CRM consulting gig

This morning I had someone from a pharmaceutical company call me with questions about conducting a CRM dose-finding trial and I mentioned it to my wife.

Then this afternoon she was reading a book in which there was a dialog between husband and wife including this sentence:

He launched into a technical explanation of his current consulting gig—something about a CRM implementation.

You can’t make this kind of thing up. A few hours before reading this line, my wife had exactly this conversation. However, I doubt the author and I had the same thing in mind.

In my mind, CRM stands for Continual Reassessment Method, a Bayesian method for Phase I clinical trials, especially in oncology. We ran a lot of CRM trials while I worked in biostatistics at MD Anderson Cancer Center.

For most people, presumably including the author of the book quoted above, CRM stands for Customer Relationship Management software.

Like my fictional counterpart, I know a few things about CRM implementation, but it’s a different kind of CRM.

More clinical trial posts

Simple clinical trial of four COVID-19 treatments

A story came out in Science yesterday saying the World Health Organization is launching a trial of what it believes are the four most promising treatments for COVID-19 (a.k.a. SARS-CoV-2, novel coronavirus, etc.)

The four treatment arms will be

  • Remdesivir
  • Chloroquine and hydroxychloroquine
  • Ritonavir + lopinavir
  • Ritonavir + lopinavir + interferon beta

plus standard of care as a control arm.

I find the design of this trial interesting. Clinical trials are often complex and slow. Given a choice in a crisis between ponderously designing the perfect clinical trial and flying by the seat of their pants, health officials would rightly choose the latter. On the other hand, it would obviously be good to know which of the proposed treatments is most effective. So this trial has to be a compromise.

The WHO realizes that the last thing front-line healthcare workers want right now is the added workload of conducting a typical clinical trial. So this trial, named SOLIDARITY, will be very simple to run. According to the Science article,

When a person with a confirmed case of COVID-19 is deemed eligible, the physician can enter the patient’s data into a WHO website, including any underlying condition that could change the course of the disease, such as diabetes or HIV infection. The participant has to sign an informed consent form that is scanned and sent to WHO electronically. After the physician states which drugs are available at his or her hospital, the website will randomize the patient to one of the drugs available or to the local standard care for COVID-19.

… Physicians will record the day the patient left the hospital or died, the duration of the hospital stay, and whether the patient required oxygen or ventilation, she says. “That’s all.”

That may sound a little complicated, but by clinical trial standards the SOLIDARITY trial is shockingly simple. Normally you would have countless detailed case report forms, adverse event reporting, etc.

The statistics of the trial will be simple on the front end but complicated on the back end. There’s no sophisticated algorithm assigning treatments, just a randomization between available treatment options, including standard of care. I don’t see how you could do anything else, but this will create headaches for the analysis.

Patients are randomized to available treatments—what else could you do? [1]—which means the treatment options vary by site and over time. The control arm, standard of care, also varies by site and could change over time as well.  Also, this trial is not double-blind. This is a trial optimized for the convenience of frontline workers, not for the convenience of statisticians.

The SOLIDARITY trial will be adaptive in the sense that a DSMB will look at interim results and decide whether to drop treatment arms that appear to be under-performing. Ideally there would be objective algorithms for making these decisions, carefully designed and simulated in advanced, but there’s no time for that. Better to start learning immediately than to spend six months painstakingly designing a trial. Even if we could somehow go back in time and start the design process six months ago, there could very well be contingencies that the designers couldn’t anticipate.

The SOLIDARITY trial is an expedient compromise, introducing a measure of scientific rigor when there isn’t time to be as rigorous as we’d like.

Update: The hydroxycloroqine arm was dropped from the trial because a paper in the Lancet reported that the drug was neither safe nor effective. However, it now appears that the data used in the Lancet paper were fraudulent.

Update: The Lancet retracted the paper in question on June 4, 2020.

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[1] You could limit the trial to sites that have all four treatment options available, cutting off most potential sources of data. The data would not be representative of the world at large and accrual would be slow. Or you could wait until all four treatments were distributed to clinics around the world, but there’s no telling how long that would take.

Dose finding != dose escalation

You’ll often hear Phase I dose-finding trials referred to as dose escalation studies. This is because simple dose-finding methods can only explore in one direction: they can only escalate.

Three-plus-three rule

The most common dose finding method is the 3+3 rule. There are countless variations on this theme, but the basic idea is that you give a dose of an experimental drug to three people. If all three are OK, you go up a dose next time. If two out of three are OK, you give that dose again. If only one out of three is OK, you stop [1].

Deterministic thinking

The 3+3 algorithm implicitly assumes deterministic thinking, at least in part. The assumption is that if three out of three patients respond well, we know the dose is safe [2].

If you increase the dose level and the next three patients experience adverse events, you stop the trial. Why? Because you know that the new dose is dangerous, and you know the previous dose was safe. You can only escalate because you assume you have complete knowledge based on three samples.

But if we treat three patients at a particular dose level and none have an adverse reaction we do not know for certain that the dose level is safe, though we may have sufficient confidence in its safety to try the next dose level. Similarly, if we treat three patients at a dose and all have an adverse reaction, we do not know for certain that the dose is toxic.

Bayesian dose-finding

A Bayesian dose-finding method estimates toxicity probabilities given the data available. It might decide at one point that a dose appears safe, then reverse its decision later based on more data. Similarly, it may reverse an initial assessment that a dose is unsafe.

A dose-finding method based on posterior probabilities of toxicity is not strictly a dose escalation method because it can explore in two directions. It may decide that the next dose level to explore is higher or lower than the current level.

Starting at the lowest dose

In Phase I studies of chemotherapeutics, you conventionally start at the lowest dose. This makes sense. These are toxic agents, and you naturally want to start at a dose you have reason to believe isn’t too toxic. (NB: I say “too toxic” because chemotherapy is toxic. You hope that it’s toxic to a tumor without being too toxic for the patient host.)

But on closer inspection maybe you shouldn’t start at the lowest dose. Suppose you want to test 100 mg, 200 mg, and 300 mg of some agent. Then 100 mg is the lowest dose, and it’s ethical to start at 100 mg. Now what if we add a dose of 50 mg to the possibilities? Did the 100 mg dose suddenly become unethical as a starting dose?

If you have reason to believe that 100 mg is a tolerable dose, why not start with that dose, even if you add a lower dose in case you’re wrong? This makes sense if you think of dose-finding, but not if you think only in terms of dose escalation. If you can only escalate, then it’s impossible to ever give a dose below the starting dose.

More clinical trial posts

[1] I have heard, but I haven’t been able to confirm, that the 3+3 method has its origin in a method proposed by John Tukey during WWII for testing bombs. When testing a mechanical system, like a bomb, there is much less uncertainty than when testing a drug in a human. In a mechanical setting, you may have a lot more confidence from three samples than you would in a medical setting.

[2] How do you explain the situation where one out of three has an adverse reaction? Is the dose safe or not? Here you naturally switch to probabilistic thinking because deterministic thinking leads to a contradiction.

 

Multi-arm adaptively randomized clinical trials

This post will look at adaptively randomized trial designs. In particular, we want to focus on multi-arm trials, i.e. trials of more than two treatments. The aim is to drop the less effective treatments quickly so the trial can focus on determining which of the better treatments is best.

We’ll briefly review our approach to adaptive randomization but not go into much detail. For a more thorough introduction, see, for example, this report.

Why adaptive randomization

Adaptive randomization designs allow the randomization probabilities to change in response to accumulated outcome data so that more subjects are assigned to (what appear to be) more effective treatments. They also allow for continuous monitoring, so one can stop a trial early if we’re sufficiently confident that we’ve found the best treatment.

Adapting randomization probabilities

Of course we don’t know what treatments are more effective or else we wouldn’t be running a clinical trial. We have an idea based on the data seen so far at any point in the trial, and that assessment may change as more data become available.

We could simply put each patient on what appears to be the best arm (the “play-the-winner” strategy), but this would forgo the benefits of randomization. Instead we compromise, continuing to randomize, but increasing the randomization probability for what appears to be the best treatment at the time a subject enters the trial.

Continuous monitoring

By monitoring the performance of each treatment arm, we can drop a poorly performing arm and assign subjects to the better treatment arms. This is particularly important for multi-arm trials. We want to weed out the poor treatments quickly so we can focus on the more promising treatments.

Continuous monitoring opens the possibility of stopping trials early if there is a clear winner. If all treatments perform similarly, more patients will be used. The maximum number of patients will be enrolled only if necessary.

Multi-arm trials

Randomizing an equal number of patients to each of several treatment arms would require a lot of subjects. A multi-arm adaptive trail turns into a two-arm trial once the other arms are dropped. We’ll present simulation results below that demonstrate this.

Running a big trial with several treatment arms could be more cost effective than running several smaller trials because there is a certain fixed cost associated with running any trial, no matter how small: protocol review, IRB approval, etc.

There has been some skepticism whether two-arm adaptively randomized trials live up to their hype. Trial design is a multi-objective optimization problem and it’s easy to claim victory by doing better by one criteria while doing worse by another. In my opinion, adaptive randomization is more promising for multi-arm trials than two-arm trials.

In my experience, multi-arm trials benefit more from early stopping than from adapting randomization probabilities. That is, one may treat more patients effectively by randomizing equally but dropping poorly performing treatments. Instead of reducing the probability of assigning patients to a poor treatment arm, continue to randomize equally so you can more quickly gather enough evidence to drop the arm.

I initially thought that gradually decreasing the randomization probability of a poorly performing arm would be better than keeping the randomization probability equal until it suddenly drops to zero. But experience suggests this intuition was wrong.

Simulation study

I designed a 4-arm trial with a uniform prior on the probability of response on each arm. The maximum accrual was set to 400 patients.

An arm is suspended if the posterior probability of it being best drops below 0.05. (Note: A suspended arm is not necessarily closed. It may become active again in response to more data.)

Subjects are randomized equally to all available arms. If only one arm is available, the trial stops. Each trial was simulated 1,000 times.

In the first scenario, I assume the true probabilities of successful response on the treatment arms are 0.3, 0.4, 0.5, and 0.6 respectively. The treatment arm with 30% response was dropped early in 99.5% of the simulations, and on average only 12.8 patients were assigned to this treatment.

|-----+----------+----------------+----------|
| Arm | Response | Pr(early stop) | Patients |
|-----+----------+----------------+----------|
|   1 |      0.3 |          0.995 | 12.8     |
|   2 |      0.4 |          0.968 | 25.7     |
|   3 |      0.5 |          0.754 | 60.8     |
|   4 |      0.6 |          0.086 | 93.9     |
|-----+----------+----------------+----------|

An average of 193.2 patients were used out of the maximum accrual of 400. Note that 80% of the subjects were allocated to the two best treatments.

Here are the results for the second scenario. Note that in this scenario there are two bad treatments and two good treatments. As we’d hope, the two bad treatments are dropped early and the trial concentrates on deciding the better of the two good treatment.

|-----+----------+----------------+----------|
| Arm | Response | Pr(early stop) | Patients |
|-----+----------+----------------+----------|
|   1 |     0.35 |          0.999 |     11.7 |
|   2 |     0.45 |          0.975 |     22.5 |
|   3 |     0.60 |          0.502 |     85.6 |
|   4 |     0.65 |          0.142 |    111.0 |
|-----+----------+----------------+----------|

An average of 230.8 patients were used out of the maximum accrual of 400. Now 85% of patients were assigned to the two best treatments. More patients were used in this scenario because the two best treatments were harder to tell apart.

Related posts

Valuing results and information

Chris Wiggins gave an excellent talk at Rice this afternoon on data science at the New York Times. In the Q&A afterward, someone asked how you would set up a machine learning algorithm where you’re trying to optimize for outcomes and for information.

Here’s how I’ve approached this dilemma in the past. Information and outcomes are not directly comparable, so any objective function combining the two is going to add incommensurate things. One way around this is to put a value not on information per se but on what you’re going to do with the information.

In the context of a clinical trial, you want to treat patients in the trial effectively, and you want a high probability of picking the best treatment at the end. You can’t add patients and probabilities meaningfully. But why do you want to know which treatment is best? So you can treat future patients effectively. The value of knowing which treatment is best is the increase in the expected number of future successful treatments. This gives you a meaningful objective: maximize the expected number of effective treatments, of patients in the trial and future patients treated as a result of the trial.

The hard part is guessing what will be done with the information learned in the trial. Of course this isn’t exactly known, but it’s the key to estimating the value of the information. If nobody will be treated any differently in the future no matter how the trial turns out—and unfortunately this may be the case—then the trial should be optimized strictly for the benefit of the people in the trial. On the other hand, if a trial will determine the standard of care for thousands of future patients, then there is more value in picking the best treatment.

Interim analysis, futility monitoring, and predictive probability

An interim analysis of a clinical trial is an unusual analysis. At the end of the trial you want to estimate how well some treatment X works. For example, you want to how likely is it that treatment X works better than the control treatment Y. But in the middle of the trial you want to know something more subtle.

It’s possible that treatment X is doing so poorly that you want to end the trial without going any further. It’s also possible that X is doing so well that you want to end the trial early. Both of these are rare. Most of the time an interim analysis is more concerned with futility. You might want to stop the trial early not because the results are really good, or really bad, but because the results are really mediocre! That is, treatments and Y are performing so similarly that you’re afraid that you won’t be able to declare one or the other better.

Maybe treatment X is doing a little better than Y, but not so much better that you can declare with confidence that X is better. You might want to stop for futility if you project that not only do you not have enough evidence now, you don’t believe you will have enough evidence by the end of the trial.

Futility analysis is more about resources than ethics. If X is doing poorly, ethics might dictate that you stop giving X to patients so you stop early. If X is doing spectacularly well, ethics might dictate that you stop giving the control treatment, if there is an active control. But if X is doing so-so, there’s usually not an ethical reason to stop, unless X is worse than Y on some secondary criteria, such as having worse side effects. You want to end futile studies so you can save resources and get on with the next study, and you could argue that’s an ethical consideration, though less direct.

Futility analysis isn’t about your current estimate of effectiveness. It’s about what you think you’re estimate regard effectiveness in the future. That is, it’s a second order prediction. You’re trying to understand the effectiveness of the trial, not of the treatment per se. You’re not trying to estimate a parameter, for example, but trying to estimate what range of estimates you’re likely to make.

This is why predictive probability is natural for interim analysis. You’re trying to predict outcomes, not parameters. (This is subtle: you’re trying to estimate the probability of outcomes that lead to certain estimates of parameters, namely those that allow you to reach a conclusion with pre-specified significance.)

Predictive probability is a Bayesian concept, but it is useful in analyzing frequentist trial designs. You may have frequentist conclusion criteria, such as a p-value threshold or some requirements on a confidence interval, but you want to know how likely it is that if the trial continues, you’ll see data that lead to meeting your criteria. In that case you want to compute the (Bayesian) predictive probability of meeting your frequentist criteria.

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Mathematical modeling for medical devices

We’re about to see a lot of new, powerful, inexpensive medical devices come out. And to my surprise, I’ve contributed to a few of them.

Growing compute power and shrinking sensors open up possibilities we’re only beginning to explore. Even when the things we want to observe elude direct measurement, we may be able to infer them from other things that we can now measure accurately, inexpensively, and in high volume.

In order to infer what you’d like to measure from what you can measure, you need a mathematical model. Or if you’d like to make predictions about the future from data collected in the past, you need a model. And that’s where I come in. Several companies have hired me to help them create medical devices by working on mathematical models. These might be statistical models, differential equations, or a combination of the two. I can’t say much about the projects I’ve worked on, at least not yet. I hope that I’ll be able to say more once the products come to market.

I started my career doing mathematical modeling (partial differential equations) but wasn’t that interested in statistics or medical applications. Then through an unexpected turn of events, I ended up spending a dozen years working in the biostatistics department of the world’s largest cancer center.

After leaving MD Anderson and starting my consultancy, several companies have approached me for help with mathematical problems associated with their idea for a medical device. These are ideal projects because they combine my earlier experience in mathematical modeling with my more recent experience with medical applications.

If you have an idea for a medical device, or know someone who does, let’s talk. I’d like to help.

 

Bayesian adaptive clinical trials: promise and pitfalls

This afternoon I’m giving a talk at the Houston INFORMS chapter entitled “Bayesian adaptive clinical trials: promise and pitfalls.”

When I started working in adaptive clinical trials, I was very excited about the potential of such methods. The clinical trial methods most commonly used are very crude, and there’s plenty of room for improvement.

Over time I became concerned about overly complex methods, methods which were good for academic publication but may not be best for patients. Such methods are extremely time-consuming to develop and may not perform as well in practice as simpler methods.

There’s a great deal of opportunity between the extremes, methods that are more sophisticated than the status quo without being unnecessarily complex.

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Frequentist properties of Bayesian methods

Bayesian methods for designing clinical trials have become more common, and yet these Bayesian designs are almost always evaluated by frequentist criteria. For example, a trial may be designed to stop early 95% of the time under some bad scenario and stop no more than 20% of the time under some good scenario.

These criteria are arbitrary, since the “good” and “bad” scenarios are arbitrary, and because the stopping probability requirements of 95% and 20% are arbitrary. Still, there’s an idea in lurking in the background that in every design there must be something that is shown to happen no more than 5% of the time.

It takes a great deal of effort to design Bayesian methods with desired frequentist properties. It’s an inverse problem, searching for the parameters in a high-dimensional design space, usually via lengthy simulation, that cause the method to satisfy some criteria. Of course frequentist methods satisfy frequentist criteria by design and so meet these criteria with far less effort. It’s rare to see the tables turned, evaluating frequentist methods by Bayesian criteria.

Sometimes the effort to beat frequentist designs at their own game is futile because the frequentist designs are optimal by their own criteria. More often, however, the Bayesian and frequentist methods being compared are not direct competitors but only analogs. The aim in this case is to match the frequentist method’s operating characteristics by one criterion while doing better by a new criterion.

Sometimes a Bayesian method can be shown to have better frequentist operating characteristics than its frequentist counterpart. This puts dogmatic frequentists in the awkward position of admitting that what they see as an unjustified approach to statistics has nevertheless produced a superior product. Some anti-Bayesians are fine with this, happy to have a procedure with better frequentist properties, even though it happened to be discovered via a process they view as illegitimate.

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Related postBayesian clinical trials in one zip code

Reproducible randomized controlled trials

“Reproducible” and “randomized” don’t seem to go together. If something was unpredictable the first time, shouldn’t it be unpredictable if you start over and run it again? As is often the case, we want incompatible things.

But the combination of reproducible and random can be reconciled. Why would we want a randomized controlled trial (RCT) to be random, and why would we want it to be reproducible?

One of the purposes in randomized experiments is the hope of scattering complicating factors evenly between two groups. For example, one way to test two drugs on a 1000 people would be to gather 1000 people and give the first drug to all the men and the second to all the women. But maybe a person’s sex has something to do with how the drug acts. If we randomize between two groups, it’s likely that about the same number of men and women will be in each group.

The example of sex as a factor is oversimplified because there’s reason to suspect a priori that sex might make a difference in how a drug performs. The bigger problem is that factors we can’t anticipate or control may matter, and we’d like them scattered evenly between the two treatment groups. If we knew what the factors were, we could assure that they’re evenly split between the groups. The hope is that randomization will do that for us with things we’re unaware of. For this purpose we don’t need a process that is “truly random,” whatever that means, but a process that matches our expectations of how randomness should behave. So a pseudorandom number generator (PRNG) is fine. No need, for example, to randomize using some physical source of randomness like radioactive decay.

Another purpose in randomization is for the assignments to be unpredictable. We want a physician, for example, to enroll patients on a clinical trial without knowing what treatment they will receive. Otherwise there could be a bias, presumably unconscious, against assigning patients with poor prognosis if the physicians know the next treatment be the one they hope or believe is better. Note here that the randomization only has to be unpredictable from the perspective of the people participating in and conducting the trial. The assignments could be predictable, in principle, by someone not involved in the study.

And why would you want an randomization assignments to be reproducible? One reason would be to test whether randomization software is working correctly. Another might be to satisfy a regulatory agency or some other oversight group. Still another reason might be to defend your randomization in a lawsuit. A physical random number generator, such as using the time down to the millisecond at which the randomization is conducted would achieve random assignments and unpredictability, but not reproducibility.

Computer algorithms for generating random numbers (technically pseudo-random numbers) can achieve reproducibility, practically random allocation, and unpredictability. The randomization outcomes are predictable, and hence reproducible, to someone with access to the random number generator and its state, but unpredictable in practice to those involved in the trial. The internal state of the random number generator has to be saved between assignments and passed back into the randomization software each time.

Random number generators such as the Mersenne Twister have good statistical properties, but they also carry a large amount of state. The random number generator described here has very small state, 64 bits, and so storing and returning the state is simple. If you needed to generate a trillion random samples, Mersenne Twitster would be preferable, but since RCTs usually have less than a trillion subjects, the RNG in the article is perfectly fine. I have run the Die Harder random number generator quality tests on this generator and it performs quite well.

Need help with randomized trials? Let’s talk.