1 FDA CLINICAL TRIAL REQUIREMENTS FOR MEDICAL DEVICES NEIL F. OFLAHERTY PRINCIPAL OLSSON FRANK WEEDA TERMAN BODE MATZ PC MEDICAL DEVICE CLINICAL RESEARCH

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FDA CLINICAL TRIAL REQUIREMENTS FOR MEDICAL DEVICES

NEIL F. O’FLAHERTYPRINCIPAL

OLSSON FRANK WEEDA TERMAN BODE MATZ PC

MEDICAL DEVICE CLINICAL RESEARCH AND REIMBURSEMENT CONFERENCE

Q1 PRODUCTIONSJANUARY 11-12, 2010PHOENIX, ARIZONA

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FDA LEGAL FRAMEWORK FOR DEVICE TRIALS

• The purpose of an Investigational Device Exemption (IDE) is to encourage the discovery and development of medical devices and to maintain optimum freedom for investigators to do so, while at the same time putting controls in place to assure the adequate safety and effectiveness of the investigational device and the protection of the human study subjects.

• An approved IDE allows an investigational device that otherwise would have to comply with requirements for commercial distribution to be lawfully shipped for use in a clinical trial in order to collect safety and effectiveness data.– 21 U.S.C. § 360j(g) (statute)– 21 C.F.R. Parts 50, 54, 56 and 812 (implementing regulations)– Guidance documents

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FDA LEGAL FRAMEWORK FOR DEVICE TRIALS

• Clinical studies are almost always conducted to support a premarket approval application (PMA). Some premarket notification (510(k)) submissions also require clinical study data.

• All clinical studies of investigational devices, unless exempt, must have an approved IDE before the study is initiated.

• Clinical studies can also include clinical evaluation of certain design modifications to, or new intended uses for, legally marketed devices.

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MAJOR PLAYERS IN CLINICAL RESEARCH

• Sponsor -- A person who initiates, but does not actually conduct, the investigation.

• Investigator -- An individual who actually conducts the clinical investigation.

• Institutional Review Board (IRB) -- Any board, committee or other group formally designated by an institution to initially review, approve and periodically review clinical research involving human subjects which is established and operated in conformance with 21 C.F.R. Part 56.

• Subject -- A human participating in an investigation on whom or on whose specimen an investigational device is used or who is used as a control.

• Monitor – An individual designated by the sponsor to oversee the progress of an investigation.

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Significant Versus Nonsignificant Risk Device Studies

• A Significant (SR) Risk Device is an investigational device that:

– Is intended as an implant and presents potential for serious risk to the health, safety or welfare of subjects.

– Is intended to be used to support or sustain human life and presents a potential for serious risk to the health, safety or welfare of subjects.

– Is for a use of substantial importance in diagnosing, curing, mitigating or treating disease or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety or welfare of subjects.

– Otherwise presents a potential for serious risk to the health, safety or welfare of subjects.

• A Nonsignificant (NSR) Risk Device is generally a device that does not meet the criteria listed above.

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RESPONSIBILITIES OF THE SPONSOR

• A sponsor of an SR device study needs FDA approval of an IDE application before starting the study.

• Sponsors of NSR device studies are deemed to have an approved IDE (without FDA approval) if they comply with the abbreviated IDE requirements set forth in § 812.2(b).

• The NSR device study sponsor must:– Label the device in accordance with 21 C.F.R. § 812.5, including

the statement “CAUTION – Investigational device. Limited by Federal (or United States) law to investigational use”;

– Obtain and maintain IRB approval of the investigation per 21 C.F.R. Part 56;

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– Ensure that the participating investigator(s) in the study obtains informed consent under 21 C.F.R. Part 50 from each study subject and documents the consent;

– Comply with the requirements of § 812.46 with respect to monitoring investigations;

– Maintain certain records and submit certain reports to FDA, the IRB or investigators under §§ 812.140 and 812.150 respectively; and

– Comply with the prohibitions in § 812.7 against promotion and commercialization of, and certain other practices relative to, investigational devices.

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• IRB approval (§ 812.42)– A sponsor cannot begin an investigation or

any part of the investigation until the IRB approves the study.

• Selecting Investigators (§ 812.43(a))– A sponsor must select investigators qualified

by training and experience to investigate the device and provide them with the information that they need to conduct the investigation properly.

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• Selecting Monitors (§ 812.43(d))– A sponsor must select monitors qualified by

training and experience to monitor the investigational study in accordance with the IDE and applicable FDA regulations.

• Device Control (§ 812.43(b))– A sponsor can ship investigational devices

only to qualified investigators participating in the investigation.

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• Investigator Agreements (§ 812.43(c))– A sponsor must obtain a signed agreement

from each participating investigator that includes certain regulatory commitments.

• Informing investigators (§ 812.45)– A sponsor must supply all participating

investigators with copies of the investigational plan and a report of prior investigations of the device.

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• Monitoring (§ 812.46)– A sponsor who discovers that an investigator is not

complying with the signed agreement, the investigational plan, the IDE or other applicable FDA regulations, or any conditions of approval imposed by the reviewing IRB or FDA, must promptly either a) secure compliance, or b) discontinue shipments of the device to the investigator and terminate the investigator’s participation in the investigation.

– A sponsor must also require that the noncompliant investigator dispose of or return the device, unless this action would jeopardize the rights, safety, or welfare of a subject.

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– The sponsor must immediately conduct an evaluation of any unanticipated adverse device effect experienced during the study. A sponsor who determines that an unanticipated adverse device effect presents an unreasonable risk to subjects must terminate the investigation, or parts of the investigation presenting that risk, as soon as possible.

• Resumption of Terminated Studies (§ 812.46(c))– For an SR device study, a sponsor may not resume the

terminated investigation without IRB and FDA approval. For an NSR device study, a sponsor may not resume the terminated investigation without IRB approval. If the NSR device study was terminated for an unanticipated adverse device effect, the sponsor must also obtain FDA approval before resumption.

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• Sponsor Records (§ 812.140)– The sponsor must maintain accurate and complete records

relating to the investigation as detailed in the regulation.• Sponsor Reports (§ 812.150)

– The sponsor must provide certain reports in a timely manner to FDA, the IRB and/or the investigators as detailed in the regulation.

• Labeling (§ 812.5)– An investigational device or its immediate package must bear a

label with the following information:• The name and place of business of the manufacturer, packer, or

distributor of the investigational device;• The statement, “CAUTION – Investigational device. Limited by

Federal (or United States) law to investigational use;”• The quantity of contents, if appropriate; and

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• All relevant contraindications, hazards, adverse effects, interfering substances or devices, warnings, and precautions.

– The labeling also must not contain any false or misleading statements nor imply that the device is safe or effective for the purposes being investigated.

• Promotion of Investigational Devices (§ 812.7)– A sponsor, investigator, or any person acting for or on

behalf of a sponsor or investigator cannot:• Promote or test market an investigational device, until after

FDA has cleared or approved the device for commercial distribution;

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• Commercialize an investigational device by charging the subjects or investigators a higher price than that necessary to recover costs of manufacture, research, development, and handling;

• Unduly prolong an investigation; or• Represent that the device is safe or effective for the investigational

purpose.– However, the sponsor may advertise for research subjects and

investigators to solicit their participation in a study. FDA has issued guidance on how this is to be appropriately done, without promoting the investigational device.

– The guidance states that advertisements for research subjects should be reviewed and approved by the IRB to assure that they are not unduly coercive and do not promise a certainty of result. Moreover, the guidance states that no claims should be made, either explicitly or implicitly, that the device is safe or effective for the purposes under investigation, or that the test article is known to be equivalent or superior to any other device.

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RESPONSIBILITIES OFINVESTIGATORS

• The investigator must protect the rights, safety, and welfare of subjects.

• An investigator must conduct the investigation in accordance with the signed agreement with the sponsor, the investigational plan, the IDE and other applicable FDA regulations, and any conditions of approval imposed by the reviewing IRB and FDA (§ 812.100).

• An investigator may determine whether or not potential subjects would be interested in participating in an investigation, but cannot request written informed consent or allow any subjects to participate before obtaining IRB approval (and FDA approval in the case of an SR device) (§ 812.110).

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• An investigator is responsible for obtaining informed consent from each study subject under 21 C.F.R. Part 50 (§ 812.100).

• In general, an investigator can permit use of the investigational device only with subjects under his/her supervision and cannot supply an investigational device to any person not authorized to receive it (§ 812.110(c)).

• Upon completion or termination of a clinical investigation, or the investigator’s part of the investigation, or at the sponsor’s request, an investigator must return to the sponsor any remaining supply of the device or dispose of the device as the sponsor directs (§ 812.110(e)).

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• The investigator must disclose to the sponsor sufficient accurate financial information to allow the sponsor to submit certification or disclosure of financial interests under 21 C.F.R. Part 54 (§ 812.110(d)).

• The investigator must maintain certain accurate and complete records relating to the investigation as detailed in the regulation

(§ 812.140).• The investigator must provide certain reports in

a timely manner to the sponsor and/or the IRB as detailed in the regulation (§812.150).

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RESPONSIBILITIES OF IRBs

• In accordance with FDA regulations, an IRB has the authority to approve, require modifications in (to secure approval), or disapprove research.

• The purpose of IRB review is to assure, both in advance and by periodic review, that appropriate steps are taken to protect the rights, safety and welfare of humans participating as subjects in research.

• To accomplish this purpose, IRBs use a group process to review research protocols and related materials (e.g., informed consent documents).

• The IRB must monitor and review an investigation throughout the clinical study.

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• If an IRB determines that an investigation involves an SR device that the sponsor thought was an NSR device, it must notify the investigator and, if appropriate, the sponsor. If this occurs, the sponsor may not begin the investigation until an IDE application is approved by FDA.

• An IRB must comply with all applicable requirements of the IRB regulation (Part 56) and applicable portions of the IDE regulation (Part 812) in reviewing and approving device investigations involving human testing.

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Criteria for IRB Approval of Research (21 C.F.R. § 56.111)• Risks to subjects are minimized.• Risks to subjects are reasonable in relation to the anticipated

benefits to subjects and the importance of the knowledge that may be expected as a result.

• Selection of subjects is equitable.• Informed consent is obtained and documented for each subject.• The research plan makes adequate provision for data monitoring, if

required.• There are adequate provisions to protect the privacy of subjects and

confidentiality of data.• No coercion or undue influence is used to include subjects in the

study.

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INVESTIGATOR AGREEMENTS

• Investigator agreement requirements – 21 C.F.R. § 812.43(c).

• Sponsors should carefully prepare and institutions, IRBs and participating investigators should carefully review investigator agreements:– To avoid FDA compliance actions.– To avoid later disputes over terms and obligations.

• Make sure participating investigators fully understand what they are agreeing to do under the agreement.

• Review of agreement by legal counsel.

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INFORMED CONSENT

• Informed consent form requirements – 21 C.F.R. § 50.25.

• Sponsors and investigators should carefully prepare and institutions, with their IRBs, should closely scrutinize informed consent forms:– To avoid FDA compliance actions.– To avoid liability problems.

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INFORMED CONSENT

• Investigators, institutions, and their IRBs should closely scrutinize model forms if provided by the sponsor for compliance with regulatory requirements; no one should just accept them.

• All relevant parties should closely evaluate modifications to model informed consent forms to assure continuing compliance.

• Review of form by legal counsel.

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OTHER KEY CONSIDERATIONS

• Make sure the clinical investigation protocol and plan will generate the data needed to support PMA approval or 510(k) clearance.

• Use the pre-IDE meeting process or more informal mechanisms (e.g., telephone calls to ODE) to pin down as best you can what the PMA or 510(k) data requirements will be and whether the protocol will generate that data.

• Determine whether your study involves an SR or NSR device – it affects whether you are subject to full or abbreviated IDE requirements.

• Make sure all relevant parties (sponsor, investigator, IRB, monitor, etc.) understand and carry out their responsibilities.

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HOT TOPICS AND ENFORCEMENT

• Mandatory registration and results reporting of certain device clinical trials.– Applies to controlled product trials with health outcomes which

are subject to FDA regulation as well as pediatric postmarket surveillance studies.

– Excludes small feasibility studies.– Trial sponsor or designated principal investigator must register at

ClinicalTrials.gov.– Required by U.S. Public Law 110-85 (Food and Drug

Administration Amendments Act of 2007, Title VIII, Section 801).

• Proposed rule to require statement in informed consent regarding the requirement (74 Fed. Reg. 68750 (Dec. 29, 2009)).

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• August 2009 – FDA announces enhancement of speed and transparency of actions against misconduct in the development of drugs and devices.

• September 2009 – GAO report critical of FDA oversight of clinical investigators and recommends action to improve timeliness and enhance scope of FDA’s debarment and disqualification processes for medical product investigators, including device investigators.– FDA agreed with GAO’s recommendations.

• October 2009 – H.R. 3932, “Strengthening of FDA Integrity Act of 2009.”– Would give FDA greater power to remove problem researchers.– Not close to passing but demonstrates Congressional interest in

FDA’s handling of investigator misconduct.

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• Bioresearch monitoring compliance continues to be an area of high enforcement activity for FDA, including CDRH.

• Many Warning Letters issue to sponsors, investigators and IRBs each year for clinical trial regulatory noncompliances.

• 2008/2009 Warning Letter Issues for Device Trial Sponsors– Failure to secure investigator compliance with the signed

investigator agreement, the investigational plan, applicable FDA regulations and/or any other conditions of approval imposed by the reviewing IRB or FDA.

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• 2008/2009 Warning Letter Issues for Device Trial Sponsors (cont’d)– Failure to ensure adequate monitoring of the

investigation and to include written procedures for monitoring of the investigational plan.

– Failure to accurately document device shipments in records.

– Failure to prepare and submit progress reports at regular intervals and at least yearly to FDA and the reviewing IRB.

– Failure to obtain adequate signed investigator agreements for each investigator participating in a study.

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• 2008/2009 Warning Letter Issues for Device Trial IRBs– Failure to conduct initial and continuing review of

research at least annually and failure to follow written procedures for the same.

– Failure to ensure that the IRB reviews proposed research at convened meetings at which a majority of the members are present.

– Failure to prepare and maintain adequate documentation of IRB activities, including minutes of IRB meetings.

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• 2008/2009 Warning Letter Issues for Device Trial IRBs (Cont’d)– Failure to have adequate written procedures

governing the functions and operations of the IRB.– Failure to assure that information given to subjects as

part of informed consent is compliant.– Failure to follow written procedures for ensuring

prompt reporting to FDA of any unanticipated problems involving risk to human subjects or others.

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• 2008/2009 Warning Letter Issues for Device Trial Investigators.– Failure to adhere to informed consent requirements,

including obtaining IRB approval prior to requesting written informed consent of a subject.

– Failure to conduct an investigation according to the signed agreement, the investigational plan and applicable FDA regulations.

– Failure to obtain approval prior to implementing a change to the investigational plan.

– Failure to maintain accurate, complete and current records related to the investigation.

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• 2008/2009 Warning Letter Issues for Device Trial Investigators (cont’d)– Failure to ensure proper oversight of the

investigation.– Failure to submit progress reports on the

investigation to the sponsor and reviewing IRB at regular intervals but at least yearly.

– Failure to maintain accurate, complete and current records of receipt, use or disposition of the investigational device.

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• Disqualification of device investigators.– FDA has the authority to “disqualify,” or remove, researchers

from conducting clinical testing of new drugs and devices, when the agency determines that the researcher has repeatedly or deliberately not followed the rules intended to protect study subjects and ensure data integrity.

– Further, FDA can disqualify a clinical investigator who has repeatedly or deliberately submitted false information to the agency or the sponsor in a required report.

– Since the early 1960’s, FDA has disqualified approximately 190 investigators.

– From 2006 to present, FDA has initiated approximately 21 disqualification proceedings.

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FDA ENFORCEMENT

• Form FDA-483/Warning Letter.• Notice of Initiation of Disqualification Proceedings

and Opportunity to Explain (NIDPOE) Letter – Initiation of a proceeding to determine whether an investigator should be disqualified from receiving investigational products.

• Notice of Opportunity for Hearing – If an investigator’s written or oral response to a NIDPOE letter is deemed unsatisfactory, a consent agreement cannot be reached or the investigator fails to respond to the NIDPOE letter, the investigator is given the opportunity for a hearing on the disqualification action held before an FDA presiding officer.

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CLINICAL INVESTIGATOR LISTS

• All clinical investigators who have received a Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE).

• All clinical investigators who have received a Notice of Opportunity for Hearing (NOOH).

• All clinical investigators who have been disqualified or “totally restricted.”

• All clinical investigators who have received a Presiding Officer Report and/or a Commissioner’s Decision.

• All clinical investigators who have agreed to certain restrictions with respect to their conduct of clinical investigations.

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CLINICAL INVESTIGATOR LISTS

• All clinical investigators who agreed to certain restrictions, which have now been removed.

• All clinical investigators who, under regulations in effect until 1987, have provided FDA with adequate assurances of their future compliance with requirements.

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QUESTIONS?

Documents

1 FDA CLINICAL TRIAL REQUIREMENTS FOR MEDICAL DEVICES NEIL F. OFLAHERTY PRINCIPAL OLSSON FRANK WEEDA TERMAN BODE MATZ PC MEDICAL DEVICE CLINICAL RESEARCH