# Presentation: 529736

## Lotronex:  Clinical Trials

- Thomas Permutt
- Division of Biometrics II
- with David Hoberman, Ph.D.
- Zili Li, M.D.

**Notes:**
The questions the committee has to cope with today have statistical aspects to them, so let me tell you what they are and why I think they are important.  I’ll be talking about data from clinical trials; later you’ll hear some discussion of the same issues as they relate to postmarketing data.  The views expressed are my own, but much of the work was done by Drs. Hoberman and Li.

## Statistical Issues

- Risk
- What is the risk?
- How does it change over time?
- Are there risk factors?
- Benefit
- Populations with big benefit?
- Populations with little benefit?

**Notes:**
The most basic question is how we quantify the risk of adverse events so that it can be properly weighed against the benefit.  A part of the answer to that, and an important question in itself, is how the risk varies with the time of exposure.  And once we have some estimate of the risk in the overall population, we have to ask how the risk varies within the population:  can we distinguish subpopulations at greater or lesser risk? or, in other words, can we identify risk factors?
The question of subpopulations is also important on the benefit side. If there are serious risks to be borne, they may nevertheless be tolerable in patients for whom the benefit is big.  Similarly, if we find subgroups less likely to benefit, we would want to avoid exposing them to the risk.

## What Is the Risk?

- Complications of constipation
- 11/11,000 in controlled trials
- 3/3,000 on placebo
- Stopping rules
- 10% dropout on alosetron
- 1% on placebo
- Ischemic colitis

**Notes:**
The risks that we are most concerned about are serious complications of constipation and ischemic colitis.  Let’s take complications of constipation first.  There were 11 cases by our counting among 11,000 patients treated with alosetron in controlled trials, a crude rate of 1 per thousand.  Most required hospitalization, and one required surgery.  There were also 3 cases in 3000 placebo patients, a nearly identical rate, and the times of exposure were also comparable, 3 months in most cases.  A statistician might stop there, except for a feature of the design of the controlled trials.  Patients were, of course, monitored closely in the trials, and there were rules requiring discontinuation of certain patients with constipation.  In fact, about 10 percent of alosetron patients did discontue for this reason, compared to only 1 percent of placebo patients.  So the absence of excess risk over placebo in the trials might not be representative of what would be seen in marketing.  We think the post-marketing experience is therefore particularly relevant here, as you will hear later.
The other potentially life-threatening risk is ischemic colitis.

## Ischemic Colitis at 3 months

- 20 studies
- >100 patients each
- 11,000 patients on alosetron
- 12 studies with no cases
- Overall rate 2/1000
- Study 20 has 10 of 18 cases
- late study:  better ascertainment?
- rate 5/1000

**Notes:**
Excluding a few studies with fewer than a hundred patients, there are 20 controlled trials in our database for alosetron.  Between them, as you have heard, they account for 11,000 patients treated with alosetron, mostly for 3 months.  Ischemic colitis occurred on alosetron in 8 of these studies, and there was also a single case of ischemic colitis in a placebo patient.  I’ve plotted here the Kaplan-Meier estimates of cumulative incidence at 3 months, with 95% confidence intervals, from the 8 studies that had cases on alosetron.  Considering all 20 studies, including the 12 with no cases, the pooled cumulative incidence is 2 per thousand at 3 months; I’ve marked that with a horizontal line.
I have to call your attention especially to Study 20.  More than half the cases occurred in this study.  It was of six months’ duration, but again, for comparison, what I’ve plotted here is the 3-month cumulative incidence.  The confidence interval barely touches the pooled rate, so there is some reason to think this study is really different.  Of course, it comes to our attention, after the fact, precisely because the rate is different, so the difference may not be as striking as it seems.  If it really is different, though, one reason to consider is the possibility of better ascertainment of ischemic colitis in this large study that took place relatively late in the course of development, after ischemic colitis was already an issue.  Anyway, if you look at this study alone, you get an estimated three-month incidence of 5 per thousand.
If asked:  UCB for pooled rate is 2.5.

## Change over Time(12 months)

- Little information past 6 months
- 700 alosetron patients at month 7
- 12,000 at month 1
- 1 case of ischemic colitis (placebo)

**Notes:**
What do we know about the risk over time?  I’ve borrowed a figure from the applicant’s background package to illustrate this.  They’ve used a slightly larger pool of studies, but it doesn’t make any difference.

There is a lot of useful information in this picture, but hardly any of it is in the right half.  Only 700 patients were exposed to alosetron for more than six months, though, compared to 12,000 for one month. There was one case of ischemic colitis after 6 months, and it happened to be in a placebo patient, but we wouldn’t have expected more than one case with so few patients.  So, no, there is no reason to think the risk with alosetron levels off, nor to think that the placebo risk catches up to it.

## Change over Time(6 months)

- Cumulative risk keeps rising
- Risk per unit time may decrease
- Cumulative risk is important
- Most cases in month 1, but 30% of exposure also in month 1

**Notes:**
There, that’s better.  Now, over the first six months, and especially the first three months, we do have some information.  What is plotted here is the cumulative risk.  For example, of patients exposed for 3 months, how many got ischemic colitis at some time during those three months?  About 2 in a thousand, as I said before.  This risk continues to rise over six months.  Well, it can’t go down:  the longer I watch you, the more likely you are to have had the event.  The point is that it doesn’t flatten out, either.  The slope of this curve, which is called the hazard, does seem to be bigger in the first month than in the second and third month, perhaps as much as double, although we are still looking at small numbers of events with a lot of uncertainty.  In any case, although the cumulative risk may rise less steeply later on, there is every reason to think it continues to rise.  How high it might rise after more than 6 months of treatment, I’m not in a position to say, and I don’t think anyone else is, either.  Unfortunately, this is really what you want to know, if you are a patient contemplating taking alosetron over a long period.
Now you heard Dr. Carter say that most cases of ischemic colitis were in the first month.  This is true, but it is not as dramatic an effect as it might seem because 30 percent of the exposure was in the first month.  So, it’s not as if you are out of the woods after a month or three months.  Rather, it’s that most of the cases happened where most of the exposure happened.  That is, if we watched many people for a year or more, rather than for only three months, we might not expect most of the cases to be in the first month any more.

## Risk Factors for Ischemic Colitis

- Known in broad population
- None identified with alosetron
- Everyone is at risk

**Notes:**
What about risk factors?  Well, a number of risk factors for ischemic colitis are known in general populations, but in the trial data with alosetron, we have been unable to identify subgroups more or less likely to develop ischemic colitis.  I think the sponsor has been diligent in looking for them, but they are not to be found.  This doesn’t mean there aren’t any.  What it means is that with 18 cases of ischemic colitis, we haven’t been able to figure out what distinguishes the cases from the noncases.  We wouldn’t be able to figure this out, unless the association were extremely strong.
What that means is, so far as we can tell, everybody who takes alosetron shares the risk of developing ischemic colitis.

## Benefit:  Populations with Big Benefit?

- Urgency
- Quality of Life (Productivity)

**Notes:**
If the risk is unavoidable, are there patients in whom it is tolerable in relation to a large benefit?  In this connection I’d like to discuss some of the data on urgency and also comment briefly on some quality of life data Dr. Traber showed you.

## Urgency

- Responder:
- Start above 5 days per week
- End below 2 days per week (3 months)
- Studies 3001, 3002
- alosetron 32%
- placebo 19%
- Studies 30011, 30012 (more severe)
- alosetron 50%
- placebo 29%

**Notes:**
Four studies focused on an urgent need to go to the bathroom. I’ve pooled together two relatively early studies, and also, separately, two later studies in which the patients were worse off at baseline.  I’ve looked at the subset of patients who began the study reporting urgency more than 5 days a week, and counted how many of them finished the three-month study reporting urgency less than 2 days a week.  In the first two studies, it was 32 percent, compared to 19 percent with placebo.  In the two later studies it was 50 percent, compared to 29 percent for placebo.  So in this group of patients with a lot of room to improve, substantial numbers of them did improve a lot.

## Productivity

- Treatment difference 1 hour per week
- Less than spontaneous improvement in placebo

**Notes:**
Now we have heard about the burden of irritable bowel syndrome in terms of time lost from work, among other things.  This would also be a natural place to look for big benefits.  The sponsor showed these data in a slightly different form, and, again, I’ve cribbed the graph from their background package.  There are unquestionably statistically significant differences between alosetron and placebo in hours of work lost, but I want to call your attention to the scale here.  The differences between treatments are on the order of an hour a week, and they are less than the spontaneous improvement with placebo.

## Populations with Little Benefit

- Stool consistency hard or lumpy
- Stool frequency <2 per day
- May also be at higher risk

**Notes:**
So we have some evidence of a big benefit in urgency, but not so much in productivity.  It’s also useful to look for groups less likely to benefit, so as to avoid unnecessary risk to these patients.  The applicant has been able to identify a few such risk factors for lack of efficacy, based on the patients’ condition at baseline.  In particular, patients with hard or lumpy stools or fewer than 2 stools per day were less likely to be successfully treated than others.  You might also suspect that such patients could be at higher risk for complications of constipation, although we don’t know that.

## Clinical Trials:  Conclusions

- Risk
- What is the risk?
- Complications of constipation
- no excess over placebo, but ...
- possible dropouts before complications
- Ischemic colitis
- excess over placebo
- 2 to 5 per 1000 over 3 months
- How does it change over time? (ischemic colitis)
- Cumulative risk rises
- Hazard may decrease somewhat after 1 month
- Very little information past 6 months
- Are there risk factors?  No.
- Benefit
- Populations with big benefit?  Yes, e.g., urgency
- Populations with little benefit?  Yes, e.g. hard stools

**Notes:**
Well, I posed a number of questions at the beginning, and here is what I think we know about the answers.  What is the risk?  For complications of constipation, we don’t see any excess compared to placebo, but this may be partly because many patients with constipation were discontinued.  For ischemic colitis, there is an excess of 2 to 5 per thousand patients over 3 months.
How does it change over time?  The cumulative risk continues to rise over six months, although perhaps less steeply after the first month.  After six months, we have too little information to know.
Risk factors for ischemic colitis in patients treated with alosetron have not been identified.  As far as we know, everyone who takes alosetron shares the risk.
Some patients with a lot of room for improvement did improve a lot, and patients with harder or less frequent stools at baseline did not benefit much.