September 4, 2013
Centers for Medicare & Medicaid Services Department of Health and Human Services Attention: CMS–1600–P
Mail Stop C4–26–05 7500 Security Boulevard Baltimore, MD 21244–1850
In reference to docket number: CMS-2013-0155-0010
The Association of Clinical Research Professionals (ACRP) is the primary resource for clinical research professionals in the pharmaceutical, biotechnology and medical device industries, and those in hospital, academic medical centers and physician office settings. ACRP was founded in 1976 to address the educational and networking needs of research nurses and others who supported the work of clinical investigations. More than 35 years later, ACRP is a global
association comprised of more than 18,000 individuals in over 65 countries dedicated to clinical research and development. Our mission is “To provide global leadership to promote integrity and excellence for the clinical research profession”. The Academy of Physicians in Clinical Research (APCR) is an affiliate of ACRP and is the leading professional organization, exclusive to physicians, that supports and addresses these unique issues and challenges of all physicians involved in clinical research.
We are writing to provide comment on the Proposed Rule entitled “Coverage of Items and Services Furnished in FDA-Approved Investigational Device Exemption (IDE) Clinical Trials” as published in the Federal Register /Vol. 78, No. 139. As always, our constituents appreciate the opportunity to comment on proposed rules like this so that CMS can take into consideration their reactions and interpretations as those that would be most impacted. Our constituency of clinical research professionals in the United States has certainly weighed in on this proposed rule and we take this opportunity on their behalf to, as comprehensively as possible, express their areas of support and areas of concern. The use of the word “we” throughout this response refers to the representative opinion of these constituents.
Overall, our constituents support the elimination of any and all unnecessary and/or duplicative review in an effort to keep healthcare costs affordable to the consumer and assure that the delivery of improved therapeutics are not unnecessarily delayed. We know from the community of research professionals historically engaged in the process of obtaining coverage
determinations of IDE studies that they have been frustrated with the delays, inconsistencies and duplication of effort the current system brings. Having a single entity provide a single review for coverage determinations of an IDE study is certainly one viable and promising
potential solution to this dilemma. With that said, we are taking this opportunity to comment on the newly proposed process in the hopes of assuring that it maximizes the efficiencies that this model promises.
While we do not question CMS’s authority to set additional criteria, we call to CMS’s attention a very serious issue with the addition of these criteria, which although is bigger than this draft regulation and really pertains to the NCD in general, is appropriate to bring up here as it relates to these additional criteria. The NCD defines routine costs in clinical trials (roughly) as 1) items or services that are typically provided absent a clinical trial (e.g. conventional care); 2) items or services solely for the provision of the investigational item or service; and 3) items or services needed for reasonable and necessary care arising from the provision of an investigational item or service. While we understand CMS’s desire to add additional criteria to assure they do not pay for items or services in research of a study that would not hold potential benefit to the Medicare population, we take issue with putting these barriers as a means of denying the “conventional care” part of routine care. Under the strict definition of CMS paying the “routine costs of qualifying trials” of which “routine costs” includes conventional care; it follows that if a trial does not meet these criteria that CMS does not cover the routine care which includes conventional care as part of its definition. Providers and Medicare recipients remain confused about why the recipient loses their coverage and must pay out of pocket for some or all of their conventional care (i.e. routine physicals, routine labs etc.) simply because the study they are in uses that data as part of the research. Additionally, this is potentially contrary to other laws, rights and benefits (i.e. a study on a device for sedation or improved colonoscope used in a study of legally mandated free screening colonoscopy). We, as well as the beneficiaries we talk to every day, are of the opinion that “conventional care” is “conventional care” and should be covered without prejudice of any supplemental activity the recipient engages in. Beneficiaries only perceive denying their conventional care for this reason as 1) an imposition to their autonomy; 2) Medicare trying to be a social engineering organization by “dictating-through-benefits” what studies they want the beneficiary to join and what ones they do not; and/or 3) Medicare just looking for any way they can to deny coverage. Our constituents state they do their best to answer these questions from beneficiaries but admit it is challenging to explain and make the beneficiaries feel good about it. We implore CMS to remove any and all barriers to conventional care (including but not limited to extra paperwork, approvals, criteria etc.) as this arguably has no financial impact on CMS and does not remove rights or benefits to which the beneficiary is otherwise entitled to as these conventional care items or services, by definition, are 1) needed out of medical necessity, 2) would have been provided absent a study, and 3) would have been covered by Medicare absent a study. Perhaps CMS could be clear that these additional criteria (as well as the NCD itself) only apply to the second and third bullet of routine care and not the first (i.e. “conventional care”).
In moving on to the proposed regulations themselves, we do not have any issues leaving unchanged the sections of 42CFR405 Subpart B. As to the proposed changes put forth, we will summarize the comments from our constituents on each of these sections in sequence and then pose some remaining question and comments of a more general nature.
§ 405.201 Scope of subpart and definitions.
We do not have any issue with the proposed removals, additions or edits to the definitions. § 405.207 Services related to a noncovered device.
With exceptions noted below for § 405.212, we have no issue with this change. § 405.211 Coverage of items and services in FDA approved IDE studies.
Regarding § 405.211(a), we understand the need for “(1) The FDA approval letter” and “(2) IDE Study Protocol” but wish to bring up some logistical issues concerning “(3) IRB approval letter” and “(4) clinicaltrial.gov identifier” [sic]. We believe that these elements should be dropped due to confusion and/or non-necessity which we will describe below.
Before getting to those points, we wish to clarify something related to the unit of approval as it relates to item “(2) IDE Study Protocol”. When a protocol is approved, does that mean that its subsequent revisions are deemed approved as part of that unit of approval or would each revision need to be submitted for review? This issue is relevant as protocol revisions are not assigned a new clinicaltrials.gov number, yet CMS may determine that changes made to the protocol may affect their previous approval decision. It is more common than not that IDE protocols, as indeed most study protocols, are amended at least once if not more during their course. There are no studies known to us as to how often this occurs for devices but for drugs, one study by Tufts Center for The Study of Drug Development demonstrated a completed protocol changed an average of 2.3 times. We have no reason to believe that device studies would be any different in their number of amendments. For CMS’s evaluation purposes, these changes will range from glaringly benign (e.g. changing study staff contact information) to the potentially more relevant (e.g. changing inclusion/exclusion criteria). If CMS intends to reevaluate these protocol amendments for coverage, they will need to have an additional method for uniquely identifying protocols in addition to the NCT number (such as adding the “Version Number” or “Revision Date”) as the NCT number does not change with these protocol amendments. Complicating this is that in a multicenter study, it could take months or even over a year to transition everyone to the same version of the protocol. In following, this would not only affect the CMS website posting but also the provider claims thus necessitating both clinicaltrials.gov number and version date/number. Currently, the contractors do not review protocol amendments for additional coverage and we hope that the central reviewing agency
would not introduce this practice either- given its problems of implementing and the fact that changes will not likely alter the decision.
Moving on to the requirement for “(3) IRB Approval Letter”, we have several questions and comments leading to our suggestion that this requirement be dropped. First, this item is also affected by the issue pointed out above of what to do about protocol changes. A protocol change cannot be implemented without approval from the IRB and thus the same issue of the need for submitting updates to protocols (if requested) would pertain to IRB approvals as well. Next, we call to your attention that while some institutions obtain IRB approval prior to or in parallel with budgetary feasibility, a great number institutions do not seek IRB approval until the budget feasibility is complete. Medicare coverage analysis and approval is an integral part of that budget feasibility. In these cases, by waiting on the coverage analysis and approval to be done after the IRB has approved the protocol for enrollment only stands to delay Medicare recipients from participating until such review is done or, for those who cannot wait, necessitates a HINSS or ABN form which is intimidating to the beneficiary.
The next issue with “(3) IRB Approval Letter” stems further from the uncertainty as to what the unit of approval actually is when there is a multicenter study. This issue extends beyond IRB approval but, as it is the first time this multicenter issue is brought up in this response, we will describe the issue in general and then bring it back to the issue of the IRB letter. Specifically, is the unit of approval the protocol itself or each individual provider site conducting the protocol (i.e. essentially is a multicenter protocol with 30 participating sites a single approval or 30 approvals)? Certainly one of the potential efficiencies of this review process is to only have a single approval across all sites conducting the same protocol. This would necessitate that if the protocol is approved once, then each additional participating site would not have to submit to this central review process. If this is not the case, then CMS will have to post not only the approved protocol and NCT number on the website, but also the provider numbers as well to which they have approved payment. As to how this impacts the requested item “(3) IRB Approval Letter”, we call to your attention that IRB approval is investigator-specific in a multicenter study and not all study sites use the same IRB (i.e. our 30 site study may have 17 sites using a “central IRB” and the other 13 sites reviewing it on their own for a total of 14 IRBs). Thus if the unit of approval is the protocol (and not the matching of the protocol-site), then only one site needs to be approved for all sites to be approved. If the unit of approval is institution-specific, then we will not be able to gain the efficiencies that this centralized review promises as CMS will have to request and track the IRB approvals for each site. This issue of what exactly is the unit of approval needs to be clear as it is fundamental to many points in this proposed rule. In summary for “(3) IRB Approval Letter”, we believe that this requirement should be dropped. To be clear, we only take issue with the requirement to submit the letter and not conducting clinical investigations under existing federal laws outside of CMS. There are ample regulations
set forth by FDA (and OHRP if the study is federally funded) that require IRB approval prior to study startup as well as sponsor audits to assure no shipment of devices occurs until such IRB approval is obtained and maintained. We hope that CMS will let other governmental agencies police this as they have and that this additional documentation requirement can be eliminated, especially since its introduction seems to cause more confusion and problems as demonstrated above.
As to item “(4) ClinicalTrial.gov number” [sic], first we believe that this is a typo and should have been clinicaltrials.gov number (with an “s”) as that is the official title of the website. Secondly, at the time of submission to CMS, this number may not be available as other information is required to register than just the protocol. Thirdly, as pointed out above, the clinicaltrials.gov number does not uniquely identify protocol amendments under that number and if CMS wishes to reevaluate each amendment, you would need other supplemental identifiers as well (such as NCT number PLUS a version date or version number). Fourthly, the clinicaltrials.gov number is specific to a single protocol which may have multiple sites, therefore the NCT number does not uniquely identify individual sites conducting that protocol so only requesting the NCT number is indicative that CMS is wanting to approve the protocol as the unit of approval and not each individual site. We hope that is the case but then the IRB approval letter issue pointed out above needs to be resolved. If this is not the case, there will have to be additional identifiers such as NCT number PLUS provider number. We understand that requesting this item is an attempt to catalogue by a universally accepted unique identifier (which we applaud) instead of CMS creating its own nomenclature. We believe that listing the approved protocols and their dates of approval on a publically available website will be an asset to those billing for services pursuant to that protocol by clearing up any ambiguity on if the protocol is approved.
Regarding § 405.211(b), (c) & (d), with exceptions noted below for § 405.212, we have no issue with this change.
§ 405.212 IDE study criteria.
Overall, we appreciate the intent of each of these criteria in § 405.212(a) but consider most (if not all) duplicative on what other government agencies are doing and/or impractical as written/understood. In the following table, we itemize each of these criteria and provide our comments. In addition to our comments below, we maintain as stated earlier in this response, that coverage of conventional care should be immune to any and all additional criteria including but not limited to the below. Finally, we offer some suggestions as an alternative to these criteria.
Proposed Regulation Comments
(1) The principal purpose of the study is to test whether the item or service
This is very confusing as written. Is it asking about outcome of patients of which are represented in the
meaningfully improves health outcomes of patients who are
represented by the Medicare-enrolled subjects.
Medicare-enrolled population? Outcomes of patients in the broader population of which the Medicare-enrolled subjects in the study are a representative sample of? If the latter, how would a site or sponsor know if
Medicare recipients would even enroll at the time of submission? How will “meaningful” be defined and who decides that? What is meant by “outcome”? Is “outcome” purely the targeted clinical indicator or is it overall quality of life?
(2) The rationale for the study is well supported by available scientific and medical information, or it is intended to clarify or establish the health outcomes of interventions already in common clinical use.
While we would support this rationale, we believe this is overly duplicative of the FDA’s oversight. We suggest that the criteria be eliminated as there is well
established government oversight of this area as well as well-established self-governance through IRBs and scientific review committees.
(3) The study results are not
anticipated to unjustifiably duplicate existing knowledge.
Although Medicare may cover the routine care, there are other expenses that a study entails giving
commercial pressure to not duplicate existing studies. We believe the commercial incentives are aligned with Medicare’s when the studies are under an IDE.
Additionally, an IRB would weigh this in the
risk/benefits equation of the study stating that if there is not sufficient new knowledge to be gained, there is no benefit this the study is not worth the risks. We do not believe it is CMS’s role to second-guess the IRBs thus we suggest that this criterion be eliminated as this is done in IRB and scientific review.
(4) The study design is
methodologically appropriate and the anticipated number of enrolled subjects is adequate to answer the research question(s) being asked in the study.
Similar to one of the above, while we would support this rationale, we believe this is overly duplicative of what the FDA would be doing as these are IDE studies already governed for this. We suggest that the criteria be eliminated as it is duplicative.
(5) The study is sponsored by an organization or individual capable of completing it successfully.
While we support the intent of this criterion, we are unsure how this will be determined by CMS. First, we are assuming that this means both operationally capable and financially capable and there is no published criteria on how this will be objectively determined. Complicating how this will be objectively measured in a transparent way at the initial review, this is also not a static statistic. A sponsoring organization’s operational and financial capability over time may change thus if this is important once, it should be important throughout the duration of the study. Also, many studies are run through Contract Research Organizations of which the financial relationship
between them and the sponsor is unknown to providers therefore it could be the CRO, not the sponsor, responsible for the cost. Although well intentioned, we recommend that this criterion be eliminated unless it is supported with how it will be measured in an open, objective and valid manner taking into consideration how a Contract Research Organization plays into the equation. There are other regulatory and economic pressures keeping this in check as best it can be to the extent that, with all due respect, we are unsure how CMS will add value unless they intend to provide additive support by evaluating each sponsor (analyzing the financial statements, business plans and competence of key personnel), or will be requiring the posting of a completion bond or other sort of “study completion” insurance for each study. We do not believe CMS is intending to do such; therefore we are curious as to what the additive value is for this request.
(6) The study is in compliance with all applicable Federal regulations
concerning the protection of human subjects found at 45 CFR part 46.
45CFR46 only pertains to studies conducted or supported by HHS (or other organizations under this Common Rule). Outside of those institutions which have chosen to apply their Federal-Wide Assurance (if they have one) to all studies regardless of funding source, this regulation does not apply to industry or other non-HHS funded research. Besides, IDE fit more plainly under FDA regulations at 21CFR50 (Informed Consent) and 21CFR56 (Institutional Review Board oversight) as, unlike 45CFR46, these regulations capture IDEs regardless of payer and alleviate the extra paperwork that comes with HHS funded studies as well as the inconsistencies between 45CFR46 and FDA regulations. For instance, 45CFR46 has additional subparts, particularly Subpart C, that is problematic and poses extreme additional burdens for clinical trials of this nature or could possibly exclude a Medicare recipient prisoner (or on probation) from volunteering for a study. Also, should 45CFR46 remain, you have to coordinate with OHRP and answer the question as to if each institution needs to obtain a Federal-Wide Assurance as there will be mass confusion on this as organizations that do not do federally-funded studies, even if they know what an FWA is (and many do not) have chosen not to obtain one when not doing any federally funded studies where they will feel it required
if CMS requires following Common Rule. We
recommend that should this criterion remain, that it be changed to FDA regulation instead of OHRP/Common Rule. To be clear, we have no issues with compliance with OHRP and/or FDA regulations as they apply to these studies. Our issue has to do with the additional time and resources to do yet another justification and/or attestation. With that said, we believe this criterion is unnecessarily duplicative as, being an IDE study, it by default must fall under FDA regulations. We also believe that this is unnecessary based on its intent as disclosed in the preamble as CMS’s response to “egregious misconduct in the past in endeavors to conduct clinical research”. We do not see it as CMS’s (or any other payer’s) mission to be an additive agency to FDA and OHRP in this area of human subject
protection, and even if it was, it does not seem to be necessary as the current system has been determined adequate as determined by President Obama’s convened Presidential Commission for the Study of Bioethical Issues. Fueled to assure such egregious misconduct in the past could not repeat itself (such as. the highly publicized research in Guatemala in the 1940s), President Obama charted this commission to evaluate the current regulations to see if they were adequate. In December 2011, this commission published their findings entitled Moral Science: Protecting Participants in Human Subjects Research, stating that while any system can always be improved, quoting from the report, the “current rules and
regulations provide adequate safeguards to mitigate risk.” We hope that as sponsors and providers already have to follow these recently reevaluated regulations that this duplicative attestation can be eliminated. (7) All aspects of the study are
conducted according to appropriate standards of scientific integrity set by the International Committee of Medical Journal Editors.
We are unsure what this means and are also confused by its inclusion based on potential meanings as well as issues of timing and scope. Is CMS referring to being in accordance with their document entitled “Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical
Publication”? If so, please specify that document, which version is desired and if it this is intended to automatically endorse subsequent revisions by ICMJE. If this is not referring to this document but another document or concept, please give a more concrete idea
of what is meant by this and how it will be measured. As to our confusion on its inclusion, the ICMJE “Uniform Requirements” in their own words “address the ethical principles related to the process of evaluating,
improving, and publishing manuscripts in biomedical journals and the relationships among editors and authors, peer reviewers, and the media [and to] address the more technical aspects of preparing and submitting manuscripts.” Given that the write-up of the study manuscript occurs after the study interventions are completed and Medicare has paid for what they have paid for, we are unsure of how this will apply to the medical necessity of the payments for routine care and if it did, how this criteria will apply when the standard pertains to the publishing of the conclusion of the study and not it’s conduct.
Finally, although we have great respect for the ICMJE committee and its uniform requirements, we are aware that first, its standards are aspirational and not
mandatory. There has been evidence of dissent from major journals from time to time when they disagree with a certain component(s). Second, there are numerous other journals not proclaiming ICMJE standards (but perhaps adhering to alternatives to ICMJE such as Council of Science Editors, World Association of Medical Editors and Committee on Publication Ethics) that may be more suitable for a sponsor to pursue publication of study results in (or more likely to publish the results in as the submission-to-acceptance ratio for major journals proclaiming ICMJE is abysmally low and also despite the ICMJE’s encouragement to publish “negative results”, their journals publication % of negative results is just as abysmal). While the Uniform Requirements of the ICMJE is a popular standard in the private sector, we caution CMS against “picking winners” in this decision as well as hardwiring private organizations (which may change their philosophy or go out of business) in federal regulations.
(8) The study has a written protocol that clearly demonstrates adherence to the standards listed here as Medicare requirements.
We do not believe that IDE protocols evaluating overall safety and efficacy should reference any particular payer. Clinical investigations of IDEs are not designed with specific payers in mind thus we recommend that this criterion be eliminated. We understand that the
protocol should address a population that includes Medicare beneficiaries but do not agree that anything related to payers be hard-wired in the protocol. Medicare coverage is an insurance coverage issue, not a scientific issue and protocols are payer agnostic. Should there need to be the scientific necessity to study issues where any payer (including Medicare) is a
variable, this would be a marketing study or other economic study and not part of the IDE clinical investigation process and thus outside of the scope of this regulation. Additionally, many of these protocols are multinational and thus referencing “Medicare” in the protocol would be confusing to non-U.S. countries and to eliminate it would require two protocols- one that would enroll Medicare recipients and one that would not- which just doesn’t make sense. Should Medicare require further justification in this or any other area pertaining to insurance coverage, we strongly recommend that it be in a separate document outside of the written research protocol.
(9) Where appropriate, the clinical research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Trials of all medical technologies measuring therapeutic outcomes as one of the objectives may be exempt from this standard only if the disease or condition being studied is life threatening as defined in 21 CFR 312.81(a) and the patient has no other viable treatment options.
The only issue we have with this criterion is rooted in the fact that Medicare is only paying for “conventional care”. We have addressed this issue before in this response and maintain that this criterion should not apply.
(10) The study is registered on the ClinicalTrials.gov Web site and/or the Registry of Patient Registries (RoPR) by the principal sponsor/investigator prior to the enrollment of the first study subject.
Note that very many, if not the vast majority of IDE studies are multicenter and the individual providers have little to no control on when the sponsor registers this thus as, at least currently (which we address later in this response) the submissions are coming from the providers and not the sponsors, this could be
problematic thus we request that this be harmonized with what the sponsors already have to do for FDA. As these IDE studies would fall under the FDA law, Section 801 of FDAAA states that registration needs to occur in essentially all non-phase-1 cases (regardless of intent to publish) within 21 days of first enrollment. While ICMJE (and other alternative codes of conduct for editors as referenced above) require registration prior to first
enrollment, this is a voluntary standard should the sponsor desire to publish the results in one of the ICMJE adhering journals. As mentioned, there are numerous other methods of publishing study results outside of ICMJE journals (such as on clinicaltrials.gov or on the sponsor’s website). We recommend that as ICMJE is a voluntary standard where FDAAA is a regulatory standard, that should this item remain, it be changed to the FDA standard so that regulations are harmonized. IF CMS is concerned that Medicare beneficiaries enrolled in the study during the first 21 days will not be informed about the study via this website, we respond that these individuals will have a much more of a robust and complete disclosure of the study particulars through the informed consent process/documentation that they will ever get through the clinicaltrials.gov posting.
Additionally, we are also unsure how the RoPR registration fits in. As we understand the criteria for placing a study on RoPR (being only a “Registry”) is mutually exclusive for listing on clinicaltrials.gov (being a “Clinical Trial”), is this an implication that the
requirements for coverage of routine care in clinical trials is to be extended into routine care provided when data is submitted to a registry? If so, then nearly every hospitalized patient will have to go through this process given the rapid growth of numerous registers
sponsored by manufacturers, professional societies and the like; most of which are de-identified data, do not involve IDEs and have no bearing on routine care. Secondly, if for some reason this is the case, as only the clinicaltrials.gov identifier is placed on the bill, will the RoPR ID be a forthcoming requirement for approval via this system and for billing?
We wholeheartedly support a system that offers the NCT number as the unique identifier for the study. We request that the posting be harmonized with FDA’s requirements and that CMS helps us understand how the RoPR registration fits in to this clinical trials
coverage policy and, in following, if there will then be a similar website posting and billing requirement for those RoPR listed registries.
(11) The study protocol specifies the method and timing of public release of
We maintain that the protocol should remain purely scientific and not include the multitude of methods of
results on all pre-specified outcomes, including release of negative outcomes. The release should be hastened if the study is terminated early. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors. However a full report of the outcomes must be made public no later than three (3) years after the end of data
collection.
dissemination of the research results as that is more sponsor operations and often cannot be even closely ascertained with any degree of validity until the protocol is near completion. Certainly a generic statement could be made but we are uncertain what value a broad generic statement about plans to publish would bring. We believe the merits of assuring proper publication lie in the actual acts of the sponsor after the data is gathered and not simply because there was a written plan which they may or may not choose to (or be able to) follow. Anyone wanting to commit fraud in this manner would write up whatever they believed CMS wanted to hear. Also, given that the write-up of the study manuscript occurs after the study
interventions are completed (and Medicare has paid for what they have paid for), we are unsure of how this will apply to the medical necessity of the payments for routine care and if it did, how this criteria will apply when the standard pertains to the publication of the conclusion of the study and not it’s conduct. Finally, what is the recourse if the results are not published in this manner? How will CMS audit this? Will CMS desire a refund of the payments years after the service if not published according to this criterion?
Additionally, while our constituents fully understand and appreciate the concerns of publication bias, we hope that CMS understands that there are legitimate reasons that a study may not be published. These reasons include things like failure to recruit a representative sample size or problems with invalid data (e.g. from problems in the research design or conduct which may or may not be the result of research misconduct, such as falsification or fabrication, on behalf of the investigators or sponsor staff). Publishing these study “results” would be injurious to subjects. At best, the sponsor could only publish that the results were inconclusive and even that can be confused with a so called “negative outcome”. Even for studies that have a “negative outcome” that unequivocally demonstrate inferiority of the sponsor’s product, although even the ICMJE Uniform Requirements encourage their editors to publish negative results, the bottom line is that they generally do not publish them despite this encouragement and the sponsors and
providers have no control over what is accepted. Why would a journal waste their reader’s time on the results of an IDE study of a device that will never make it to market? We hope CMS understands these issues and takes them into consideration should they require the “full report” to be made public.
Finally and in following with the above, even the ICMJE states that “it is important to note that the ICMJE requires registration of trial methodology but does not require registration of trial results; it recognizes the potential problems that could arise from the posting of research results that have not been subjected to an independent peer-review process.” In fact, this
requirement to make the results publically available no later than 3 years after data collection could actually hinder the peer review process as ICMJE does not allow publication in their journals when results have had “prior publications” (excluding the minimum standards of FDAAA when posted on the same registry as the study was initially listed on). Thus a sponsor posting a study in haste simply to meet the CMS requirement may jeopardize the more rigorous peer review process and actually misinform the public. In 2012, a cross-sectional analysis of NIH funded studies listed on clinicaltrials.gov done by British Medical Journal showed that one-third of NIH funded studies remained unpublished 51 months after completion. We do not know how many of these were IDE studies but the fact remains that the system, even with government funding, is not yet at a level to meet this time requirement. As FDA already has to enforce this law, we do not see this as the role of CMS to duplicate this process.
(12) The study protocol explicitly discusses subpopulations affected by the item or service under investigation, particularly traditionally
underrepresented groups in clinical studies, how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the retention and reporting of said populations in the study. If the inclusion and exclusion criteria are expected to have a negative effect on
As is mentioned throughout this response, we believe that the protocol is not the right place for this kind of communication to CMS. These populations may have absolutely nothing to do with the Medicare population anyway and this criterion runs the risk of creating accusations of CMS becoming a “social engineering” or an “advocacy” organization which it is not. We do not believe it is CMS’s role (nor any other payer’s) to use a beneficiary’s coverage of medically necessary
procedures as a means to advocate for any
the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary.
numerous private advocacy organizations representing those subpopulations. We believe this criterion should be deleted.
(13) The study protocol explicitly discusses how the results are or are not expected to be generalizable to
subsections of the Medicare population to infer whether Medicare patients may benefit from the intervention. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility.
As has been mentioned, study protocols of clinical investigations are not written with a particular payer in mind and any information requested that is payer specific should not be in the protocol but in other supporting documentation. We maintain that the protocol should remain purely scientific and not enter into debates on whether, when and how any particular payer should determine coverage. With that said, we believe this criterion should be eliminated as logically the same conclusion is seemingly drawn regardless of the answer. The very nature of Medicare participants enrolling in the study demonstrates that there is potential benefit of the intervention to the statutory Medicare population. If the intervention is for
something that would statutorily exclude the Medicare population (i.e. a pediatric device), then these
individuals would not be included in the
inclusion/exclusion criteria for the study and if the intervention does not benefit the Medicare population because it evaluates a non-covered category (e.g. a cosmetic device), then Medicare would not process the claim.
Regarding § 405.212(b) and (c), we appreciate the clarity that protocols that meet these additional criteria (that is, additional to the criteria in .212(a)) are automatically considered coverable where the rest need to be further evaluated. While non-inferiority studies are not automatically deemed covered, we read that they are not statutorily excluded and appreciate that as these studies also result in benefit to the Medicare population by bringing more choices for the physician/patient, price competition and assistance with clinical decision support when differentiating between treatment options.
Suggested alternative. The historical purpose of Medicare coverage of IDE clinical trials has been to provide Medicare beneficiaries with access to promising treatments and improved devices under study by FDA, not to gather outcomes data on the Medicare population. In addition, many IDE trials are evaluating a type of device and procedure which are standard of care treatments already covered by Medicare. We recommend that CMS consider alternative criteria focusing on whether outcomes data would fill significant gaps in the clinical evidence.
Where CMS finds that it would do so, we recommend that CMS require sponsors to gather this data via a suitable method unencumbered by FDA needs and goals.
A suitable method has already been defined and described by CMS as part of Coverage for Evidence Development (CED.) Criteria are specified in CMS’ guidance document, and application of the criteria is effectively modeled in National Coverage Determinations, which include CED. See, for example, Decision Memo for Transcatheter Aortic Valve Replacement (TAVR) (CAG – 00430N.)
Under this alternative, for example, CMS would cover an IDE trial of the Nth generation cardiac pacemaker without any additional evidence requirements. Where CMS finds a significant gap in the clinical evidence for a treatment or diagnostic method, however, as it did for TAVR, the sponsor’s facilitation of a suitable registry, either concurrent with the IDE trial or to follow it, could be a condition of approval for the IDE trial.
Having provided detailed comments to specific sections of the proposed regulations, we wish to provide some additional or supplemental comments on some of the general processes
proposed. We recognize that some of these may not be device specific and resolutions here may entail larger efforts beyond this proposed rule.
Routine Costs: The preamble mentions that this proposed rule is set forth, at least partially, to help address current inconsistencies of both study qualification and the costs of routine items and services within IDE studies. While the proposed rule addresses study qualification, we could not find where it attempts to bring consistency in the determination of routine costs. Is it CMS’s intent to determine through this process what the itemized routine costs in the protocol are (or at least which ones are coverable should a provider determine that the procedure is part of their usual care)? If so, how will this be determined and communicated to the sponsors and
providers?
Obligation To Pay: There are two items that cause great confusion in the industry due to the inconsistent interpretations that this centralized process could solve. One is will CMS work with the sponsors to determine for each protocol if the sponsor’s commitment to pay for routine care (or injury) “if insurance denies” activates the secondary payer provision? The other is will CMS want to review the consent forms to see if it contains language that they interpret preempts Medicare payment (i.e. items promised “free of charge” or “at no cost to you”)? Public Posting: Would you consider (instead of or in addition to the proposed posting) integrating this decision somehow with the clinicaltrials.gov website? One might envision a “Medicare Covered” field on the protocol page or providing a study-specific hyperlink to the CMS page so that the public has a “one stop shop”? We believe Medicare beneficiaries and providers that search the clinicaltrials.gov site will appreciate having everything (or at least a link
to everything) in one space. This would help improve the goal of transparency of the CMS decision indicated in the preamble as a goal of this process.
Integration with Core Measure Reporting: We would greatly appreciate if CMS would use this process to validate whether or not the submitted protocol is related to one or more “core measure” reporting statistic(s). Having CMS make this decision up front and posting it on the website will greatly reduce provider variability and cost in making this determination and gathering the supporting documentation only to have it second guessed by CMS later. It will also save CMS auditing costs as this decision would be relatively inexpensive to make on the front end via this process. We recognize that this request is beyond devices but it could possibly be started with devices and moved on to other areas if as successful and appreciated as we believe it will be.
Turnaround Time: The concern many of our constituents have voiced is if this process will slow down the review process instead of speeding it up. Some contractors promise 7-10 days (and actually deliver in that timeframe) but some have taken months to provide this decision placing the providers in a position of having to turn down Medicare participants or provide them a HINSS/ABN which is intimidating to the beneficiary. In following, adding to the turnaround time for a decision to be made will be the turnaround time to post the decision on the website. This will be crucial as multisite studies start multiple sites around the same time so if the unit of approval is the protocol (as opposed to each individual site), a rapid posting will alleviate duplicate submissions saving effort on both the sponsor/provider and CMS’s part. It would be easiest for the sites (and CMS) in a multicenter protocol if the sponsor submitted once on behalf of all sites.
Encouragement of Sponsor Submittal: While under the ideal assumption that it is one approval for multiple sites, the materials would be ideally submitted by the study sponsor as stated in the proposed rule. It is our experience, however, that the great majority of sponsors that are not providers themselves (i.e. manufacturers) are vehemently opposed to submitting to the MACs directly on behalf of a provider- partially if not solely out of fear they will be brought into a false-claims suit as an entity that helped “cause” a false claim (or in the case of a clinical trial enrolling hundreds or thousands of subjects, many false claims) to be filed. They often state “CMS billing is a provider issue” and remain as hands-off that process as they can. Under the proposed rule of submitting directly to CMS, we would expect no difference in (or in fact, fewer) sponsors submitting because the materials would be going directly to CMS. Perhaps CMS can make diligent efforts to alleviate any of these fears a sponsor may have of their contributing to false-claims liability by participating in this process. Having all providers wait on a sponsor submittal certainly taps into the benefit of this process as opposed to everyone either wondering who will submit first or all submitting the same information thinking they need to be the first.
Implementation/Grandfathering: This proposed rule did not address any transition plan or if/how studies currently approved by the contractors will be “grandfathered in” after the
effective date. Please provide a transition plan and if there will be any grandfathering provisions in the regulation and guidance.
Transparency of Process: The preamble of the document stated that CMS was proposing a “transparent” process but there was no description on how this process would be transparent. Will the proceedings be open to the submitter or even the public? Will there be a live dialogue between CMS and sponsor or just a paper process? Will sponsors and providers have access to CMS comments on their materials? Will sponsors know the reasons their request was denied? Will providers and sponsor have access to review materials of other sponsors?
Additionally, how will significant financial interests (or lack thereof) held by reviewers or their immediate family be assessed and addressed prior to review (i.e. according to the PHS standards)? We ask that the regulations address how CMS will be transparent in this process and that those issues pertaining to the review of significant financial interests of the decision makers harmonize with the amounts and processes in the PHS rule on disclosing significant financial interests (42CFR50 and 45CFR94)-noting that these interests can not only cause a person to approve a product they have interest in, but also disapprove a product in which they hold interest in a competing product.
Authority of Review: We ask that CMS be very clear in the final regulation that that local contractors cannot add any additional requirements or request duplicative submissions to obtain coverage.
In conclusion, although we have provided critique on many of these items, please do not see this as an overall negative review of the proposed overall process. We see real potential in a single-entity review not only in-and-of-itself but as a platform to decrease variability and cost on both CMS and provider side on many other things (such as core measure reporting consistency). We are certainly willing to provide expert assistance in any task force or extramural committee pertaining to these discussions or other items pertaining to CMS’s intersection with the clinical research professionals. Our constituents are among those closest to this issue and thus have the most hands-on experience. Do not hesitate to contact us for formal or informal discussions. Our final request is that our constituents would greatly appreciate CMS supplying presenters at our annual conference (or for our webinars) to help clear up issues related to clinical trial billing. For many years we have found this kind of dialogue very fruitful with the FDA and OHRP and are told that they also appreciate the dialogue and learning how they can improve communication, education and policy. We hope CMS would look favorably upon this request and ask that you please provide us with a coordinating person to schedule this with.
Thank you for your consideration of our comments and requests. Please let me know if ACRP may otherwise serve as a resource on issues related to clinical research.
Sincerely,
James D. Thomasell, CPA Executive Director
