FDA Requirements for Clinical Investigations of Medical Devices: A Review for European Manufacturers

FDA Requirements for Clinical Investigations of Medical Devices: A Review for European Manufacturers Autumn Dawn Ediger, 1, * Birgit Limbach 2 and Dieter Dannhorn 3 1 Regulatory Affairs, Clinical QM and Marketing, mdt medical device testing GmbH, 88416 Ochsenhausen, Germany 2 QA and Monitoring, mdt medical device testing GmbH, 88416 Ochsenhausen, Germany 3 Scientific Director, mdt medical device testing GmbH, 88416 Ochsenhausen, Germany Summary The purpose of this article is to provide European manufacturers with a review of the USA s requirements for clinical investigations of medical devices. It is an introductory guide to what European manufacturers need to plan for and what is expected from them when conducting a clinical investigation in the USA. The Food and Drug Administration s (FDA) Investigational Device Exemption (IDE) process is outlined and specific FDA and other web pages are listed to enable the reader to obtain official documentation that provides more detailed information on the IDE process. Copyright 2003 John Wiley & Sons, Ltd. Key Words IDE; clinical investigation; clinical trial; FDA; medical devices Introduction The term clinical investigation (or clinical trial) applies to any systematic study of human subjects undertaken to verify the safety, efficacy and performance of a specific medical *Correspondence to: Autumn Dawn Ediger, Regulatory Affairs, Clinical QM and Marketing, mdt medical device testing GmbH, 88416 Ochsenhausen, Germany E-mail: autumn.ediger@mdt-gmbh.com device under normal conditions of use. The clinical investigation is a means of verifying the anticipated behavior of the device in situations where there are no other means by which to demonstrate device behavior (i.e. safety, efficacy and performance) through the use of available data. The need for a clinical investigation should be one of the fundamental questions answered at the beginning of the design and development process of a device. A clinical evaluation (i.e. review of available clinical data) should always be undertaken as part of the design process of the product to assist in determining whether or not an investigation is necessary. When it is determined that a clinical investigation must be undertaken, country-by-country laws and regulations for clinical investigations of medical devices must be considered. Since the largest medical device market in the world is in the USA, more European manufacturers are seeking the Food and Drug Administration (FDA s) approval to sell their medical devices in the USA. Therefore, this article reviews the FDA s requirements for clinical investigations of medical devices. Investigational Device Exemption The FDA requirements concerning clinical investigations are governed by the Investigational Device Exemption (IDE) rules of the Food, Drug and Cosmetic Act. In practice, the IDE provides permission to undertake a clinical investigation in the USA. Because a foreign device manufacturer cannot sponsor an IDE, the manufacturer DOI: 10.1002/qaj.210

FDA Requirements for Clinical Investigations 33 must first select and identify a sponsor in the USA. The USA sponsor can be the foreign manufacturer s subsidiary in the USA or a US agent for devices. Therefore, an IDE application may only be submitted by the foreign manufacturer s USA subsidiary or US agent. The FDA must give formal written approval of the IDE application before the IDE clinical investigation in the USA site(s) and, when applicable, European (foreign) site(s) may begin. Note that only one US agent may be hired to take on all the responsibilities of that of a sponsor identified in the FDA s IDE regulation. The FDA has developed the following web page to assist foreign device manufacturers to find a US agent: http://www.fda.gov/cdrh/ usagent/. The ultimate goal of the IDE application is to obtain permission to conduct the IDE clinical investigation. The goal of the IDE clinical investigation is to obtain valid scientific evidence that the risks to humans are outweighed by anticipated benefits and that the device will be effective as used. The clinical data gathered in an IDE clinical investigation are essential to obtaining the overall USA pre-market approval (PMA) or premarket notification (510(k)). For a complete overview of the IDE process, the following FDA documents are located on the web at: Investigational Device Exemptions Manual (http://www.fda.gov/cdrh//manual/idemanul.html) and Guidance on IDE Policies and Procedures (http://www.fda.gov/cdrh/ode/idepolcy.html). CFR 812.35(a)); Treatment Use (21 CFR 812.36 and 62 FR 48490); or Continued Access (Blue book Memo #D96-1 Continued Access to Investigational Devices During PMA Preparation and Review ). An Emergency Use circumstance would be a life-threatening condition that needs immediate treatment where no alternative treatment exists and there is no time to get FDA approval. Compassionate Use may be chosen when a serious but not life-threatening condition exists where no alternative device is available. FDA approval is required prior to Compassionate Use of the investigational device. Treatment Use may be granted if a serious or life-threatening disease/condition is presented where no alternative device exists. Continued Access allows for the continued enrollment of subjects in an FDA approved clinical investigation while an FDA marketing application is being prepared/reviewed. An IDE supplement must be submitted and approved by the FDA before Treatment Use or Continued Access may commence. These Other Types of IDEs may be utilized during a certain time-frame in a pre-existing IDE process (e.g. during the IDE application or IDE clinical investigation) if the criteria for the particular Other Type of IDE are met. FDA approval of the Other Type of IDE is required except in the case of emergency use. Detailed information on the Other Types of IDEs is located on the web at: http://www.fda.gov/cdrh/ devadvice/ide/early.shtml. Other Types of IDEs There are circumstances when an unapproved medical device may be used to save the life of a patient or to help a patient suffering from a serious disease or condition for which no other alternative therapy exists. Patients/physicians faced with these circumstances may have access to investigational devices under one of four Other Types of IDEs by which the FDA may make an unapproved device available: Emergency Use (21 CFR 812.35(a) and 50 FR 42866); Compassionate Use (or Single Patient/Small Group Access) (21 Foreign Clinical Investigations The FDA does permit the use of foreign clinical investigation data to support an application for marketing approval of a human device. It is the responsibility of the foreign manufacturer to ensure that the foreign clinical data submitted to the FDA are: (1) applicable to the US population and US medical practice, (2) that the clinical investigation design meets FDA s scientific standard (e.g. requirements for statistical analysis), (3) that the clinical investigators have recognized

34 A. D. Ediger et al. competence and (4) that the FDA can validate the data by performing on-site inspections or other appropriate inspection activities. Therefore, it is strongly recommended that any proposal for using foreign clinical investigation data is thoroughly discussed with the US Office of Device Evaluation (see below) when planning a foreign clinical investigation. This is the best way to confirm that the foreign clinical data will be accepted in the application for the US marketing approval. FDA s Guidance for Industry: Acceptance of Foreign Clinical Studies (March 2001) states that one of the following conditions must be met for foreign data to be reviewed by the FDA: the foreign investigation is performed under an IDE (see IDE Regulations below); or the foreign investigation not performed under an IDE must conform to the ethical principles contained in the 1983 version of the Declaration of Helsinki or with the laws and regulations of the country in which the research was conducted, whichever provides greater protection of the human subjects. The complete Guidance for Industry: Acceptance of Foreign Clinical Studies is located on the web at: http://www.fda.gov/cder/guidance/fstud.htm. The 1983 version of the Declaration of Helsinki has been updated several times. The FDA provides the 1989 version of the Declaration of Helsinki on the web at: http://www.fda.gov/oc/ health/helsinki89.html. The 1983 and 1989 versions differ in only one important respect. Both versions state that the design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol, which should be transmitted for consideration, comment, and guidance to a specially appointed committee. However, the 1989 version continues that the specially appointed committee should be independent of the investigator and the sponsor provided that this independent committee is in conformity with the laws and regulations of the country in which the research experiment is performed. Each time the Declaration of Helsinki has been revised, the FDA reviews its foreign clinical studies regulations. To this date, the FDA has not amended its regulations to incorporate the 2000 amendments to the Declaration of Helsinki. However, the harmonized European Standard (EN) 540:1993 Clinical investigations of medical devices for human subjects requires that the latest amendment of the Declaration of Helsinki be applied to European clinical investigations. The most current World Medical Association Declaration of Helsinki, October 2000, is found on the web at: http://www.wma.net/e/policy/17-c_e.html. Office of Device Evaluation The FDA is a highly organized bureaucracy. A Commissioner and the Office of the Commissioner control the agency. Other organizational elements include the Office of Policy, Office of External Affairs, Office of Management and Systems, and Office of Operations. Most device manufacturers affected by FDA interact with either the Office of External Affairs or the Office of Operations. The Office of Operations operates nine offices that deal with regulatory oversight of biologics, drugs, devices, food, animal health, toxicological research, orphan products development, regulatory affairs, and science. Under the Office of Operations, the organization charged with most medical device oversight is the Center for Devices and Radiological Health (CDRH). CDRH s website (http://www.fda. gov/cdrh) provides an overview of its responsibilities and the various offices that constitute the CDRH. A limited number of devices fall under the oversight of the Center for Biologics Evaluation and Research (CBER), which is also under the Office of Operations. The Office of Device Evaluation (ODE), one of the offices under CDRH, advises CDRH s Director and other agency officials on all premarket notification 510(k) submissions, PMA applications, product development protocols (PDPs), device classifications, and IDEs. The ODE plans, conducts, and coordinates CDRH s actions regarding approval, denial, and withdrawal of approval of PMAs, PDPs, and IDEs; makes substantially equivalent determinations for 510(k)s; and monitors sponsors conformance with requirements of all programs. It conducts ongoing review, surveillance, and medical

FDA Requirements for Clinical Investigations 35 evaluation of the labeling, clinical experience, and required reports by sponsors for approval applications. The ODE also develops and interprets regulations and guidelines regarding device classification, PDPs, IDEs, PMAs, and 510(k)s. ODE s website (http://www.fda.gov/cdrh/ode) provides further device evaluation information. IDE Regulations The IDE regulations define the US principles of Good Clinical Practice (GCP) including the ethical requirements for protecting human research subjects (i.e. National Research Council s Belmont Report). The Belmont Report is a non-regulatory guideline that defines the primary ethical framework for protecting human research subjects participating in clinical investigations in the US. Because the US is not a signatory to the Declaration of Helsinki, the National Research Act of 1974 created a National Committee for the Protection of Human Rights. This committee produced the Belmont Report, which in effect reiterates the basic principles found in bio-ethic documents worldwide and in the Declaration of Helsinki. The Belmont Report is found on the web at: http://www.fda.gov/ oc/ohrt/irbs/belmont.html. The International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use is a standard of international quality management guidelines for designing and conducting clinical investigations for medicinal products that involve participation of human subjects. Compliance with ICH GCP requirements provides public assurance that the rights, safety and well-being of the trial subjects are protected, consistent with the principles of the Declaration of Helsinki, and that data are correct, properly recorded and credible. The ICH GCP guideline influences the way clinical investigations are conducted regardless of product (pharmaceutical, device, biological) or objective. GCP for devices in Europe is found in the harmonized European Standard (EN) 540:1993 Clinical investigations of medical devices for human subjects and its international counterpart, the International Organization for Standardization (ISO) 14155:1996 Clinical investigations of medical devices. In the near future, EN540 and ISO 14155 will be combined to become the EN ISO 14155 Clinical investigations of medical devices for human subjects Part 1: General requirements and Part 2: Clinical investigation plans. GCP requirements for the US are described in FDA regulations and requirements that apply to the manufacturers, sponsors, clinical investigators, institutional review boards, and investigational devices. The primary regulations that govern the conduct of clinical studies are included in the Code of Federal Regulations (CFR), Title 21 (21 CFR). Applicable IDE regulations include Part 812 (IDE), Part 820 Subpart C (Design Control), Part 50 (Protection of Human Subjects), Part 56 (Investigation Review Boards), Part 54 (Financial Disclosure by Clinical Investigators), and Part 11 (Electronic records and signatures). All IDE regulations are found on the web at http://www.fda.gov/cdrh/devadvice/ ide/index.shtml. More restrictive than European regulations, the IDE regulations state: requirements for the investigation of nonsignificant risk (NSR) and significant risk (SR) devices, methodology on how to format the application (exact layout, content, format), responsibilities of the parties (monitor, sponsor and investigator), requirements for the protection of human subjects and institutional review boards (IRB). Significance of Risk At the basis of the IDE process is the issue of significance of risk. A SR device is either an implantable device, a life-sustaining device, or a device used in diagnosis, treatment or prevention of disease and/or impairment. Devices that do not fall into any of these categories are considered to

36 A. D. Ediger et al. be NSR. More information on determining if a device is SR or NSR is located on the web at: http://www.fda.gov/oc/ohrt/irbs/devices.html#risk. For both NSR and SR devices, an IRB approval is mandatory because the IRB will make the initial risk determination of NSR or SR. If the IRB determines that an NSR device is indeed an SR device, an IDE application to the FDA must be made and written approval from the FDA must be obtained prior to starting the IDE clinical investigation. An NSR IDE investigation can be started when the IRB approval has been issued and an IDE application is not necessary. Table 1 compares the IDE requirements for SR and NSR devices. The only difference between an SR and an NSR IDE is that the SR IDE must have FDA approval. The FDA Information Sheets (1 October, 1995): Significant Risk and Non- Significant Risk Medical Device Studies (http://www.fda.gov/cdrh/d861.html) provide further FDA guidance. Pre-IDE Meetings/Submissions Professional preparation of the application and subsequent submission of an SR IDE request is essential to receiving a prompt approval from the FDA. Device manufacturers (sponsors) are strongly advised to begin a dialogue with the ODE reviewing division during the early planning stages of the device development and clinical investigation planning. This dialogue may consist of informal or formal meetings that may take the form of telephone conference calls, video conferences, or face-to-face discussions. All meetings will be recorded by the ODE reviewing division. The Final Guidance for Industry and Staff: Early Collaboration Meetings Under the FDA Modernization Act (FDAMA) is located on the web at: http://www.fda.gov/cdrh/ode/guidance/ 310.html. Pre-IDE informal meetings are a chance for sponsors to receive guidance from the ODE at a stage when no ODE determinations or agreements are binding. For example, informal meetings may review existing non-clinical data/foreign clinical data or the current draft of the clinical investigation plan (trial protocol). Informal meetings can also facilitate preparation for any upcoming formal meetings. Formal meetings take place when the device manufacturer writes a request to meet with the FDA. The written request must include a detailed description of the device, detailed description of Table 1. SR versus NSR IDE requirements Requirement NSR SR Device labeled with the name and address of the manufacturer, quantity, contraindications/indications, hazards, adverse effects, interference with other devices or substances and the statement 'Caution: Investigational Device. Limited by US law to investigational use. X X IRB approval X X FDA approval X Informed consent X X Monitoring of investigational sites X X Record maintenance and retention for sponsor and investigator X X Clinical investigation reports for sponsor and investigator X X Auditing of sites X X Prohibition of device advertising (printed and digital e.g. website), test marketing or commercialization X X Prohibition of undue prolongation of the investigation X X Strict adherence to the clinical investigation plan (protocol) X X

FDA Requirements for Clinical Investigations 37 the intended use of the device, and the clinical investigation plan (trial protocol). The FDA will give a determination as to whether there is reasonable assurance of effectiveness, and, if available, information regarding the expected performance of the device. The goal of the formal meeting is that an agreement is reached between FDA and the sponsor regarding the details of the clinical investigation plan (trial protocol). The terms of the agreement are binding and will be documented as part of the FDA s administrative record. Pre-IDE Submissions should be submitted to the ODE reviewing division whenever the sponsor requests informal or formal guidance/meetings from the FDA. In submitting a Pre-IDE Submission, the ODE reviewing division has all the required documentation to facilitate prompt reviewing and appropriate guidance on difficult parts of the IDE application, e.g. clinical investigation design, non-clinical data, foreign trial protocols, foreign data, etc. Please refer to Blue Book Memorandum #99-1, entitled, Pre-IDE Program: Issues and Answers (http://www.fda. gov/cdrh/ode/d99-1.html) for additional guidance. The following points are recommended by the authors to facilitate pre-ide communications with the ODE reviewing division: The sponsor should be able to completely describe the device and how it functions, and explain the intended use and anticipated performance. Appropriate staff members should take part in all FDA communications. The sponsor s determination of whether a device is SR or NSR should be based on risk analysis. Preparation of a list of changes or possible changes to the device or the clinical investigation plan should be made by the sponsor to help the FDA determine if the changes affect form, fit and function of the device which require notification to, and approval from the FDA. Pre-IDE and IDE submissions are to be on US format paper (8.5 11 in) with 3-hole punch, multiple copies (3) and a left margin of 3.5 cm (approx. 1.5 in). Applications exceeding 5 cm in thickness must be split into volumes, each numbered accordingly (e.g. Vol [number] of [total volumes], copy [number]). Scientific and validated endpoints of the clinical design must be formulated. They should be simple and concise. The information and documents to be included in SR IDE applications are: Name and address of the sponsor. Complete reports of any prior non-clinical and clinical investigation. Description of methods, facilities, controls used for production, processing, storage and installation. Labeling. Price charged for the clinical investigation device to recover some R&D costs. (The price cannot be the same as or higher than the anticipated list price for the device.) Justification of why the sale of the device does not constitute commercialization, if a price is being charged for the clinical investigation device. Investigator s Agreement. Investigator s Curriculum Vitae. Investigator s Financial Disclosure. List of all investigators with names and addresses. List of members in the Data Monitoring Committee, if applicable. Evidence that the agreements have been signed either by a statement or a matrix overview showing which agreements have been signed. List of IRB members and their addresses. Complete identification of the clinical investigation sites where the investigation is to be conducted. Informed consent form. Patient information form. Complete and signed investigation plan (trial protocol) or summary. Case report form (CRF).

38 A. D. Ediger et al. The following FDA documents may be of further assistance in preparing an SR IDE application: Device Advice. Responsibilities Reports. Application http://www.fda.gov/cdrh/devadvice/ide/print/application.html Suggested Content for Original IDE Application Cover Letter (02/27/1996) http://www.fda.gov/cdrh/manual/idemanul. html Financial Interest Forms: Disclosure: Financial Interests and Arrangements of Clinical Investigators FDA Form 3455. http://forms.psc.gov/forms/fda/fda3455.pdf Draft Guidance for Clinical Trial Sponsors On the Establishment and Operation of Clinical Trial Data Monitoring Committees (11/16/2001). http://www.fda.gov/cber/gdlns/ clindatmon.htm Conducting an IDE Investigation After an IDE application is approved, the following requirements must be met when conducting the IDE investigation: Labeling: The statement CAUTION Investigational Device. Limited by Federal (or United States) law to investigational use must be on the device label. See IDE regulation 21 CFR812.5 (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/show CFR.cfm?FR=812.5) for further labeling provisions. Foreign clinical sites need to follow the above labeling and also comply with the country-specific labeling regulations. Distribution: Investigational devices can only be given to qualified investigators (21 CFR 812.43(b) http://www.accessdata.fda. gov/scripts/cdrh/cfdocs/cfcfr/showcfr. cfm?fr=812.43. Informed Consent: Each subject must be given and sign an informed consent form before being enrolled in the investigation. See 21 CFR 50 for the requirements for formulating and obtaining informed consent http://www.accessdata.fda.gov/scripts/cdrh/ cfdocs/cfcfr/showcfr.cfm?cfrpart=50. Monitoring: All investigations must be monitored according to 21 CFR 812.46 http://www.accessdata.fda.gov/scripts/cdrh/ cfdocs/cfcfr/showcfr.cfm?fr=812.46. Also see Guidance for Industry: Guideline for the Monitoring of Clinical Investigations from January 1988/1998 http://www.fda. gov/ora/compliance_ref/bimo/clinguid.html Prohibitions: Commercialization, promotion, and misrepresentation of an investigational device and prolongation of the investigation are not allowed under 21 CFR 812.7 http://www.accessdata.fda. gov/scripts/cdrh/cfdocs/cfcfr/showcfr. cfm?fr=812.7. Records and Reports: Sponsors and investigators are required to maintain essential documentation, records and make reports to investigators, ethic committees, and FDA as according to 21 CFR 812.140 http://www.accessdata.fda.gov/scripts/cdrh/ cfdocs/cfcfr/showcfr.cfm?fr=812.140 and 21 CFR 812.150 http://www.accessdata. fda.gov/scripts/cdrh/cfdocs/cfcfr/showcfr. cfm?fr=812.150. Managing IDE Clinical Investigation Changes The IDE clinical investigation is a crucial part of the design and device development process during which the sponsor may want to (or must) make changes to the clinical investigation plan. The changes to the plan might include changes to the investigation device or trial protocol while the IDE clinical investigation is being implemented. The FDA s Changes or Modifications During the Conduct of a Clinical Investigation; Final Guidance for Industry and CDRH Staff, May 2001 (http://www.fda.gov/cdrh/ode/guidance/1337.html) details the submission routes on how to (1) obtain prior FDA approval via an IDE supplement, (2) to notify the FDA upon implementation via a 5-Day Notice or (3) to report periodically via progress or annual reports. The

FDA Requirements for Clinical Investigations 39 sponsor is responsible for managing any IDE investigation changes. The successful management of changes during the IDE investigation will ensure that the clinical data submitted to support the US pre-market notification/ approval application (510(k) or PMA) is promptly accepted by the FDA. Bioresearch Monitoring by the FDA The FDA s Bioresearch Monitoring (BIMO) program conducts on-site inspections and data inspections designed to monitor all aspects of the conduct and reporting of FDA regulated research. Its objectives are to verify the quality and integrity of data and protect the rights and welfare of human research subjects. The program is implemented agency-wide through multi-center compliance programs resulting in over 1000 inspections annually. Within CDRH s Office of Compliance, the Division of Bioresearch Monitoring (DBM) is responsible for (1) inspections of clinical data (GCP) contained in PMAs and some 510(k) submissions, ordinarily prior to approval; (2) inspections of IDE sponsor submissions; (3) inspections of nonclinical (Good Laboratory Practice (GLP)) laboratories that perform medical device-related safety testing; (4) inspections of IRBs that monitor investigational device studies; (5) enforcement of the prohibition against commercialization of investigational devices; (6) providing education, training and guidance to regulated industry and (7) implementation of the FDA s Application Integrity Policy (AIP). CDRH assesses the requirements domestically and internationally. BIMO compliance programs advise the FDA s field inspection and compliance staffs as to the Agency s standards and procedures to be applied when determining industry compliance. Therefore, the compliance program guidance manuals are excellent reference materials for IRBs, laboratories, clinical investigators, clinical research organizations (CROs) and manufacturers of medical devices in preparing for an FDA inspection. The following compliance program guidance manuals are located on the web at http://www.fda.gov/ora/compliance_ref/bimo/defa ult.htm#compliance%20programs Good Laboratory Practice Compliance Program 7348.808 (Non-clinical Laboratories) Date of Issuance: 21 February 2001 Good Laboratory Practice Compliance Program 7348.808A (EPA Data Audit Inspections) Date of Issuance: October 2000 Institutional Review Boards Compliance Program 7348.809. Date of Issuance: 1 October 1994 Sponsors, Contract Research Organizations and Monitors Compliance Program 7348.810. Date of Issuance: 21 February 2001 Clinical Investigators Compliance Program 7348.811. Date of Issuance: 1 October 1999 IDE Final Report Within 6 months after the last follow-up of all enrolled subjects has been completed, the sponsor must submit a final report to the FDA and all IRBs. The ODE Guidance Suggested Format for IDE Final Report (http://www.fda.gov/cdrh/ devadvice/ide/reports.shtml#suggested_format_ ide_final) outlines the information that must be included in the final report. The sponsor has the option to reference a PMA or 510(k) application to fulfill the IDE requirement for submitting a final report. The IDE is officially closed when the final report is complete. Conclusion In order for European device manufacturers to keep the US approval costs to a minimum, it is essential that time and personnel resources (e.g. regulatory personnel) are allotted for planning and executing an IDE application and clinical investigation. Prompt completion of an IDE application and clinical investigation will save device manufacturers time and money because much of the IDE documentation can be

40 A. D. Ediger et al. referenced to in the US market application (i.e. parts of the market approval submission documentation are already completed during the IDE process). In conclusion, it is important to keep in mind the goals of the IDE process. The ultimate goal of the US s IDE process (application and clinical investigation) is to produce valid and scientific data on the performance, efficacy and safety of an investigational device. The ultimate goal of the device manufacturer is to produce FDAapproved IDE clinical data in order to obtain prompt US market approval of their investigational medical device.