Today we published a post on the Covington eHealth blog regarding the HHS Office of Inspector General’s (OIG) Work Plan for fiscal year 2016. The post describes OIG’s plan to review FDA’s oversight of medical devices networked to electronic medical records and hospital systems.
Two recent reports cite gains made by the Center for Devices and Radiological Health (CDRH) in strengthening the clinical trial enterprise and shortening the review times for marketing applications for medical devices. The reports suggest that CDRH’s review processes are becoming more efficient, and that on average applicants can expect shorter review times for investigational device exemption (IDE) submissions, premarket approval (PMA) applications, and premarket notification (510(k)) applications, relative to years past.
In its 2014–2015 Strategic Priorities, CDRH announced that it intended to strengthen and streamline its review process related to clinical trials. CDRH announced two specific goals to support this effort: (1) improve the efficiency, consistency, and predictability of the IDE process to reduce the time and number of cycles needed to reach appropriate IDE full approval for medical devices, in general, and for devices of public health importance, in particular; and (2) increase the number of early feasibility/first-in-human IDE studies submitted to FDA and conducted in the United States. CDRH set various targets over the course of 2014 and 2015 to achieve these goals.
On September 24, 2015, CDRH issued an update on its progress. Overall, CDRH claims to have met its clinical trial program goals. For example, the report states that:
- CDRH had reduced the number of IDEs requiring more than two cycles to an appropriate full approval decision by 53% compared to FY 2013 performance. The goal had been a 50% reduction. For FY 2015, 73.5% of IDE studies were fully approved within two cycles as compared to 14.8% in FY 2011.
- CDRH had reduced the overall median time to full appropriate IDE approval to 30 days, meeting its goal. In 2011, the median number of days to full IDE approval was 442 days.
- CDRH had increased the number of early feasibility/first-in-human studies submitted to each premarket Division compared to FY 2013. Specifically, there was a 50% increase in the number of early feasibility study submissions, and a 100% increase in the number of approvals, for the first nine months of FY 2015 compared to FY 2013.
CDRH discussed these and other improvements to its clinical trial program in a blog post (see here).
Also, on October 15, 2015, the California Life Sciences Association and Boston Consulting Group—with cooperation from FDA—released an infographic report titled “Recent Trends in FDA Medical Device Regulation.” The report addresses trending data about the medical device review process over the last fifteen years, including PMA review times, 510(k) decision times, and variation in performance across CDRH’s review divisions and branches. The report found that:
- PMA average review times have declined steadily since FY 2010, with the exception of FY 2013 when there was a notable uptick in the percentage of devices referred for panel review (36% in 2013 versus 8% in 2012). PMA average review times for FY 2014 are likely to reach their shortest time since 2000.
- Although they are still above historic averages, 510(k) decision times have decreased over the last three fiscal years and the backlog has decreased.
- While previously review division and branches varied significantly in meeting MDUFA PMA and 510(k) performance goals, recent overall performance improvements have also resulted in more consistent performance across the Center.
These reports suggest that CDRH has made strides in improving its IDE and marketing application review processes over recent years. If sustained, these efforts should improve the predictability and timeliness of FDA reviews of medical device submissions going forward.
The pace and process used by FDA for the review of combination products has been the subject of considerable concern by many device companies. On October 14, 2015, FDA’s Office of Planning issued a report summarizing a study of the intercenter consultation process for the agency’s review of combination products. The report identifies several challenges faced by FDA staff in reviewing combination products and makes recommendations for addressing the issues identified by the study.
As noted in the report, FDA initiated the study last year following concerns expressed by industry regarding the consistency and clarity of FDA’s communications related to combination product reviews, including in a 2014 industry survey. Consultations between agency centers during review of combination products are currently governed by internal procedures that were last updated in 2004.
The purpose of the study was twofold: (1) to “examine coordination within FDA for consulting across agency centers, including management, timing, timeliness, and workload challenges,” and (2) to “investigate interactions between applicants and FDA around combination product applications.” The study team conducted focus group discussions within CDRH and CDER and interviewed agency employees in leadership positions and key roles related to the review of combination products. The study team obtained input from industry representatives on issues faced by industry prior to developing the questions posed to focus group participants and interviewees.
Yesterday we published a post on the Covington eHealth blog regarding the FDA Center for Devices and Radiological Health (CDRH) Regulatory Science Priorities for FY 2016. The post describes CDRH’s top ten regulatory science priorities with a particular focus on those related to leveraging Big Data and health information technology to inform regulatory decision making.
On October 5, 2015, after three years of continued discussions and negotiations on the modernization of EU medical devices and IVD rules, the Council of Ministers of the EU countries (“the Council”) agreed on a full General Approach on the review of the medical devices and IVD framework. The European Commission considers this as “a major step forward towards the adoption of new regulations on medical devices to help guarantee a high level of health and safety protection for EU citizens using these products.”
This agreement is based on the technical work of the Permanent Representatives Committee of EU countries which finalized the Council’s position on the draft Medical Devices and IVD Regulations on September 23, 2015. The core substance of the Council’s position was already agreed in a partial General Approach on the draft EU medical devices package on June 19, 2015 (for details please see our previous post of early September). The final agreement of October 2015 does not deviate from the substance of that partial agreement of June 2015. The main difference is that it includes a general approach on the recitals of the draft Regulations on medical devices and IVD. Preambles of EU legislative instruments do not have a binding effect; however, they are useful in the interpretation of rules and usually consulted by EU and Member State institutions and courts in their application of the law.
For example, as we noted earlier in our September post, the Council’s General Approach does include clarifications on companion diagnostics in the recitals of the draft IVD Regulation, which will be useful in the application of the relevant rules in the future. The compromise text of those recitals is slightly different from the one adopted back in February 2015 and is as follows:
“ (11a) Companion diagnostics are essential to define patients’ eligibility to specific treatment with a medicinal product through the quantitative or qualitative determination of specific markers identifying subjects at higher risk of developing adverse reaction to the specific medicinal product or identifying patients in the population for whom the therapeutic product has been adequately studied, and found safe and effective. Such biomarker(s) may be present in healthy subjects and/or in patients.”
“(11b) It should be clarified that devices monitoring the response to treatment by the corresponding medicinal product for the purpose of adjusting treatment to achieve improved safety or effectiveness of that corresponding medicinal product are considered companion diagnostics. Devices that are used in treatment drug monitoring to ensure that the drug concentration in the human body is within the therapeutic window of the drug are not considered companion diagnostics.”
The final agreement on the Council’s General Approach of October 2015 will enable the Council to initiate the “trilogue” discussions with the European Parliament and the European Commission. The aim is to reach an agreement for the adoption of the new Regulations as soon as possible, in theory even before end of 2015; a more realistic prediction, however, would be to have an agreement sometime in 2016.
Please note that the draft Regulations include transitional periods for application of their rules. The Medical Devices Regulation will apply three years after its entry into force and the IVD Regulation will apply five years after entry into force. Devices which comply with the new rules may be placed on the market even during the transitional periods.
It is important to note, however, that the application of the new framework will have an impact on devices that are already on the market on the basis of the currently in force Directives 90/385/EEC (Active Implantable Devices Directive), 93/42/EEC (Medical Devices Directive) and 98/79/EC (IVD Directive). E.g., based on the draft Medical Devices Regulation, devices that have been lawfully placed on the market before its date of application may continue to be made available only until five years after that date. Similarly, the new framework will also affect the validity of certificates issued by notified bodies before and after the entry into force of the Medical Devices Regulation.
The full texts of the General Approach are available online at:
On October 5, the Office for Civil Rights (OCR) at the U.S. Department of Health and Human Services launched a new platform to enable developers of mobile health technology, as well as others “interested in the intersection of health information technology and HIPAA privacy protection.” OCR notes that there is currently “an explosion of technology using data about the health of individuals in innovative ways to improve health outcomes.” The platform allows for individuals to both submit and review questions on the HIPAA implications of these mobile health applications.
The platform invites mobile health developers to submit questions and topics for future guidance. The portal asks:
What current provisions leave you scratching your heads? How should this guidance look in order to make it more understandable, more accessible? Use this page to submit your questions about HIPAA. Or present a use case. Look at what your peers are discussing, comment on it and vote on which topics or use cases would be the most helpful or important to your work.
As of now, the platform features questions (though no answers yet) regarding:
- what entities are covered by HIPAA;
- the application of HIPAA to cloud computing;
- what aspects of the application (environment) must be HIPAA compliant;
- the content of business associate agreements;
- the flow of patient-generated data; and
- the use of audit logging by developers.
Anyone can browse the site, but users who wish to submit questions must register. Registered users may also offer comments on other submissions or vote on the relevance of a topic. The portal represents that the entities and email addresses associated with posts by registered users will be anonymous to OCR. OCR also states that posting or commenting on a question on the portal will not subject anyone to enforcement action. While OCR will moderate comments posted by users, it will not vouch for the accuracy of these comments. Thus, users must pay close attention as to whether guidance appearing on by the portal is endorsed by OCR before taking action in reliance on this guidance.
The release of the portal comes at a time of particular uncertainty for medical application developers. HHS has acknowledged that existing HIPAA guidance has not addressed all of the questions raised by emerging technologies and has said that it plans to seek guidance from mobile application developers themselves. Depending on the timeliness of, and level of detail contained in, OCR’s responses to questions, the portal could prove a useful resource to a quickly evolving industry.
On September 24, 2015, FDA published a proposed rule that, if finalized, would amend the agency’s regulations defining “intended use” for drugs and devices. Given the central role that “intended use” plays in FDA’s regulatory system, we regard this as an important development.
The concept of “intended use” has long served as a fundamental tenet of FDA’s regulatory system. The intended use of a product determines whether it meets the definition of a drug, device, or other regulated product under the Federal Food, Drug, and Cosmetic Act (FDCA) and thus may be regulated by FDA. Intended use also gives rise to the concept of off-label use or promotion. For example, most medical devices are approved or cleared for a particular intended use described in that product’s labeling. If evidence demonstrates that the manufacturer’s actual intended use is different than the approved or cleared use, this can result in the product becoming misbranded, triggering civil or criminal penalties. Therefore, one of the most critical questions in FDA law is how intended use is defined. What evidence should be considered when defining the intended use for a drug or device?
Both the drug and device regulations broadly define intended use. The current regulation for devices, 21 C.F.R. § 801.4, states:
The words intended uses or words of similar import … refer to the objective intent of the persons legally responsible for the labeling of devices. The intent is determined by such persons’ expressions or may be shown by the circumstances surrounding the distribution of the article. This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements by such persons or their representatives. It may be shown by the circumstances that the article is, with the knowledge of such persons or their representatives, offered and used for a purpose for which it is neither labeled nor advertised. The intended uses of an article may change after it has been introduced into interstate commerce by its manufacturer. If, for example, a packer, distributor, or seller intends an article for different uses than those intended by the person from whom he received the devices, such packer, distributor, or seller is required to supply adequate labeling in accordance with the new intended uses. But if a manufacturer knows, or has knowledge of facts that would give him notice that a device introduced into interstate commerce by him is to be used for conditions, purposes, or uses other than the ones for which he offers it, he is required to provide adequate labeling for such a device which accords with such other uses to which the article is to be put.
This regulation (as with the counterpart drug regulation, 21 C.F.R. § 201.128) has long posed interpretive challenges. For example, the regulation defines intended use according to the “objective intent” of the manufacturer as expressed in promotional activity of the manufacturer, but then suggests that other evidence, such as how the product is actually used by physicians/consumers, can also determine intended use. With very limited exceptions (in cases with unusual facts), courts have determined “intended use” by reference to the claims used by manufacturer to promote its products. For example, as stated by the Fourth Circuit, “no court has ever found that a product is ‘intended for use’ … within the meaning of the FDCA absent manufacturer claims as to that product’s use.” Brown & Williamson Tobacco Corp. v. FDA, 153 F.3d 155, 163 (4th Cir. 1998), aff’d, 529 U.S. 120 (2000), but see U.S. v. Travia, 180 F. Supp. 2d 115 (2001).
FDA’s Proposed Rule
FDA’s proposed regulation arises out of its regulation of tobacco products. The proposed rule primarily addresses the circumstances when a tobacco product would be considered to have an intended use that triggers regulation as a drug or device. The preamble, however, more broadly addresses the concept of intended use. FDA continues to assert that intended use can be determined broadly, stating that “[i]n the context of medical products, generally, circumstantial evidence often ensures that FDA is able to hold accountable firms that attempt to evade FDA medical product regulation by avoiding making express claims about their products.” However, FDA “would not regard a firm as intending an unapproved new use for an approved or cleared medical product based solely on the firm’s knowledge that such product was being prescribed or used by doctors for such use.”
The primary change to both the drug and device intended use regulation would be to strike the last sentence of the regulation (“But if a manufacturer knows ….”). According to FDA:
[T]he Agency does not regard a firm as intending an unapproved new use for an approved or cleared medical product based solely on that firm’s knowledge that such product was being prescribed or used by doctors for such use. Accordingly, FDA is taking this opportunity to amend §§ 201.128 and 801.4 to better reflect FDA’s interpretation and application of these regulations. These changes would not reflect a change in FDA’s approach regarding evidence of intended use for drugs and devices. These clarifying changes to the intended use regulations would apply to drugs and devices generally, and not just to products made or derived from tobacco and intended for human consumption.
If finalized, these changes would clarify aspects of FDA’s approach to assessing the intended use of a drug or device. But given the importance of this concept and the lack of clarity on how intended use is determined, drug and device companies should review FDA’s proposal and consider submitting comments to the docket on ways in which FDA could further clarify its policies. The agency will accept comments until November 24, 2015.
CDRH has scheduled two next generation sequencing (NGS) workshops on November 12 and 13, 2015 (see here and here for the Federal Register announcements) to further advance the conversation with stakeholders on the Agency’s development of new regulatory strategies for NGS-based clinical tests. These workshops will build upon a discussion paper published in December 2014, which we summarized in a previous blog post, and a public workshop with stakeholders held earlier this year.
As we discussed in our previous blog post, NGS refers to technologies that can perform sequencing of large segments of an individual’s DNA, and even the individual’s entire genome. NGS tests pose regulatory challenges to FDA, because they can “generate large amounts of data and consequently may have relatively broad or undefined intended uses or indications.” 79 Fed. Reg. 78092, 78093 (Dec. 29, 2014). The agency states in a blog post that FDA seeks “to ensure that these tests provide accurate, reproducible, and meaningful results relevant to a person’s medical condition while continuing to foster innovation so that people have access to the best available results generated by the most cutting-edge medical technologies.”
The first of the two workshops held in November will focus on obtaining feedback on “possible analytical standards and approaches to develop or build on existing standardization efforts in order to optimize FDA’s regulatory approach to NGS-based in vitro diagnostic tests.” The second workshop will address current challenges in clinical validation of NGS tests. According to FDA’s blog post, the workshop will discuss how scientists, patient groups, and private industry can work together to develop “high-quality, curated clinical databases of genomic information that associate specific genetic changes with various diseases.”
FDA plans to publish additional discussion papers in advance of these two workshops. These papers will include general questions for stakeholder consideration and also provide a “high level overview” of regulatory considerations for the two issues to be covered by the workshops. We will provide updates when the two papers are published.
On August 26, 2015, the Medicare Advisory Panel on Clinical Diagnostic Laboratory Tests (hereinafter the “Panel”) held its inaugural meeting. The Panel was established by the Secretary of Health and Human Services under the authority of Section 216 of the Protecting Access to Medicare Act of 2014 (“PAMA”), which prescribes a new market-based payment system for laboratory tests paid under the Clinical Laboratory Fee Schedule. PAMA directs the Secretary to consult with the expert outside advisory Panel for (1) input on the establishment of payment rates under the new law for new clinical diagnostic laboratory tests, including whether to use crosswalking or gapfilling processes to determine payment for a specific new test, (2) input on the factors used in determining coverage and payment processes for new clinical diagnostic laboratory tests, and (3) recommendations under the new law. See Charter for the Medicare Advisory Panel on Clinical Diagnostic Laboratory Test.
The 16-member Panel is chaired by Centers for Medicare & Medicaid Services (“CMS”) Medical Officer Steve Phurrough. A full list of the panel members can be found here.
The August Panel meeting occurred in advance of CMS’s implementation of the PAMA payment system, yet the Panel discussed new test codes for 2016, voting to make recommendations on codes relating to molecular pathology, drug of abuse testing, and other areas previously discussed at the Annual Laboratory Public Meeting held in July. The Panel heard from several presenters discussing these codes, which included representatives from the American Medical Association and the Association for Molecular Pathology. A full list of the presenters can be found on CMS’s website. The Panel also considered and made recommendations on requests for reconsideration of 2015 payment decisions. CMS is expected to release its preliminary decisions for 2016 by the end of September.
With the first Panel meeting now complete, the pathology and laboratory communities continue to wait for CMS to publish regulations implementing PAMA’s new mandates. The regulations will likely also provide additional information on the scope of the Panel’s role in addressing coverage and payment processes under the market-based pricing system. Although PAMA required a final rule to be released by June 30, 2015, CMS has missed the deadline. CMS announced at the meeting that the proposed rule is almost completed and should be issued in the next several weeks. The proposed rule has been received by the Office of Management and Budget and can be tracked here.
On June 19th, 2015, the Council of EU Ministers reached a partial General Approach on the review of the medical devices and in vitro medical devices (IVD) rules in the EU (an overview of the texts is accessible here). The General Approach does not yet include the recitals to the new medical devices and IVD regulations.
The Council’s text on the new IVD Regulation significantly amends the Commission’s proposed definition of ‘companion diagnostics’, an evolution relevant to sponsors of both medicinal products and diagnostic devices. The Council’s definition of companion diagnostics is almost identical to the definition used by the FDA, but significantly different from the European Commission’s proposal and the European Parliament’s suggested amendments. An overview is set out below. Continue Reading