Diabetes and the Growing Investment in Drugs, Devices, and Diagnostics 

The Rising Complexity of Diabetes Drug-Device Combination Therapies

The diabetes drug market is expansive, with many drug classes and therapeutics options to choose from. Often, patient characteristics such as age, weight, cardiovascular risk, and race create overlapping patient subgroups for which specific therapies may be most appropriate. Along with drugs, there is an ever-increasing array of devices, and drug-device combination products for the treatment and management of diabetes. Diabetes devices have been developed for testing, monitoring, and treatment and may include:

Increasingly, chronically ill patients, such as those with diabetes, are relying on combination products that include drugs and devices for their care, and manufacturers are delivering more advanced products with technologic innovations. Therapeutic options such as drug injectors and medication-coated devices have been designed to increase safety and efficacy compared to their constituent parts alone. Combination products create tremendous development and commercialization challenges for manufacturers of these products, as medical devices and pharmaceutical products used to exist in different worlds, with distinct regulations. 

Regulatory Approval Process of Medical Devices

While approval pathways are different in the US vs European Union (EU), regulatory approval processes for drug-device combinations have become clearer and easier to navigate (Table 1).

HTA Evidentiary Hurdles

In addition to legal-regulatory hurdles, the communication of value and navigating reimbursement for a drug-device (and therapeutic) combination product can be more complex than for a drug alone. Regulators and HTA agencies are in the midst of developing their appraisal methodology for these new technologies; requiring manufacturers working within this space to monitor the activities and decisions of the agencies in the US and EU to stay prepared in this dynamic environment. Across Europe, current HTA frameworks do not fully meet the challenges that arise from intrinsic differences of health technologies, and in particular medical devices and drug-device combination technologies. To investigate ways to improve HTA methods to allow for more comprehensive evaluation of medical devices, and to develop a tool that provides structured, evidence-based input into health policies, the European Commission funded the MedtecHTA project for 3 years over the period 2013 to 2015.

The research conducted by MedtecHTA served an important role to review current process and offer recommendations for HTA improvement. MedtecHTA researchers published 5 key recommendations for improving the process for HTA of medical devices. However, it has been the discretion the individual health authorities to adopt changes to their processes, and these recommendations raise many more pragmatic questions than answers. It remains to be if this academic exercise translated to meaningful changes in medical device HTA and adoption policies across the EU. 

To be fast, flexible, and responsive to the need for information on innovative technologies, the National Institute for Health and Care Excellence (NICE) has established Medtech Innovation Briefings (MIB) to provide a description of the technology, how it’s used and its potential role in the treatment pathway. The MIB outlines cost for the system including the device itself and consumables needed for operation, but the MIB is not NICE guidance and does not make any recommendations on the value of using the technologies (although it does complement existing NICE guidance products by providing rapid, responsive, information on new and novel technologies). Since program inception in 2013, over 140 MIBs have been completed and NICE aims to complete an additional 40 each year. 

Case Examples

There are several recent examples that illustrate the challenges faced by manufacturers in bringing novel technologies for the treatment of diabetes to market. 

Case #1: Xultophy
The combination therapy pen Xultophy is a once-daily combination of a long-acting basal insulin (insulin degludec) and a glucagon-like peptide 1 (GLP-1) receptor agonist (liraglutide) for patients with type 2 diabetes. While the manufacturer has secured regulatory approval and reimbursement from payers in the US, the combination therapy received unfavorable appraisals in France and Germany.

In France, Xultrophy was evaluated by the Transparency Committee (TC) of the Haute Autorité de Santé (HAS) in 2016 for the treatment of adults with type 2 diabetes to improve glycemic control in combination with oral antidiabetic agents when these, alone or in combination with basal insulin, do not achieve adequate glycemic control. HAS found an important medical benefit Service Médical Rendu (SMR) for the therapy when the dose of the individual components could be optimized. However, as a fixed-dose combination product, HAS found no improvement to the current medical benefit Amélioration du Service Médical Rendu (ASMR) for Xultrophy. In 2017, Xultrophy was reassessed for the treatment of adults with type 2 diabetes to improve glycemic control in combination with oral antidiabetic agents when they, combined with a GLP-1 analogue, do not provide adequate glycemic control. In this appraisal, the TC found an insufficient medical benefit (SMR). One of the main concerns cited in the published TC opinion was the inability to adjust insulin doses to achieve glycemic goals due to the fixed dosing of the combination therapy.

In Germany, Xultrophy was assessed in 2 populations: 

• in combination with oral antidiabetics (OADs) compared to metformin + human insulin in adult patients with type 2 diabetes mellitus when OADs combined with GLP-1 receptor agonist do not provide adequate glycemic control
• in combination with OADs compared to metformin + human insulin in adult patients with type 2 diabetes mellitus when OADs alone or combined with basal insulin do not provide adequate glycemic control
  In both assessments, IQWiG found no added benefit with Xultrophy as the company presented no studies in its dossier that were suitable to investigate the added benefit of Xultrophy in comparison with the active comparator treatment (ACT). In particular, there was a lack of direct randomized, controlled comparison to the ACT arm and the ACT arms lacked a meaningful escalation for their insulin therapy.

Case #2: Afrezza
Afrezza, an inhaled insulin technology, also experienced significant regulatory and reimbursement challenges. The device was designed to overcome many of the issues that limited the success of the first inhaled insulin product, Exubera. However, as a combination drug-device, Afrezza has faced its own unique challenges and current market access and reimbursement is limited to the US. Even with access in the US, payers have restricted reimbursement and have required providers complete prior authorizations, which include extensive respiratory testing that is not required for injectable insulin products. To overcome this barrier, the manufacturer has developed a spirometry loan program for prescribers to conduct the testing. This example highlights the unique clinical testing requirements and challenges that can arise for the reimbursement and access of drug-device combination technologies. 

Conclusion

As exemplified by these case examples, drug manufacturers bringing a drug-device (and, increasingly, diagnostic) combination product to market need to develop solutions to address these key issues that do not typically arise while developing the market access strategy for a drug alone:

Because diabetes is primarily a chronic disorder that manifests itself over years, there are numerous opportunities for drug manufacturers and device makers to develop products that incrementally improve the lives of patients who suffer with diabetes. HTA organizations will face daunting challenges in the evaluation of new technologies, and particularly drug-device (and diagnostic) combination products, which have become more technologically advanced and complex. Given the numerous technologies available for diabetes treatment, defining the appropriate place in therapy may be more difficult for authorities.

The existing gaps in regulations between drugs and devices have become more apparent as the line between drugs, devices, and diagnostics in diabetes has blurred when considering regulatory approval or access/reimbursement. Recent HTA decisions and reimbursement restrictions highlight the challenges manufacturers face in demonstrating the value of novel technologies in a crowded therapeutic area. While drug-device combinations have the potential to improve patient adherence and outcomes, the devices can also introduce new obstacles and reimbursement restrictions (as seen with Afrezza). Ultimately, manufacturers of diabetes drugs, devices, and drug-device (and diagnostic) combination products need to have an effective evidence generation strategy to obtain and retain access for their products.

The article should be referenced as follows: 

Campbell D, Healey M, Clark R. Diabetes and the growing investment in drugs, devices, and diagnostics. HTA Quarterly. Winter 2019. Feb. 25, 2019.

Sources

• AFREZZA. [package insert]. Danbury, CT. MannKind Corporation. October 2018.
• Caremark—BlueCross BlueShield. Afrezza prior approval request form. https://www.caremark.com/portal/asset/FEP_Form_Afrezza.pdf.
• Datamonitor Healthcare. Diabetes type 1 marketed drugs. https://service.datamonitorhealthcare.com/.
• Haute Autorité de Santé (HAS). XULTOPHY (insulin degludec/liraglutide), antidiabetic brief summary of the Transperency Committee Opionion. 2016. https://www.has-sante.fr/portail/plugins/ModuleXitiKLEE/types/FileDocument/doXiti.jsp?id=c_2660940
• Haute Autorité de Santé (HAS). XULTOPHY (insulin degludec/liraglutide), antidiabetic brief summary of the Transperency Committee Opionion. 2017. https://www.has-sante.fr/portail/upload/docs/application/pdf/2017-11/xultophy_summary_ct15551.pdf.
• IQWiG. [A15-15] Insulin degludec/liraglutide—Benefit assessment according to §35a Social Code Book V (dossier assessment). https://www.iqwig.de/en/projects-results/projects/drug-assessment/a15-15-insulin-degludec/liraglutide-benefit-assessment-according-to-35a-social-code-book-v-dossier-assessment.6732.html.
• IQWiG. [A15-30] Insulin degludec/liraglutide (new therapeutic indication)—benefit assessment according to §35a Social Code Book V (dossier assessment). https://www.iqwig.de/en/projects-results/projects/drug-assessment/a15-30-insulin-degludec/liraglutide-new-therapeutic-indication-benefit-assessment-according-to-35a-social-code-book-v-dossier-assessment.6905.html.
• Jamieson J. Update on Regulation of Drug/Device Combination Products—Europe and Beyond. International Pharmaceutical Quality, 2017. https://cdn.ymaws.com/www.casss.org/resource/resmgr/cmc_japan_speaker_slides/2017_CMCJP_Jamieson2.pdf.
• Medtech Innovation Briefings (MIB) frequently asked questions. https://www.nice.org.uk/Media/Default/About/what-we-do/NICE-advice/Medtech-innovation-briefings/MIB-faq-document.pdf.
• MedtecHTA. Methods for health technology assessment of medical devices: a European perspective. http://www.medtechta.eu/wps/wcm/connect/710e78e7-54b0-4d1c-ab06-f62035fe3f59/MedtecHTA_brochure_def.pdf?MOD=AJPERES&CVID=jXWsuvT.
• NICE. MiniMed 640G system with SmartGuard for managing blood glucose levels in people with type 1 diabetes. https://www.nice.org.uk/advice/mib51/chapter/Technology-overview.
• Norgaard K, Shin J, Welsh JB, Gjessing H. Performance and acceptability of a combined device for insulin infusion and glucose sensing in the home setting. J Diabetes Sci Technol. 2015;9(2):215-220.
• Ortman JM, Velkoff VA, Hogan H. An Aging Nation: The Older Population in the United States. May 2014. https://www.census.gov/prod/2014pubs/p25-1140.pdf.
• Raza A. Development of diabetes medicines: sweet or sour outcomes. Presented at: Conference of Drug Discovery and Development. March 16-17 2017. https://www.slideshare.net/AmmarRaza/development-of-diabetes-medicines-final2.
• Schäefer E, Karch A. Reimbursement for Diabetes Medical Devices in Germany. J Diabetes Sci Technol. 2014;8(1):186-187.
• Schäefer E, Schnell G, Bobáková T. Diabetes device reimbursement in the EU-5. J Diabetes Sci Technol. 2013;1;7(4):1084-1092. 
• Tarricone R, Torbica A, Drummond M. MedtecHTA Project Group. Key Recommendations from the MedtecHTA Project. Health Econ. 2017 Feb;26(Suppl 1):145-152.
• Van Norman GA. Drugs and Devices: Comparison of European and U.S. Approval Processes. JACC Basic Transl Sci. 2016;29;1(5):399-412.
• Zittartz M. The rise of the medical device/pharmaceutical product combination and how it affects traditional pharmacovigilance. 2015. https://www.pharmasol.de/pv-day-frankfurt-june-2015/.