May 27, 2021; Virtual; Highlights Report – Draft

Top Four Highlights

1. Panelists Split on Whether Data Meets “Substantial Evidence of Effectiveness” Threshold: Call into Question Small Study Size, Most Find C-Peptide Data Unconvincing

All panelists voiced confidence that teplizumab conferred some type of clinical type 1 diabetes delay benefit to participants in TN-10, but many also stated that the small sample size precluded them from determining the true magnitude of benefit. In turn, this made weighing the benefit and risk profile of teplizumab quite difficult, as true benefit was undetermined. Representing the more positive panelists, Dr. Marvin Konstam highlighted the low hazard ratio, strongly significant p-value, and consistency across subgroups in TN-10. By contrast, Dr. Cecilia Low Wang stated that differences in baseline characteristics between the teplizumab and placebo arm which could bias the primary endpoint made her question the strength of the evidence. More consensus was also formed around the meta-analysis data provided on C-peptide decline in individuals in the Stage 3 type 1 diabetes trials (which Provention had submitted as its “confirmatory evidence” to meet the FDA’s bar for “substantial evidence of effectiveness”) with nearly all panelists agreeing that data on (i) an unvalidated surrogate endpoint; and (ii) in individuals from a slightly modified trial population was not compelling. Dr. David Cooke went so far as to say that the C-peptide data provided “no additional information,” and Dr. Michael Blaha stated he was “not particularly moved” by it.

• Given the uncertainty surrounding C-peptide as a surrogate endpoint for clinical benefit, HMS’s Dr. David Nathan requested to see A1c data between teplizumab vs. placebo (selected because A1c is already well-established as a predictor of important, long-term complications). A supplementary analysis of Provention's meta-analysis of Stage 3 trials revealed only a ~0.1-0.2% absolute difference in A1c between teplizumab and placebo arms at one- or two-years post-treatment, which Dr. Nathan referred to as a “trivial difference in A1c.”
  • We would certainly agree that this appears not to be a big difference though given accuracy issues with A1c, we’d love to see Time in Range data, just to better understand the A1c data. Particularly if the standard deviation of the TIR data was extremely low, we’d also agree this is a trial difference – we pause slightly over his comment due to limitations of A1c that we’ve heard, but given that TIR data isn’t available (particularly with the improving accuracy of today’s sensors), we’d certainly acknowledge that beyond the C-peptide data, A1c data doesn’t bolster the case. During the discussion period, Dr. Nathan further stated that he would be “extremely surprised” if the A1c benefits, given they are so low, conferred long-term complication benefits. As a reminder, in DCCT, published in NEJM in 1993, every “point” lower A1c typically indicates significantly lower chance of microvascular damage (retinopathy, neuropathy, nephropathy), with no lower threshold. That said, Dr. Nathan noted that in his view, a ~0.1-0.2% absolute difference isn’t likely to itself indicate a difference in, say, retinopathy or kidney benefits.
• In response, patient advocate Ms. Anna McCollister did voice that the A1c reduction was not the only relevant endpoint to consider during this meeting; that said, other endpoints were not given. We also point out the fact that A1c data was not available for participants in the TN-10 study, given that they had not yet developed type 1 diabetes – we would be curious to see if any long-term follow-up data could be collected from these participants, particularly to see if any differences in A1c had emerged for those who had developed type 1 diabetes.

2. Panelists Agree That Two-Year Delay is Clinically Meaningful, But Strength of Data Could Use Improvement

The second discussion question surrounded the clinical meaningfulness of the observed median two-year delay of onset of type 1 diabetes demonstrated in TN-10. In general, all panelists agreed that a two-year delay is a meaningful clinical result, particularly in light of the moving testimonies given during the OPH. As a person with type 1 diabetes herself, Ms. McCollister shared the undoubtedly positive effect that the two-year delay would have had on her life if treatment with teplizumab was offered to her, recounting how her diagnosis in college led to severe negative consequences in her career, academic prospects, and personal life. At the same time, many panelists, including Dr. Cooke, Dr. Ellenberg, Dr. Chrischilles and Dr. Konstam, questioned the confidence and replicability of the two-year delay, given the small sample size in the trial (n=44). Although all panelists acknowledged the value in a two-year delay, many expressed hesitancies regarding whether teplizumab truly provides such a result. Dr. Nathan noted that while he had no doubts that everyone would say yes to delaying the diagnosis of diabetes, there could be unintended consequences if, for example, diagnosis was pushed from around age eight to the pubertal period for a child. 

3. Safety Concerns for Teplizumab Centered on Unknown Long-Term Risks

Most of the panel voiced concern over teplizumab’s safety profile, universally agreeing post-marketing studies and surveillance are needed to better quantify the short- and long-term risks. Some panelists believed the safety data was insufficient due to the small sample size of the TN-10 trial and the lack of follow-up data after diagnosis with type 1 diabetes, resulting in consensus on the need for additional studies. Specifically, panelists were concerned with the higher rates of DKA, cytokine release syndrome (CRS), and viral infection observed in the teplizumab treatment groups compared to placebo. Dr. Nathan stated this data was “very striking” and cautioned these observations were trending “in a potentially dangerous direction,” since clinical trials are not always representative of the real world where rates could be higher due to the absence of careful, persistent observation. Dr. Chrischilles echoed these sentiments and called for substantial real-world safety evidence, including a registry and an additional trial with a large sample size conducted over a prolonged period – recommendations that most panelists reiterated.

• Dr. Cooke drew significant attention to the three deaths observed in the teplizumab treatment groups of the Protégé trial, while none occurred in the placebo group. Dr. Cooke found these deaths “striking” due to the absence of deaths in the control arm, and he said they were “hard to make sense of.” For instance, he noted a 20-year-old died from DKA and had microvascular complications only two years after type 1 diagnosis, which is unusual. The two other deaths were also in individuals in their 20s. As a result, Dr. Cooke emphasized very little is known about teplizumab’s long-term safety, implicitly cautioning against approval. Dr. Nathan also mentioned this data in his comments, which made him “very concerned” about the risk/benefit balance.
• A few panelists noted their safety concerns were assuaged by the transient nature of some adverse events and the one-dose administration. As a pediatric rheumatologist that often works with immunotherapies, Dr. Becker stated she felt “at risk of being an outlier,” since she believed the safety concerns were “less worrisome” than the rest of the panel, especially in the context of teplizumab’s mechanism of action and low risk of opportunistic infection. Since some adverse events were transient and teplizumab is only administered once across 14 days, Dr. Becker stated she was reassured since she assumed post-marketing studies would be required to truly quantify the risk – an argument that was supported by Ms. McCollister and Dr. Chrischilles. Dr. Weber concluded discussion by stating the short-term adverse events would be acceptable as long as “clear efficacy” was established for the reasons raised by Dr. Becker.
• Elevated rates of DKA in participants taking teplizumab seemed to remain a mystery to both panelists and Provention. To note, elevated DKA rates were only seen in the Stage 3 type 1 diabetes trials (not TN-10), though panelists still seemed concerned with this signal. Provention called Dr. Steve Edelman (UC San Diego Health) to speak to this issue, who emphasized that these trials were conducted over the past 20 years, across three continents. The vast majority of DKA events were from India, which Dr. Edelman chalked up to being because of overall poor glycemic management in that geography (participants had “extremely high” A1cs). Despite this explanation, certain panelists were still not convinced, particularly Dr. Nathan, who stated that Dr. Edelman’s description in fact made him “more concerned,” as irrespective of the geography, the studies were randomized and blinded; as such, elevated DKA rates with teplizumab still remain a mystery, though Provention’s management shared plans to monitor DKA rates in a post-marketing surveillance registry.

4. Panelists Largely Agree that Teplizumab Indication Should Remain Restricted to TN-10 Inclusion Criteria Until Further Study

The fourth discussion question of the meeting focused on how the population indicated for teplizumab should be described, with most panelists agreeing that it should be individuals age 8 and older with a family history of type 1 diabetes, two or more positive antibodies, and dysglycemia – of these recommendations, a family history of type 1 diabetes was the most heavily debated, given that just 15% of people with type 1 diabetes have a familial connection. This aligns directly with the inclusion criteria of the TN-10 trial, which supports teplizumab’s ability to delay type 1 diabetes by two years in this specific patient group. Most panelists agreed that due to the small sample size in TN-10, it would be unwise to broaden the patient population that teplizumab is indicated for if it were to gain regulatory approval due to lack of evidence in a wider group. A more restrictive indication population would also ensure that those who take teplizumab right after its approval are the ones who are most likely to respond– a point aptly made by Dr. Yanovski. Similarly, Dr. Cooke worried about the risk of treating children with high risk of diabetes (instead of with Stage 2 disease) if the indication were broadened, as the benefit of teplizumab in this population has not been quantified and potential side effect risk may undermine the benefit of diabetes delay. Panelists agreed that for the indicated population to be broadened, more trials are needed – and a restrictive initial population indication would motivate Provention to continue investigations in larger populations. As brought up by Dr. Konstam it is also important to only determine the drug’s indication based on the direct study performed, as subgroup analyses (such as the HLA-DR4 study which showed greater benefit for those HLA-DR4 positive – see graphic below) are notorious for lower reliability. Of course, even if the population in teplizumab’s indication remains restricted, the possibility remains that patients who do not meet these criteria will use teplizumab off-label, as is sometimes the case with therapies like SGLT-2 inhibitors in the type 1 population. 

• Committee members provided interesting commentary on whether family history of type 1 diabetes is a valid requirement for treatment with teplizumab. As shared (and represented) by Ms. McCollister, some people with type 1 diabetes are the first to develop the condition in their families, and many individuals, like those who are adopted, do not have access to their family disease history. The family history requirement may inhibit people who meet all the other disease-state criteria from accessing a medication that can clinically delay type 1 onset. Many committee members agreed that family history is not integral to being in a group that would benefit from teplizumab treatment, as there is virtually no difference in whether a person with Stage 2 disease will develop the condition or not based on their family history.

• A question on dose regimen in a broader population of people younger than age 8 was also posed by industry representative Dr. Gary Meininger. Dr. Ramos responded that Provention intends to test younger participants with the same dose regimen, and after assessing safety, titrate as needed. 

Open Public Hearing

Today’s Open Public Hearing featured 17 speakers, including Ms. Kelly Close (Close Concerns), Ms. Jackie Tait (dQ&A), Dr. Aaron Kowalski (JDRF), Dr. Mark Atkinson (University of Florida), Dr. Louis Phillipson (University of Chicago), and Dr. Jeff Hitchcock (Children with Diabetes). Presentations largely focused on similar concepts: the significant unmet need in type 1 diabetes treatment, the physical and psychological burden of the disease, and the health benefits of a two-year delay. See brief summaries of each speaker’s remarks below:

• We heard several personal stories from patients who received teplizumab in clinical trials. Leading off the public commentary period, Claire, a 15-year-old who has been involved in type 1 diabetes research since she was 2, discussed her experience entering a clinical trial studying teplizumab and the impact the treatment had on her life. After testing positive for four autoantibodies at 9, she enrolled in teplizumab clinical trials, and she shared that she has not developed type 1 diabetes 66 months later and does not need to administer insulin or track blood glucose. She stressed teplizumab has removed a significant burden from her life and has allowed her to have a normal childhood, which compelled her to encourage the FDA to consider its approval to provide other children with this opportunity.

  • Madison Buff, a college senior who tested positive for type 1 autoantibodies five years ago, echoed Claire’s sentiments. She shared that she participated in TrialNet teplizumab study following her positive test, and her A1c levels have remained at normal levels since entering the trial. She stated she was “forever thankful” for teplizumab since it allowed her to live a “normal young adult life,” enabling her to be “more confident” in her future health and well-being. As a result, she encouraged the FDA to approve teplizumab because of the massive psychological and physical “strain” a type 1 diabetes diagnosis places on a family, which she witnessed first-hand after her older brother with type 1 diabetes suffered a seizure from severe hypoglycemia.

  • Catherine Price, who was diagnosed with type 1 diabetes in college, shared that her treatment with teplizumab in a clinical trial substantially benefited her life. She shared that her A1c never exceeded 7.0%, that she never passed out from hypoglycemia, and that she was able to have a healthy and safe pregnancy because she was still able to produce insulin at the time. She mentioned it was an “overwhelming relief” discovering her daughter was not positive for autoantibodies at six-years-old since a positive test (and eventual diagnosis) would have “plunged” her family into anxiety, fear, and constant monitoring. If she does test positive for autoantibodies, Ms. Price stated she would undoubtedly give her daughter teplizumab if available, and she encouraged the committee to make this available to many families like hers.

• A multitude of parents advocated for teplizumab approval, focusing on the benefits a two-year delay would have on their ability to care for their children with type 1 diabetes. Tim Ryan, a parent living with type 1 diabetes who has two children both with type 1, said a two-year delay would “not have devastated his family but would have softened the blow.” He emphasized teplizumab would have been highly beneficial to caring for his children since a delay would have provided his children (who were both diagnosed at ages 2 and 5) more time to develop better communication skills, would have caused less damage to their bodies, and would have eliminated many sleepless nights wondering if his children’s blood glucose was stable. Angie Platt, a mother to a 17-year-old with type 1 diabetes, echoed Mr. Ryan’s comments, saying a delay would give families a valuable “soft entry” into the disease so they can better prepare to care for their children, which was particularly poignant for her since she also has two younger sons at-risk for developing the disease. Elizabeth, who lives with type 1 diabetes and has three daughters, gave an emotional plea to the committee, stating a delay would be invaluable since it would give children more time to “just be kids.”

  • We also heard valuable perspectives from parents living with type 1 diabetes who are also clinicians treating people with diabetes. Dr. Jeremy Pettis, an endocrinologist at UC San Diego living with type 1 diabetes and a father to two boys, called teplizumab “the literal first step to addressing type 1 diabetes at its root cause” since as a researcher he knows diseases are not typically cured through one magic pill. He stated a two-year delay would result in 3,000 fewer insulin injections, 7,000 fewer finger pricks, and 200 fewer hypoglycemic episodes, and as a result, if given the choice to give his sons this treatment to delay type 1 diabetes, he shared it would be an “unequivocal yes.” Dr. Sean Oser, a diabetes researcher with type 1 diabetes and family physician for people with diabetes, echoed these sentiments and noted teplizumab would be a “giant step” toward what so many people have wanted for so long: a therapy that could prevent or delay diabetes onset.

• JDRF’s CEO Dr. Aaron Kowalski focused on the significant unmet need and burden with type 1 diabetes, emphasizing that insulin, which has been around for 100 years, is not a cure. According to Dr. Kowalski, 4/5 children and 2/3 adults in the US do not meet A1c targets, with over 90 minutes a day spent in hypoglycemia. He argued that the approval of teplizumab would put us on a critical pathway to finding cures and eventually preventing type 1 diabetes entirely. From our view, it was incredibly notable that Dr. Kowalski was “in the house” – it surely signaled greater certainty, as well, about the safety profile of tepluzimab that JDRF’s own most senior scientist and spokesperson was investing major time in the meeting.

• University of Florida’s Dr. Mark Atkinson eloquently expressed that the use of teplizumab will change the course of type 1 diabetes progression and reverse the unacceptable lifestyle patients endure. With over 500 publications related to the disease over the course of 37 years, Dr. Atkinson drew upon his background as an expert on diabetes pathogenesis as well as efforts seeking prevention and care. He stated that he knows of no other agent that has demonstrated more capacity to delay the onset of type 1 diabetes, referencing teplizumab’s impressive track record in terms of its safety, in particular. Like Dr. Kowalski, there is major credibility to a compound that comes with Dr. Atkinson’s confidence – he stressed, of course, the appropriate guardrails that would guide FDA in charting a course that would help the field learn more.  

• Dr. Korey Hood focused on the psychological burden of living with type 1 diabetes and how teplizumab can offer some relief. Dr. Hood, a licensed clinical psychologist at Stanford University living with type 1 diabetes, emphasized delaying the onset of type 1 diabetes would also delay the “psychological grind” of managing the disease or caring for someone with the disease. He stressed the time around diagnosis is particularly traumatic and stressful for parents, children, and caregivers, and he stated those diagnosed with diabetes are 2x more likely to suffer from depression or other psychological factors that can worsen decision making and health outcomes. From a personal side, Dr. Hood added he will have his two sons screened for type 1 autoantibodies, and if the treatment was made available, he would allow them to receive it since the “chance to not have [type 1 diabetes] on the mind all the time would be very welcome.”

• Dr. Nicholas Argento (Maryland Endocrine) similarly emphasized the mental burden of type 1 diabetes. As someone who has lived with type 1 diabetes for 53 years and treats people with diabetes, Dr. Argento stated the mental toll of the disease is “staggering,” and on a personal level, he shared he has not had more than an hour in his adult life without thinking about the disease, referring to diabetes management as “chaos.” He reinforced type 1 diabetes as chaos when he provided his own devastating experience as a clinician needing to sign a death certificate for a young woman who miscalculated her insulin dose, and he reiterated elevated risks for depression, eating disorders, poor work performance, and martial discourse in those with type 1 diabetes. He viewed teplizumab as the key to delaying this chaos, acknowledging that while he has been “lucky, many of [his] patients have not been.”

• Dr. Louis Phillipson (University of Chicago) shared a clinical perspective as someone who organized trials studying teplizumab. He shared his involvement in these studies has convinced him that the side effects of teplizumab are amiably acceptable relative to the results due to the devastating complications of the disease, especially among socioeconomically disadvantaged individuals. He shared the effects of type 1 diabetes he has observed in socioeconomically disadvantaged individuals are “dismal,” and the complications for these people are “terrifying” since they cannot take advantage of current diabetes technology. As such, any delays in disease onset that could be achieved would be hugely beneficial.

• Dr. Kimber Simmons offered additional insight as someone both living with type 1 diabetes and as a clinician treating those with diabetes. She began with how devastating her diagnosis was to her family as a child, remarking her parents took between one and two hours each night to prick her finger in the first two years following diagnosis. When she asked her parents if they would have made her take teplizumab if it was available to them, her parents said they would have done anything to delay her disease onset. She estimated she has completed 100,000 finger pokes, 26,000 injections, 5,000 pump infusion changes, and 1,000 CGM insertions – which she noted many of her patients are on the same trajectory – and is forced to make 200 additional decision a day. As a clinician, she remarked her center sees 450 individuals diagnosed with type 1 diabetes each year and mentioned that their messaging to these individuals always reminds patients there was nothing they could do to prevent or delay type 1 diabetes. Therefore, she emphasized this unmet need and asked the committee to approve teplizumab since it would be “a necessary paradigm shift.”

• Ms. Kelly Close (Close Concerns) and Ms. Jackie Tait (dQ&A) focused on the benefits of a two-year delay in disease onset, presenting data from a survey sent last Friday to ~3,300 adults with type 1 diabetes. The invitation to this audience garnered an impressive response rate and a flat-out fast response from 1,078 people (32.5%) that found a sizeable population finds a delay beneficial (see details from slides – the detail was distributed on social media #EMDAC as the three-minute time given enabled time enough only for summary data). The survey found 46% of respondents strongly agreed that a delay in onset would have made them better prepared for the disease, and 39% also strongly agreed that they would have learned more about how to better manage their health; we were also moved that “net response” was shown so that balance of opinions of all the people with T1D was clear. Even though Close, who was in the emergency room 24 times in her first 12 years with diabetes, clearly showed hope about the compound, she and dQ&A health researcher Jackie Tait, alongside whom Ms. Close shared results, were clear in the pros and cons they heard from the 1,000+ patients. While they conveyed the hopes of some patients that teplizumab could ultimately change the treatment paradigm even just by reducing the likelihood of disease onset in DKA, providing patients an opportunity to implement lifestyle changes before disease onset to improve immediate outcomes, and even while they noted that parental stress in the immediate year following diagnosis could be reduced, they also noted the potential downsides as well, such as clear concern on safety (see below), more uncertainty for some, and possible attention away from other therapies being tested for T1D delay or prevention such as AGT and others. Ultimately, the two urged the committee to consider the unmet needs of patients that, while “changed fundamentally by the closed loop” still persist and still blindside the newly diagnosed. In closing, they noted that the approval decision would have significant implications on whether there was additional investment in delay and prevention. While we didn’t hear from Ms. Close today about the legion of companies that have left diabetes research (“Amgen, BMS, Gilead, Takeda …” and on and on, as we’ve heard from her before), that is, of course, foremost in our minds.

  • As noted, Ms. Close reinforced to the committee that addressing the safety concerns surrounding teplizumab was critical to patients. She encouraged the committee to support additional post-marketing studies to better identify safety risks, such as increased infection risk, and to better define which populations would specifically benefit from this treatment.

  • There was concern that in all the discussion about “more data” desired and “more studies,” it may be lost on some members of the Ad Comm that easy financing of such studies is virtually impossible; that said, after today, given the potential for beta cell sparing that was raised and given that this is not well understood, the potential for NIH funding could be back. While speculative, this is something that certainly could take place with a coherent narrative and accompanying compelling and data-driven, fact-based, compelling requests from the public.

• Dr. Nina Zeldes (National Center for Health Research) was the lone public speaker who advocated against approval for teplizumab. She suggested results may have been biased in favor of teplizumab due to demographic imbalances in the treatment groups and the small sample size of the clinical trials. Dr. Zeldes noted there were twice as many adults as children enrolled in the study, and she argued results may have favored teplizumab since rates of type 1 diabetes progression are lower in adults. In addition, she argued lower BMI rates in the teplizumab group compared to the placebo group may have biased the data since a higher BMI is associated with a higher risk of disease progression. Furthermore, she identified that 97% of patients who received teplizumab in TN-10 were white, stating “it is impossible to know” if the drug benefits non-white populations. While T1D is largely a Caucasian disease, we certainly agree with the preference for diversity in trials; we also acknowledge the difficulty in recruiting experienced by the sponsor most recently; that said, we’d like to better understand this in comparison to the n=530+ pivotal trial conducted by Lilly/Macrogenics. In conclusion, she highlighted safety concerns regarding possible immunosuppression and elevated DKA risk, arguing the efficacy and safety data are insufficient to grant approval.

• Dr. Jeff Hitchcock (Children with Diabetes) shared another powerful personal account, detailing his experience as a parent with a daughter living with type 1 diabetes and communicating the immense burden it had on his family. He mentioned he diluted insulin doses 10 to 1 to ensure his daughter’s body could tolerate the injections, and he even had to squirt cake frosting into her mouth once to prevent a seizure – experience and stress Dr. Hitchcock said were “something no one should have to know.” He stressed a delay in disease onset could allow “more people to simply live” for longer, emphasizing it could allow many to meet their college roommate without having to explain emergency glucagon or to go to prom without worrying about a CGM alarm sounding. As a result, Dr. Hitchcock urged the committee to approve teplizumab because “you must do so” when giving the opportunity to lessen the burden.

• Christina Roth, CEO of the College Diabetes Network and a person living with type 1 diabetes, suggested today’s meeting was about hope. She emphasized the possibility to delay disease onset with teplizumab gave her hope that she would not have children who will not have to live with the disease. She then cited her own work with college-age students who have had their “worlds turned upside down” by a type 1 diagnosis, referring to this diagnosis as “a moment of crisis.” She shared many college students are forced to drop out of college because of the “suffocating burden” placed on them due to the need to recalibrate their academics and social life while managing diabetes. Because of this significant burden, Ms. Roth asked the FDA to give these individuals more time to process and adjust to their new life, which she believes teplizumab can do.

• Mutual respect shown: Although as Advisory Committee members, they did not participate in OPH, of course, the value from patients on the Ad Comm who have type 1 diabetes was striking, including Ms. Anna McCollister and Carling Skvarca. In particular, Ms. McCollister was deft in her interaction with the chair of the committee – while at one stage, he began to summarize the proceedings of a discussion as something akin to “Well, it sounds like a small majority of us do not believe effectiveness has been established …”, she interjected, effectively pointing out that the conversation hadn’t been a vote and shouldn’t be characterized as such. Both conveyed various valuable points by fellow panelists, also artfully, and we felt each contributed to the value of the panel by encouraging exchange across the tables (virtual ones, of course). Ultimately, we virtually always appreciate enormously the summary comments – we comment in this case because it was so striking to hear disagreement from any panelists on what we’d ordinarily see as the “Chair’s prerogative” to summarize the conversation.

• In sum, the OPH was characterized by multiple Advisory Committee members as useful, compelling, and thought-provoking. While biased, as we participated, we agree. This commentary, as well as others from OPH and official speakers educated us more about the compound and made us wonder more about multiple items. We’ll expand this report to comment further on this and for now, point out a couple of them:

  • Trial enrollment: this seems to have been much harder in more recent years and we wonder if that’s due to competition for those with T1D in device or other trials;

  • Endpoints used: we imagine that time in range data would’ve been sought back in 2009 if this had been available and considered reliable; given the issues discussed today with A1c and given that A1c isn’t considered as accurate across all populations, we wonder if future trials will use CGM as a tool to garner measures like GMI, time in range, etc.; and

  • Patient reported outcomes: we wonder about the discussions on these and how the benefits and risks would be assessed in a conjoint analysis.  

Summary of Committee Votes

Discussion on Commentary from Voting Members

Yes

• Dr. Michael Blaha voted “a very qualified” yes, noting he was “very conflicted.” While he believes teplizumab is a “promising, paradigm-shifting therapy that needs to move forward,” he stated the risk/benefit profile is “very narrow,” and he has “a lot of skepticism” about the whole body of data. As a result, he recommended only approving teplizumab for the exact indication of the TN-10 trial. He would like to see a second confirmatory trial covering a population that did not meet TN-10’s entry requirements, and he advocated for a “carefully thought-out, rigorous” REMS program.

• Dr. Mara Becker voted yes, as the one panelist who was “unconflicted” in her vote since she felt the data presented by both the sponsor and the FDA was “convincing enough” to prove the need for teplizumab was “great.” She supports a label for children ≥8 years old with at least Stage 2 disease, regardless of family history. Although she mentioned she was “more convinced now than ever before” about teplizumab’s potential, she requested post-marketing safety surveillance to determine the long-term effects of the treatment.

• Dr. Erica Brittain voted yes, which she remarked was a “hard decision” and “close call.” She believed the TN-10 results demonstrated strong efficacy, but she noted there were “somewhat concerning” safety signals. Nevertheless, she viewed the risk/benefit balance as “marginally sufficient” to approve since she believed patients should be able to make the decision for themselves. Following approval, she would like to see more randomized studies performed (one dose vs. two doses and a placebo-controlled trial in younger populations), as well as additional data following diagnosis with type 1 diabetes. In response to recruitment concerns for post-marketing trials, she recommended finding ways to implement autoantibody screening into routine pediatric care to expedite trial recruitment.

• Dr. Elizabeth Chrischilles voted yes and supported an indication for individuals ages ≥8 years old with stage 2 disease, and she stated she did not support restricting the medication to only individuals who had relatives with type 1 diabetes since it has “the potential to change and improve the lives of so many.” She strongly endorsed robust post-marketing and safety programs to better quantify the risk/benefit profile.

• Dr. Susan Ellenberg voted yes while emphasizing the need for more supportive data to qualify an approval. Echoing the thoughts of many committee members, Dr. Ellenberg struggled with her decision based on the lack of substantial evidence from the meta-analysis but great impact teplizumab would have on the unmet need in type 1 diabetes. While the study that results were garnered from is small, Dr. Ellenberg voted yes to not deny people who want to weigh the risk and benefit of delaying type 1 diabetes in themselves or their children personally. For teplizumab to gain approval, she agrees that a rigorous, post-market program and additional randomized control trial need to be carried out and show efficacious results.

• Dr. Marvin Konstam’s positive vote was driven by the positive effects teplizumab could have on the lives of individuals. Though he expressed candid shock that he is for approval of a drug studied in a sample size so small as a cardiovascular clinical trialist, he emphasized that the number of endpoints studied in the small trial make for strong, supportive data. He believes the trial was well-defined and internally consistent, with a primary endpoint that carries a lot of strength among multiple other endpoints, which showed large magnitude in its primary outcome of delay of type 1 diabetes. Still, he is not very confident in the data and supports a restricted approval that requires a post-market study. Ultimately, Dr. Konstam voted yes because if he were to decide if his 15-month-old grandchild at high risk for type 1 diabetes could receive teplizumab, he would choose yes.

• Ms. Anna McCollister voted yes in her role as consumer representative, citing the robust benefit on delay to type 1 diabetes diagnosis represented in TN-10. Although Ms. McCollister acknowledged that trial design was “not perfect,” she voiced that the panelists should be “realistic about what is possible” for immune intervention trials, given the challenges of recruitment. Ms. McCollister also stated that randomized clinical trials are not “the only tool in the regulatory science tool kit” and recommended a rigorous REMS program. Uniquely, Ms. McCollister also implored the FDA to consider the approved label as an issue of drug access, citing that certain insurance companies would use a limited label to deny access to patients. 

• Dr. Kashif Munir voted in favor but acknowledged that it was a “difficult decision” due to limited data provided. Dr. Munir wished follow-up data on individuals who developed type 1 diabetes had been collected post-diagnosis, as a more robust A1c benefit or compelling safety profile could have been shown. In terms of labeling, Dr. Munir recommended teplizumab be approved for individuals ≥8 years old with two autoantibodies and dysglycemia (Stage 2 type 1 diabetes). He does not believe a family history of type 1 diabetes should be necessary for usage.

• Dr. Carling Skvarca voted yes, mainly pointing to the hope that teplizumab provides. She believes there needs to be post marketing studies, and she stated that the indications are appropriate.

• Dr. Jack Yanovski voted yes, noting that “he had his finger hovering over the no button for a long time during the voting period.” He was eventually compelled to vote yes because of the hope teplizumab provides after 30 years of unsuccessful attempts to modify the course of type 1 diabetes. Dr. Yanovski stated that he is in favor of a restricted label with very important follow-up studies involving rigorous registration and follow-up with patients for 20-40 years. He also mentioned a need for studies to determine whether the impact for the first year could be augmented by additional doses in the stage 2 cohort, as well as studies in slightly younger ages to see if teplizumab can be administered safely with the same efficacy. Finally, Dr. Yanovsky noted that he decided the risk-benefit was favorable, because there were “unknown potential risks but no shown risks that worried me.”

No

• Dr. David Cooke voted no based on the lack of evidence on whether the benefit of delaying type 1 diabetes outweighs the risk of receiving teplizumab. Although data from the TN-10 trial showed that teplizumab delays the onset of type 1 diabetes in Stage 2 patients, it’s critical to understand the magnitude of this delay. Dr. Cooke does not have the highest confidence in findings based on a sample size of 44 teplizumab-treated people, as well as the possible side effects that can occur after treatment with teplizumab. He believes that a second, well-controlled study is needed to determine the magnitude of the type 1 delay.

• Dr. James deLemos found that data supporting teplizumab is insufficient. He agrees that the drug is promising in changing the natural history of diabetes but cautions that evidence on its efficacy is far from adequate. Dr. deLemos went as far as saying that he doesn’t believe the FDA “should accept shortcuts” in regulatory decisions. Though he believes results will be replicated in an additional study, he cannot support a single phase 2 study at half-enrollment with confidence on the magnitude of teplizumab’s effects. He also questioned how strong confirmatory evidence from the C-peptide endpoint is, emphasizing that the trial did not show results strong enough to merit teplizumab’s regulatory approval. As with most committee members who voted no, Dr. deLemos believes teplizumab has promise but requires a replicative study.

• Dr. Cecilia Low Wang was not convinced of teplizumab’s magnitude of efficacy. She agrees that there is great clinical need for therapies that delay type 1 diabetes and that teplizumab is potentially paradigm changing. Most strikingly, Dr. Low Wang pointed out that no analysis was performed that combined the potential confounds of age, BMI, and number of positive autoantibodies, which could bias results toward showing a benefit after treatment with teplizumab. With this, the trial’s small sample size and lack of diverse population pushed Dr. Low Wang to conclude that teplizumab’s benefit does not outweigh potential risks. She would like to see analyses that combine confounding factors, as well as a second clinical trial with more matched groups and safety data, including in a population at risk for type 1 diabetes instead of only those who already have the condition. 

• Dr. Martha Nason voted no, despite her being “optimistic that [teplizumab] will work.” In terms of rationale behind her negative vote, Dr. Nason cited the need for replication of efficacy data, more safety data, follow-up beyond diagnosis, and data in a more diverse population. If approved, Dr. Nason recommended teplizumab only be approved for those with family members with type 1 diabetes, as included in the TN-10 study, and that a second trial be launched in at-risk individuals without a family member. In the second trial, Dr. Dason would like to see further racial diversity and HLA-DR4 positive individuals pre-specified as a subgroup of interest.

• Dr. David Nathan ultimately voted against approval, although “struggling…tremendously” with his decision. Citing his more than 40 years as a leader in clinical research, Dr. Nathan emphasized that more data is needed – both in terms of safety and efficacy. Dr. Nathan pointed out that he would hate to find out in a number of years down the road than an approval had caused “more harm than good,” especially given the rapidly evolving tools for type 1 diabetes management.

• Dr. Connie Newman voted no because she does not feel there is enough data for safety, particularly long-term safety, though she called it a difficult decision on a promising therapy. She stated that she hopes there will be more studies to confirm efficacy and support safety.

• Dr. Thomas Weber voted no, though he noted that it was a very difficult decision. On one hand, he stated that he is aware, especially after listening to the powerful OPH presentations, of the tremendous burden of type 1 diabetes and how clinically meaningful it would be to delay onset. However, he believes that the uncertainties about target population and who would truly benefit from the treatment outweighed the significant trial results. He stated without clear efficacy, the safety issues associated with teplizumab are not acceptable.

Close Concerns’ Questions

• Given that multiple panelists were unconvinced by the C-peptide meta-analysis data, will FDA still find teplizumab’s data set able to fulfill the “one adequate and well-controlled clinical investigation” and “confirmatory evidence” requirements for “substantial evidence of effectiveness” needed for approval?

• What is the range of options under which FDA could approve this therapy in terms of registries, mandated post-marketing studies/surveillance, populations considered/indications that could be later updated, etc.?

• It sounds like the decision on post-marketing study and indication changes be made collaboratively between FDA, given the company’s’ Breakthrough Therapy Designation and given this is a Priority Review. Is it possible to get more details on this?

• Can Provention follow-up with TN-10 participants post-diagnosis? Could another organization be in touch with TN-10 participants (given there are a relatively small number, under 100) to find out anything about outcomes, particularly if many or virtually all have CGM and therefore GMI?

• If only approved for individuals ≥8 years of age, would Provention move to launch a pediatric patient trial? What might the range of cost be for such a trial? What would be different about the design vs. the TN-10 trial?  

• If only approved for individuals at Stage 2 type 1 diabetes, would Provention seek to expand usage to Stage 1?

• What is the actual status of the PK/PD comparability issues? Given that Provention updated in the press release that the expected timeline may be delayed, is it possible to get any more detailed sense of to what degree would the July 2, 2021 PDUFA date be impacted?

• Can any more data be provided on the elevated DKA rates seen in the teplizumab arm of the safety meta-analysis?

• To what degree may it be possible that C-peptide could be validated as a surrogate endpoint?

• All endocrinologists on the panel voted against approval. Given that endocrinologists will likely be the ones prescribing this therapy, what types of more detailed or longer-term or just more data could be collected to assuage their concerns?

• If teplizumab is approved, how might average HCPs best communicate the efficacy and risk trade-offs of this therapy? 

Interview with Provention Bio Chief Commercial Officer Mr. Jason Hoitt

Following the momentous FDA AdComm, our team was fortunate to connect with Provention’s management team for a short Q&A with Chief Commercial Officer Mr. Jason Hoitt. Big picture, Provention is preparing for follow-up conversations with FDA to determine what other data is needed to resolve PK incomparability issues between the intended AGC Biologics manufactured product and historical Lilly product. Provention will also discuss label plans with FDA, hoping to obtain an indication for not just relatives of people with type 1 diabetes with Stage 2 disease (as included in TN-10 and suggested by some panelists) but all people with Stage 2 type 1 diabetes.

Rhea Teng: Hi Jason, thank you to you and everyone at Provention on the positive AdComm presentation and discussion today and congratulations on this progress. Many have remarked that it was one of the most informative AdComms in recent history, with strong presentations from both Provention and FDA as well as extremely valuable discussion by those involved. It would be helpful if we could hear about next steps for Provention. Could you please walk us through what will happen next between now and hearing an FDA response, from your understanding?

Mr. Jason Hoitt: Sure, thank you very much. Yes, it's a good question. So, we’ve got a July 2^nd PDUFA action date with FDA, and – as I think you know – during our mid-cycle review meeting, the FDA raised a PK issue that they felt was significant that we're working to address with them in parallel to the BLA review. Our next steps will be connecting with them again on that and figuring out what the pathway forward looks like and what the associated timeline for that looks like. We'll also be working with them on any follow-ups coming out of the advisory committee. Obviously, we were happy to see a 10-7 positive vote in favor of approval. We'll work to clarify any remaining questions that they have and work toward that PDUFA action date.

As we’ve mentioned before, we did a single low dose PK bridging study in healthy volunteers, and it showed a slight miss on the low side of that 80 to 125% bioavailability that they typically use for biosimilars. Our thought is that given the way monoclonal antibodies, the way teplizumab is dosed, and the fact that it’s a 14-consecutive day infusion, a single low dose administration and the associated clearance after one single dose, in our opinion, shouldn’t have a clinical or a meaningful impact on the result. Over 14 days, our take is that we'll be saturating the receptors effectively. And that, we're looking to work with the agency to find specifically what additional information they need and how we can go about collecting that information in as expeditious a way as we can. But as thorough a way as we can so that we provide them with meaningful feedback that they need. As a result of that, however, we would anticipate that there would be a slight delay to the potential decision point around teplizumab. But, at the same time, we can’t speculate yet because we need to have those follow-up conversations with the agency to figure out exactly what it is they need to be meaningful and how long it will take us to generate and pressure test the data and then get that over to them for their review.

Rhea: Just to clarify on our end, so it sounds possible that there may be a delay of the PDUFA date itself?

Mr. Hoitt: It would be possible, yes.

Rhea: Great. At the AdComm, there was also some conversation from panelists about changing the indication or additional post-marketing studies. Is the decision making around that a collaborative process with the FDA or will they more so come back to you with their own thoughts?

Mr. Jason Hoitt: No, it’ll be a collaborative process. We’ll work and engage with the division to talk about specifically what post marketing requirements they’d like to see. We’ve already put forward the notion, as you saw during Dr. Ramos’s presentation yesterday, our intent to have a registry post-approval to follow these patients over time. We’ve already been planning for post-marketing surveillance to track how patients are doing in the real-world setting.

One thing that I think is incredibly helpful is knowing that under Breakthrough Therapy Designation and under a Priority Review, we have really enhanced access to the agency. And it’s been a very collaborative process with the division. I think, given that, we would anticipate that same collegial engagement to continue now on the other side of the AdComm.

In terms of indication, I think you heard during Dr. Ramos’s presentation that based on the published literature, we wouldn't expect a family member vs. a non-family member to progress in any different way. When TrialNet and NIDDK were running the TN-10 study, it was run in relatives simply based on enriching the pool of patients that they were screening. It became a way of identifying patients in the absence of universal population screening for autoantibodies. Once we get into label discussions with the agency, we would start talking through that during the labeling discussions.

Rhea: Great, thank you so much and congratulations again. We look forward to connecting with you further and following the path ahead to FDA’s decision.

--by Andrew Goyette, Lucy Fu, Rebecca McClure, Jackie Tait, Ursula Biba, Rhea Teng, and Kelly Close

Appendix: Sentiment Analysis of dQ&A Survey on Teplizumab and Comments

The 1,112 people that answered the dQ&A survey on “Should the FDA approve a drug to delay the onset of type 1 diabetes?" (32.5% response rate) were given the opportunity to leave personalized, write-in responses to this important question. Our analysis of these responses was additional confirmatory evidence (as it were!) of how heterogeneous the type 1 community is, which we often discuss in our work at Close Concerns. This is true in temperament and approach to diabetes as well as other factors. Unlike with type 2 diabetes, people with type 1 diabetes don’t have as much diversity related to factors like race and ethnicity; as far as socioeconomic status goes, people with lower SES are not disproportionately affected by T1D. It is important to note that all those surveyed were type 1 adult diabetes patients and not children or adolescents or caregivers; however, many responded from the point of view of their parents/caregivers and pointed out how delaying their T1D diagnosis would ultimately have impacted their caregivers’ lives. We attempted to characterize the responses of nearly 500 people as positive, negative, or neutral in their tone and found the trends below. For more detail on how this group of respondents perceived the question (all else equal), we urge readers to see the full scope of quotes by people with diabetes on the following pages.

• Nearly half of the responses were positive leaning. Common threads among these responses included the belief that teplizumab would provide precious needed time to prepare a healthcare team, educate themselves, and emotionally mature. Many respondents reasoned that the two-year delay could improve overall long-term health and potentially delay or diminish the occurrence of serious complications related to type 1 diabetes. Moreover, multiple respondents expressed that better treatments and technology could be developed during that two-year timeframe. While there are no representative quotes, per se, several quotes that came in during the time the survey was open are included below for Closer Look readers’ interest:

  • “It would have given me 2 years to learn how to live on insulin, perhaps not lead to a nervous breakdown which in turn led me to leave my job. More time for more education and preparation, compared to being thrown into fear, confusion, and a steep learning curve.”

  • “The longer to live without diabetes the better for prolonging life without complications.  I am all for it.”

  • “I was 8 years old when I was diagnosed.  It absolutely turned mine and my parents’ world upside down. Having a delay in the regimens that I had to take immediately would have allowed me to become a little older to comprehend something.  Allowed my mother (who was a considerably older mom) the time to comprehend all the lifestyle changes we needed to do as a family.  Also, there was a big transition time in the early 80s away from animal insulin to synthetic insulin. Letting technology get a sure footing in the 2-year delay is also helpful -- especially now that technology is the absolute wave of the future in Type 1 diabetes care.”

• A quarter of the responses were neutral or ambivalent. This largely involved people who considered the delay in the context of their own diagnosis or wanted more information on side effects before answering completely. We did not offer detail in the survey and more detail may well have changed the nature of the comments, which we ignore for the purposes of this analysis. For many in this category, their diagnosis occurred decades ago, which led some to express that this treatment would not have helped them since the technology then was especially poor – that is certainly not true for all, and the survey did not attempt to assess this. Some believed that although a two-year delay would not have positively changed their own experience, it would have benefitted their parents or caregivers in terms of planning and management when they were children. While there are no representative quotes, per se, several quotes that came in during the time the survey was open are included below for Closer Look readers’ interest: 

  • “I was diagnosed with T1D in 1976. There was not any technology to help manage it. Disposable syringes had just come out and glucometers would come out a few years later. A 2-year delay would not have changed much in my life.”

  • “I really don't think it would have mattered back then!  There were no CGMs or pumps in the good old days.  Maybe for someone diagnosed today??  I would be concerned with side effects of the so-called drug?”

  • “I have an extensive family history of Type 1, so I was already pretty familiar with what life would look like. However, it's still VERY different when it’s you dealing with it. Two years would have been a nice buffer. But I do wonder if those two years would almost create a false sense of hope and potentially make the actual onset more frustrating? I'm not sure.”

• Just over a quarter of the responses were negative. Negative responses included some beliefs that the two-year delay would result in heightened levels of emotional stress in anticipation of a looming diagnosis. The survey did not aim to assess whether this knowledge would’ve been helpful, regardless, though that is certainly of interest. Many respondents thought that the focus should be on finding a cure rather than offering a delay and that extending the inevitable is not a desirable option – in these cases, of course, there was no information on whether, if work on tepluzimab did not proceed, the funds for this research would have been deposited into research on other trials related to cures for T1D. Some mused on whether the two-year delay would push diagnosis to a more challenging time in their lives - most commonly if they were diagnosed at a very young age or if they were diagnosed before their early teens or pubertal period or before they may have left home for work experiences, college, etc. While there are no representative quotes, per se, several quotes that came in during the time the survey was open are included below for Closer Look readers’ interest: 

  • “It was better to be able to start immediately because if I had to wait, then that would be more stress and always knowing subconsciously that one day it would change drastically to taking insulin. Starting from the beginning on taking insulin shows how important this disease is to manage from day one instead of saying I will deal with that in the future. I was more willing to take the insulin first because I knew ultimately that it would make me feel better and live a better life if I was able to control the blood sugars.”

  • “I was diagnosed just before I turned 10. A two-year delay would have meant diabetes right before my teenage years, and I believe that would've made my receptivity to changes much worse.”

  • “There are still a lot of unknowns about this drug.  It should be researched more before it is approved.”

  • “Regardless of a two-year delay, diabetes is stressful, scary, and unpredictable. Plus, it’s only “up to two years” it might not even last that long or work at all. Not to mention, diabetes care hardly goes by the books so you can spend all that time prepping for it and still have a difficult time managing it. Experience is the only thing that helps you learn something like this. You can’t plan for a diagnosis. I think it sounds kind of fake and a little pointless.”

Positive Comments

1. The difference between a diagnosis at age 4 and age 6 would have been enormous, especially if my parents had 2 more years to prepare rather than being thrust into the deep end immediately.

2. Not to feel so overwhelmed with all the changes in my life.

3. Insulin (although much cheaper when I was diagnosed) was a hardship for my family to afford.  It is a huge hardship now for millions because of its cost.  To be able to delay taking it is well worth having a two-year delay before needing to start on it.

4. I would have known a lot more about diabetes and that would’ve been really helpful.

5. For me, it would have allowed more time to absorb the diagnosis, put a care team and plan in place and allowed for a controlled entry into the T1 world.

6. Two years would reduce the number of glycemic excursions incurred on my body (thousands of ups and downs in two years).  Two years would give me a chance to hope that high insulin prices would come down (insulin is not a cure) and that more devices are approved by my insurance company (continuous blood glucose meters) and that competitive products/generics could come on the market by the time I need those products.  Two years is a lot of time for research into what's going on during that period that is causing beta cell destruction.

7. I was 12.  I had questioned whether I had diabetes 3 -4 months prior to DKA/diagnosis and ER visit

8. This would make the diagnosis process less jarring and allow people to be better prepared.

9. What delaying really would do is reduce the number of years my body spends with abnormal blood sugars and prolonged both my quality of life then as well as my life expectancy and quality of life when I get older. It would not only have given me two more years of childhood but likely a healthier end of life when I grow old.

10. I would have had more time to research diabetes while my eyes were not affected. At first diagnosis my eyes were so blurry I had a difficult time reading to get information.

11. I was 27 and I’m the thrall of an eating disorder. It took me close to seven years to accept my diagnosis. I might have had an easier time of it if there was a two-year lead-up.

12. A two-year delay would have meant starting college as a normal student and not having to cope with newly diagnosed T1D at the same time.

13. I was 10 years old when diagnosed 55 years ago. Two years may have given me access to better treatment regimens. I would have a bit more maturity to accept and learn to handle the disease. My parents--always in denial--may have been able to be more helpful to me with greater lead time to learn and adapt. I would have two fewer years to develop complications. Diabetes sucked then and it sucks now. Two years before its onset? All good. No downsides. None. (I assume the drug of which you speak has no deleterious effect.).

14. Mainly would have given me more time to gather information and prepare family. I was diagnosed before the advent of pumps and CGM's otherwise it would have been great to have that time to investigate those devices.

15. More time to establish healthy lifestyle choices.

16. I was still growing so it could have had positive impacts in this area.

17. I think that if I had that delay, I could have learned how to take care of myself physically and mentally, change my diet radically to a very low carb diet and lots of green veggies and some fruits, learn how to combine diet with exercise and healthy habits to avoid or delay the onset of Type 1 for possibly a longer time.  Also learning about the options for possible medications, meeting with a diabetes educator, learn how other people with diabetes manage their diabetes, etc. instead of the crash course that you get when you are already diagnosed, and diabetes becomes a 24/7 endeavor.

18. I was a graduate student when I was diagnosed, and I was responsible for the costs not covered by insurance. Financially, avoiding a costly hospital stay would have helped stress. Additionally, delaying the need for all of the supplies and medications needed for type 1 diabetes would have helped because I might have had a good job by the time, I needed insulin.

19. 2 Years is 2 more years of normal lifestyle but a great amount of time to prepare from what's to come. This can be a huge game changer for those newly diagnosed.

20. A 2-year delay would help in preparing oneself and one's family for the ordeal ahead. Now, with no delay, you have to learn about taking insulin, blood tests, diet, etc., immediately.

21. People die from DKA, and this could delay this significantly and can prevent complications from setting in sooner or at all!

22. I was diagnosed at age 12 more than 66 years ago and started on insulin right away. With more time, my family and I would have had time to learn best practices without the trauma of doing everything immediately. My family would have been able to learn and adjust gradually to the many adjustments necessary.

23. It would have given me 2 years to learn how to live on insulin, perhaps not lead to a nervous breakdown which in turn led me to leave my job. More time for more education and preparation, compared to being thrown into fear, confusion, and a steep learning curve.

24. If I had advanced notice, I would have taken extra care of what I eat and exercise to try to stop it.

25. I would strongly advocate for an option which would delay the need to start taking insulin.  In my case, I was misdiagnosed as type 2 at first because of the lack of commonality of type 1 for my age and population.  I did not know enough at the time and was subsequently prescribed metformin for years before a different doctor in a different city recognized that I should be on insulin.  I think my health during the subsequent years was worse than it could have been.  Now, nearly 20 years later, my mother is facing high blood sugars, and (in my non-expert opinion) may be on a similar path of transitioning from non-insulin dependent to becoming more so in the future.  I believe such a medication could help her, and I would like to promote the spread of the knowledge of such "type 1.5" symptoms and transition state.

26. I actually had a similar transition to diabetes because I had slow onset and misdiagnosis because I wasn’t in DKA. So, my personal path would have been quite similar to having this drug. However, there would have been less frustration at my lack of success managing the disease and made the path to insulin less of a failure and more as the natural progression of a disease I was managing in the best way possible. It would have given me even longer to need insulin and get used to the idea and been so much less stressful. Plus, I would have understood better what was happening BG and know it was not my fault.

27. It, in my opinion, is a no-brainer question - of course delaying diabetes by two years, or more, is good. It would be similar to asking someone would they like their cancer to start now or in two years!!

28. I would not have done so much damage to my body prior to diagnosis.

29. I was diagnosed in 1974, and we didn't have many tools available to us. All we knew was that it was a death sentence. A two-year delay would have given me and my family a chance to learn about what we were facing and begin to make changes in our lifestyle that could have potentially made my teenage years more bearable, as it relates to t1d.

30. Generally, just having that extra time before it became a constant, chronic and all-consuming condition would have been amazingly helpful.

31. I was feeling poorly for about two months.  From Thanksgiving to New Years.  My job was stressing me out, wrong time for sick days.  Was ill tempered and visited my primary care once or twice a week including blood tests.   Didn't feel better, thirsty all the time.  During New Years, my primary said if I didn't feel better, go to the ER.  I didn't feel better, my wife said we're going.  She woke me up 45 minutes later.  When we got there, the triage nurse said, you're a diabetic'.  I argued.  I was in the best physical shape of my life.  I would bike in distance races, I would jog.  She knew what my primary care didn't just from the symptoms.  No one in my family was a diabetic.  So, until being in the hospital, no one had any idea.  It was learning on the clock.  If any of those tests would've shown something, maybe it would've helped.  Hope this helps many. (The drug that is, not my story.).

32. Diagnosed at 19 yrs. old in 1973, a two-year delay before starting insulin could have changed my life completely by giving me more time to become educated about this chronic condition, instead of reading a slim blue book while in the ER.

33. I could have understood the role of an endocrinologist instead of a doctor of internal medicine and utilized their services and knowledge to avoid kidney complications and multiple trips to the ER. I might have been able to finish college, etc.

34. I became T1 in 1982 at the age of 28. Out of the blue with no warning. Anything that delays the way this disease can ravage your body and mind is a Positive.

35. I was so sick before I was diagnosed. I was going to the bathroom every 30 minutes, I was vomiting, I was tired, I was drinking several "Big Gulps" per hour... if I knew it was coming, I would have known what was going on.

36. A bit of fore warning would always incite better preparation.

37. I would think there should be a result that showed the strong possibility of diabetes.  I got type 1 as an adult and was immediately put on insulin, for which I was so grateful. No one in my family had type 1.

38. I think it's hard enough to learn everything that goes in to managing your diabetes and once it's there that's it for the long haul. I'm afraid there could be a false sense of ease in the family that would be shaken when you become insulin dependent. That all said, i would have taken that medication in a heartbeat anyway.

39. It’s not all “needing to start on insulin.” The longer you have this disease, the greater the toll on your body, your family, your psyche, your wallet. If you can shave 2 years off that, why would you deny anyone that?

40. Maybe my brother would not have been diagnosed 2 years after me, when he was 6.

41. I was diagnosed 40 years ago, so a two-year delay would have been less helpful to me then than it would be to someone today. A two-year delay today would be very helpful to someone and their loved ones and their hcp team.

42. I had a three-day crash course on how to manage my Diabetes while in the hospital at 14 years old before being discharged on insulin.  The first day in the hospital I felt horrible and wasn’t able to participate much. I knew very little when I was discharged. A delay in onset would have made my first few years much easier as I would have been able how to learn how to PROPERLY care for myself versus figuring it out as I went along.

43. I was dx. in 1955 at the age of 8. My parents could have used that 2 yr. delay to prepare/educate themselves and be of actual help in my education/understanding. That's not what occurred. I was suddenly told what I could, could not do, without explanations.

44. I was diagnosed 31 years ago at 7 years old, and they didn't start me on insulin immediately...maybe they would've known to start sooner if there had been some kind of delay. I have only had DKA once, so I know I'm very lucky. Kids are resilient, it's my mom who went through the most difficulty and this would've given her lots of time to research and feel comfortable.

45. I was 8 years old when I was diagnosed.  It absolutely turned mine and my parents’ world upside down. Having a delay in the regimens that I had to take immediately would have allowed me to become a little older to comprehend something.  Allowed the time my mother (who was a considerably older mom) the time to comprehend all the lifestyle changes we needed to do as a family.  Also, at that time was a big transition time in the early 80s away from animal insulin to synthetic insulin.   Letting technology get a sure footing in the 2-year delay is also helpful -- especially now that technology is the absolute wave of the future in Type 1 diabetes care.

46. Wish this were available when I was diagnosed!

47. The two-year delay can add to the process of adjusting to diabetes, plus a lot can happen in two years cures and maybe more likely better treatments.\

48. In a way, I had 3 years to think about it. I had gestational diabetes with both pregnancies that became Type 1 three years later.  As a nurse, I felt quite confident managing diabetes.  For some, the delay could be very beneficial.

49. I think the main difference in a delay would have been that perhaps it might have delayed slightly any possible effects of long-term complications.

50. My 2-year delay would have been almost 44 years ago - I was in my early teens - so maybe a period of time knowing it was coming and learning more would have helped me/my family, but there weren't the options then (CGM, pump, MDI, meds other than insulin) that there are today. I think it's a good option and hope the FDA approves, as well as providing other info on how to delay onset based on scientific research that I believe has been ongoing (preservation of islets, diet changes, etc.).

51. The 'drug' (an oral med?)  might well have had side effects I would have preferred to avoid...   If the same amount of blood sugar monitoring would have been advised, insulin would have been the same adjustment to start at any time. 
    Delaying onset of DM on the other hand, should delay long term effects of the disease, and would be desirable....

52. I was seven when I was diagnosed. Two years would have given me more maturity and my family the opportunity to learn more what to expect. As it was, in the 1960s when I was diagnosed, there wasn't much information on childhood diabetes. That changed with time, but two years would have given us a better start.
    

53. If I knew it was coming, I would have avoided near death and 8 days in the hospital 33 years ago.

54. I was a 15-year-old girl who had to deal with the stigma of being “different” and missed school due to hospitalization. In my case delaying it would have possibly gotten me out of school.

55. I was lucky that high blood sugar prior to my diagnosis did not send me to the hospital or worse, but that's just it. It was luck.  I wouldn't count on that for someone else.  If you have the chance to delay the disease, I would want to take it.

56. This is a giant step towards finding a cure.  The delay gives hope and confidence to those affected with the disease.

57. Not have been sick for months and possibly prevented some of the eye issues I had when first diagnosed.

58. No one deserves to be diabetic, it's a horrible disease.  I've had it for 49 years so i know.  None of my children or grandchildren have been diagnosed yet, and i live in fear that they will be. Anything you can do to prevent that will be very much appreciated.

59. Not talking about me as my diagnosis was 58 years ago. My oldest daughter would likely still be alive if she had a two-year lead time. Unfortunately, she didn't and with that she died during a seizure. Would really like "do overs".

60. For those of us diagnosed in childhood, that 2-year delay would help us mature and start building good eating and exercise patterns.  As a T1D for 51 years, anything that would reduce the number of years of diabetes would be beneficial.  I've suffered from many, many complications due to diabetes - every day counts, so this would be like getting 2 extra years of life.

61. Because I am a T1, my daughter is markedly more at risk of the disease. I would strongly advocate for her to have a chance to delay onset if T1 is to become her reality!

62. When misdiagnosed as a type 2 diabetic by my PCP, I was still producing a small amount of insulin.  Prolonging the production of that insulin with proper medical guidance and/or a vaccine would have made a huge difference.  Two years later, when an insurer’s nurse convinced me, I should see an endocrinologist, I was producing no insulin and had lost the opportunity to delay the onset of eye floaters and other secondary effects of diabetes.

63. I would have been learning about the lifestyle and nit hit hard with all the changes.

64. Would have enjoyed my freedom while educating myself.  Possibly less fear if I had good resources to learn about how to manage.

65. If the drug allowed for normal blood sugars and A1c with less effort that insulin: great. Biggest advantage would be a 2-year delay before damage to blood vessels begins accumulating, and a delay in complications down the road.

66. The time is needed, to educate yourself and relief the unnecessary stress. The one week in the hospital was a nightmare! I needed more time at age 14 to deal with it.

67. My diagnosis was so hard. I almost died and was misdiagnosed for weeks.

68. The longer to live without diabetes the better for prolonging life without complications.  I am all for it.

69. Wish it happened 50 years earlier.

70. The 2-year delay is much more beneficial today versus in the 70’s.  There are more options available and more information on how to treat diabetes.

71. I think that I may have had more time to adjust my thinking.  I was a teenager when I was diagnosed, and life was rough just being a teenager.  Having more time to prepare may have helped.

72. So, I have been a type one diabetic for 37 years. But my daughter was just diagnosed two years ago. Despite being a type on myself for all those years, when my daughter got it was a shock! Luckily, I have been raising her to eat and live a similar lifestyle to my own because Deas how I lived. That made the transition much easier for her. And knowing everything that I do about diabetes made it much easier. I couldn’t imagine being a parent with no information or experience with type one diabetes. Going home and giving your Child shots without the experience and information that I have would have been terrifying. If I were a non-type one myself and have been given an extra two years to be able to get all the information that I needed to feel secure and confident in managing my child’s disease, that would’ve been awesome. And it’s also two less years at the kid hast to deal with diabetes as well. It would give them an opportunity to get into the right mindset. To change bad habits and to become ready for the changes that would happen so abruptly if you did not have those two years. I think that this is awesome that they are able to do this. And I think that the FDA should definitely give approval as long as this is safe and effective.

73. I would have saved money on the cost of insulin.

74. It would have affected me some, but I was 11 years old. I think it definitely would have helped me avoid complications. Also, back then they didn't even have blood glucose monitors!

75. I would have had an easier transition through puberty.

76. This would greatly change my life as well as my family's.

77. I would have avoided living with very high blood sugars for the months prior to diagnosis. I would have avoided yeast infections and I would have learned how to eat more properly before my blood sugars were shooting up to 300. It would be a heavy weight to bear knowing it was just a matter of time, but I would not look back with regret for unknowingly causing my blood sugars to be so high. Perhaps my original A1c would not have been 10.3 with a fasting of 260.

78. Compared to when I was diagnosed in 1975, there have been many improvements.  If this pill does what it says, there is always a chance that a wo year delay may bring about even more improvements...possibly a cure.  I am not sure anyone is ever ready when diabetes becomes the "normal".

79. Having options is always good. Unless there are good reasons not to approve this drug, I, as a patient, should be given the option to choose this path of treatment.

80. It was 1969 when I became diabetic at the age of 13. CGM and pumps did not exist. There were two types of insulin. Today I feel the two-year warning would prepare one way better. However, even a two-year warning back in 1969 would have prevented my first hospital admission with an 800-glucose level. Not even sure why this needs to be discussed. If this test is available, it should immediately be routine in physicals.

81. No "teams" of healthcare for support for diabetes.

82. I was stubborn and fortunate and started to teach myself anything I could find about diabetes.

83. Buck up, learn everything you can, accept the decision/results and continue on.

84. Would have been a little better prepared mentally, since I was only 16 when I found out I had diabetes.

85. After being diagnosed with type 1 diabetes nearly 70 years ago, a child could learn all the pre-warning changes necessary to keep their health under control much better.

86. It would make it easier.

87. An ounce of prevention is worth a pound of cure. If you know, you know. Start the process and embrace your new normal.

88. A 2-year delay would help educate the diabetic with treatment, management, and organize medical team. I personally would have been able to find out I had a CHOICE of pump which my original Endo did not let me know.

89. Anytime you can be more prepared for such a life altering event you will always be in better shape to take it on both physically, mentally and emotionally!

90. No matter what, I could have been more prepared and learned more about the disease if I had more knowledge.

91. Would have spoken with more mental health workers to help me cope and have the feeling of less guilt.

92. If this drug is a step towards a cure, it should be explored.

93. Extra time is everything! For me this would have meant having time to educate myself instead of finding out overnight and spending a week in the hospital upon my type 1 diagnosis. Perhaps I would not have gone into DKA?

94. I have been diabetic for 56 years...things have changed so much with controlling diabetes! I think that if I had a child now, this delay would allow me to study and learn more about the care I would need.

95. I was diagnosed when I was 15 months old, and almost died from it before it was realized that I was diabetic. I lived on an island and there was no doctor on the island only a medical clinic. I was losing weight and constantly shouting for water which are classic symptoms but since I was the first person in my family to ever be diagnosed with diabetes nobody really knew what was going on with me. And I was a baby, and I couldn't really say what was happening. As my mother tells it, if they had waited one more week to take me to the mainland to the hospital for testing, I would have died from diabetes. So clearly if there had been a two-year delay before I needed to start on insulin it would have had a major impact on my life at that time and on my family's ability to care for me.

96. Earlier diabetes education with a certified dietician, physiologist and psychologist in addition to my endo would have made a huge difference rather than being thrown into it unaware. Thank you!

97. For me, I was wrongly diagnosed with Type 2 for 3 years! It took me changing doctors 5 times before I got to an endocrinologist who knew what he was doing and properly diagnosed me with Type 1 within 10 minutes. The other doctors were family practitioners. Not specialists. SO, for me, the 2 years wouldn’t have done any good. There’s no Type 1 history in my family. There IS a Type 2 history (grandmother and mother). So, me getting Type 1 at 37 years old with no history was fairly rare. But my family doctors didn’t even test me for Type 1. I just kept feeling terrible taking Metformin. It was making me super sick to the stomach. BUT, if I had 2 years warning, that would have been awesome. I just don’t see how that would work. I went to the doctor, and they tested my fasting glucose at 225 and I had full blown diabetes. There would have been no warning.

98. This could be a wonderful game changer for newly diagnosed diabetics! Fantastic!

99. Diabetes is such a complicated disease, and there are innumerable factors to take into consideration.  Being able to learn about them beforehand would have been so much easier than being tossed in and trying to learn so much.  Every time you think you've figured it out, something new would come up that you didn't know about.  Two years (or even one!) would have been a huge benefit.

100. I would have been able to have another child. I miscarried children because of the effects of diabetes and one within the 2-year window.

101. If there was a test to determine if I was to be a type 1, I would've most certainly have done that test. I had a very difficult time accepting my diagnosis. I also have complications that could have been avoided if I had known I was a diabetic.

102. Had more quality of life.

103. It would have given me two more years of being a kid. A child with chronic illness takes on so much responsibility and knowledge burden about grave consequences of what are normal actions for other kids their age (eating a cupcake, not counting carbs properly, skipping a meal, etc.).

104. Two years of not paying for expensive medication, test strips, etc. would have been optimal. And I would have been more informed, confident, and prepared for the 24/7 management of this disease.

105. I think those two years would have helped me research and prepare for care management rather than being thrust into it with only a vague idea of what my new normal would look like.

106. If I had known before, I actually ended up in the hospital. I wouldn’t have gotten so sick.

107. I became pregnant soon after diagnosis and had an awful diabetic pregnancy. I was told to keep my blood sugars way too low and passed out on a daily basis.
     A two-year delay would have allowed me a normal pregnancy.

108. I think this would be great.

109. I would hope that then your health care provider would be able to educate their patients more effectively. Mine just called after my tests to determine that I was a type 1 and said “You have diabetes. Make an appt for diabetes education it will be in a MONTH and eat less carbs” THAT'S IT ... HORRIBLE.

110. To elaborate on some of the points of being more prepared with this new drug, I've often compared getting diagnosed with Type 1 like one of those dreams where it's the day of a test and you haven't studied at all...only you also didn't even know you were enrolled in the class to begin with, and if you fail, you might end up in the hospital or die.
     Having a lot more time to get prepared for living with T1 would have helped me a ton in the early days.

111. Knowing what I now know about the disease and its impact on my life, having such a drug would have made all of the difference in the world. Forewarned would have been forearmed.

112. I was 24, and with a two-year delay before insulin, I wouldn’t have had to be so overwhelmed with so many changes at once and warnings from doctors that I could die if I don’t pay attention. Plus having to explain over and over to everyone I knew that now I am taking shots all the time. Also, my husband and I could have had time to think about how we were going to restructure parts of our lives rather than winging it like crazy at work, mealtimes in public, and during times of intimacy. It was so awful; I felt like I had become a total freak, overnight. My parents panicked and lots of my friends all talked about me without talking TO me. The trauma of it changed me—and I still feel afraid when I remember those first couple weeks and months. To have had time to adjust…what a difference that would have made. I tear up when I think of this possibility for my fellow type-1s in the future.

113. Any amount of less time on insulin is a blessing.  The post diagnosis period is so stressful and having some time to prepare would make a big difference with having time to prepare physically and emotionally for the lifelong journey ahead.

114. If this two-year delay would eventually lead to longer delays I would favor it more.

115. The delay could be used to train and practice living life as a diabetic without the serious consequences.

116. The delay would allow me to get in routine on checking, monitoring and even getting into healthier habits without the the burden of been sick or while been medicated giving me an option to accept rather than react.

117. I was diagnosed very young, before CGM and pumps were available. I also had a very young mom. She was 15 when I was born and 22 when I was diagnosed. So, I doubt a 2-year delay really would have helped her. But I understand the importance of those 2years for many other families. If I was a parent, I definitely would have my child take that drug to help delay the start of insulin and help them transition into diabetes and get them counseling as well as a great Endocrinologist.

118. It would allow for more education related to type 1 diabetes before being thrust into the deep end and getting a firehouse of information all at once on how to drastically change my lifestyle. Better education would also allow time to cope with the new disease diagnosis and in turn I believe allow better management as a new diagnosis would allow one to learn how to carb count as well as how to properly take insulin and monitor blood glucose levels. This would in turn decrease the related costs of complications from diabetes as well. Though it is still a huge life change when being diagnosed with type 1 diabetes, being able to learn some basics of self-care before being thrust into managing diabetes would allow for a much easier transition.

119. I’m curious how the drug delays the onset of T1D. Does it prolong the life of the pancreas? Extend the insulin being used in the body? And what are the side effects? I think it’s great if the drug can help families and patients get prepared for being diabetic as it potentially changes things for them. I’m just curious to know how it works.

120. Mental and emotional health is half the battle, 2 years to prepare and get healthy is a blessing I wish I would have had.

121. Probably would have had a second child before being on insulin, instead of after.

122. It would overall change the way we live our lives and been able to get the help we need, the information, and been more informed of everything that would happen.

123. This seems like a good advancement to inform patients.

124. Sixty years ago, when I became a Type 1 diabetic the two-year extension would have made me more mature and more able to deal with this disease.

125. I think that an extra 2 years would help those who aren’t expecting a diagnosis to prepare better. I fully expected to be diagnosed with diabetes because of my family history.

126. I was diagnosed in 1990 at age 35. I was very lucky with good insurance and a great Diabetes Doctor. A 2-year delay would have meant a better BG meter and 2 years closer to starting on an insulin pump. Currently I think any medication that would delay Diabetes gives everyone more time to avoid developing Diabetes. With all the current research any delays are important for the soon to be diagnosed.

127. This would have been “spring training” for diabetes like in baseball, and I think my mother would have cried less.

128. Having 2 years to learn about what diabetes is and how your lifestyle and habits must change would be game changing!  And having that time to learn and hone in your carb counting skills & confidence would help prevent the huge swings both high & low!  I knew nothing about diabetes and spent 6 days in ICU once I got diagnosed. Got minimal training and had to learn much on my own. Suffered through extreme highs and lows until I finally got a pump and more guidance/coaching.

129. It would have given my parents and I more time and resources to help the nuns in my catholic school to deal with it better I was the only one in my school to have Type 1 and the nuns sometimes thought I was faking or over exaggerating the situation.

130. I was only 6 years old, so my parents managed everything for my diabetes until I was 10 years old. My stress wasn’t as difficult as my parents’ stress who had to structure a new meal plan around a chronically ill child AND manage my insulin injections as well as all doctor visits and hospitalization. Needless to say, my parents especially would have benefited greatly from a 2-year delay!

131. Being diagnosed with a chronic disease is stressful enough...being able to ease into the treatment regimen would be invaluable.  Thinking specifically of children being diagnosed it would afford the whole family to adjust to the diagnoses without the fear of low(s)...i.e. adjust to change in diet, exercise, medical team, learn about all of the care options.

132. If I had two years to prepare, I would have been able to avoid some very embarrassing situations that occurred during my high school years.

133. Since I became diabetic in 1967 in a small town in central Pennsylvania, I would not have many other options at that time.  Hopefully, it would give me time to be more serious about my personal care.

134. There is no history of any sort of diabetes in my family, which is part of why I waited to see a doctor until I was admitted to the ER with a blood sugar so high, I had to be hospitalized for four days. Having notice would have allowed me to safely realize I was diabetic.

135. I was diagnosed 45 years ago and went on insulin immediately. That is a shock to the system and the psyche.  A two-year transition period would have been so very helpful.

136. It is time this is done for future generations. If we can overcome a pandemic in a year, other long known chronic conditions need the attention and fast efficiency that led to the vaccine. In 2021, oncoming research for diabetics needs to be handled with WARP SPEED.
     We should not need to manage this we should be able to cure it. Like the COVID vaccine nothing will be perfect, but we have to outweigh the risks with the benefits.  Please approve this.  Please act swiftly for others waiting on approval for technology such as improved CGMs and Smart Pens who never had the chance to delay the onset.

137. Gradual transition to being diabetic rather than a being thrown in the deep end.

138. My primary care physician told me that he didn’t believe in prediabetes. If I’d been referred to a dietitian, I’d have been more equipped to handle the symptoms of diabetes when they started, or if they’d have started. I would have known what to do.

139. It can prepare the person better.

140. A two-year delay would probably have made my overall transition into treatment safer. I was only 3 years old when I was diagnosed, and the effects of developing T1D are very dangerous, especially for those who are so young. I think if I had developed T1D at 5 years old instead of 3, I probably would have been in an overall safer position, and my parents would have probably experienced less stress.

141. With so many Americans now with Type 2 Diabetes, it would be wonderful to have this drug to help so many. In my case, it would have really helped me manage my diabetes two years early.

142. This would be cost-efficient as well.

143. I was diagnosed over 53 years ago, so things might not have been as easily improved then. But for someone who is diagnosed now, preparing to use a CGM, changing eating habits, and understanding the new normal would help immensely. I was diagnosed at 12; knowing that at 14 I would have a new regimen would have helped my family take better care of me beforehand and also have gotten me to the doctor quicker. As it was, I almost died.

144. Any delay in the start of insulin-dependent diabetes would be a win. I just wish there would be more research into long-term insulin-dependent diabetes.

145. If I had been diagnosed as a child, a 2-year delay would probably have been less stressful for my family.

146. I was diagnosed at 18 in the spring semester of my senior year of high school without a trip to the ER, and I was eager to start insulin as I knew I’d feel better once my blood sugar came down. (My A1C was 14.7.) A delay before starting insulin might not have served me, but if we’d known sooner, I could have avoided having to deal with school policies and nosiness that year. I might also have made certain family planning decisions at that point rather than looking forward to being a high-risk expectant mother when my A1C and financial circumstances align.

147. Any amount of time given to someone where their blood sugars are being regulated by their own pancreas decreases their risk of complications later in life, regardless of how well they try to control their diabetes once that time comes. I would give a lot to have had 2 more healthy years under my belt before full-blown diabetes took hold.

148. Would have avoided 4 nights in hospital and 6 months of not being able to work.

149. Delaying all of the Type 1 diabetes daily entities regarding insulin dosing and very frequent blood sugar checks while managing 5 young children would have been very helpful. Learning more during the 2 years would definitely have helped me to manage it better along with access to education about Type 1 diabetes.

150. I would have been prepared financially. I was diagnosed at age 58 with LADA. My A1c was 11. I am now 8. I still feel diabetes has interrupted my life. Between the pandemic n stress of my job my #s rose. It has been difficult at times, but I remind myself it could be worse. I could have been diagnosed with something I couldn't control. That is my silver lining....

151. Better preparation for myself and my family would’ve been invaluable. We would have been better educated than having to learn on the fly.

152. It would have been ok but if I knew where I was headed, I would just want to get started with a CGM for sure and pump if necessary. I was treated as a Type 2 with Metformin for a year before my correct diagnosis of Type 1, but my life had already changed, and it was a relief to feel like I had a bit more control with insulin.

153. Having a transition period would have been helpful to my mental health.  It would have allowed my time to educate myself and prepare for the challenges.

154. My Type 1 diabetes was discovered by a trip to ER and a blood sugar of 1739. I could have avoided my complications by being prepared with more knowledge.

155. Prior knowledge would give a patient and family more time to learn about self-care.

156. I'm one of the "lucky ones" because my mother has had T1 since I was a toddler, and my sister-in-law had had T1 for over 20 years by the time of my diagnosis, so I was very familiar with the disease and the treatment options. A two-year delay would have likely created an opportunity for a bit less stress for me and for my husband following my diagnosis.

157. I have had Type 1 since Thanksgiving 1966, anything that can delay diabetes is a godsend.

158. A two-year delay would have made my diagnosis less of a shock and would have given me time to prepare and learn about type 1 diabetes without the stress and threat of dying if I messed up.

159. With knowledge that I was developing diabetes, I would have known to watch for the symptoms and been aware of what was happening as my health declined, instead of being rushed to urgent care and the emergency room with no idea what was wrong with me.

160. Mostly, it would have given me a greater sense of what to expect when that delay is complete. Very interesting drug!

161. I oils have led a happier less stressful more controlled life. Fewer highs and losses with the emotional terror and physical terror that accompanies diabetes. Spent less money and been less of a diabetes prisoner and had a freer social life.

162. A two-year delay before having to start insulin wouldn't have helped me; I was already in DKA when I was diagnosed. I was also only 9 years old at the time of diagnosis, so I think I actually benefited from it becoming my new normal sooner rather than later.
     None of that changes that I think it is great to have the option to delay the need for insulin for those who can and want to take advantage of it.

163. The long-term consequences of elevated blood sugar are cumulative, so l feel I might have benefited from the delay, assuming the drug would keep users in a better glucose range than when needing to be on insulin. Whether or not this is true, a delay would have likely given me time to get a new patient appointment with the physician who had been most highly recommended to me. Because of the urgency, I needed to start with a different endocrinologist who had an opening. Also, a two-year delay would enable the patient to benefit from whatever advances occurred in those years. I started on insulin in January 1976, when advances were slow, but now changes affecting patient care such as improvements in CGMs are likely to occur if there is a two-year delay in starting insulin. And there certainly would be more time to educate the patient and the patient’s family or other support network.

164. I am not sure if a two-year delay would have helped me or my family since I was young (9yrs. in 1973) and not a lot of advances were made between 1973 and 1975, that I was aware of.  However, a two-year delay nowadays can make a huge difference in medications available and advances in CGM's and pumps which greatly help control this disease.  If the trials seem safe to start, I believe they should begin asap.

165. I would have been able to do more research that would have prepared me so much more.

166. I would have been a little older and more mature. Hopefully I would have been more comfortable with the whole thing. I was eleven and I didn’t have any help from my family much. I realized that I could lose weight if I didn’t take my insulin. So, I stopped taking it for a year and a half. I weighed under 100 lbs., and I looked great-ish. But I had cataracts before I was twenty. Gastroparesis at thirty... A two-year delay before all of this may have been just what I needed to get the maturity level I needed to handle everything.

167. Would have avoided er trip with blood sugar of 1054 and subsequently passing out due to the amount of insulin the hospital gave me that dropped my blood to 400 within 2 hours.