Concerns over cost should lead FDA to recommend adjustments to these trials, which many say have led to unexpected knowledge and changed the field of diabetes care.
Large cardiovascular outcomes trials (CVOTs), which began a decade ago, will likely remain part of the drug approval process for companies that develop treatments for type 2 diabetes (T2D). But based on a 2-day hearing and the October 25, 2018, vote of an FDA panel, changes to the trials seem likely.
The question to the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee was “Should an unacceptable increase in cardiovascular risk be excluded for all new drugs to improve glycemic control in patients with type 2 diabetes, regardless of the presence or absence of a signal for cardiovascular risk in the development program?” Panelists voted 10-9 to keep the trials, but on both sides, there were calls to adjust the 2008 guidance that created the current system.1
“We now have 8 clinical trials conducted under the guidance. All 8 have demonstrated no excess cardiovascular risk with any of the therapies studied,” wrote William Chong, MD, acting director of the FDA’s Division of Metabolism and Endocrinology Products, in an analysis presented to panel members ahead of the meeting. “Notably, [results of] some of the trials have shown a reduced risk for adverse cardiovascular events.”2
It is not so simple, said Steven Nissen, MD, of the Cleveland Clinic, in an interview with Evidence-Based Diabetes Management™ (EBDM) ahead of the meeting. Nissen’s 2007 meta-analysis of rosiglitazone in the New England Journal of Medicine,3 which suggested an increased risk of myocardial infarction and cardiovascular death, led to the 2-step process that
he recommended, which guides drug development for T2D to this day. At the time, he received backing from cardiologist Robert Califf, MD, who would go on to become FDA commissioner.4
Conducting CVOTs would lead to more than their expressed purpose of informing physicians and the FDA about whether drugs for T2D increased the risk of major adverse cardiovascular events (MACEs), Nissen predicted. “We also knew that if you did outcomes trials, you would learn things you didn’t otherwise know,” he said.
For example, he said, CVOTs have caused the FDA to add information about heart failure risk to the label of saxagliptin (Onglyza),5 and the trial for canagliflozin (Invokana), the
sodium-glucose cotransporter 2 (SGLT2) inhibitor, showed an increased risk for lower-limb amputations.6
At the same time, results of other trials have shown that SGLT2 inhibitors appear to have cardiovascular benefits,6,7 as does the glucagon-like peptide-1 (GLP-1) receptor agonist (RA) liraglutide (Victoza).8 Novo Nordisk, which makes liraglutide, announced in late November that top-line results of the PIONEER 6 trial showed that another GLP-1 RA, oral semaglutide, reduces cardiovascular and all-cause mortality risk but not the overall number of cardiovascular events.9 Nissen noted that results of CVOTs have shown that GLP-1 RAs do not cause pancreatitis, which had been a concern.
The FDA’s guidance sets standards that allow drugs for T2D to reach the market, while these giant randomized controlled trials often continue in a postmarketing phase, depending on the phase 2 and 3 results (see Table). The trials are huge, involving thousands of patients and laboratories around the world to ensure the studies are adequately powered. As a result, some stakeholders argue that the trials have become too expensive and stifle innovation while driving up the cost of drugs currently on the market.
Nissen said using claims data and other “real-world” observational sources just would not do, and 2 of the 3 experts who testified before the FDA—cardiologist Marc Sabatine, MD, MPH, of Harvard Medical School and the TIMI Study Group, and Jennifer Green, MD, of the Duke Clinical Research Institute—agreed.
“Adequately powered and randomized CVOTs of individual agents should continue,” Green said. “There is no substitute.”
“I don’t think loosening regulatory standards is good public policy,” Nissen said in the interview with EBDM. He added that it was “unlikely” that doing so would make drugs for T2D
But Robert Ratner, MD, former chief scientific and medical officer at the American Diabetes Association (ADA) and now with Georgetown University, and several panelists said the knowledge gained from the first decade of CVOTs could allow the FDA to recommend adjustments, which would make premarket trials stronger and more streamlined. Nissen agrees there are approaches that can achieve this goal without going back to pre-2008 standards. Among the ideas offered during the meeting:
• Strengthen the phase 2 and 3 trial requirements and require CVOTs only if a signal is detected.
• Tighten premarket requirements, and use registry or observational data to detect safety signals post approval.
• Add premarket requirements beyond MACE for other safety issues, based on findings in the first decade of CVOTs. CVOTs have prompted major professional
societies, including the ADA and the American College of Cardiology (ACC), to update their clinical guidelines based on findings about newer classes of therapy, especially SGLT2 inhibitors GLP-1 RAs (see SP610-SP613). And pharmaceutical companies have gone back to the FDA to add cardiovascular indications after their initial drug approvals to gain a
leg up in the market.10-12
The ADA published a paper in January 2018 that discussed the issues surrounding CVOTs; the authors rejected the idea that the trials were discouraging drug development but acknowledged their contribution to drug costs.13 ACC Vice President Richard Kovacs, MD, FACC, similarly cited the FDA panel’s effort to balance competing concerns in
an email to EBDM:
“Over the course of the last decade, our awareness of the connection between diabetes treatments and cardiovascular outcomes has increased tremendously. Outcomes trials performed since publication of the guidance provided us with a great deal of additional information, but they also raised many new questions. The Committee has appropriately highlighted the need for pausing to consider whether we have the correct information or whether we should be asking different questions and/or using different types of trials. The information generated by the guidance has forced clinicians to face the realities of cost and value consideration, generating winners and losers among the drugs
In the January paper in Diabetes Care,13 authors led by William T. Cefalu, MD, the ADA’s current chief scientific, medical, and mission officer, offered several ways in which “the next generation of diabetes trials should be smarter, simpler, and innovatively designed to make more efficient use of resources and produce more generalizable results while still addressing safety issues.” Suggested areas for improvement included:
• Involvement of lower-risk populations. Because the FDA sought to show that new therapies for diabetes were safe, the guidance called for studying patients with
higher levels of cardiovascular risk. But some trial designs have included only those with advanced cardiovascular disease and failed to measure whether a therapy could stop it
from advancing. Larger, longer trials would tell investigators more about the value of therapies in prevention.
• Longer-term follow-up. The ADA authors suggested innovative trial designs that include lifelong follow-up through electronic health records (EHRs), along with FDA approval of methods to track clinical outcomes in this manner. Such trials would give more information about cost-effectiveness, they wrote.
• Comparisons of drugs. The authors noted the need for trials with other therapies as a control, including tests of combinations of drugs known to be cardioprotective. Cost
sharing between pharmaceutical companies should be encouraged to free up resources for innovation.
• Diverse trial designs. Methods that use big data, or factorial designs that test multiple interventions at once, are more efficient. Pragmatic trials that make use of health systems’ EHRs can boost treatment persistence. Data from earlier trials can help investigators modify how the analysis is conducted, especially if they are exploring new end points.
• Inclusion of advocacy groups. Patient-reported outcomes should be included in future studies, and digital reporting tools can increase these abilities. Although some have cited the cost of CVOTs to pharmaceutical companies, the trials have also helped drugs like empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly) stand apart from competitors; the SGLT2 inhibitor was the first to demonstrate a cardiovascular benefit in the EMPA-REG OUTCOME trial, according to results released in September 2015.7
Thomas Seck, MD, vice president of US clinical development and medical affairs, primary care, at Boehringer Ingelheim, said in an interview with EBDM that the FDA guidance changed the discussion about glucose-lowering agents. “To say [an] agent should not increase the risk of cardiovascular events was not only appropriate, [but] it was something
that society in general should expect,” he said.
Seck shares the view that broader use of real-world evidence would be useful, and he would like to see more flexibility to allow more attention to other end points, including heart failure. “This would add more information for patients and for the healthcare system overall,” he noted.References
1. FDA Center for Drug Evaluation and Research. Guidance for industry: diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. www.fda.gov/downloads/Drugs/Guidances/ucm071627.pdf. Published December 2008. Accessed December 4, 2018.
2. FDA Center for Drug Evaluation and Research. FDA background document: Endocrinologic and Metabolic Drugs Advisory Committee Meeting, October 24-25, 2018. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM623913.pdf. Accessed December 4, 2018.
3. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457-2471. doi: 10.1056/NEJMoa072761.
4. Herper M. The great drug debate. Forbes website. forbes.com/2008/07/03/fda-nissan-diabetes-biz-healthcare_mh_0703diabetes.html#5cd838774355. Published July 3, 2008. Accessed December 3, 2018.
5. FDA drug safety communication: FDA adds warnings about heart failure risk to labels of type 2 diabetes medicines containing saxagliptin and alogliptin [news release]. Silver Spring, MD: FDA; April 5, 2016. www.fda.gov/drugs/drugsafety/ucm486096.htm. Accessed December 3, 2018.
6. Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi: 10.1056/NEJMoa1611925.
7. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi: 10.1056/NEJMoa1504720.
8. Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322. doi: 10.1056/NEJMoa160382.
9. Caffrey M. Oral semaglutide shows reduction in cardiovascular death, all-cause mortality in type 2 diabetes. The American Journal of Managed Care® website. ajmc.com/newsroom/oral-semaglutide-shows-reduction-in-cardiovascular-death-allcause-mortality-in-type-2-diabetes. Published November 24, 2018. Accessed December 3, 2018.
10. FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetes [news release]. Silver Spring, MD: FDA; December 2, 2016. www.fda.gov/newsevents/newsroom/pressannouncements/ucm531517.htm. Accessed November 27, 2018.
11. FDA approves Invokana (canagliflozin) to reduce the risk of heart attack, stroke or cardiovascular death [news release]. Titusville, NJ: Janssen; October 30, 2018. janssen.com/us-fda-approves-invokanar-canagliflozin-reduce-risk-heart-attack-stroke-or-cardiovascular-death. Accessed November 27, 2018.
12. Mattina C. Liraglutide gains new indication for reducing CV event risk. The American Journal of Managed Care® website. ajmc.com/newsroom/liraglutide-gains-new-indication-for-reducing-cv-event-risk. Published August 25, 2017. Accessed November 27, 2018.
13. Cefalu WT, Kaul S, Gerstein HC, et al. Cardiovascular outcomes trials in type 2 diabetes: where do we go from here? Reflections from a Diabetes Care editors’ expert forum. Diabetes Care. 2018;41(1):14-31. doi: 10.2337/dci17-0057.