a composite sample from the finished device 118 .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. Product Development Plan Table of Contents for Product Development Plan I. Pharmaceutical Form IV. Clinical Particular Information 119 Therapeutic indications Posology and method of administration Contraindications Special warnings and precautions for use Interaction with other medicinal products and other forms of interaction Pregnancy and lactation Effects on ability to drive and use machines Undesirable effects (based on most recent clinical data) Overdose . Qualitative & Quantitative Composition III. Name of the Medicinal Product II. 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. combination) Pharmacokinetic properties (Gel#1. Date of First Authorization / Renewal Date 120 X.Product Development Plan (Cont’d) V. Pharmacological Properties Pharmacodynamic properties (Gel #1. Marketing Authorization Holder VIII. combination) Pre-clinical safety data VI. Gel#2. Marketing Authorization Number IX. Gel#2. Date of Revision of Text . Regulatory Challenges in Developing IVR’s 121 . catalyst type used Resin grade consistency throughout Phases of study and ultimately to commercialization (eg. EVA. etc). resin equivalency data 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. impurity profile / extractables and leachables). can be influenced by the most susceptible component. the device or the drug Polymer product expirations. flexibility) .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.determined by 123 loss of physical properties (eg. Rationale for Selection of Materials Compound XYZ is an excellent candidate for a topical microbicide development due to its proven in-vitro and invivo efficacy and safety profiles …. with products already on the market Not mandatory. drug delivery system. but simplest testing & regulatory pathway 124 .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. Qualification of Materials and CMC for Combination Products 125 Quality data on gel drug substance Specifications. 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. body fluid / chemical attack. testing. migration Use of liquids. packaging Labeling. injection molding. closure system. color concentrates Effective container. instructions for use. dispersion. UV sensitivity. toxicity effects) Mixing. calendaring Particular attention to additives such as colors (fading. readability studies What constitutes a Lot / Batch size? Determining expiration dates on device alone . partial fading after use. pellets. 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.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. releasing the antibotics This allows much quicker treatment of an infection and reduces the number of times a dressing has to be changed 126 . Nanoemulsions for nasal delivery to fight viruses (such as the flu and colds) or through the skin to fight bacteria NanoBioMagnetics --.Nanotechnology in Medicine 127 BioDelivery Science --. Nanospectra --.Nanoparticles that target tumor cells.Qdots for medical imaging Smith and Nephew --. when irradiated by xrays the nanoparticles generate electrons which cause localized destruction of the tumor cells.Antimicrobial wound dressings using silver nanocrystals Luna Inovations --.Bucky balls to block inflammation by trapping free radicals NanoBio --.Diagnostic testing using gold nanoparticles to detect low levels of proteins indicating particular diseases .AuroShell particles (nanoshells) for thermal destruction of cancer tissue Nanosphere --.Oral drug delivery of drugs encapuslated in a nanocrystalline structure called a cochleate CytImmune --.Gold nanoparticles for targeted delivery of drugs to tumors Invitrogen --.Magnetically responsive nanoparticles for targeted drug delivery and other applications Nanobiotix --. Sirnaomics --.Nanoparticles for improving the performance of drug delivery by oral or nasal methods Oxonica --.Nanotechnology in Medicine (Cont’d) 128 Nanotherapeutics --.Drugs called nanoviricides™ designed to attack virus particles NanoMedia --.Delivery of siRNA molecules Nano Science Diagnostics --.Diagnostic testing using magnetic nanoparticles Z-Medica --.Targeted drug delivery Taiwan Liposome --.Drug delivery using lipsomes Traversa Therapeutics --.Nanoparticle enhanced techniques for delivery of siRNA Makefield Therapeutics --.Diagnostic testing using gold nanoparticles (biomarkers) T2 Biosystems --.Nanoparticle cream for delivery of nitric oxide gas to treat infection DNA Medicine Institute --.Diagnostic testing system .Medical gauze containing aluminosilicate nanoparticles which help blood clot faster in open wounds.Diagnostic testing system NanoViricides --. Nanoviricides A “nanoviricide” is an agent designed to fool a virus into attaching to this agent Works the same way that the virus normally attaches to receptors on a cell surface Once attached. the flexible nanoviricide glob wraps around the virus and traps it Virus loses its coat proteins that it needs to bind to a cell and is thus neutralized and effectively destroyed Nanoviricides complete the task of dismantling the virus particle without immune system assistance A nanoviricide is created by chemically attaching a virus-binding ligand. derived from the binding site of the virus located on cell surface receptor. to a nanomicelle flexible polymer 129 This binding site does not change significantly when a virus mutates Virus-specific nanoviricides have been created against important viruses such as HIV. Influenza and Bird Flu by choosing highly virusspecific ligands The National Institutes of Health (NIH) is funding research at eight Nanomedicine Development Centers . Approaches for Creating Nanodevices There are two basic approaches for creating nanodevices 1. Bottom-up approach The bottom-up approach involves assembling structures atom-by-atom or molecule-bymolecule May prove useful in manufacturing devices used in medicine 130 . 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. Nanodevices Nanodevices are small enough to enter into cells Cell Nanodevices Nanodevices Water molecule 131 White blood cell . we can refine the treatment of diseases by using biomedical. and treating cancer and HIV Cell Nanomedical robots Nano robots are nanodevices that will be used for Nanodevices the purpose of maintaining and protecting the human body against pathogens By having these Robots. nanotechnological engineering No difficulty in identifying the target site cells even at the very early stages which cannot be Water White done in the traditional treatment molecule blood cell 132 Ultimately able to track down and destroy target cells wherever they may be growing . the state-of-the art device has numerous capabilities for destroying tumors.Nanodevices & Nanomedical Robots Classified as an advanced drug delivery system. kidney stones and ulcers. biotechnology. with delayed marketing approval. worker and environmental standards .Regulating Nanodevices 133 There is significant debate about who is responsible for the regulation of nanotechnology Calls for tighter regulation of nanotechnology have occurred alongside a growing debate related to the human health and safety risks associated with nanotechnology Stakeholders concerned by the lack of a regulatory framework to assess and control risks associated with the release of nanoparticles and nanotubes Parallels have been drawn with bovine spongiform encephalopathy (‘mad cow’ disease). genetically modified food. thalidomide. reproductive technologies. and asbestosis Academics have called for stricter application of the precautionary principle. 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. nuclear energy. safety. toxicity.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. efficacy and synergy Chemical interaction Biological and physiological interaction Study Plan & testing regimen must be developed to “tell the above story” 134 . 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.Multiple Drugs in One Device Applies to multiple antiretroviral drugs within one device Ex: FDA approval of Atripla. a Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) Emtriva (emtricitabine) and Viread (tenofovir disoproxil fumarate). 3-drug fixed dose combination antiretroviral Combines the active ingredients of: Sustiva (efavirenz). their characteristics and effects are well known 135 Atripla was approved in 3 months under FDA's fast track program Safety and effectiveness of the combination of these three drugs were shown in a 48 week-long clinical study with 244 HIV-1 infected adults receiving the drugs . .Multiple Drugs from Different Drug Classes Applies to an antiretroviral drug combined with a contraceptive drug Typical Precautions: Warning Statements XXXXX may cause fetal harm when administered during the first trimester to a pregnant woman. Women should not become pregnant or breastfeed while taking XXXXX Barrier contraception must always be used in combination with other methods of contraception (e. she should be apprised of the potential harm to the fetus 136 . oral or other hormonal contraceptives) If the patient becomes pregnant while taking XXXXX.g. Counsel all women of childbearing potential after diagnosis of human immunodeficiency virus (HIV) and yearly thereafter 2. Educate patient about possible drug interactions 6. Discuss possible guardianship issues with HIV-infected women desiring to have children . Emphasize importance of barrier protection 3. Emphasize importance of maintaining optimal health 4. Be aware of reproductive options for HIV-infected women/couple 8. Be aware of safe pregnancy termination services 7. 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..Multiple Drugs from Different Drug Classes Applies to an antiretroviral drug combined with a contraceptive drug 137 Another example warning………. Consider possibility of pregnancy in all women of childbearing potential when prescribing medications 5.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. Regulatory Challenges for Imaging Devices 138 . Sunlamp products and ultraviolet lamps intended for use in sunlamp products §1040.Light Emitting Devices TITLE 21—Food and Drugs CHAPTER I--Food and drug administration.11 --. department of health and human services Subchapter J — Radiological Health Part 1040 -.30 --.20 --.High-intensity mercury vapor discharge lamps 139 .Performance Standards For Light- emitting Products §1040.Specific purpose laser products §1040.Laser products §1040.10 --.Challenges . Radiographic equipment §1020.30 --.Food and Drugs – Chapter 1 – Food and Drug Administration.Performance Standards For Ionizing Radiation Emitting Products §1020. Department of Health and Human Services .Diagnostic x-ray systems and their major components §1020.Cold-cathode gas discharge tubes §1020.Regulatory Challenges for Radiation Emitting Devices TITLE 21 -.32 --.10 --.Cabinet x-ray systems 140 .40 --.Fluoroscopic equipment §1020.20 --.33 --.Television receivers §1020.31 --.Computed tomography (CT) equipment §1020.Subchapter J — Radiological Health PART 1020 -. such as laser levels 141 . Alarm systems 9. Cell phones 4. All lasers (including low power lasers such as DVD and CD readers/writers/players) and other light emitting devices (Infrared and Ultraviolet) 11. Ultrasonic instrument cleaner 12. Electron microscopes 6. and educational) 5. X-ray machines (including medical. Computer monitors 3. research. Television receivers 2. Microwave ovens (devices that generate microwave power) 10.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. Black light sources 7. Ranging and detection equipment. Welding equipment 8. Ultrasound machines 13. industrial. 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.Classification of Light Emitting Devices 142 Classification of light emitting devices is based on: Type of light emitted Safety to clinician Safety to patient FDA regulated electronic products include any manufactured or assembled products (along with any component. 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 . 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. and the device's intended use Given the variations in LED devices. what the range of the device's wavelengths are. it's important to verify their classification with the FDA 143 .Simple design and minimum potential for harm to user Class II -. but existing methods are available to provide such assurances Class III -.General controls alone are insufficient to assure safety and effectiveness. implement ultraviolet or infrared radiation.US Classification of Light Emitting Devices The three classifications for medical devices at FDA apply to light emitting devices as well: Class I -. monitor vital physiological processes= Iia Special Rule: All devices emitting ionizing radiation and related monitors in medical procedures = IIb 144 . May supply energy for “imaging purpose”.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. Safety and Risk of Devices Identified Risk Recommended Mitigation Ineffective treatment Performance specifications Thermal or optical injury Performance specifications Electrical injury Electrical safety and Electromagnetic compatibility Electromagnetic interference Electrical safety and Electromagnetic compatibility Cross-contamination Infection control procedures Improper use Labeling 145 . initial importers.Requirements for Device Production The following FDA general controls apply to all devices classes (I. foreign establishments. III): 510(k) exempt Establishment registration 146 Requirement for organizations involved in the production and distribution of medical devices marketed in the United States Must provide the FDA with the location of medical-device manufacturing facilities and importers. II. 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 . Includes manufacturers. IDE Requirements for Imaging Devices The following requirements apply to imaging devices used for research only: IRB would be approached for NSR vs. considerations and process described under the following SR slide would be followed 147 . no IDE would be required The device use would be described in the IND application If SR. an IDE would be required The IDE. SR determination If NSR. 30 [6]) and Documentation (21 CFR 820. extensive testing is necessary Internal testing should be performed to ensure device safety Qualified consultants should conduct independent mechanical and electrical safety testing and provide safety approval documentation A prototype identical to the clinical prototype should be used for final animal testing and system validation Any new device intended for use in patient care must also be tested for safety by the clinical engineering department of the hospital prior to its clinical use After these tests are completed. an IRB application can be submitted 148 .IDE Requirements for Imaging Devices (Cont’d) 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. and should be completed as the clinical prototypes are being built Following construction.40 [6]) detailing how the system was built and tested are essential.2(b) Quality System Regulation Design Controls (21 CFR 820. an IDE application must be submitted to the FDA 149 . as well as clinical prototype testing with an equivalent system on animal models After completion of appropriate documentation and testing of the clinical prototype.IDE Requirements for Imaging Devices (Cont’d) Significant Risk Devices (for research only): SR medical devices must be designed to meet all IDE requirements and will be subject to extensive safety and failure mode analysis They must also be engineered to meet relevant subsections of the Association for the Advancement of Medical Instrumentation (AAMI)/International Electrotechnical Commission (IEC) standard #60601[7] Similar to NSR devices. extensive testing is necessary to ensure device safety. including internal and external testing by qualified consultants. IDE Requirements for Imaging Devices (Cont’d) The following requirements apply to imaging devices intended for future commercial licensing & use: Same NSR vs. SR process is followed with the IRB However. must now add documentation and auditing of the Full Quality Management system at the manufacturing location (eg. is required prior to clinical translation Documentation should be written as clinical prototypes are built 150 . as specified in the IDE instructions. ISO-13485) Full Quality System Control documentation (21 CFR 820[6]). Potential Development Process Concerns 151 . I Ph. product development. manufacturing.Development Process Concerns – Team Strategy Pre-Clinical Ph. quality. II Ph. III Resolve all issues associated with the product before proceeding with the next Phase of study Build a tracking grid Pre-clinical. regulatory. 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. legal 152 . process development. CMC. However. translatable. translatable data Discuss pre-clinical plan with Healthcare Authority (U.S.Still advantageous to know “opinion” before you start or what your later research commitments might be to support product licensing . it has “become part of the official record” 153 .Development Process Concerns – PreClinical->Ph. if you disagree with the answer.Saves “false starts” or sometimes difficult work to retrace and “add to” . FDA) prior to initiation Discuss Pre-clinical data with Healthcare Authority (U.I Defines the objectives of studies / testing (as previously described) Animal Species: availability. non- problematic species Consistency of species utilized in previous studies. relevant.S. EMA . FDA) prior to IND initiation Process globally known as “Scientific Advice” with HCA. adverse reactions Phase II: Determining efficacy Phase III: Statistical adverse reactions. I Ph. range of adverse events. III Phase I : Determining safety. II Ph. statistical efficacy data developed Strong monitoring efforts for detailed close-out of each Phase of Study Maintain consistency of drug and device utilized Long-term availability of device raw materials Data must hold up to regulatory scrutiny during “licensing phase” 154 .Development Process Concerns – Phase I-II-III Ph. Parameters and Considerations Define the parameters: How many products? How many trials? Typical trial size (patient ranges): .Phase I: 20-40 Phase II: 50-100 Phase III: 100-300 How many gels? What is the ring (or device) manufacturing process? Development process considerations: 155 Technical & Clinical Feasibility. consultants. staff.knowledge gaps defined and resolution planning established .costs.all components for each product and each design defined Identify manpower . 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 . the more set backs. 2-arm study is “X” 3 Product. the more significant holes of knowledge will develop Costs. 156 . labor demands.Risk Relationship with Study Design Non-linear relationship between study design and time. cost risk Number of Products Number of Arms Single product. the more it costs and the longer it takes However. the more risk. the more management burden. the trial must be appropriately robust in order to evaluate the endpoints Development Process Conclusions: Timing differences between trials are not linear vs. 6-arm study is a multiple of “X” The more people. effort. timing. etc. technical feasibility. the number of products in trial The more complex. with FDA It is a MA holder's responsibility to keep their product information up-to-date.Development Process Concerns – Post-Marketing 157 Determine product’s long-term effectiveness on patient Determine patient “Quality-of-Life” Compare current “studied products” to traditional therapies Cost effectiveness of New Licensed Therapy Continuing to study range and statistics of adverse reactions (helps to build PSUR [Periodic Safety Update Report] on Drug Component) PSUR= every 6 months during first 2 years. 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 .S. no renewals currently in U. then annually Data assists in Product & License Renewal in those countries possessing that process (typically every 5 years). Emerging Global Requirements for Devices with Microbicides 158 Global Challenges Regulatory pathways for combinations products need clarification in many developing countries Parallel approval pathways are needed to speed up approval process Regulatory expectations are that combination products with multiple active ingredients need to be superior to individual components Negative impact to cost and timeline to prove superiority Informed consent can be challenging due to language barriers and literacy rates Ethics review committee recommended to help guide patients The following are some recommendations for improving the regulatory process relating to microbicides and devices: Strengthen partnerships in worldwide organizations Better information sharing between organizations and countries of interest Promote quality & ICH standards Establish centers of excellence within impacted regions 159 Product Development Partnerships Product Development Partnerships work with pharmaceutical companies, research centers and other 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 160 WHO Considerations WHO has partnered with many organizations regarding HIV/AIDS prevention Develops and drives global strategy on HIV prevention WHO is helping to get these combination products to areas of need by: Partnering with organizations such as EMEA on Article 58 Helping to facilitate development and testing with other organizations Ensuring trials are conducted with high ethical standards Microbicide trials involving WHO in the last 2 years suggest: Microbicide gel alone did not change HIV infection rate Demand for devices with microbicides would be high Pre-qualification status for drugs for HIV prevention WHO can grant pre-qualification status for HIV/AIDS prevention products if need is prevalent Status is not available for microbicides due to the number of API’s involved and complexity of the drug/device interactions 161 . Zimbabwe Since risk of HIV is lower in US/EU. 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. Algeria. some countries will approve based on prior US or EU approval In some instances.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. Nigeria. regulatory decisions will carry less significance in developing countries However. conditional marketing authorizations are approved with incomplete clinical data in market need is high Some African regulatory authorities may not recognize outside opinions 162 Regulatory capacity of these countries is limited but improving Authority where product is licensed may not be as stringent . 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. local populations included in studies. how product is being brought to the country. where drug product is licensed.Considerations in Latin America Regulatory capabilities have vastly improved over the past decade Brazil. 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 163 . 30% is negotiated (Examples: where API originates. willing CT participants. South Korea. 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. India. Phillipines & Malaysia No standardization amongst countries – each country has their own RA Regulatory approval is the most complex due to differing requirements. 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. regulatory approval process & timing Combination products are handled similar to US & EU Determination made of whether it’s a drug or device 164 .Considerations in Asia Pacific Most popular growth area for new drug marketing Large populations. Conclusions & Wrap-up 165 . IIa. Microbicide gel alone = Drug review 166 .Conclusions & Wrap-up Clinical trials must be linked with the intended “Route to Commercialization” and the “Regulatory Approval Pathway” Intended regions / countries of “use” should be identified NSR vs.. In U.S. IIb depending on region. 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.mainly Class II. clinical studies. product qualification & registration Pick your suppliers / partners carefully……they will be a Big Part of the Programss success 167 Thank you for your time and attentiveness! Best of Luck! . Regulatory and Change Control / Auditing on your team for the changes that will undoubtedly occur throughout product development.Conclusions & Wrap-up Use as much published data on “Similar Products” as possible to gain an “equivalency status” When in doubt….dialogue with FDA / EMA Don’t underestimate the data needed…. For the device component review. remember this will be a Class III review if combined Long term material availability (polymers) with vendors a MUST to avoid re-testing Suggest you have team representation with experience in Material / Device Development (including formulation)... Web References U.gov European Commission – http://ec.int 168 .who.europa.eu World Health Organization – http://www.S.fda.europa. Food & Drug Administration – www.emea.eu European Medicines Agency - http://www. Inc. Inc. for Advance BioScience Laboratories. 169 . Inc. distribute. All copyrights are reserved to Advance BioScience Laboratories. scan and post or use any developed materials without the permission of Advance BioScience Laboratories. (ABL) or The Division of Acquired Immunodeficiency Syndrome (DAIDS). (ABL) and The Division of Acquired Immunodeficiency Syndrome (DAIDS). Inc.Material Copyright This presentation was developed by RJR Consulting. It is unlawful to reproduce. (ABL) and The Division of Acquired Immunodeficiency Syndrome (DAIDS) a division of the National Institute of Allergy and Infectious Diseases (NIAID). Questions? 170 .