FDA Clinical Trial Requirements for Medical Devices

8/2/2019 FDA Clinical Trial Requirements for Medical Devices

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FDA CLINICAL TRIAL REQUIREMENTS FOR MEDICAL DEVICES

NEIL F. OFLAHERTYPRINCIPAL

OLSSON FRANK WEEDA TERMAN BODE MATZ PC

MEDICAL DEVICE CLINICAL RESEARCH ANDREIMBURSEMENT CONFERENCE

Q1 PRODUCTIONSJANUARY 11-12, 2010PHOENIX, ARIZONA


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FDA LEGAL FRAMEWORK FORDEVICE TRIALS

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

An approved IDE allows an investigational device that otherwisewould have to comply with requirements for commercial distributionto be lawfully shipped for use in a clinical trial in order to collectsafety 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 FORDEVICE TRIALS

Clinical studies are almost always conducted to supporta premarket approval application (PMA). Somepremarket notification (510(k)) submissions also requireclinical study data.

All clinical studies of investigational devices, unlessexempt, must have an approved IDE before the study isinitiated.

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


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MAJOR PLAYERS IN CLINICALRESEARCH

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

Investigator -- An individual who actually conducts the clinicalinvestigation.

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 humansubjects which is established and operated in conformance with21 C.F.R. Part 56.

Subject -- A human participating in an investigation on whom or onwhose specimen an investigational device is used or who is used asa control.

Monitor An individual designated by the sponsor to oversee theprogress of an investigation.


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Significant Versus NonsignificantRisk 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 healthand presents a potential for serious risk to the health, safety or welfareof subjects.

Otherwise presents a potential for serious risk to the health, safety orwelfare of subjects.

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


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RESPONSIBILITIES OF THE SPONSOR

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

Sponsors of NSR device studies are deemed to have anapproved 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, includingthe statement CAUTION Investigational device. Limited byFederal (or United States) law to investigational use;

Obtain and maintain IRB approval of the investigation per21 C.F.R. Part 56;


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Ensure that the participating investigator(s) in thestudy obtains informed consent under 21 C.F.R. Part50 from each study subject and documents theconsent;

Comply with the requirements of 812.46 withrespect to monitoring investigations;

Maintain certain records and submit certain reports toFDA, the IRB or investigators under 812.140 and812.150 respectively; and

Comply with the prohibitions in 812.7 againstpromotion and commercialization of, and certain otherpractices 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 qualifiedby training and experience to investigate the

device and provide them with the informationthat they need to conduct the investigationproperly.


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Selecting Monitors ( 812.43(d))

A sponsor must select monitors qualified bytraining and experience to monitor the

investigational study in accordance with theIDE and applicable FDA regulations.

Device Control ( 812.43(b))

A sponsor can ship investigational devicesonly to qualified investigators participating inthe investigation.


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Investigator Agreements ( 812.43(c))

A sponsor must obtain a signed agreementfrom each participating investigator that

includes certain regulatory commitments.

Informing investigators ( 812.45)

A sponsor must supply all participating

investigators with copies of the investigationalplan and a report of prior investigations of thedevice.


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

complying with the signed agreement, theinvestigational plan, the IDE or other applicable FDA

regulations, or any conditions of approval imposed bythe reviewing IRB or FDA, must promptly either a)secure compliance, or b) discontinue shipments of thedevice to the investigator and terminate theinvestigators participation in the investigation.

A sponsor must also require that the noncompliantinvestigator dispose of or return the device, unlessthis action would jeopardize the rights, safety, orwelfare of a subject.


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The sponsor must immediately conduct an evaluation of anyunanticipated adverse device effect experienced during thestudy. A sponsor who determines that an unanticipated adversedevice effect presents an unreasonable risk to subjects mustterminate 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 theterminated investigation without IRB and FDA approval. For anNSR device study, a sponsor may not resume the terminated

investigation without IRB approval. If the NSR device study wasterminated for an unanticipated adverse device effect, thesponsor 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 theregulation.

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 ormisleading 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 onbehalf of a sponsor or investigator cannot:

Promote or test market an investigational device, until afterFDA has cleared or approved the device for commercialdistribution;


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Commercialize an investigational device by charging the subjects orinvestigators a higher price than that necessary to recover costs ofmanufacture, 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 andinvestigators to solicit their participation in a study. FDA hasissued guidance on how this is to be appropriately done, withoutpromoting the investigational device.

The guidance states that advertisements for research subjectsshould 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 forthe purposes under investigation, or that the test article is knownto be equivalent or superior to any other device.


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RESPONSIBILITIES OFINVESTIGATORS

The investigator must protect the rights, safety, andwelfare of subjects.

An investigator must conduct the investigation in

accordance with the signed agreement with the sponsor,the investigational plan, the IDE and other applicableFDA regulations, and any conditions of approvalimposed by the reviewing IRB and FDA ( 812.100).

An investigator may determine whether or not potentialsubjects would be interested in participating in aninvestigation, but cannot request written informedconsent or allow any subjects to participate beforeobtaining IRB approval (and FDA approval in the case ofan SR device) ( 812.110).


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An investigator is responsible for obtaining informedconsent 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/hersupervision and cannot supply an investigational deviceto any person not authorized to receive it ( 812.110(c)).

Upon completion or termination of a clinical investigation,or the investigators part of the investigation, or at the

sponsors request, an investigator must return to thesponsor any remaining supply of the device or dispose ofthe device as the sponsor directs ( 812.110(e)).


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The investigator must disclose to the sponsorsufficient accurate financial information to allowthe sponsor to submit certification or disclosureof financial interests under 21 C.F.R. Part 54

( 812.110(d)). The investigator must maintain certain accurate

and complete records relating to theinvestigation as detailed in the regulation

( 812.140). The investigator must provide certain reports ina timely manner to the sponsor and/or the IRBas detailed in the regulation (812.150).


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RESPONSIBILITIES OF IRBs

In accordance with FDA regulations, an IRB has theauthority to approve, require modifications in (to secureapproval), or disapprove research.

The purpose of IRB review is to assure, both in advanceand by periodic review, that appropriate steps are takento protect the rights, safety and welfare of humansparticipating as subjects in research.

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

The IRB must monitor and review an investigationthroughout the clinical study.


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If an IRB determines that an investigationinvolves an SR device that the sponsor thoughtwas an NSR device, it must notify theinvestigator and, if appropriate, the sponsor. If

this occurs, the sponsor may not begin theinvestigation until an IDE application is approvedby FDA.

An IRB must comply with all applicablerequirements of the IRB regulation (Part 56) andapplicable portions of the IDE regulation (Part812) in reviewing and approving deviceinvestigations 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 maybe 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 thestudy.


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INVESTIGATOR AGREEMENTS

Investigator agreement requirements21 C.F.R. 812.43(c).

Sponsors should carefully prepare andinstitutions, 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 underthe 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, shouldclosely scrutinize informed consent forms:

To avoid FDA compliance actions.

To avoid liability problems.


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INFORMED CONSENT

Investigators, institutions, and their IRBsshould closely scrutinize model forms ifprovided by the sponsor for compliance

with regulatory requirements; no oneshould just accept them.

All relevant parties should closely evaluatemodifications to model informed consentforms 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 willgenerate the data needed to support PMA approval or510(k) clearance.

Use the pre-IDE meeting process or more informalmechanisms (e.g., telephone calls to ODE) to pin down

as best you can what the PMA or 510(k) datarequirements will be and whether the protocol willgenerate that data.

Determine whether your study involves an SR or NSRdevice 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 theirresponsibilities.


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HOT TOPICS AND ENFORCEMENT

Mandatory registration and results reporting of certaindevice clinical trials. Applies to controlled product trials with health outcomes which

are subject to FDA regulation as well as pediatric postmarketsurveillance studies.

Excludes small feasibility studies.

Trial sponsor or designated principal investigator must register atClinicalTrials.gov.

Required by U.S. Public Law 110-85 (Food and DrugAdministration Amendments Act of 2007, Title VIII, Section 801).

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


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August 2009 FDA announces enhancement of speedand transparency of actions against misconduct in thedevelopment of drugs and devices.

September 2009 GAO report critical of FDA oversightof clinical investigators and recommends action to

improve timeliness and enhance scope of FDAsdebarment and disqualification processes for medicalproduct investigators, including device investigators. FDA agreed with GAOs recommendations.

October 2009H.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

FDAs handling of investigator misconduct.


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Bioresearch monitoring compliance continues to be anarea of high enforcement activity for FDA, includingCDRH.

Many Warning Letters issue to sponsors, investigators

and IRBs each year for clinical trial regulatorynoncompliances.

2008/2009 Warning Letter Issues for Device TrialSponsors Failure to secure investigator compliance with the signed

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


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2008/2009 Warning Letter Issues for DeviceTrial Sponsors (contd) 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 inrecords.

Failure to prepare and submit progress reports atregular intervals and at least yearly to FDA and the

reviewing IRB. Failure to obtain adequate signed investigatoragreements for each investigator participating in astudy.


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2008/2009 Warning Letter Issues for DeviceTrial IRBs

Failure to conduct initial and continuing review of

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

Failure to ensure that the IRB reviews proposedresearch at convened meetings at which a majority ofthe members are present.

Failure to prepare and maintain adequatedocumentation of IRB activities, including minutes ofIRB meetings.


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2008/2009 Warning Letter Issues for DeviceTrial IRBs (Contd)

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 unanticipatedproblems involving risk to human subjects or others.


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2008/2009 Warning Letter Issues for DeviceTrial 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 andapplicable FDA regulations.

Failure to obtain approval prior to implementing achange to the investigational plan.

Failure to maintain accurate, complete and currentrecords related to the investigation.


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2008/2009 Warning Letter Issues forDevice Trial Investigators (contd) Failure to ensure proper oversight of the

investigation. Failure to submit progress reports on the

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

Failure to maintain accurate, complete andcurrent records of receipt, use or dispositionof 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, whenthe agency determines that the researcher has repeatedly ordeliberately 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 theagency or the sponsor in a required report.

Since the early 1960s, FDA has disqualified approximately 190

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


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FDA ENFORCEMENT

Form FDA-483/Warning Letter.

Notice of Initiation of Disqualification Proceedingsand Opportunity to Explain (NIDPOE) LetterInitiation of a proceeding to determine whether an

investigator should be disqualified from receivinginvestigational products.

Notice of Opportunity for HearingIf an investigatorswritten or oral response to a NIDPOE letter is deemedunsatisfactory, 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 onthe disqualification action held before an FDA presidingofficer.


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CLINICAL INVESTIGATOR LISTS

All clinical investigators who have received a Notice ofInitiation of Disqualification Proceedings and Opportunityto 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 PresidingOfficer Report and/or a Commissioners Decision.

All clinical investigators who have agreed to certainrestrictions with respect to their conduct of clinicalinvestigations.


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CLINICAL INVESTIGATOR LISTS

All clinical investigators who agreed tocertain restrictions, which have now beenremoved.

All clinical investigators who, underregulations in effect until 1987, haveprovided FDA with adequate assurances

of their future compliance withrequirements.


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QUESTIONS?

FDA Clinical Trial Requirements for Medical Devices

Documents