Memorandum

FDA Advisory Committee – Novo Nordisk’s Insulin Degludec and Degludec/Aspart November 8, 2012; White Oak, MD; Full Commentary – Draft

Executive Highlights

Good evening from Silver Spring, MD and the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) Meeting on insulin degludec and degludec/aspart. Today, the EMDAC advisory committee voted a decisive 8-4 in favor of approval of Novo Nordisk’s novel basal insulin degludec. Given the day’s tense tone, fairly negative presentations from FDA, conservative panel members, and risk-focused discussion, the positive vote was ultimately a surprise for us since the FDA had appeared fairly negative all day and we assumed that panel members would be influenced by this. When it came down to the final vote, in act, the committee members seemed to embrace degludec’s advantages (hypoglycemia, flexible dosing, stable profile); we felt that although the data may not have been there “in spades,” the composite set of benefits is striking. As expected in light of the cardiovascular concerns leading up to the meeting, there was unanimous support (12-0) for conducting a cardiovascular outcomes trial at some point in the future. However, most panelists seemed to think that the apparent signal for degludec’s CV risk was inconclusive and should not prevent approval at this stage. The enclosed coverage highlights our themes from the day (centering on cardiovascular risk and hypoglycemia) as well as a panelist-by- panelist account on the final voting question.

Despite what seemed like FDA’s consistent lean towards non-approval today, we assume degludec will eventually be approved given the 8-4 vote in its favor. While, of course, the FDA could go against the committee, we do not expect this to happen (the last case of this occurring was after Orexigen’s Contrave was not approved despite a 13-7 positive vote in 2010). Not only does this win for degludec come as a victory for patients in the US, who will likely soon have a more stable and convenient basal insulin available to them, but we imagine that other companies developing novel insulins are also breathing a small sigh of relief that EMDAC recognizes the burden posed by pre-approval outcomes trials on both patients (who would be denied access to improved drugs) and drug developers (who need to plan ahead in order to garner the necessary resources for such an undertaking). We hope that the FDA takes away from this situation that more clarity and consistency would be useful around insulin development programs to avoid the potential need to unexpectedly and dramatically change a development program.

On the losing end of today’s decision, of course, is Sanofi whose Lantus may finally face meaningful competition in the basal-analog sphere. However, we would not be surprised, based on the FDA’s strong denunciation of Novo Nordisk’s hypoglycemia data, if degludec does not receive a hypoglycemia benefit over Lantus in its US label, which would slightly soften the blow to Lantus. Today’s discussion also gave us a sense of how challenging it will be for biosimilars to come to market –Novo Nordisk had an incredibly robust clinical development program (the largest ever conducted for an insulin). The fact that the discussion could have gone either way is a testament to the continued strict regulatory environment and barriers to entry for anyone trying to enter the US insulin space.

CARDIOVASCULAR SAFETY DISCUSSION

  • As a reminder, the phase 3 program for degludec was commenced under Novo Nordisk’s agreement with the FDA that degludec and degludec/aspart would not be subject to the FDA’s cardiovascular (CV) guidelines for type 2 diabetes drugs, but that Novo Nordisk would still collect and analyze CV safety data from its phase 3 program. CV safety data submitted at the time of degludec’s NDA submission included 16 phase 3 trials including one completed extension trial. These data demonstrated a 10% increased risk (HR 1.10; 95% CI 0.68-1.77) for cardiovascular death, non-fatal stroke, non-fatal myocardial infarction, and unstable angina (MACE+). The FDA, concerned about a potential CV signal, requested additional data and conducted post-hoc analyses on an updated dataset including the addition of one more phase 3 trials and six more extension studies. The FDA’s post-hoc analysis using the updated dataset found a 1.30 hazard ratio (95% CI: 0.88, 1.93) using MACE+ as the endpoint and a 1.67 hazard ratio (95% CI: 1.01, 2.75) using the FDA’s traditional MACE (MACE+ excluding unstable angina) as the endpoint. Panelists of the advisory committee discussed the reliability of the CV risk assessment based on the original meta-analysis compared to the analysis performed on the updated dataset, the validity of the two endpoints used, and whether the CV safety signal identified represented a clinical concern. For more background please see our preview at: http://www.closeconcerns.com/knowledgebase/r/685e2535.
  • In discussing the datasets used in the CV meta-analyses, speakers representing Novo Nordisk contended that no conclusions about CV risk could reasonably be drawn from the data for a number of reasons. First, the degludec phase 3 program was designed to assess glycemic efficacy, not CV safety, so the trials were not long enough, large enough, or properly powered (through enrollment of a CV-risk-enriched population to allow for sufficient accrual of events) to provide reliable safety data. Secondly, the number of patients remaining in trials at the end of two years was very low: only 12.7%of the initial 6,389 patients enrolled in the degludec and degludec/aspart arms and 7.7% of the initial 3,461 patients enrolled in the active comparator arms remained under examination at the end of full two years in extension studies. Therefore, Novo Nordisk argued that the small number of patients and events, along with the unequal exposure of patients under review, made CV safety analyses highly questionable. Further, enrollment in the extension trials required re-establishing consent after degludec treatment continuation, potentially compromising randomization since patients had a choice of whether to continue in the extension trials. Lastly, enrollment in the extension trials was also preceded by use of NPH (to wash out degludec use and test for immunogenicity) followed by another degludec titration period.
  • The FDA believed the validity of the data used in its meta-analyses were supported by a variety of compelling factors: the strategy for CV risk evaluation was prospectively planned and thoroughly carried out; the extension trials added to the updated dataset were originally agreed-upon to be included in the initial analysis (but were not initially included because at the time of NDA submission they had not yet been completed); the extension trials were controlled and applied the same methodology and rigor as the main trials for the purpose of providing long-term safety data; and retention through the end of extension studies was high (~70%). Furthermore, the updated dataset increased the patient-years of exposure in the analysis from 5444 to 7716 (a 42% increase) and the number of CV events by 60%. Finally, the trend towards CV harm held up when the analysis was performed across different endpoints (MACE vs. MACE+), using different analysis methods (time-to-event, risk difference, and incidence ratedifference analyses were performed), and across different subgroup analyses (patients with type 1 diabetes*, patients with type 2 diabetes, insulin glargine-controlled trials only, and trials with only degludec and no aspart).
  • Most EMDAC panelists were skeptical about the authenticity of the cardiovascular signal given the very low sample size and event rate, but also maintained that the potential for harm could not be excluded. Panelists generally agreed that including more data by adding the extension trials to the analysis was appropriate, but erred on the side of caution that data should be interpreted carefully due to the low sample sizes. Thus, not surprisingly, panelists agreed that a definitive conclusion about cardiovascular risk could not be drawn from the available data and would have to wait until a larger, dedicated cardiovascular outcomes trial (CVOT). One Kaplan Meier curve for MACE+ events drew significant attention, as it showed that the degludec and comparator curves were virtually superimposable until ~week 70 when events suddenly stopped occurring in the comparator group for roughly 20 weeks while events continued to accrue at a steady pace in the degludec and degludec/aspart group. Several panelists were skeptical of this curve separation because at week 52, 39% of the initial 9,214 patients remained under investigation, which dwindled to just 12% at week 104. However, most panelists maintained that safety data had to be interpreted much more liberally than efficacy data and that no safety signal should be ignored.

o Some panelists questioned the lack of a potential mechanism for why degludec would increase CV risk compared to glargine – the associated CV risk factors that were measured [lipids, blood pressure, and ECG] did not track the trend for increased MACE+ risk in the degludec and degludec/aspart group. Such an understanding why degludec might elevate CV risk would of course help in drawing a conclusion about the risk’s clinical relevance. Since Novo Nordisk repeatedly highlighted that the only functional difference between degludec and human insulin was the long pharmacokinetic profile, Dr. William Hiatt implied that that might offer a place to start looking for a mechanism for why there might be a CV signal.

  • Another point of discussion was whether appropriate endpoints were used in the meta-analyses for CV risk; Novo Nordisk contended that the FDA’s post-hoc redefinition of the MACE endpoint to exclude unstable angina skewed the analysis towards harm. Dr. Steven Marso defended Novo Nordisk’s use of the MACE+ endpoint, stating that it had been pre-specified after discussions with the FDA, that each component of the endpoint had been rigorously defined, that the adjudication was performed shrewdly, and that including unstable angina was appropriate given that it is involved in a causal pathway for myocardial infarction; the panel solidly agreed on all fronts. Additionally, the panel agreed that the FDA’s decision to also examine MACE was warranted to potentially unmask any effects of including unstable angina in the composite endpoint.
  • Novo Nordisk proposed a post-approval CVOT: 7,500 patients with type 2 diabetes, randomized 1:1 to degludec plus standard of care or another insulin plus standard of care, will be followed for five years. The proposed primary endpoint is time until first MACE (CV death, non- fatal MI, non-fatal stroke) with the trial enrolled to produce an ~2.0% event rate per year (for context, the event rate seen in the degludec phase 3 program was about 1% so the proposal of this event rate may be “too low”.

*The trend towards harm was only seen for MACE and not MACE+ in the type 1 diabetes sub-analysis.

 

  • Ultimately, the 8-4 vote to approve degludec and degludec/aspart with a post- approval outcomes trial was based on the panelists’ belief that requiring a pre- approval CVOT would delay bringing a meaningfully improved basal insulin to market. Those voting “yes” typically noted that the benefits of a truly once-a-day basal insulin for patient quality of life and adherence outweighed the incremental sense of assurance of ascertaining cardiovascular safety prior to approval. Those voting “no” maintained that, with the current state of uncertainty, the potential to unnecessarily expose patients to this risk outweighed the benefits of the drug beyond available basal insulins. Interestingly, two of the four who voted “no” were cardiologists, one was a biostatistician, and one an endocrinologist. The other five of the total six endocrinologists voted “yes.”
  • We are curious whether this situation will set a precedent for other novel insulins in development or whether it will prompt the FDA to formulate a specific guidance for pre-approval safety requirements for insulins. Even though Novo Nordisk designed its degludec program in compliance with the FDA’s guidance for CV safety, at some points today it seemed like a very real possibility that the panel might vote in favor of a pre-approval CVOT, which could have dramatically changed the course of insulin development for other candidates being developed under the same assumption that they would not have to adhere to specific CV safety guidelines. In the future, we hope that, the FDA can offer clear, consistent, and predictable guidance for companies developing novel insulins, especially on the level of risk that should be considered acceptable. This way, companies can be prepared to address the CV safety issue from the start of clinical development and get new options to patients as efficiently as possible.

HYPOGLYCEMIA DISCUSSION

  • Overall, panelists seemed split on whether use of degludec is associated with less hypoglycemia (nocturnal or overall) vs. glargine. Committee Chair Dr. Kenneth Burman thought that the insulins were fairly comparable in terms of hypoglycemia. Despite a “yes” vote to approve the drug, Dr. Thomas Weber was “not overwhelmed by the data” on the potential for reduced hypoglycemia. Dr. Marvin Konstam took a more moderate stance, noting that the hypoglycemia benefits of degludec were modest except in type 2s and in the nocturnal period (“where it really starts to pick up steam”). And in their remarks on why they voted to approve the insulin, Drs. Ed Hendricks, David Cooke, and Charles Stanley all mentioned the hypoglycemia benefits of degludec. In discussions of hypoglycemia throughout the day, the focus was more on whether the data was reliable, whether appropriate cutoffs were used, why there were geographic differences, etc. We appreciated comments from many of the endocrinologists on the panel that acknowledged the significant burden hypoglycemia places on patients’ glycemic control and daily quality of life.
  • Dr. Alan Moses, Novo Nordisk’s Global Chief Medical Officer, made a very persuasive case for the hypoglycemia benefits of insulin degludec relative to glargine, emphasizing the nocturnal data and benefits in type 2s. Dr. Moses noted that since most hypoglycemia in type 1s and 2s on basal-bolus therapy occurs around mealtimes (i.e., caused by bolus insulin), nocturnal hypoglycemia really reflects a basal insulin’s true risk of hypoglycemia. Indeed, the biggest hypoglycemia benefit of degludec relative to glargine was seen in the nocturnal period (see tables below).
  • Type 1 patients in the degludec studies had less impressive reductions in hypoglycemia relative to type 2s, though Dr. Moses explained that this finding was expected from the get-go. Degludec was associated with a 10% increased risk of overall hypoglycemia in type 1s on degludec, though the results were not statistically significant. Most panelists did not seem concerned by this finding given degludec’s advantage in the nocturnal period and the general challenges of managing type 1 diabetes.
  • Below, the key hypoglycemia meta-analyses are presented – these include overall confirmed hypoglycemia (severe episodes requiring third party assistance + self-treated episodes with a measured plasma glucose <56 mg/dl or a whole blood glucose <50 mg/dl, both asymptomatic and symptomatic) and nocturnal confirmed hypoglycemia (same but between midnight and 6 am). The results presented below were consistent when only symptomatic episodes were included. Results improved in favor of degludec when only the maintenance phase of the phase 3 trials was considered (i.e., after week 16). The hypoglycemia advantage of degludec also improved when only patients with an A1c <7% were included.

Meta-Analysis – Overall Confirmed Hypoglycemia by Treatment Type

 

Rate Ratio IDeg/Glargine Estimate [95% CI]

Change in Risk of Hypoglycemia with Degludec

Basal-Only Therapy

0.83 [0.70, 0.98]*

 17%

Type 2 diabetes

0.83 [0.74, 0.94]*

 17%

Type 1 diabetes

1.10 [0.96, 1.26]

 10%

T1+T2 Pooled

0.91 [0.83, 0.99]*

 9%

*p <0.05

Meta-Analysis – Nocturnal Confirmed Hypoglycemia by Treatment Type

 

Rate Ratio IDeg/Glargine Estimate [95% CI]

Change in Risk of Hypoglycemia with Degludec

Basal-Only

0.64 [0.48, 0.86]*

 36%

Type 2 diabetes

0.68 [0.57, 0.82]*

 32%

Type 1 diabetes

0.83 [0.69, 1.00]

 17%

Type 1+Type 2 Pooled

0.74 [0.65, 0.85]*

 26%

  • The FDA raised a number of objections to the hypoglycemia data collected by Novo Nordisk. Overall, the Agency seemed quite critical of the data quality and reliability, calling into question whether there actually was any hypoglycemia advantage. Most of the committee’s discussion today centered on the cardiovascular risk and largely avoided addressing these objections.

The degludec phase 3 trials excluded patients with important risk factors for hypoglycemia: history of recurrent severe events; hypoglycemia unawareness; and significant end-organ dysfunction (e.g., renal failure). In interpreting this fact, Dr. Jean- Marc Guettier (Diabetes Team Leader, Clinical Reviewer, CDER) asserted that the “generalizability of hypoglycemia findings to those most at risk is limited.”

 

  • Results are confounded by between group differences in the timing of basal insulin injection. Dr. Guettier highlighted the different pharmacodynamic profiles of glargine and degludec, noting that the time needed to reach maximal glucose lowering effects differs between the two insulins. In most of the phase 3 trials, degludec was injected in the evening and was expected to peak 12 hours after injection (i.e., in the morning). Conversely, glargine was allowed to be dosed at any time of the day, including in the evening. Unfortunately, Novo Nordisk did not capture the timing of glargine injection in most of the trials.
  • Did Novo Nordisk capture hypoglycemic episodes accurately? First, the FDA noted that defining hypoglycemia based on a low glucose values alone can be misleading. For example, point-of-care blood glucose meters “lack accuracy” (this was great to hear from the Drug division!), especially at low blood glucose values. This was one of the main ways in which Novo Nordisk characterized hypoglycemic episodes. Second, the Agency emphasized that defining hypoglycemia based on the presence of hypoglycemic symptoms alone can also be misleading – since symptoms lack specificity, the most specific definitions rely on demonstrating concurrent presence of low glucose and hypoglycemic symptoms.
  • Was Novo Nordisk’s definition of hypoglycemia appropriate? While the ADA definition of hypoglycemia includes severe episodes plus documented symptomatic episodes of hypoglycemia (i.e., the patient must have both symptoms and a low measured plasma glucose <70 mg/dl), Novo Nordisk’s definition was much broader – it also included asymptomatic episodes (i.e., the patient had no symptoms but a measured blood glucose <56 mg/dl or plasma glucose <50 mg/dl). Asymptomatic episodes accounted for 32% of events in type 1s and 53% of events in type 2s. When the stricter ADA definition of hypoglycemia was applied to the phase 3 trials, results often changed markedly from those observed with Novo Nordisk’s definition – in some cases (including the large 3582 and 3579 trials), a degludec advantage for hypoglycemia turned into an increased risk for hypoglycemia relative to glargine. Dr. Guettier also highlighted that the thresholds for the two definitions are different (70 mg/dl vs. 56 or 50 mg/dl) and Novo Nordisk used both plasma and whole blood glucose values (vs. just plasma in the ADA definition). Panelists– especially Chair Dr. Kenneth Burman – seemed to prefer the more specific andsensitive ADA definition, though none explicitly objected to Novo Nordisk’s definition.
  • Nocturnal hypoglycemia data quality is affected by a number of issues. First, there were a low number of confirmed events at night (10 times fewer events than in the 24-hour period). Second, Dr. Guettier explained, “a drug that has a hypoglycemia advantage should show benefit in both the daytime and nocturnal hours.” This inconsistency was characterized on the slide as “difficult to interpret.” We disagreed with this statement on the grounds that night and day are completely different – different insulin doses, different use of insulin types (e.g., rapid-acting), and different activity levels. Panelists were not concerned about this objection.
  • Lower rates of hypoglycemia were not associated with better A1c outcomes. Since hypoglycemia is often called a significant barrier to glycemic control, the FDA analyzed whether less hypoglycemia was associated with better efficacy. However, degludec was non-inferior to glargine in terms of A1c lowering, suggesting no efficacy despite less hypoglycemia. In fact, A1c results trended in favor of insulin glargine in eight of nine studies on the slide. Of course, we would note that by reducing hypoglycemia, one would expect A1c to increase. This did not strike us as a very valuable point by FDA and in fact, was a somewhat discouraging reminder of the Agency’s continued focus on A1c.
  • Adding two hours to the nocturnal period (i.e., midnight to 8 am) negates or lessens the nighttime hypoglycemia benefit of degludec. In type 1s, the overall rate ratio goes from 0.85 [0.68, 1.06] to 1.05 [0.33, 3.35]. In type 2s, it goes from 0.69[0.59, 0.81] to 0.89 [0.47, 1.72]. Panelists thought this was an unfair time extension (e.g., breakfast boluses) and preferred 10 pm to 6 am or midnight to 6 am (Novo Nordisk’s original analysis).
  • A subgroup analysis revealed dramatic differences between rates of hypoglycemia based on region of randomization. The table below shows that while hypoglycemia was highly comparable between glargine and degludec in the US, the results outside the US exhibited stark differences: a 28% increased risk for hypoglycemia with degludec among type 1s outside the US and an 21% reduced risk for hypoglycemia with degludec in type 2s outside the US. Few panelists directly addressed this in questions to the committee section. Dr. Robert Smith felt this was not a particularly valuable analysis, potentially because there were a small number of patients being compared to larger group. He hypothesized that it is unknown what the difference is, but “it probably isn’t real.”

Region of Randomization and Overall Hypoglycemia Rate Ratio

IDeg/Glargine Estimate [95% CI]

 

Overall

USA

Outside USA

Type 1

1.11 [0.94, 1.31]

0.99 [0.81, 1.20]

1.28 [0.96, 1.71]

Type 2

0.84 [0.76, 0.93]

0.97 [0.81, 1.15]

0.79 [0.69, 0.90]

  • We wonder how FDA’s concerns about degludec’s hypoglycemia data and potential advantage relative to glargine will ultimately translate into a label. This will have critical commercial and marketing implications in our view, especially for pricing. If Novo Nordisk cannot claim superiority to glargine on hypoglycemia, we wonder if it will be challenging to charge a premium for the new insulin or effectively market to encourage patients to switch from glargine. Dr. Ellen Seely explained that the drug should not be presented to patients as a drug that decreases hypoglycemia because 1) it does not seem to help with daytime control in type 1 diabetes; and 2) the studies excluded patients with hypoglycemia unawareness. With patients in tighter and tighter control, she noted that hypo unawareness becomes more and more of a problem. Whether the regimen decreases nocturnal hypoglycemia in those with hypoglycemia unawareness remains to be seen. Dr. Charles Stanley shared her view on the label: “I don’t think you could claim [hypoglycemia] as a definite in the package insert.”

 

ADDITIONAL DISCUSSION TOPICS

Degludec’s stable pharmacokinetic profile was cited by many panelists and patients as a major advantage. Dr. Robert Smith called the stable pharmacokinetics “very appealing” and “a very good option to change the game and do better.” Dr. Charles Stanley, a pediatric endocrinologist, also highlighted degludec’s stability as a particularly good option for type 1 patients. Dr. Ellen Seely took it a step further, noting that since glargine and detemir fell “veryshort” of lasting a full day, “there’s been a longtime search for an insulin that would last 24 hours.” Dr. Ed Hendricks argued even more emphatically for the stable profile, “The sponsor has achieved one of perhaps the holy grails of diabetes treatment – one time a day injection of insulin.” Numerous degludec trial participants in the open public hearing also echoed these remarks – many specifically cited the hassles and challenges of splitting basal insulin doses, something that is not necessary with degludec.

  • Thought not a focus of Novo Nordisk’s presentations, many panelists and patients were favorably disposed to the flexible dosing advantage of degludec (a minimum of eight hours, a maximum of 40 hours). Dr. Thomas Weber felt that the ability to variably dose degludec would improve both adherence and patient care. Dr. Ellen Seeley concurred that it’s an important advantage, as did many patients during the open public hearing. In his sponsor presentation, Dr. Bernard Zinman also framed this as a critical issue: 35% of patients miss insulin doses or don’t take them as prescribed; on average, patients miss 3.4 doses per month; and there are currently no clear instructions on what to do when there is a delayed or missed dose. The latter was emphasized by Dr. Robert Smith, who added that the first thing endocrine fellows are taught is how to handle the very common patient phone call, “I forgot to take my insulin; what do I do?” In his view, missed doses are “something we experience all the time in clinical practice. I don’t think we have ideal insulins now to provide stable, baseline, round the clock levels.”
    • Given the focus on hypoglycemia and cardiovascular risk, Dr. Alan Moses devoted just two slides to this novel dosing flexibility feature – as a reminder, Novo Nordisk is recommending that degludec be taken at the same time every day, though patients have the possibility of postponing or advancing the injection time with a minimum of eight hours and a maximum of 40 hours between the injections. Importantly, degludec’s advantage over glargine in nocturnal confirmed hypoglycemia was maintained with these extreme dosing intervals.

COMMENTARY FROM VOTING COMMITTEE MEMBERS – “YES” VOTES

  • Though Dr. William Hiatt (University of Colorado School of Medicine, Aurora, CO) struggled a bit in deciding which way to vote, he ultimately voted in favor of approval, in part due to the “onerous” burdens a pre-approval study would create. He suggested there be an interim analysis in the post-marketing cardiovascular outcomes trial, such that if there continued to be an imbalance in risk, the Agency could take appropriate actions sooner rather than later. As a cardiologist, Dr. Hiatt did not personally find the benefits of insulin degludec to be overwhelmingly compelling, but he trusted the opinion of his endocrinology colleagues on the panel that insulin degludec represented a significant advance beyond currently available insulin therapy.
  • Also noting his decision was a tough call, Dr. David Cooke (Johns Hopkins University School of Medicine, Baltimore, MD) voted “yes” because he believed the pharmacokinetics of insulin degludec are an advance for the treatment of both type 1 diabetes and type 2 diabetes. He stated that obviously there is concern about whether or not the agent increases cardiovascular risk, but that the risk is far from proven. Dr. Cooke commented that he thought it would be important for clinicians to have access to insulin degludec so that they could decide whether the benefit/risk profile of the drug justifies its use on a patient- by-patient case.
  • Acting chairperson Dr. Kenneth Burman (Washington Hospital Center, Washington, DC) voted “yes,” since he thought the potential benefits outweighed the potential risks of the drug. He noted that one potential advantage of insulin degludec is its ability to be mixed with rapid-acting insulin; he did not seem to think it conferred an advantage in hypoglycemia risk, commenting that it seemed similar to comparators. In addition, Dr. Burman requested further research on the use of insulin degludec at different times of the day, and its use with GLP-1 agonists. He acknowledged the possible increase in cardiovascular risk, but thought that a cardiovascular outcomes trial should be performed post-approval since it would be impractical to require such studies prior to approval.
  • Dr. Ed Hendricks (Center for Weight Management, Roseville, CA) voted in favor of approval, as he thought insulin degludec would achieve one of the holy grails of diabetes management – once-daily insulin injections. In addition, he believed that insulin degludec did indeed lower hypoglycemia risk; he did not think the CV signal was strong enough to delay or deny approval of the drug.
  • Patient representative Rebecca Killion (Washington, DC) voted in favor of approval– she believed insulin degludec represents an important step forward for basal insulin therapy. She thought the benefits outweighed the risks and was not convinced that the cardiovascular safety signal was real. On a personal note – we were very happy to see Ms. Killion back on the panel and believe she has done a great deal to move forward life with diabetes for patients.
  • Though it was a difficult decision for Dr. Thomas Weber (Duke University Medical Center, Durham, NC), he ultimately voted “yes” because he was impressed by the pharmacokinetic profile of the drug, its once-daily administration, and flexible dosing. He believed that these benefits would improve adherence and patient care. Meanwhile, Dr. Weber was not wholly convinced by the data that insulin degludec conferred a significant benefit in hypoglycemia.
  • Dr. Charles Stanley (Children’s Hospital of Philadelphia, Philadelphia, PA) voted “yes,” noting that insulin degludec would provide important benefits for patients with diabetes, especially those with type 1 diabetes. He believed there was some good evidence that it would reduce the risk of nocturnal hypoglycemia. Though the safety signal made the decision difficult, he was uncertain how strong the signal actually was and seemed comfortable with the issue being explored in a post-marketing setting.
  • Participating remotely, Dr. Ellen Seely (Harvard Medical School, Boston, MA) ended up voting “yes” even as she expressed this was a hard decision, mainly because she thought degludec provided benefits beyond currently available insulins and because of the potential negative ramifications a pre-approval cardiovascular outcomes trial would have on drug development. She noted that insulin degludec would: 1) be the first 24-hour insulin, commenting that both insulin detemir and insulin glargine fell short of this expectation; 2) be able to be mixed with insulin aspart, which would allow patients to take fewer injections per day; 3) provide some flexibility in the time of administration; and 4) potentially be associated with less hypoglycemia. Dr. Seely also expressed concerns that the increasing burden the FDA is placing on industry to perform cardiovascular outcomes trials for an increasing number of drugs would delay potentially beneficial agents from reaching the market, or worse, halt drug development altogether. Despite her remote presence, we thought Dr. Seely was one of the most eloquent and valuable members of today’s panel. Though Dr. Seely was concerned about the cardiovascular safety signal, she was not convinced it was real, and was comfortable with characterizing insulin degludec’s cardiovascular safety profile post-approval. She suggested that the FDA work with Novo Nordisk on the design of the study to ensure reporting of interim results, so that it wouldn’t take five or six years to find out the answer.

COMMENTARY FROM VOTING COMMITTEE MEMBERS – “NO” VOTES

  • Dr. Brendan Everett (Harvard Medical School, Boston, MA) voted “no,” because he would not want to a significant number of patients with diabetes to be exposed to insulin degludec before its cardiovascular safety is demonstrated. As a cardiologist, he explained that his biggest worry for his patients with diabetes is if and when they’re going to develop heart disease. Given the history of antidiabetic medications with adverse cardiovascular risk profiles that made it to the market, were used widely, and put patients at risk, Dr. Everett preferred to err on the cautious side. He acknowledged that it was not an easy decision for him to make, especially since some patient advocates who spoke during the open public hearing spoke so movingly about the challenges they face caring for themselves and their loved ones, and that they believed insulin degludec would provide an improvement in quality of life.
  • Though he characterized the vote as an extremely difficult decision for him, Dr.Robert Smith (Alpert Medical School of Brown University, East Providence, RI) ultimately voted “no” because the magnitude of benefit did not outweigh the cardiovascular risk signal. He commented that insulin degludec is addressing a true need; however, there are already alternatives available. Given the potential safety signal, he personally did not feel comfortable supporting approval without cardiovascular risk being characterized first.
  • Similar to Dr. Everett, Dr. Erica Brittain (National Institutes of Health, Bethesda, MD) did not feel comfortable exposing millions of patients to a drug when there is this much concern about CV risk. She suggested that a two-stage procedure that would allow approval based on interim results would be a good approach to use in this case. Dr. Brittain stated that she very much appreciated the potential substantial advantages insulin degludec would provide, but that the safety signal was just too great not to be addressed first.
  • Dr. Marvin Konstam (Tufts University School of Medicine, Boston, MA) voted definitively against approval, citing his belief that the potential risks clearly outweighed the potential benefits – he did not think that a 9% reduction in hypoglycemia (most of which were asymptomatic) appropriately balanced the potential cardiovascular risk (with a point estimate for insulin degludec somewhere in the 1.3-1.67 range, by his best guess). He noted that he would be willing to consider an approval for the subset of the population that is particularly prone to hypoglycemia and at low cardiovascular risk (if such a patient population could be identified); however, he would not be willing to support broad approval in people with diabetes until the drug’s cardiovascular safety was further assessed.

-- by Adam Brown, Jessica Dong, Vincent Wu, and Kelly Close