AdvaMed has both general and specific comments on the draft guidance below.

Transcription

1 701 Pennsylvania Avenue, NW Suite 800 Washington, D.C Tel: Fax: July 1, 2015 Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane, Room 1061 Rockville, MD Re: Docket No. FDA 2015 D 0975: Acceptance of Medical Device Clinical Data from Studies Conducted Outside the United States; Draft Guidance for Industry and Food and Drug Administration Staff; Availability Dear Sir/Madam: On behalf of AdvaMed, the Advanced Medical Technology Association, we are pleased to submit these comments in response to FDA s draft guidance entitled: Acceptance of Medical Device Clinical Data from Studies Conducted Outside the United States; Draft Guidance for Industry and Food and Drug Administration Staff. AdvaMed represents manufacturers of medical devices, diagnostic products, and health information systems that are transforming health care through earlier disease detection, less invasive procedures, and more effective treatments. Our members produce nearly 90 percent of the health care technology purchased annually in the United States and more than 50 percent of such technology purchased annually around the world. These members range from the smallest to the largest medical technology innovators and companies. Nearly 70 percent of our members have less than $30 million in sales annually. AdvaMed has both general and specific comments on the draft guidance below. General Comments AdvaMed strongly supports efforts to standardize medical device Good Clinical Practice (GCP) as a mechanism to help ensure human subject protection. We commend the Food and Drug Administration (FDA) for developing this guidance and promoting GCP as the standard for conduct of clinical investigations across the globe. Continued Concerns about Lack of Harmonized International GCP Guidelines for Devices Based on the Unified Agenda in the Docket No. FDA-2013-N-0080, it appears FDA plans to issue a final rule on its proposed rule on Human Subject Protection: Acceptance of Data from Clinical Studies for Medical Devices (issued on Feb. 25, 2013) in December As we stated in our May 28, 2013 comments on the proposed rule, AdvaMed believes a harmonized international medical device GCP guideline is needed for medical device and IVD clinical investigations prior to finalizing the proposed rule. Absent a harmonized international guideline, Bringing innovation to patient care worldwide

2 Dockets Management Branch July 1, 2015 Page 2 of 5 FDA-2015-D-0975 we anticipate that FDA and industry will encounter challenges to aspects of the proposed rule (as FDA itself acknowledged in the proposed rule), including resistance by countries to allow FDA to audit local clinical investigations, inability of Sponsors to obtain names of Independent Ethics Committee (IEC) members needed to document the qualifications of IEC members for FDA (as required by the proposed rule), and numerous definitional issues as detailed in our comments including the term qualification, significant risk studies versus non-significant risk studies, and the differing directives governing IVDs and medical devices in the European Union. We sincerely appreciate FDA s effort to add a work item to create a harmonized international GCP guideline for medical devices to the International Medical Device Regulator s Forum (IMDRF) under the chairmanship of Dr. Jeff Shuren. However, ultimately the IMDRF rejected the work item. We believe continued efforts should be made at IMDRF to establish a new work item in this area prior to FDA s issuance of a final GCP rule. Barring that, explicit changes to the proposed rule should be made in recognition of the many issues and concerns identified in the AdvaMed comments (please see enclosed comments). Provide Sponsors an Opportunity to Explain Potential Non-Compliance with GCP We are also appreciative of FDA s willingness to meet with AdvaMed in March 2014 to provide us with an opportunity to clarify our written comments to Docket No. FDA-2013-N-0080 and to respond to questions. As noted in the Minutes of the March 3, 2014 meeting (included in Docket No. FDA-2013-N-0080), AdvaMed recommended that the rule allow industry to explain potential non-compliance with GCP to FDA. We believe the draft guidance should also explicitly allow industry to explain potential non-compliance with GCP to FDA. Lastly, the draft guidance should be re-opened for public comment again once the proposed GCP rule has been finalized. It is anticipated that the final rule may establish additional requirements that may need further clarification in guidance including FDA s proposed revisions to 21 CFR and expanding FDA s authority to deny or withdraw PMA approval based on submission of non-compliant foreign data. In addition, the draft guidance should be updated to reflect the final rule (e.g., Section V of the draft guidance would require revision). Specific Comments AdvaMed s specific comments on the guidance are presented below in tabular form. In closing, thank you for the opportunity to comment on Acceptance of Medical Device Clinical Data from Studies Conducted Outside the United States; Draft Guidance for Industry and Food and Drug Administration Staff. Please don t hesitate to contact me if you have any questions. Sincerely, /s/ Tara Federici Vice President, Technology and Regulatory Affairs Enclosure

3 AdvaMed Comments on Acceptance of Medical Device Data from Studies Conducted Outside the United States: Draft Guidance for Industry and Food and Drug Administration Staff Edit # Line # Change Reason 1 73 Add the following:.valid clinical data from foreign clinical studies in support of premarket submissions for devices including In Vitro Diagnostics. In the US, In Vitro Diagnostic tests are defined by regulation as devices Under 21 CFR (b), FDA will accept OUS clinical studies submitted in support of a PMA, which began on or after November 19, 1986, if the applicant demonstrates that such data are valid and if the clinical investigator conducted the OUS studies in conformance with the 1983 version of the Declaration of Helsinki (Declaration) or the laws and regulations of the country in which the research was conducted, whichever accords appropriate or greater protection to the human subjects and ensures that the rights, safety and welfare of human subjects has not been violated. If the standards of the country are used, the applicant is required to detail any differences between those standards and the Declaration and explain why they offer appropriate or greater protection to the human subjects and ensures that the rights, safety and welfare of human subjects has not been violated. Since this document is intended for international use, and since the EU has separate directives for devices and IVDs, adding the proposed sentence clarifies the FDA position for those who might not be aware. The applicant should be able to conduct the OUS studies in conformance with the 1983 Declaration of Helsinki or the laws and regulations of the country in which the research was conducted if they accord appropriate or greater protection to the human subjects and the applicant can demonstrate they are appropriate or greater. We have also moved the language of footnote 4 into the body of the document Add the following: If the standards of the country are used, the applicant is required to detail any differences between those standards and the Declaration and explain why they offer appropriate or greater protection to the human subjects and ensures that the rights, safety and welfare of human subjects has not been violated.. Although the regulation states that the manufacturer must explain why the patient protection measures are greater, an explanation of why they are similar or sufficient should be accepted. We have also moved the language of footnote 4 into the body of the document. 7/1/2015 Page 3 of 5

4 AdvaMed Comments on Acceptance of Medical Device Data from Studies Conducted Outside the United States: Draft Guidance for Industry and Food and Drug Administration Staff Edit # Line # Change Reason Add the following at the end of line 183: Non-Significant risk studies as defined in 21 CFR 812.2(c) (3) will also be eligible as evidence in US submissions when they follow the same GCP considerations such as Consent and Ethics Committee approval Add the following: Where there are known or foreseeable differences between the clinical conditions of the OUS study population and the intended US patient populations, the sponsor should mitigate the differences or adequately describe why they do not believe those differences would impact evaluation of the safety and/or effectiveness of the device Add the following: When evaluating supplemental activities to support the use of OUS data to support an application, points to consider can include the following: Details have been provided for PMA devices and FDA is stating that other submission types will be acceptable as well. Clarification is needed in the framework section that this also applies to nonsignificant risk studies, which would apply to many IVD tests. IVD developers source patient samples, and prepare samples for shipment to the US for testing and for non-significant risk studies fully conducted OUS. To clarify the scope of differences in clinical conditions that the sponsor could reasonably be expected to identify and address. The examples include methodologies. However, pulling these out into a separate sentence will aid future applicants. Additional analysis of existing data, Small confirmatory studies, Bayesian analysis with the OUS data serving as prior information, or Re-analysis of foreign data against US performance standards established in scientific literature FDA should clarify on line 441 whether it was a US or OUS study. If it was a US study, it is inconsistent with the outcome on line 459. Lines suggest that the sponsor conducted a US study that supported the approval, but 7/1/2015 Page 4 of 5

5 AdvaMed Comments on Acceptance of Medical Device Data from Studies Conducted Outside the United States: Draft Guidance for Industry and Food and Drug Administration Staff Edit # Line # Change Reason 459 lines suggest that FDA approved the PMA based solely on the OUS clinical trial data Add the following: Valid scientific evidence, as described under 21 CFR 860.7, is only one factor in determining whether FDA can use the data to support a decision on a 510(k), PMA, HDE or de novo but generally does not address ethical considerations in premarket applications. The draft guidance references HDE on line 129, and lines but neglects to mention them here Strike and add the following: GCP includes review and approval (or provision of a favorable opinion) by an independent ethics committee (IEC) before initiating a study, continuing review of an ongoing study by an IEC, and obtaining and documenting the freely given informed consent of the subject (or subject s legally authorized representative, if the subject is unable to provide informed consent) before initiating a study. the subject participates in the study. Please clarify that the sentence means that individual patients must have informed consent before they enroll in the study not prior to initiating the study. 7/1/2015 Page 5 of 5

6 701 Pennsylvania Avenue, Ste. 800 Washington, DC Tel: Fax: May 28, 2013 Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane, Room 1061 Rockville, MD Re: Docket No. FDA-2013-N-0080; RIN 0910-AG48: Proposed Rule on Human Subject Protection; Acceptance of Data From Clinical Studies for Medical Devices Dear Sir/Madam: On behalf of AdvaMed, the Advanced Medical Technology Association, we are pleased to submit these comments in response to FDA s Proposed Rule on Human Subject Protection; Acceptance of Data From Clinical Studies for Medical Devices. AdvaMed represents manufacturers of medical devices, diagnostic products, and health information systems that are transforming health care through earlier disease detection, less invasive procedures, and more effective treatments. Our members produce nearly 90 percent of the health care technology purchased annually in the United States and more than 50 percent of such technology purchased annually around the world. These members range from the smallest to the largest medical technology innovators and companies. Nearly 70 percent of our members have less than $30 million in sales annually. AdvaMed has both general and specific comments on the draft guidance below. General Comments AdvaMed strongly supports efforts to standardize medical device Good Clinical Practice (GCP) as a mechanism to help ensure human subject protection. We commend the Food and Drug Administration (FDA) for promoting GCP as the standard for conduct of clinical investigations across the globe. Concerns about International Implications of Proposed Rule AdvaMed is very concerned, however, that the proposed rule indirectly outlines requirements for clinical studies conducted outside the United States (OUS) without having common definitions for medical devices, and corresponding and explicit Bringing Innovation to patient care worldwide

7 Division of Dockets Management (HFA-305) May 28, 2013 Page 2 of 12 Docket No. FDA-2013-N-0080; RIN 0910-AG48 international regulator support. In the US, in vitro diagnostics (IVDs) are classified as medical devices. However, in the European Union (EU), there are separate directives governing medical devices and in vitro diagnostic devices. The Global Harmonization Task Force (GHTF) guidance documents on Clinical Evidence for IVD Medical Devices further differentiate IVDs, and these differences are not reflected in US GCP regulation or guidance. In the proposed rule, FDA cites the precedence established in drug and biological product regulations by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), through which the ICH E6 guideline entitled Good Clinical Practice: Consolidated Guideline was developed. Importantly, the ICH GCP guideline was developed by both international regulators and pharmaceutical and biological manufacturers through a collaborative approach with all stakeholders having an equal voice. Unfortunately, no such harmonized international medical device GCP guideline exists for medical device and IVD clinical investigations. Absent a similar common foundation for medical devices, FDA and industry alike may run into resistance from the OUS regulatory and clinical community to implementation of the proposed rule. FDA itself acknowledges some of these challenges in the proposed rule, including potential resistance by countries to allow FDA to audit local clinical investigations and the inability of Sponsors to obtain the names of Independent Ethics Committee (IEC) members. This latter point, for example, would preclude Sponsors from ensuring the adequacy of the Independent Ethics Committee (IEC) membership by obtaining and documenting the qualifications of the IEC members, and making these records available to the Agency upon request as is proposed by the rule. In addition, AdvaMed has several specific concerns with the proposed rule s regulation regarding IEC membership: As discussed above, unlike drugs and biologics, there is no underlying international harmonized medical device GCP guideline that all countries have agreed to, making implementation of this requirement difficult for both Agency and industry. The term qualification is open to interpretation absent a harmonized international GCP guideline. Without a common guideline, IECs from other countries may also not be familiar with the terminology of significant risk (SR) and non-significant risk (NSR) medical device clinical investigation classification. As a result, they will be unable to provide oversight to the Sponsor s determination of SR/NSR as is done in the US. There is no parallel US requirement for Sponsors to qualify Institutional Review Boards (IRBs). In addition, US IRBs do not have an obligation to provide this type of information to the sponsor. Thus, FDA s requirements for OUS IECs are broader than US requirements for IRBs, which the Agency has in place to protect human subjects. FDA has not specified, and we are unaware of, any specific rationale to require greater regulation OUS than is required in the US.

8 Division of Dockets Management (HFA-305) May 28, 2013 Page 3 of 12 Docket No. FDA-2013-N-0080; RIN 0910-AG48 Proposed Rule Should Not Be Finalized Until Harmonized International Medical Device GCP Guidelines and Medical Device Definitions Have Been Established For these and other reasons, AdvaMed recommends that the proposed rule not be finalized until a harmonized, international medical device and IVD GCP guideline has been established and adopted. In addition, memoranda of understanding between FDA and some foreign countries may be needed in advance of the proposed rule being finalized in order for Sponsors and FDA to meet some of the requirements outlined in the proposed rule. We recommend FDA establish a forum of international regulators and industry representatives to fast track development of a harmonized medical device GCP guideline and common definitions prior to issuance of the final rule. The International Medical Device Regulator s Forum (IMDRF) may provide the foundation for such an initiative if industry representatives are integral to the process as was done in the development of ICH E6. The development of a harmonized international medical device GCP guideline and standardized medical device definitions will help ensure that the rule, once finalized, can be implemented without major hurdles for FDA and industry. It will also help to ensure that the final rule is not viewed by sovereign nations outside the US as FDA unilaterally imposing FDA GCP standards on international device regulators and the international clinical community. Once a harmonized guideline is issued and adopted, many of the requirements identified in the proposed rule should be waived for countries that adopt the harmonized guidelines. Timing of Implementation of the Rule Once the rule is finalized, FDA should make clear that the requirements are prospective and are not retroactive, to avoid arbitrary and capricious consequences for ongoing trials and pending applications. Outlining a specified transition period or delineating a phasedin approach will be helpful as well. Definition of Clinical Trials and Other Terms FDA should also replace the term clinical studies with clinical investigations throughout the proposed rule to be consistent with 21 CFR 812.3(h) which defines investigation as a clinical investigation or research involving one or more subjects to determine the safety or effectiveness of a device. Clinical studies is not defined in the regulations, whereas investigations is. This definitional change will also ensure that per the proposed rule, potential FDA withdrawals of PMAs and 510(k)s related to a clinical investigation will be based only on clinical investigations of safety and effectiveness, rather than on technical or analytical (bench) testing (including those that use either identified or de-identified human specimens), or marketing or preference studies.

9 Division of Dockets Management (HFA-305) May 28, 2013 Page 4 of 12 Docket No. FDA-2013-N-0080; RIN 0910-AG48 In addition, when FDA uses new terms such as certified or case records (see Lines ), FDA should define the terms and include the new definitions in the amendments to the regulations. Proposed Rule Puts New Requirements on In Vitro Diagnostic Devices Without a definitional change, the proposed rule will put new requirements on in vitro diagnostic companies who conduct technical and analytical (or bench) studies using human specimens. If not clearly exempted, these studies, which are non-clinical in nature, could be pulled under the Good Clinical Practice ( GCP ) rules. Instead, these studies, which typically are performed in-house or by contracted laboratories, are subject to Good Laboratory Practices. In addition, they are covered by FDA and HHS Human Subject Protections that provide for IRB oversight and informed consent, except where compliant with FDA s Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable. The application of GCP in this context would provide no additional protection and would slow innovation significantly. For that reason, we urge FDA to replace the term clinical studies with clinical investigations and clarify that technical and analytical studies are not within the scope of this rule. Implications for Postmarket Evaluations The proposed rule is somewhat ambiguous in parts and we are concerned some may interpret it as expanding the types of studies that must be submitted with a PMA or 510(k) to include all OUS studies and to require GCP for all studies. For example lines 823 through 834 indicate that clinical studies conducted outside the US to be submitted in support of an IDE or a device marketing application or submission... are subject to... for a significant risk device,... the principles of good clinical practice, as defined in Sec (a),... [and]... for a device other than a significant risk device... the principles of good clinical practice as defined in Sec (a),.... If true, the proposed rule would set a higher bar for certain OUS studies than for US studies. For example, Sponsors are not required to obtain informed consent or IRB approval for postmarket evaluations of approved or cleared medical devices in the US. However, under the proposed rule, it appears that a Sponsor of a postmarket evaluation in a foreign country would have to apply investigational requirements where none are required (or even allowed) by the regulators in that country because the product is already in commercial distribution. For example, in the United Kingdom, Ethics Committees will not review on-label studies of CE-marked products. Companies frequently obtain a CE mark, then conduct a postmarket evaluation to support reimbursement needs, publication strategies or for purposes other than establishing safety or effectiveness (e.g., marketing or preference studies). The requirements under the proposed rule should only be applied to postmarket clinical investigations related to safety and effectiveness.

10 Division of Dockets Management (HFA-305) May 28, 2013 Page 5 of 12 Docket No. FDA-2013-N-0080; RIN 0910-AG48 Further, the proposed rule will amend Section (a)(5) and to include as a reason for denial of approval of a PMA or withdrawal of approval of a PMA failure to comply with GCP for any clinical investigation involving human subjects described in the PMA application which was subject to GCP. FDA should not deny or withdraw approval because an investigation(s) was not GCP-compliant unless the investigation(s) were essential for the determination of safety and effectiveness. For these reasons, AdvaMed again recommends that FDA be consistent with the definition in 812.3(h) (as described above) to ensure that postmarket evaluations conducted for reasons other than determining the safety or effectiveness of the device are clearly excluded. Create Exceptions for Use of De-Identified Leftover Human Specimens We also urge FDA to consider codifying the concepts embodied in FDA s Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable, in the final rule by adding to the exceptions to the Good Clinical Practice (GCP) informed consent requirement: Investigations of in vitro diagnostics that are conducted using only specimens that are not individually identifiable, and Specimens obtained from specimen repositories, or specimens that are leftover from specimens previously collected for other unrelated research. The use of de-identified specimens poses no threat of subject identification where results of the investigational tests are not communicated or associated with the subject, and does not cause a new medical risk for the subject. As further explained in FDA s Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable, IVD device investigations can be conducted using leftover specimens obtained without informed consent while protecting the human subjects who are the source of such specimens. This practice raises no patient risks and is critical to continued innovation in the IVD sector. Please see AdvaMed s specific comments in the table below. The line numbers reference the enclosed line-numbered version of the draft guidance. Sincerely, /s/ Tara Federici Vice President Technology and Regulatory Affairs Attachments

11 AdvaMed Comments on Proposed Rule on Human Subject Protection; Acceptance of Data From Clinical Studies for Medical Devices Edit ID # Change Reason # And The sentences beginning on lines 128 thru 130 and lines 134 thru 137 are confusing and require clarification. Clarify informed consent provisions should not apply to clinical studies involving human specimens collected as de-identified, leftover specimens or banked samples. FDA must approve IDEs so it is not clear why data from a study that is run according to an approved IDE would not be acceptable for clinical studies conducted inside the US. These studies do not involve human subjects either on a prospective basis or with interventional activities. For human subject protection, the human specimens used in these studies would be deidentified leftover specimens or banked samples as explained in the FDA s Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable Change from: number of members with the qualifications and experience to perform the IEC s functions To: number of members authorized to perform the IEC s functions It may be difficult to quantify the number of members with qualifications and experience to perform the IEC s functions as the committee is made up to include lay members that could be members of the public. Their qualifications and experience may not be perceived to be relevant yet they are still able to and approved to perform their role within the committee And 284 Clarify documenting the freely given informed consent of study subjects would not apply to IVD investigations involving human specimens collected as de-identified, leftover specimens and fully compliant with the FDA s Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable. The use of de-identified specimens poses no threat of subject identification, where results of the investigational tests are not communicated or associated with the subject, and do not cause a new medical risk for the subject. As further explained in FDA s Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable, IVD device investigations can be conducted using leftover specimens obtained without

12 AdvaMed Comments on Proposed Rule on Human Subject Protection; Acceptance of Data From Clinical Studies for Medical Devices informed consent while protecting the human subjects who are the source of such specimens. This raises no patient risks, and is critical to continued innovation in the IVD sector Strike and add the following: Proposed Sec (a)(1) states that GCP includes review and approval (or provision of a favorable opinion) by an IEC before initiating a study, continuing review of an ongoing study by an IEC, and obtaining and documenting the freely given informed consent of a subject (or the subject's legally authorized representative if the subject is unable to provide informed consent) before initiating a study that subject participates in the study. Expand " Proposed Sec (a)(1) to further state that GCP does not require informed consent in life-threatening situations when the IEC reviewing the study finds, before initiation of the study, that informed consent is not feasible and that either the conditions present are consistent with those described in Sec or 50.24(a) of this chapter (concerning exemptions from informed consent requirements in life-threatening situations), or the measures described in the study protocol or elsewhere will protect the rights, safety, and well-being of subjects to include situations for studies involving de-identified, leftover human specimens or banked samples. Change from: Names and addresses of investigators and research facilities Subjects will enroll in a clinical study throughout the enrollment phase of a study. So, stating that informed consent will be obtained from a subject before initiating a study is not realistic. The use of de-identified specimens poses no threat of subject identification, where results of the investigational tests are not communicated or associated with the subject, and do not cause a new medical risk for the subject. As further explained in FDA s Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable, IVD device investigations can be conducted using leftover specimens obtained without informed consent while protecting the human subjects who are the source of such specimens. This raises no patient risks, and is critical to continued innovation in the IVD sector. Suggest rewording as it sounds as if the addresses of investigators will be required. Addresses of investigators are not routinely obtained and personal

13 AdvaMed Comments on Proposed Rule on Human Subject Protection; Acceptance of Data From Clinical Studies for Medical Devices To: details such as this can be subject to more stringent regulations in EU Names and addresses of research facilities, in addition to names of Investigators Delete the following: (4) A detailed summary of the protocol and results of the study and, should FDA request, certified copies of case records maintained by the investigator or additional background data such as hospital or other institutional records. Add and strike the following: The name and address of the IEC that reviewed the study and a statement obtained from the IEC that the IEC it meets the definition in Sec. 812(t) and is organized and operates according to applicable laws and regulations. The Sponsor or applicant must maintain records supporting such a statement, including records describing the qualifications of IEC members, and make these records available for Agency review upon request. The laws of other countries typically prohibit any export of their citizen s patient medical records, however, these records would be available for inspection at the hospital should the need arise. The proposed guidance states the Sponsors will have to obtain records describing the qualifications of IEC members. In the various countries where research is conducted this may not always be feasible, as the document notes, names of IEC members can be difficult to obtain. ICH E6 & the FDA guidance (E6 Good Clinical Practice: Consolidated Guidance) requires that Sponsors obtain the name and address of the IEC and a statement from the IRB/IEC that it is organized and operates according to GCP and the applicable laws and regulations. (Section FDA Guidance). It is important to note the IRB section of the E6 guidance states Sponsors may request membership lists and procedures. It is not a requirement to hold supporting documents relating to IECs. In the UK it is the responsibility of appointing authorities to establish IECs and it is they who would hold information such as qualifications Change from: A summary of the IEC S decision to The approval letter would be more clear and less ambiguous than a summary which could be interpreted differently by

14 AdvaMed Comments on Proposed Rule on Human Subject Protection; Acceptance of Data From Clinical Studies for Medical Devices approve. different people. To: Correspondence relating to IEC s decision to approve Delete the following: A description of what incentives, if any, was provided to subject to participate in the study Include the following statement: As IECs outside the United States may not be familiar with the terms significant risk or non-significant risk, the Sponsor will document the Sponsor s own determination. This information is a new requirement and may lead to unnecessary burden of review for the FDA especially for nonsignificant risk and IVD studies. This information is reviewed by the IRB/IEC as part of consent, and held by the Sponsor as part of their records, and is subject to audit by the Agency. Lines describe that different information must be provided for devices classified as significant risk from those determined to be non-significant risk (line 404). IECs outside the United States will likely not be familiar with this classification of a device or the related requirements. In the United States, IRBs review the Sponsor s determination of significant or non-significant risk. As IECs outside the US may not be willing or able to confirm this determination, the Sponsor s determination must be used FDA should clarify that it is not eliminating the ability for Sponsors to utilize studies that may not meet GCP requirements (e.g., peer-reviewed literature where Sponsors will not have access to GCP type information) and clarify that FDA is not giving such studies less weight because these studies provide further documented evidence of device use. Since these reports can include reports from literature based on studies that were not conducted by the submitter of the IDE or marketing application, it is not always possible to have this information to be able to make such a statement Clarify obtaining and documenting human subjects informed consent should not apply to clinical studies The use of de-identified specimens poses no threat of subject identification, where results of the investigational tests are not

15 AdvaMed Comments on Proposed Rule on Human Subject Protection; Acceptance of Data From Clinical Studies for Medical Devices involving de-identified, leftover specimens or banked samples. Add and strike the following: We propose that any final rule based on this proposal be prospective and become effective 180 days for newly initiated (first person enrolled) clinical investigations, conducted outside the United States and used as support for an FDA submission, commencing 18 months after the final rule is published in the Federal Register. communicated or associated with the subject, and do not cause a new medical risk for the subject. As further explained in FDA s Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable, IVD device investigations can be conducted using leftover specimens obtained without informed consent while protecting the human subjects who are the source of such specimens. This raises no patient risks and is critical to continued innovation in the IVD sector. It is necessary to allow adequate time for internal SOP revision, training study planning, and negotiating and contracting with the necessary parties for future clinical studies conducted outside of the United States intended to be used to support an FDA submission Add (continuing paragraph): For the purpose of definition, device GCP does not include requirement for Sponsor collection and analysis of (i) adverse events beyond those specified in the protocol and those that would meet the definition of a UADE, (ii) concomitant medications and concomitant therapies beyond those specified in the protocol, (iii) any other data not specifically required of clinical investigations conducted under an IDE or not specified in the protocol. Clarify that the requirements for a drug clinical study are not being systemically required of OUS medical device study Add and strike the following: Clarify that the statement refers to authorization by law in the geography of

16 AdvaMed Comments on Proposed Rule on Human Subject Protection; Acceptance of Data From Clinical Studies for Medical Devices And , and if otherwise authorized by local law, or through other appropriate means. Delete the following: (4) A detailed summary of the protocol and results of the study and, should FDA request, certified copies of case records maintained by the investigator or additional background data such as hospital or other institutional records. Add and strike the following: The name and address of the IEC that reviewed the study and a statement obtained from the IEC that the IEC it meets the definition in Sec. 812(t) and is organized and operates according to applicable laws and regulations. The Sponsor or applicant must maintain records supporting such statement, including records describing the qualifications of IEC members, and make these records available for Agency review upon request. Add the following: Sec Denial of approval of a PMA. (a) * * * (5) Any clinical investigation involving human subjects described in the PMA, which is relied upon for a determination of safety or effectiveness and subject to the institutional review board regulations in part 56 of this chapter or informed consent regulations in part 50 of this the site. FDA should also strike or clarify what is meant by through other appropriate means as it is unclear what types of activities would satisfy the requirement. The laws of other countries typically prohibit any export of their citizen s patient medical records, however, these records would be available for inspection at the hospital should the need arise. IRBs and IECs are not routinely audited by Sponsors and may be unwilling to make membership lists available, and may be subject to legal restrictions on the release of such information. The FDA s expansion of authority to deny or withdraw approval of an IDE, PMA, etc., based on non-compliant foreign data is a concern, particularly when the proposed rule amends FDA s regulations to expressly provide that failure or inability to comply with GCP requirements for foreign clinical studies is not a justification for excluding those studies. The language any is too broad without further qualifying that it applies only to

17 AdvaMed Comments on Proposed Rule on Human Subject Protection; Acceptance of Data From Clinical Studies for Medical Devices chapter or GCP referenced in Sec (a) and described in Sec (a) of this chapter, was not conducted in compliance with those regulations such that the rights or safety of human subjects were not adequately protected or the supporting data were determined to be otherwise unreliable. Sec Withdrawal of approval of a PMA. (a) * * * (4) Any clinical investigation involving human subjects described in the PMA, which is relied upon for a determination of safety or effectiveness subject to the institutional review board regulations in part 56 of this chapter or informed consent regulations in part 50 of this chapter or GCP referenced in Sec (a) and described in Sec (a) of this chapter, was not conducted in compliance with those regulations such that the rights or safety of human subjects were not adequately protected or the supporting data were determined to be otherwise unreliable. Note to FDA similar language appears in the preamble to the proposed rule and would need to be modified as well. those clinical investigations that the applicant relies upon for a determination of safety and effectiveness. - Therefore, Any should be replaced with pivotal studies, or narrowed to the study or studies upon which reliance is made to establish safety and effectiveness of the current design of the device. Particularly with PMAs, FDA requires that ALL prior studies be reported despite not all being relied upon for a determination of safety and effectiveness, such as: - Studies that were conducted by a Sponsor other than the current applicant, and which became owned by the current applicant through acquisition. - Postmarket evaluations in other countries that are not considered clinical studies in those countries. - Early feasibility studies on a different iteration of the device. - The language used in the proposed rule also does not leave any room for studies that may not have complied with GCPs, but for which appropriate justification was provided as described elsewhere in the proposed rule. - For all these reasons, any should be replaced with investigations upon which reliance is made to establish safety and effectiveness.

18 [Federal Register Volume 78, Number 37 (Monday, February 25, 2013)] [Proposed Rules] [Pages ] From the Federal Register Online via the Government Printing Office [ [FR Doc No: ] ======================================================================= DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Parts 807, 812, and 814 [Docket No. FDA-2013-N-0080] RIN 0910-AG48 Human Subject Protection; Acceptance of Data From Clinical Studies for Medical Devices AGENCY: Food and Drug Administration, HHS. ACTION: Proposed rule SUMMARY: The Food and Drug Administration (FDA) is proposing to amend its regulations on acceptance of data from clinical studies for medical devices. We are proposing to require that clinical studies conducted outside the United States as support for an investigational device exemption (IDE) application, a premarket notification (510(k)) submission, a premarket approval (PMA) application, a product development protocol (PDP) application, or a humanitarian device exemption (HDE) application be conducted in accordance with good clinical practice (GCP), which includes obtaining and documenting the review and approval of the study by an independent ethics committee (IEC) and obtaining and documenting freely given informed consent of study subjects. The proposed rule is intended to update the standards for FDA acceptance of data from clinical studies conducted outside the United States and to help ensure the protection of human subjects and the quality and integrity of data obtained from these studies. As part of this proposed rule, we are also proposing to amend the IDE and 510(k) regulations to address the requirements for FDA acceptance of data from clinical studies conducted inside the United States. The proposed amendments are intended to provide consistency in FDA requirements for acceptance of clinical data, whatever the application or submission type. 1

19 DATES: Submit either electronic or written comments on the proposed rule by May 28, See section VIII of this document for the proposed effective date of a final rule based on this proposed rule. Submit comments on information collection issues under the Paperwork Reduction Act of 1995 by March 27, 2013, (see the ``Paperwork Reduction Act of 1995'' section of this document). ADDRESSES: You may submit comments, identified by Docket No. FDA-2013-N-0080 and/or Regulatory Information Number (RIN) number 0910-AG48, by any of the following methods, except that comments on information collection issues under the Paperwork Reduction Act of 1995 (the PRA) must be submitted to the Office of Information and Regulatory Affairs, Office of Management and Budget (OMB) (see the ``Paperwork Reduction Act of 1995'' section of this document): Electronic Submissions Submit electronic comments in the following way: Federal erulemaking Portal: Follow the instructions for submitting comments. Written Submissions Submit written submissions in the following way: Mail/Hand delivery/courier (for paper or CD-ROM submissions): Division of Dockets Management (HFA- 305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD Instructions: All submissions received must include the Agency name and Docket No. FDA-2013-N-0080 and RIN 0910-AG48 for this rulemaking. All comments received may be posted without change to including any personal information provided. For additional information on submitting comments, see the ``Request for Comments'' heading of the SUPPLEMENTARY INFORMATION section of this document. Docket: For access to the docket to read background documents or comments received, go to and insert the docket number(s), found in brackets in the heading of this document, into the ``Search'' box and follow the prompts and/or go to the Division of Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD FOR FURTHER INFORMATION CONTACT: Sheila Brown, Center for Devices and Radiological Health, Food and Drug Administration, New Hampshire Ave., Bldg. 66, Rm. 1651, Silver Spring, MD 20993, ; and Stephen Ripley, Center for Biologics Evaluation and Research (HFM-17), Food and Drug Administration, 1401 Rockville Pike, Suite 200N, Rockville, MD , SUPPLEMENTARY INFORMATION: 2

20 Table of Contents I. Background A. Current Regulations on Clinical Studies for Medical Devices B. Reasons for Proposing To Revise the Regulations II. Description of the Proposed Rule A. Definitions B. Clinical Studies Conducted Outside the United States C. Revisions to Sec Applicability D. Requirements for Report of Prior Investigations in IDE Applications E. Requirements for 510(k) Submissions F. Requirements for PMA Applications G. Correction to the Regulations Regarding Record Retention for Clinical Studies Conducted Under IDE III. Legal Authority IV. Analysis of Economic Impacts A. Introduction B. Summary V. Environmental Impact VI. Paperwork Reduction Act of 1995 VII. Federalism VIII. Proposed Effective Date IX. Request for Comments X. References I. Background 3

21 A. Current Regulations on Clinical Studies for Medical Devices 1. Clinical Studies Conducted Outside the United States FDA regulations for PMA of medical devices in part 814 (21 CFR part 814) permit the acceptance of data from clinical studies conducted outside the United States and submitted in support of a PMA application if certain conditions are met. Current Sec (a) states that a study conducted outside the United States submitted in support of a PMA and conducted under an IDE shall comply with part 812 (21 CFR part 812). The provision in Sec (a) further states that a study conducted outside the United States submitted in support of a PMA and not conducted under an IDE shall comply with the provisions in paragraph (b) or (c) of Sec , as applicable. Under Sec (b), FDA will accept studies submitted in support of a PMA which have been conducted outside the United States and begun on or after November 19, 1986, if the data are valid and the investigator has conducted the studies in conformance with the Declaration of Helsinki or the laws and regulations of the country in which the research is conducted, whichever accords greater protection to the human subjects. If the standards of the country are used, the applicant must state in detail any differences between those standards and the Declaration of Helsinki and explain why they offer greater protection to the human subjects. Under Sec (c), FDA will accept studies submitted in support of a PMA that have been conducted outside the United States and begun before November 19, 1986, if FDA is satisfied that the data are scientifically valid and that the rights, safety, and welfare of human subjects have not been violated. Additionally, Sec (d) specifies criteria for acceptance of a PMA application for marketing approval based solely on foreign clinical data, and Sec (e) encourages applicants to meet with FDA officials prior to submission of a PMA application that will be based solely on foreign clinical data. Currently, FDA regulations for premarket notification in part 807, subpart E (21 CFR 807, subpart E), commonly referred to as a ``510(k) submission,'' and investigational device exemptions in part 812 do not address the requirements for FDA acceptance of data from clinical studies conducted outside the United States. 2. Clinical Studies Conducted Inside the United States FDA's PMA regulations require applications that include the results of clinical investigations involving human subjects to include a statement with respect to each study that: (1) It was conducted in compliance with the institutional review board regulations in part 56 (21 CFR part 56), or was not subject to those regulations under Sec. Sec or , and it was conducted in compliance with the informed consent regulations in part 50 (21 CFR part 50); or (2) if the study was not conducted in compliance with those regulations, a brief statement of the reason for the noncompliance (see Sec (b)(6)(ii)(A)). The regulations also require a statement that each study was conducted in compliance with part 812 concerning sponsors of clinical investigations and clinical investigators, or if 4