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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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RESPONSIBILITIES OF THE SPONSOR
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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RESPONSIBILITIES OF THE SPONSOR
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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RESPONSIBILITIES OF THE SPONSOR
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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RESPONSIBILITIES OF THE SPONSOR
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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RESPONSIBILITIES OF THE SPONSOR
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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RESPONSIBILITIES OF THE SPONSOR
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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RESPONSIBILITIES OF THE SPONSOR
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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RESPONSIBILITIES OF THE SPONSOR
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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RESPONSIBILITIES OF THE SPONSOR
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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RESPONSIBILITIES OFINVESTIGATORS
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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RESPONSIBILITIES OFINVESTIGATORS
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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RESPONSIBILITIES OF IRBs
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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RESPONSIBILITIES OF IRBs
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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HOT TOPICS AND ENFORCEMENT
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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HOT TOPICS AND ENFORCEMENT
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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HOT TOPICS AND ENFORCEMENT
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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HOT TOPICS AND ENFORCEMENT
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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HOT TOPICS AND ENFORCEMENT
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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HOT TOPICS AND ENFORCEMENT
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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HOT TOPICS AND ENFORCEMENT
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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HOT TOPICS AND ENFORCEMENT
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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