Memorandum

ADA-EASD Release Joint Statement on Improving CGM’s Clinical Value and Utility – October 25, 2017

Executive Highlights

  • The ADA/EASD Diabetes Technology Working Group has published an eight-page joint statement on improving the clinical value and utility of CGM (Diabetes Care, Diabetologia). The short eight-page article is optimistic about CGM’s “great progress,” but very honest about the current barriers to adoption.
  • The authors call for better pre-marketing evaluation of CGM performance, more investment in large CGM trials in broader populations (especially type 2), better standardization of CGM outcomes/data reporting, improved safety reporting for regulators, and stronger communication between stakeholders.
  • There is a slightly negative tone to the piece (most of the focus is on barriers), though we know many of these authors are huge CGM proponents. The paper, therefore, is that a snapshot that reminds us far more progress is needed before CGM is widely adopted as standard of care.

Today, the ADA/EASD Diabetes Technology Working Group published an eight-page joint statement on improving the clinical value and utility of CGM (Diabetes Care, Diabetologia). The authors are highly regarded: Drs. John Petrie, Anne Peters, Rich Bergenstal, Reinhard Holl, Zan Fleming, and Lutz Heinemann. We’ve expected this document ever since the group’s 2014 insulin pump position statement.

The succinct eight-page article is optimistic about CGM’s “great progress,” but very honest about the current barriers to adoption – and the authors list many. The paper is evidence-based (59 citations), with clear recommendations for the field grouping under five themes:

  • More systematic and structured premarketing evaluation of CGM performance;
  • Greater investment in trials to provide evidence of CGM value and reliability for all patient groups;
  • Standardization of CGM-measured glucose data reporting from clinical trials;
  • Improved consistency and accessibility of safety reports to regulatory authorities after approval; and
  • Increased communication and cooperation across stakeholder groups.

We agree with those recommendations, as well as the more detailed list of 31 recommendations that appear on page six – read it below, sorted by the different audiences they are addressed to.

In reading the full paper text, there is a slightly negative tone, as the authors devote the most attention to adoption barriers – cost, accuracy/reliability (“particularly with earlier-generation systems”), human factors issues, lack of report standardization, and clinical trials. We know many of these authors are huge proponents of CGM, so in another sense, this article is really an honest “state of the evidence” – a snapshot that reminds us far more progress is needed before CGM is widely adopted as standard of care.

By far, the most positive section concerns using CGM to assess diabetes therapies in development – e.g., measuring hypoglycemia for a new insulin. We love seeing that so explicitly in the piece and hope the drug side of the FDA gets the message – CGM data is incredibly valuable for making more informed benefit:risk decisions! (EMA is already on board, per Dr. Bart Van der Schueren EASD and Outcomes Beyond A1c presentations.)

Hopefully, this ADA/EASD paper moves the needle on the goals noted above, aligning the field on a core shopping list of areas to improve. Coming from these two organizations and jointly published in both journals, this definitely carries weight. That said, we also hope CGM skeptics (especially payers) don’t use this as ammunition to downplay the technology – yes, barriers exist, but CGM is not the technology of five years ago and is only getting better.

Read the eight-pager here and see more highlights and Close Concerns’ questions below.

  • We believe the field has made the most progress on standardizing CGM outcomes reporting (e.g., July’s Outcomes Beyond A1c meeting and a slew of upcoming papers). Similarly, communication and cooperation across stakeholder groups has also improved – at least from what we can tell.
  • Some great strides have been made on more robust CGM trials in type 1 (e.g., DiaMonD, GOLD, IMPACT, REPLACE-BG are all mentioned), though there remains a huge dearth of type 2 studies on CGM – the paper only mentions Dr. Vigersky’s 2011 (!) study and Abbott’s REPLACE. We expect this to change as the current/upcoming generation of easier-to-use, factory-calibrated, less expensive sensors are ready for testing in a broader population. Large-scale CGM studies in hypoglycemia unawareness are definitely needed too, as are more head-to-head device studies and more cost-effectiveness analyses.
  • We also agree that little progress has been made on safety reporting to regulators after market approval – the FDA MAUDE database is nearly impossible to analyze, with substantial company-to-company differences in reporting, poor granularity, and no ability to identify root causes. (See our report on a recent controversial JAMA viewpoint related to G5 and the FDA adverse event report database.)

 

Key Conclusions

  • “Great progress has been made in CGM technology in recent years, but several barriers remain that prevent it from reaching its full potential either as a method for improving glycemic control in diabetes (with sufficient rigor for payers to reimburse) or as a means of assessing the efficacy of diabetes therapies (e.g., a novel insulin potentially associated with lower rates of hypoglycemia).”
  • “Insufficient evidence of clinical utility and reliability and the lack of consistent reimbursement contribute to limited use of CGM across large populations of people with diabetes who could potentially benefit. A more concerted commitment to seeking robust evidence by industry, regulators, clinical and technical experts, and funding and patient organizations is required for the necessary trials to be conducted and for the field to progress. CGM is a critically important technology for enabling AID systems. With further confirmation of the safety and utility of freestanding CGM technology, a more widespread uptake might be achieved.”
  • The authors support using 70-180 mg/dl (time-in-range) and the ambulatory glucose profile (AGP) for standard data visualization – both are in line with the Outcomes Beyond A1c conference in August and what we expect from upcoming journal publications.
  • Regarding FDA adverse event reporting, “..it is clear that reporting procedures for these two device manufacturers [Dexcom and Medtronic] differ substantially and change over time. Many of the reports of death could not have been related to the CGM systems, as the harmed individual was not wearing the glucose sensor at the time of death, but were noted by the manufacturer as CGM supplies were no longer required. Although we found several reports of death due to hypoglycemia while wearing a CGM system, none were considered a device issue.” We’d note that Dexcom’s US users base is substantially larger than Enlite’s, so this difference is not particularly surprising. As noted a few weeks ago, most of Dexcom’s reports concern lost communication between sensor and phone, something Medtronic does not currently have to deal with.

  • The paper goes on to note that a set of five questions was sent to Medtronic, Dexcom, Abbott, and Roche, and the “most interesting variation” was in response to the question “most common patient complaints reported through FDA’s MAUDE system?” One company “provided specific answers,” while another “replied that it considered this information confidential. In our view, this latter approach illustrates a fundamental impediment to improving the safety of CGM systems: if safety data reported for regulated health products are considered proprietary and are not made publicly available, a cycle of safety improvement cannot occur.”
  • The authors are fairly negative on the DIY community (Nightscout is mentioned), noting, “[these] informal solutions raise safety concerns and present a challenge for the regulatory establishment, as open-source software is not regulated by regulatory agencies like the FDA. There are also issues of privacy and consent…”
  • “We envision an ongoing role of the ADA, EASD, and other professional medical associations in supporting the virtuous cycle of CGM innovation, confirmation of value to users, increased utilization, and greater resources reinvested to support innovation. For this vision to be realized without further delay, we call upon regulators and manufacturing companies to work urgently with health professionals and people with diabetes to create an environment with much greater standardization of outcome measures, a high level of attention to safety issues, and full transparency of adverse event reporting.”
    • Neither ADA nor EASD have historically focused on diabetes technology, so we’ll be interested to watch what role they play going forward. We believe both could help drive CGM adoption with position statements, clinical guidelines, and advocacy. Payers do watch the guidelines, so perhaps this is a nice area for the organizations to push for greater use of CGM. We hope to see stronger, more pro-CGM language in future statements/guidelines.

Summary of Recommendations for Different Audiences

The List below appears on page six of the paper.

Regulatory agencies should:

a) Introduce a systematic, independent, and structured premarketing and post-approval evaluation of the performance of CGM systems including assessment of “human factors”

b) Promote the development of a consensus on which parameters should be analyzed and reported to characterize the performance of a CGM system

c) Specify a standardized CGM output format for reporting time in range and hypoglycemia for use in clinical trials


d) Review available outcome measures (including patient-related outcomes) and specify those best used in CGM and AID studies


e) Assess available models for cost–benefit calculations and specify which should be used for CGM studies 


f) Rapidly and transparently disseminate safety-related data reports on CGM to health care professionals 


g) Protect the security and confidentiality of patient data in the era of connectivity 


Manufacturing companies should:

a) Cooperate to standardize output formats and software used for analysis


b) Provide interfaces that can be personalized according to the needs of the user


c) Report all safety-related data transparently to the regulatory authorities


d) Cooperate with academia and health care professionals to provide balanced and adequate information to people with diabetes and package the output data in standardized formats to make it easy for major electronic health record companies to access and incorporate for clinical use


e) Incorporate a wider range of existing outcome measures including patient-reported outcomes in study designs of adequate statistical power


f) Publish all relevant data/information collected during the clinical development of a given CGM system, e.g., the results of human factors studies

g) Communicate frequently and regularly with users, user groups, and families affected by diabetes in order that real needs can be identified and promptly addressed as soon as the relevant technology becomes available (e.g., remote monitoring)

h) Observe high standards of data security and patient confidentiality 


Researchers/academics should:

a) Develop better algorithms to improve the performance of CGM and AID systems


b) Openly report and share the patient-level results of all clinical studies


c) Develop and validate specific and appropriate patient-related outcome measures
d) Develop better models for cost-benefit analyses (in partnership with industry and regulatory bodies)

e) Work to develop and perform studies that fill genuine “gaps” in the evidence 


f) Follow the recommendations made by Pickup (33) when interpreting or performing meta-analyses 


g) Involve people with diabetes and their family members/caregivers in the development of CGM and AID systems for guidance and feedback 


Research funding bodies should:

a) Fund fewer small, underpowered studies of specific devices; instead fund well-designed larger “class” studies with clinically relevant end points using more than one CGM system and including head-to-head comparisons 


b) Fund large independent registry studies 


Patient groups, health professionals, and medical associations should:

a) Provide and regularly update recommendations on CGM


b) Provide minimum standards of training for providers and people with diabetes using CGM, isCGM [FreeStyle Libre], and AID


c) Work to develop and disseminate structured company-independent education programs, e.g., SPECTRUM, and standardized output of glucose 
metrics and glucose and insulin profiles, e.g., Ambulatory Glucose Profile (AGP)


d) Work together (AACE, AADE, ADA, EASD, Endocrine Society, IDF, ISPAD, JDRF, and other patient advocacy groups) to provide wider access to CGM for all people with diabetes who are willing and able to use these devices on a near-daily basis 


Consumers of CGM technology – patients, family members, caregivers – should:

a) Report device errors and malfunctions to the manufacturers and appropriate regulatory agencies


b) Provide input to the policy development processes of professional and patient advocacy associations and regulatory authorities

c) Advocate for standardization and improved accessibility of CGM safety data to facilitate product comparisons 


Close Concerns’ Questions

Q: Will this article move the needle? Will it change manufacturers’ priorities? How will payers view it? How will HCPs view it?

Q: Which of the recommendations will have the biggest impact on CGM adoption? Which is the easiest to accomplish near-term? Which is the hardest near-term?

Q: To overcome cost/reimbursement barriers, how much focus should be put on better products vs. clinical studies? These are obviously not mutually exclusive, though it does present a big resource allocation question – R&D vs. evidence.

Q: Will insulin dose decision support and automated insulin delivery significantly enhance the value of CGM?

Q: What will it take to double CGM adoption in type 1 diabetes? Is this realistic in the next five years? How long will it take to get similar CGM adoption in type 2 insulin users? Will we see CGM broadly used in prediabetes and early-stage type 2 diabetes? Who will do these studies?

Q: How will HCPs and payers balance 24/7 CGM vs. intermittent CGM? Will anyone compare professional, blinded CGM vs. real-time CGM head to head?

Q: Will funders support larger-scale CGM studies in broader populations? Head-to-head studies of devices?

Q: How will larger/longer CGM trials keep up with the pace of innovation? Could devices be updated throughout the trial as new features are rolled out?

 

-- by Adam Brown and Kelly Close