**Transcript of Cyberseminar**

**HERC Health Economics Seminar**

**The Power of Observational Data to Compare Treatments for Type 2 Diabetes on Long-Term Outcomes**

**Presenters: Julia Prentice, PhD**

**April 16, 2014**

*This is an unedited transcript of this session. As such, it may contain omissions or errors due to sound quality or misinterpretation. For clarification or verification of any points in the transcript, please refer to the audio version posted at www.hsrd.research.va.gov/cyberseminars/catalog-archive.cfm or contact herc@va.gov.*

Speaker: Welcome to the HERC Cyber Seminar Series. Today we have Julia Prentice, who is a former VA Funded and post doctoral fellow and currently with the healthcare financing and economics group as a health scientist at the VA Boston. She currently holds a joint appointment as an assistant professor at the Boston University School of Public Health and School of Medicine. She specializes in comparative effectiveness research and identifying the causal effects between access to care, health insurance choices and health outcomes. Today, she’s presenting findings from an HSR&D study entitled Comparative Effectiveness of an Anti Diabetic Medication Alternatives for Veterans, and in this seminar she’ll explain how quasi experimental methods can be applied to observational studies to examine the long term outcomes of different medications. Doctor Prentice? 

Dr. Prentice: Thank you very much. Okay, so I just want to quickly acknowledge our clinical collaborators on this study, Paul Conlin, Wallid Gellad and David Edelman are all in the VA, and then we have also been working with Todd Lee at the University of Illinois at Chicago. 

As many of you know, Type II Diabetes is a... there’s an epidemic of Type II Diabetes both within the VA and in the United States. It’s the seventh leading cause of death in the United States and individuals with diabetes are significantly more likely to suffer from micro vascular and macro vascular complications such as heart attack or stroke. 

The progressive nature of the disease requires the patients go on a sequence of medications. This raises the question of what treatments should patients get? There is overall a strong consensus that patients should start with an oral medication known as Metformin, but [electronic voice]... can I just pause and ask, am I the only one hearing... 

Speaker: Everyone is hearing it and the only way that I can call the operator and have them turn it off... I’m going to try calling them on my cell phone to do that, but everyone would hear me call the operator, so I will try calling on my cell phone again. 

Dr. Prentice: It’s no problem, I just... just asking. Okay, so once the patient has had Metformin, and if their diabetes is still uncontrolled, what drug they go to next is a bit of an open question. There are now over twelve classes of glucose lowering medications that are approved by the FDA. Some of these are very old drugs like the Sulfonylurea’s, or the SUs and these drugs are generic. But then we have more recent additions to the market like the TZDs that have entered the market about a decade ago and are brand name only. And then DPP-4 inhibitors like Januvia are even more recent and only brand name; and there are also several different types of insulin that are both in generic and brand name form. 

The evidence on what treatment a patient should use is based on both randomized clinical trials and then observational studies. Providers and researchers tend to prefer the results from the randomized clinical trials, but these trials actually have several limitations to them. Because in a clinical trial you need to enroll patients and then monitor them closely, we can often only have relatively short time-frames in the trials. Often trials last less than twelve months. So this means you can only look at short term outcomes such as glycemic control. The need to enroll patients and to monitor them closely makes these expensive studies to run and often means that they are smaller sample sizes. 

Since patients are being followed very closely, the results are generalizable in a clinical trial setting, but may not be generalizable outside of that. And often these clinical trials are focused on new medications because they are trying to gain approval and so they tend to focus on non established treatments.

The observational settings can actually overcome many of these limitations. Because in observational studies they are using data that’s being collected already for administrative purposes, it’s cheaper to get that data and you can have some very large sample sizes, longer follow up periods, and you can look at long-term outcomes such as heart attack or stroke. 

This data also reflects how a patient interacts with a treatment in a real world setting versus just a clinical trial setting, and it allows you to compare many different types of treatments, both established treatments and newer treatments. 

Clearly, the reason the randomized clinical trials are preferred is because you can identify a causal relationship between treatment and outcomes. So, in a randomized clinical trial, the randomization ensures that both the observed and unobserved characteristics between the treatment and control groups are balanced. The only difference is the assignment, the treatment the patient is assigned to, and so any differences in outcomes can be attributed to that treatment group. That is really the main reason why researchers prefer the randomized control trials is because you can get this causal relationship. 

That is clearly not the case when it comes to observational studies. In observational studies, there are many observed and unobserved characteristics that can influence both the treatment that an individual gets and their health outcomes. A good example of this is how well the patient self-manages their diabetes. A patient that tends to not carefully control their blood sugar, or not self-manage the disease very well, may cause the provider to worry to put that patient on insulin, which requires a very intensive patient participation in their treatment, because it requires... insulin will require multiple injections per day. 

The provider may not want to prescribe insulin for this patient, and they may leave them on the oral medications, which may not be the best treatment for that patient; and then that patient’s outcomes may be different. It’s unknown then if the patient’s outcomes are poorer because of the treatment they were on, or because the actual self management of the disease is poorer overall. 

In observational studies, these unobserved characteristics can influence the treatment that a patient gets, and then these outcomes can be better or worse due to these unmeasured differences. Ideally what we want... what researchers want... is to find a variable that acts like a randomization in the randomized control trial. Economists call this the instrumental variable, and previous researchers have found that local practice pattern variation is not affected by the individual patient’s health status, but it does influence what treatment an individual gets. And that influences their outcomes, so the only... a key assumption of the instrumental variable is that it can only influence the outcome through the treatment. 

I’m going to talk about two different studies today that we’ve done that compares different types of treatment for diabetes on one turn outcomes. The first is comparing the SU or Sulfonylurea to TZD as a second line agent; and the second study is looking at a generic form of insulin known as NPH, compared to the analog brand name insulin. In both of these studies, we’re using prescribing pattern practice variation as an instrumental variable. 

The first study I’m going to talk about compares the SU to the TZD. As I said, Metformin is agreed that metformin should be used as a first line treatment for patients who need to go on medication for their diabetes and for many years the SUs were consistently recommended... the guidelines recommended that a patient should then go on to an SU. That’s because the SUs are generic and they’re very cheap and they’ve been around for a long time. However, recent guidelines have moved away from recommending the SUs because there have been renewed concerns about their long-term effects. SUs are known to cause hypoglycemia, and recent studies have found increased cardiovascular risks for individuals who are on SUs. 

So if a patient doesn’t go on to an SU, what are the other choices? They could go on a TZD, or they could also go on a DPP-4 inhibitors like Januvia. Januvia... these are the most recent entries into the market, and Januvia is not actually on the VA formulary yet... the national formulary, so these DPP-4 inhibitors are not widely used in the VA. They weren’t widely used enough during our study period for us to look at it. 

We could look at TZDs, but TZDs also have been... there have been concerns about the adverse events that are associated with TZDs.  Thiazolidinediones has been found to increase cardiovascular complications and pioglitazone has been found to increase bladder cancer complications and osteoporosis. 

In this first study we’re comparing long-term outcomes for individuals who started on an SU compared to TZD. We took all patients who had a VA prescription for metformin and SU or TZD in 2000 to 2007 and we followed them through 2010. So, we have on some of these individuals, ten years of follow up. One of our outcomes is hospitalization, so we excluded anyone who wasn’t eligible for Medicare so that we’re sure that we can see all hospitalization claims; and to enter the study, the patient had to have a history of metformin during the baseline period, and then initiate a new SU or TZD prescription. So that left us about eighty-one thousand patients, seventy-four thousand of them started on an SU ad seven thousand of them started on a TZD. 

This gives an overview of the study timing. As I said, they entered the sample when... my pointer is not... it’s stuck up there... is there a trick? Okay... 

Speaker: I just clicked it down, so it’s working. 

Dr. Prentice: Thank you. So they enter the study when they actually started on the SU or TZD. The twelve months before this is the baseline period, and then we’re following these individuals until they experience their first outcome, or the end of 2010. 

Our outcome variables of interest were mortality, whether or not they had a heart attack or stroke, and then whether or not they experienced a hospitalization for an ambulatory care sensitive condition. These are thirteen hospitalizations that are defined by AHRQ that should be prevented if a patient is receiving high quality out-patient care. Several of these hospitalizations are specific to diabetes, such as uncontrolled diabetes, and several more are actually cardiovascular related. 

This slide just gives some basic descriptive statistics of the sample and their mean ages... sixty-nine years... their A1C is actually fairly well controlled with only eight percent having an average A1C over nine during the baseline period, but a significant minority of them do have some diabetes complications during the baseline period. For example, twenty-five percent of them did have some sort of severe cardiovascular events during the baseline period. Ten percent of the sample dies during the outcome period, five percent had an AMI or stroke, and seventeen percent had a preventable hospitalization. 

Our main treatment variables that we are interested in is whether or not individuals start on an SU compared to a TZD.  This slide just emphasizes that the drug that the patient started on, they tended to stay on, so over eighty percent of the individuals who started on an SU remained on an SU two years later. And about sixty five percent of those who started on TZD remained on a TZD at least two years later. 

Other control variables that we included in the model are standard demographic variables, a variety of labs, such as baseline A1C or serum creatinine, body mass index... we include measures of the Young diabetes severity index, which is a measure of how complicated the diabetes is during the baseline period, and we also included the Elixhauser comorbidity groups which includes a wide variety of physical and mental health comorbidities; and year and hospital effects. 

The instrumental variables that we are using is the provider level prescribing pattern, so in this study, it’s the proportion of prescriptions that a provider wrote for an SU of all the prescriptions that they wrote for an SU and a TZD. This provider level prescribing pattern is then predicting the likelihood of starting on an SU or TZD, and then subsequent outcomes. 

If a provider wrote fewer than ten unique patients during the baseline period, then we ended up assigning them the CBOC-level prescribing patterns. And the providers assigned the individual at the index state... or when the individuals enter the sample, so none of the individual’s actual prescriptions are included in the provider level prescribing pattern that they receive. 

This emphasizes that there is significant variation between providers and SU prescribing rates, so over time, throughout the study period, the data follow overall trends in medication use, you can see that SU prescriptions overall are decreasing throughout the study period until about 2008, when rosiglitazone became unflavored, and then SU prescribing starts going back up. But despite these overall trends, there’s a significant variation between providers and how often they’re actually prescribing an SU. For example, in June 2008 you have twenty-five percent of the providers that are prescribing an SU about eighty percent of the time or less; while another twenty-five percent of the providers are prescribing the SU ninety-five percent of the time or more. 

In a clinical trial, ideally the characteristics between the treatment groups are balanced, and so this slide compares some baseline characteristics between individuals who start on an SU, compared to TZD, and emphasizes that there are differences between these treatment groups. Individuals who start on a TZD are older than individuals who start on an SU, and they generally have more complicated during the baseline period. For example, they have higher rates of neuropathy. However, individuals who started on the TZD, are less likely to have uncontrolled A1C, and they are also less likely to have severe cardiovascular complications. 

This slide emphasizes the balancing effect the instrumental variable has. These first two columns on the left are the descriptive statistics that we just looked that emphasize the differences between he treatment groups. But the last two columns on the right split the sample up into a different way. It splits the sample up into two equal groups by the provider prescribing pattern. So the third column shows baseline characteristics of individuals who were assigned to providers that prescribes SU below the median, or in other words, providers who prescribed SU at relatively low rates. The last column shows these characteristics for individuals who were assigned to providers who prescribed SU above the median; or providers who prescribed the SU at relatively high rates. You can see when you split the sample up by this SU prescribing pattern, these differences and baseline characteristics goes away. They are similar age, similar rates of obesity, and similar rates of cardiovascular complications. 

As I said in the beginning, one of the key assumptions about an instrumental variable is that it needs to affect the outcome only through the treatment; so we were a little bit concerned about this assumption when it came to using a provider level prescribing pattern because we hypothesized that providers who the management style of providers of their diabetes patients may influence not only what treatment they choose, but the outcomes of their patients. So to control for this, we also included several provider level process quality variables, specifically the proportion of a providers labs that had uncontrolled A1C, that had uncontrolled LDL and uncontrolled blood pressure. These provider level process quality controls are calculated in the same way as the instruments. 

The next slides quickly go over how you end up implementing instrumental variables. It’s a two equation model and in the first equation, you are... the main explanatory variable of interest is the provider level prescribing pattern, and you’re using it to predict the likelihood that an individual starts on an SU or a TZD. The model controls for all the patient covariates, and for a process level for the provider process quality measures. 

What we’re interested in is whether or not provider prescribing history does in fact predict individual treatment and the coefficient is significant, and it’s a fairly strong predictor individual treatment as expected. There is also another test that can be done on how strong the instrument is, and the provider prescribing history shows that this test shows that it’s a very powerful instrument. 

The second equation is a Cox proportional hazard model that predicts the outcome. In this equation, what we’re interested in is the treatment, so whether or not the individual actually started on an SU or a TZD, and then we also include patient level controls and the provider process quality. But this equation also includes a residual that is captured from the first equation. Essentially, what this residual does is it controls for any correlation between the first equation and the second equation, and it allows you to identify a causal relationship between the treatment and the outcome. 

We have the results, the hazard ratios, for the individuals who start on an SU compared to a TZD. On all three outcomes, you can see the individuals who started on an SU were significantly more likely to die. They were significantly more likely to have a preventable hospitalization, and they were significantly more likely to experience a heart attack or stroke compared to individuals who started on a TZD. 

We wanted to do one more test to further confirm the solidity of SU prescribing rates as an instrument. To do this, we selected a completely different sample that just started on metformin and never started on an SU. This was about seventy-seven thousand individuals. We followed them for a year and we hypothesized the SU provider prescribing rates should have no influence on their outcomes because these individuals were never actually on an SU. 

This is the hazard ratios from the second stage models for this test, and we find that there is no significant relationship between provider SU prescribing rates and any of the outcomes for the sample of individuals who were only on metformin. 

This leads us to conclude that there is evidence of increased risk for patients who start on an SU compared to a TZD as their second medication. That’s actually fairly consistent with other recent research that has found increased cardiovascular complications for individuals who are starting on SUs, and it supports this overall recent guideline change that no longer recommends SUs as the preferred second agent. The main limitation is we can actually look at DPP-4 inhibitors, which are becoming even more common because there wasn’t enough use of them in the VA during this study period, and so that is on our list of future research, to further examine some of the newer medications. 

The next study I’m going to talk about compares different types of long acting insulin. Many patients with Type II Diabetes are going to require insulin eventually, and when they get to that point providers have a choice of prescribing the generic NPH insulin or analog insulin. 

The analog insulin is brand name only at the moment, and it’s designed to have a longer half life, or to better mimic the natural insulin profile that happens in the body. Because of this, it is hypothesized that patients like this analog insulin better. They find it easier to adhere to, and so it’s hypothesized that they will be more likely to continue their insulin. However, the negative of this analog insulin is that it is significantly more expensive. 

In the clinical trials they have compared analog insulin to NPH and there has been very little difference in the short-term outcome. There has been no difference in glycemic control; there has been no difference in severe hypoglycemic events between the two types of insulin. Those on analog insulin do experience fewer nocturnal hypoglycemic events. 

This lower nocturnal hypoglycemia is hypothesized to increase patient adherence overall, and this increased adherence is hypothesized then to decrease long-term complications, and lower costs. But the short timeframe of the studies that have looked at this prevent any conclusions to be actually made about long term outcomes. There have been a few cost effectiveness studies that have tried to compare analog insulin to NPH and they provide mixed results. Some of them are relying on clinical trial data where they’re modeling long term complication rates, but this trial data might not actually reflect real world clinical settings. And then there are other retrospective claim studies that don’t account for selection bias, and so some studies find that analog insulin is cost effective, while other studies do not. So, it ends up being a bit of an open question. 

We wanted to know whether there were differences in long term outcomes when comparing NPH and analog insulin. We took a similar study population, we chose all patients who had a VA prescription for diabetes medication between 2000 to 2007, and we followed them through 2010. We once again excluded those who did not have Medicare. For this study, individuals had to be on an oral medication during the baseline period, and then start a new long acting insulin prescription. That left us with a hundred and forty-three thousand patients, about a hundred and nineteen thousand of them started on NPH, and twenty-four thousand of them started on analog insulin. 

Again, the study timing is very similar to the other study. Individuals are entering the sample when they start on their NPH or analog insulin. The twelve months before that is the baseline period, and we’re following them until they experience their first outcome or the end of 2010. 

The outcomes in this sample are only mortality and preventable hospitalization. It includes the same control variables or demographics or labs, the comorbidities, and the provider process quality variables. 

This slide gives you some descriptive statistics. On this sample they are much sicker than on the previous sample we just looked at. They are only a little bit older, but here, over a quarter of them have uncontrolled A1C during the baseline period and almost thirty seven percent experience some sort of severe cardiovascular complication during the baseline period. A third of them are dying during our baseline period, and nineteen percent experience a preventable hospitalization. 

Our treatment variable that we’re interested in here is whether or not they started on analog insulin compared to NPH. Again, they tended to stay on the prescription they started with, so of those who went on NPH, about eighty percent of them stayed on NPH and had NPH as their last prescription, and this is ninety five percent for individuals who started on analog insulin. 

The instrumental variable was the provider level prescribing pattern. In this case it’s the proportion of prescriptions that a provider wrote for analog insulin of all the prescriptions, of all the long acting insulin prescriptions. This provider prescribing pattern is predicting the likelihood of starting on NPH or analog insulin, and then will subsequently predict outcomes. Again, if a provider wrote prescriptions for fewer than ten unique patients, we ended up assigning the CBOC level prescribing pattern. Once again, the provider was assigned at the index state, or when the individuals entered the study. 

Speaker: Would you clarify what you mean by fifty-three percent of the time? 

Dr. Prentice: That means that fifty-three percent of the time we ended up calculating at the clinic level. 

Again, there remain significant variations between providers and how often they prescribed analog insulin. Again, analog insulin became widely more popular in the VA throughout the study period, but for example, in June 2008, twenty-five percent of the providers are prescribing analog insulin five percent of the time or less; while another twenty-five percent are prescribing the analog insulin twenty percent of the time, or more. 

This slide shows you the differences between the individuals who started on NPH versus those who started on analog insulin. Those who started on analog insulin are older than those who started on NPH, and they are generally are in poorer health. They have higher rates of neuropathy and a little bit higher rates of peripheral vascular disease. 

This slide shows the bouncing effect of instrumental variable. The two columns on the left are the baseline descriptive statistics that we just saw that split it up by individual treatment that an individual started. But the two columns on the right are once again splitting it up by whether or not the patient is assigned to a provider that prescribed analog insulin below the median amount of time here in the third column; and above the median amount of time in the last column. In this sample, the instrumental variable doesn’t balance things perfectly; it does narrow these differences if you look across. It consistently narrows the differences on many of the provider... many of the individual characteristics.

The implementation of the actual models is the same. In the first equation we are most interested in whether or not provider prescribing patterns of analog insulin predict the likelihood of starting on NPH or analog insulin controlling for patient covariates and process quality measures. It is a significant predictor of... the provider analog prescribing history is a significant predictor of individual treatment, and it’s a powerful instrument again. 

The second equation is the same as the Cox proportional hazard model where our main variable of interest is whether or not an individual actually started on NPH versus analog insulin. We’re including the same controls we’ve been including all along, and we also include this residual from the first equation that controls for any correlation that might occur between the first and second equation, and allows us to identify a causal relationship. 

Here there is no significant effect for individuals who started on analog insulin compared to NPH. There is no significant difference for mortality or preventable hospitalizations. The other covariates in the model have a relationship in the expected direction. The older age, being diagnosed with congestive heart failure, cerebrovascular disease, drug abuse or depression significantly increases the risk of experiencing both outcomes, and if you’ve been prescribed metformin in the baseline period, you’re less likely to experience both outcomes.

Since there is no difference in mortality or preventable hospitalization risk when comparing analog insulin to NPH, we are concluding that analog insulin is not cost effective. This actually has significant cost implications. A recent study estimated that if Medicare Part D had been prescribing analog insulin at the same rates that the VA was prescribing analog insulin in 2008, Medicare Part D could have saved an estimated savings of a hundred and eight-nine million. 

The patents, of course, on the analog insulin, however, are going to start expiring this year and over the next couple of years, so that opens up the... it is possible then that generic options may enter the market. That opens up the possibility that generic options may enter the market, however to enter the market, these generic options are going to have to prove that they are as safe and as effective as the brand name options, and that is going to be difficult with these insulins because of the much more complicated protocol than some of the smaller generic molecules. So, some people are estimating that any generic option that enters the market may only be about twenty to forty percent cheaper than the current brand names. So, it could be that long-term NPH remains to be the most cost effective option. 

The major limitation of our study is that we can’t get a handle on quality of life outcomes with administrative data. We don’t know how... if patients really find the analog insulin to be much more comfortable to take long term; and so future research should focus on that question. 

In conclusion, we would argue that instrumental variable is a fairly powerful tool to define causality and observational data. Prescribing pattern variations is a consistently strong instrumental variable; and the use of observational data can overcome some of the limitations of randomized clinical trials. With the expansion of the electronic medical records, this data is going to become even more important and can be more easily accessed. I am happy to take questions.

Speaker: We have a question about the slides referencing how the patient characteristics were balanced. Would you talk about that... whether there was balancing and how the balancing was done? 

Dr. Prentice: Are we talking about these slides? The balancing effect? 

Speaker: I believe so. 

Dr. Prentice: The balancing is done by the instrumental variable, basically. So, the first two columns here... let me go back to the one where it works better. 

So, the first two slides split the sample up by what the individual actually started, and when you look at that... when you go down the list, you can see there are differences between the two groups. Those who start on TZD tend to be in poorer health. These last two columns split the sample up in a completely different way. In these two columns, we’re splitting up the individuals based on what provider they’re assigned to and we’re splitting up the sample based on providers who prescribe SU above the median, and providers who prescribe SU below the median amount of time. So it demonstrates this equalizing effect that the instrument has and essentially the instrument is splitting the sample up in a way that is equalizing the observed characteristics. Does that make sense? 

Speaker: Yes. Another question, or comment... to clarify then, there are two stages. First you ask if the exposure is related to the instrument, and then if the outcomes are related to the instrument. Is that correct? 

Dr. Prentice: The first equation asks if the instrument predicts treatment, and then the second equation predicts whether or not the treatment actually predicts the outcome. 

Speaker: Okay, I have another question about the first study and the difference between the patient characteristics and the provider characteristics, I wonder if you could go back to the... I’m sorry, go forward one... these questions... these comments of the process quality. My question is really about the patient component of these quality measures. I mean, really they’re not different from the patients... these are an aggregate of patient characteristics which the provider has some effect on, but is not a hundred percent responsible for, correct? 

Dr. Prentice: That is correct. Yes, and we were concerned the overall provider practice pattern would influence the treatment providers preferred, and at the same time outcomes. So, this was the best control we could put in, but you are right that a patient’s lab has patient characteristics. These providers’ labs are all an aggregate of patient characteristics. 

Speaker: Okay, just a very difficult question. 

Dr. Prentice: Right, I’m not sure... and we’re including a bunch of labs in the baseline period as well, so we’re controlling for patient level labs, so that’s going to help that problem, but I am not sure you can avoid it completely. 

Speaker: Okay, another question... have you considered analyzing individual’s adherence to medication and how it may affect the outcomes? 

Dr. Prentice: Yes... we have a little bit. For insulin it’s very hard... so most of the inherent literature  wants to calculate like a medication possession ratio, which is a number of days supply you have for a pill divided by the number of days, and so for the oral medications, that’s possible and we thought about doing that. But we just haven’t gotten there yet. But for the insulin study, insulin... it’s not like you take a pill a day, so we’ve never been sure how... the clinicians have never known how to really get a good measure of adherence to insulin. 

Speaker: But you do have presumably, a hundred percent of the medication records because you have both medicare and VA records, correct? 

Dr. Prentice: Yes, right. 

Speaker: Okay, are there any other questions? 

Dr. Prentice: It looks like with incidents of hypoglycemia looked at between types of medication, we tried to look at hypoglycemia, and it is not... hypoglycemia is not coded consistently at all. We did try to look at it for the SU study and since we don’t have emergency department records, there weren’t enough cases of hypoglycemia for us to make any conclusions about it. But that is actually something else that is on the long-term list of future research if we could figure out a better way to get at hypoglycemia through administrative records. Especially nocturnal hypoglycemia because most of the time that’s just not even reported. 

Speaker: Any other questions? Well, thank you very much...

Dr. Prentice:  We just have a question come in there...  

Speaker: We did? I don’t see it yet. 

Dr. Prentice:  Yes, it was NPH only or NPH regular too... so yes, the way we split up NPH or analog insulin was we included... some insulins, or some combinations of insulin like NPH and regular in the same bottle... so as long as it had NPH we included them in the NPH, so that included some regular... that included medications that were the combinations and the same was true on the analog side. There are some analog insulin that includes both long acting analog insulin and short acting analog insulin. So as long as they had long acting analog insulin in it, it was included on the analog side. 

Speaker: Okay; any other questions? Well, thank you very much; it was very interesting and straight forward presentation. I see Heidi, you have something to say. 

Heidi: Yes, I put our feedback form up if you guys could just take a few moments to fill this out. There is no submit button, the answers are taken in real time and put into our database, so if you could take a moment and fill this out, we would very much appreciate that. 

Speaker: Julia, do you have any last minute remarks you want to make before we close out here? 

Dr. Prentice:  No, feel free to contact me with any questions if they come up later. 

Speaker: Fantastic, thank you to our audience, thank so much for participating today. Julia, thank you so much for taking the time to prepare and present today’s session. Patsy, I don’t have it in front of me, do you have the information for next month’s session by any chance? 

Patsy: No.

Speaker: Well, for our audience, we will have our next HERC Health Economics Session on May 21. Most of you should have received an announcement yesterday with registration information. If you did not receive that, we will be sending one out closer to that date. We hope you can all join us for that session, and thank you everyone for joining us for today’s HSR and D Cyber Seminar. Thank you. 

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