21st Century Cures Act

At the end of July, FDA released a tangible plan for promoting innovation in the development of digital health products. In this Digital Health Innovation Action Plan, FDA acknowledges that digital health technologies are critically important in advancing health care, and that traditional FDA pathways to market are not well suited for all of these technologies. Over the last few years, FDA has taken a deregulatory approach with respect to low risk digital health products and has issued guidance regarding its enforcement discretion approach to wellness products, medical device data systems, medical imaging communication and storage devices and certain mobile apps. However, there still has been uncertainty with respect to whether, and how, other digital health technologies will be regulated. This new plan paves the way for additional regulatory clarity and streamlined pathways to market for digital health developers.

Some of the key aspects of the plan include:

  • Issuing 21st Century Cures Act implementation guidance. The Cures Act, which was passed in December of last year, includes provisions clarifying FDA’s regulation of software. Specifically, these provisions explicitly exclude certain software from FDA’s definition of a “medical device,” including electronic health records and software that encourages healthy living, displays, transmits, stores or performs limited conversion of medical device data and supports administrative activities. As a result, these products are not subject to FDA’s oversight. The planned draft guidance, which the Agency hopes to release by the end of the year, will reconcile these new Cures provisions with existing FDA guidance. Cleaning up and clarifying policies in this space will help solidify FDA’s interpretations and reduce regulatory uncertainty.
    FDA also commits to providing guidance regarding products that include regulated and unregulated functionality. The Cures Act makes clear that the fact that an unregulated application co-exists with a regulated application within a solution does not submit the unregulated functionality to FDA oversight. FDA still may consider how the unregulated software impacts the safety and effectiveness of the regulated software, but the unregulated software nevertheless remains unregulated.
  • Running a pilot program focused on “pre-certification” of digital health developers. In September, FDA will launch a pilot pre-certification program applicable to manufacturers of stand alone medical device software. The purpose of the program is to develop objective criteria that, if met, would demonstrate an entity’s ability to reliably develop high quality, safe and effective software. The intent is for FDA to use these criteria to develop a framework to pre-certify software developers that satisfy the requirements. In turn, pre-certified developers would be subject to a streamlined premarket review for new lower-risk products (e.g., less premarket submission information would be required and/or review times would be faster). FDA indicated that, in some instances, pre-certified companies would be able to market certain lower risk products, that presumably would be subject to 510(k) clearance today, without any premarket review at all. However, to account for reducing the front end requirements, FDA envisions that developers will collect real-world data once their products hit the market to assure they are safe and effective.
  • Issuing CDS software guidance. By the first quarter of 2018, FDA plans to issue draft guidance detailing which CDS is not subject to FDA regulation. The Cures Act carves out transparent, professional use CDS from the definition of a medical device. This carved-out CDS is software that is not intended to be relied upon as the primary basis for a clinical decision, but rather allows the healthcare professional to independently review and assess the underlying rationale for the software recommendation in connection with making a clinical decision. While guidance on how FDA interprets the relevant Cures language on this issue will be helpful, it is equally, if not more important, for the Agency to provide guidance on CDS that falls outside of the Cures Act exemption (e.g., consumer clinical decision support, machine learning and non-transparent CDS).
  • Finalizing 510(k) Guidance on Software Changes. FDA’s Digital Health Innovation Action Plan also includes finalizing the draft guidance on “Deciding When to Submit a 510(k) for a Software Change to an Existing Device.” This guidance is the software counterpart to FDA’s draft guidance on “Deciding When to Submit a 510(k) for a Change to an Existing Device,” which has had a controversial past. FDA first attempted to revise its guidance on when a 510(k) is required due to a change made to a device in 2011. FDA was required by Congress to withdraw its 2011 draft guidance due to the potentially significant impact the draft guidance would have on industry. In August 2016, FDA published this pair of draft guidance documents. Given the disagreement and debate that has surrounded this topic, a definitive FDA approach will provide manufacturers greater certainty regarding any submission requirements for the range of software changes made to traditional medical devices, as well as to stand alone software devices.
  • Adopting the IMDRF’s Approach to Clinically Evaluating SaMD Once Finalized. FDA also intends to adopt the final version of the Software as a Medical Device (SaMD): Clinical Evaluation guidance as published by International Medical Device Regulators Forum (IMDRF). FDA released draft guidance that incorporated this IMDRF document in 2016. While it is unclear how procedurally FDA will adopt a final version of the IMDRF policy without public review and comment, the IMDRF framework will nevertheless provide insight into FDA’s thinking on clinical evaluation requirements for medical device software given the Agency’s leadership in the IMDRF work group that drafted the document and this pre-emptive endorsement. It also serves as a reminder that despite FDA efforts to minimize regulatory burdens for low risk digital health products, moderate and high risk medical device software remains subject to FDA’s premarket review. The 21st Century Cures and CDS guidance, both of which are expected after IMDRF’s SaMD’s Clinical Evaluation document is finalized, will be instrumental in clarifying which digital health products are subject to such requirements.

Although FDA has been expected to release many of these policies for years, the Digital Health Innovation Action Plan is aggressive, promising five draft or final guidance documents in just over six months, while at the same time conducting the pre-certification pilot program.  Whether this is a reflection of the new administration, a new Commissioner or a new (or renewed) focus on digital health innovation, it is a welcome development and one that will be watched closely by software companies, traditional medical device manufacturers and patients alike.

Recent federal and state legislative efforts signal an increased focus on a significant and largely underappreciated public health threat – antimicrobial resistance (i.e., when a microorganism (such as a bacteria or virus) is able to resist the effects of medications such as antibiotics and antivirals, causing such medications to be ineffective). The results of a 2014 study underscore the magnitude of the threat of so-called “superbugs,” estimating that the number of deaths worldwide attributable to antimicrobial resistance will reach 10 million by 2050.  By comparison, the same study projected 8.2 million deaths from cancer, and 1.2 million deaths from traffic accidents by 2050.  Legislative efforts to address antimicrobial resistance span from encouraging development of new pathways to market for antimicrobial drugs to expanding data collection and monitoring efforts to better understand the scope of the problem.  The combination of new data and less-restrictive pathways to market simultaneously provide pharmaceutical companies with a faster entry into the market for antimicrobial drugs and a better understanding by local health departments and hospitals of the need for new drugs to combat resistant strains of microorganisms.

Federal Initiatives

On the federal side, the 21st Century Cures Act (the “Act”), signed into law by President Obama on December 13, 2016, includes several measures related to antimicrobial resistance.  For example, the Act creates a new approval pathway for “limited population drugs,” which are antibacterial or antifungal drugs “intended to treat a serious or life-threatening infection in a limited population of patients with unmet needs.” While the Act allows FDA to approve limited population drugs with less data than typically would be required, the approval is restricted to “the intended limited population,” and the manufacturer must meet additional labeling requirements to inform physicians of the drug’s limited approved use.  In addition, manufacturers of drugs approved through this pathway are required to submit any promotional materials to FDA at least 30 days before they plan to use them.

While adding specific labeling requirements for new drugs approved for limited populations, the Act also changes labeling requirements for susceptibility test interpretive criteria. Susceptibility test interpretive criteria includes the myriad of testing options used to determine whether a patient is infected with a specific microorganism or class of microorganism that can effectively be treated by a drug.  The Act requires pharmaceutical manufacturers to replace the currently existing susceptibility test interpretive criteria from the drug’s packaged insert or labeling with a reference to a FDA website to be built where such criteria for all drugs will be held.  Manufacturers have one year from the day the website is established to move its susceptibility test interpretive criteria to the so-called “Interpretive Criteria Website.”

The Act also increases monitoring and reporting of antimicrobial drug use and antimicrobial resistance at federal healthcare facilities, like VA hospitals and facilities run through the Indian Health Service or the Department of Defense. Further, it requires annual federal data reporting on aggregate national and regional trends related to antimicrobial resistance. A broad base of reliable data on antimicrobial resistance and the associated morbidity and mortality does not currently exist. However, along with the federal government, certain states are also making efforts to improve data collection in this space.

State Initiatives

Many states receive funding from the Centers for Disease Control (CDC) to collect data about patients with extremely resistant strains of microoganisms, like carbapenem-resistant Enterobacteriacea, or “CRE” – a bacteria that kills an estimated 600 Americans each year. The Illinois Department of Health, for example, developed a registry in 2014 that tracks positive lab tests for extremely drug-resistant organisms, including CRE.  Illinois began tracking this information following a deadly outbreak of CRE in 2013.  Health care facilities participating in the registry receive alerts when an infected patient is transferred in and must report CRE-positive culture results of patients within seven calendar days.  The most recent annual report shows a 7% increase in overall cases; however, a recent article posits that the increase may be somewhat attributable to better reporting efforts by hospitals gaining experience identifying CRE.  Similar programs exist in many states, but these programs typically do not track the outcomes of CRE cases.

A recently proposed bill in California (California Senate Bill 43) would require hospitals to include information within death certificates that identifies whether “any antimicrobial-resistant infection…was a factor in the death.”  Specifically, the bill would require the “attending physician [who] is legally obligated to file a certificate of death” to determine whether, in the physician’s professional judgment, an antimicrobial-resistant infection was a factor in the patient’s death.  State law already mandates tracking of over 80 communicable diseases, like HIV and Hepatitis (A-E), but only tracks antibiotic-resistant infections of VRE and MRSA if they are contracted while a patient is already in the hospital.

Given the magnitude of the potential threat, it is reassuring that legislative initiatives are showing an increased focus on antimicrobial resistance. New pathways to market for antimicrobial drugs and increased public awareness of the rising threat of “superbugs” should lead to additional innovation by drug manufacturers.  The limited population pathway may also cause some manufacturers to reassess their pipelines and strategies to market drugs toward limited populations.  For manufacturers facing expensive and burdensome FDA requirements to market new antimicrobials to a general population, the limited population pathway may provide a cheaper and faster entry into the market.  Early entry into the market can then fund additional efforts expand the label beyond a limited population.

Last week, the U.S. Department of Health and Human Services (“HHS”) announced that FDA intends to update its regulations governing clinical studies of new drugs.  More specifically, FDA intends to update Parts 312 and 16 of Title 21 of the Code of Federal Regulations (the “Code” or “CFR”).  In its announcement, HHS stated that the revisions will be focused on defining and clarifying “the roles and responsibilities of the various persons engaged in the initiation, conduct, and oversight of clinical investigations subject to [investigational new drug] requirements.”  The announcement also notes that the changes will “better protect the rights, safety and welfare of subjects and help ensure the integrity of clinical trial data.”

I don’t think anyone disagrees that these are important goals and that FDA should be commended for recognizing their importance and taking steps to achieve them.  However, these are not the only goals FDA should be striving to achieve as it revamps these regulations.  As noted in the January 29, 2015 Innovation for Healthier Americans report issued by Senators Alexander and Burr, clinical trials are becoming longer and the number of procedures subjects are required to undergo continues to increase.  This not only makes trials more expensive, but also makes it harder to enroll and retain subjects.  Addressing the rising costs and enrollment difficulties is one of the drivers behind the 21st Century Cures Act which is working its way through the House and the companion legislation working its way through the Senate.  Although addressing these goals has bipartisan support and FDA legislation traditionally has been less susceptible to the partisan gridlock in Congress, there is no guarantee that Congress will be able to address these issues legislatively.  Therefore, it would be advisable for FDA also to focus on streamlining the regulatory process and establishing a framework for the use of surrogate endpoints and adaptive clinical trial designs.  This can serve two purposes.  First, it hedges against the possibility that a legislative fix will not materialize.  Second, it reduces the potential that FDA will need to revisit these regulations again if a legislative fix does materialize.

In addition to expanding the goals FDA is pursuing with these changes, FDA should also expand the scope of the regulations that it will update to achieve these goals.  According to the announcement, FDA only intends to update Parts 312 and 16.[1]  However, it is unclear how FDA can achieve these goals if it limits the scope of changes to these parts of the Code.  Part 312 primarily focuses on the division of responsibilities as between the sponsor and the investigator.  However, there are other parties and entities responsible for the oversight of clinical investigations, including institutional review boards (IRBs) and the institutions where the studies are conducted.  Specifically, IRBs are responsible for ensuring the protection of rights, safety, and welfare of clinical trial subjects.  Although Part 312 requires the Sponsor and the Investigator to ensure IRB approval and continuing oversight, Part 312 does not specifically address the roles and responsibilities of an IRB or the research institutions.  Instead, these are addressed in Part 56.  Therefore, it is unclear how FDA will be able to effectively clarify the “roles and responsibilities of the various persons engaged in the initiation, conduct, and oversight of clinical investigations” and “better protect the rights, safety and welfare of subjects” without also updating Part 56.

I look forward to seeing the changes FDA proposes to make to Part 312. I just hope that these changes enhance the protection of study subjects and ensure the integrity of the data generated by clinical trials in a manner that also makes conducting and participating in clinical trials less burdensome than it is currently.

 

 

[1] 21 CFR Part 16 governs regulatory hearings to which investigators are entitled to in the event they are disqualified pursuant to 21 CFR § 312.70 or to which sponsors are entitled in the event FDA terminates an IND.