The Failure Rate at Phase Three is Probably 70% or Greater

Surya Chitra, PhD, MBA, Biostatistics and Pharmacology, and Gary Fishbein, MD, MPH, Senior Medical Director, PharmaNet Development Group, Inc, join Pharma IQ to discuss adaptive trial design.

Pharma IQ: Could you just outline your current roles?

S Chitra: Currently I’m leading the early phase – Phase One, Phase Two – clinical studies, and helping with the pharmacology and biostatistics. And our group gets involved from early stage, from protocol development to completing the study to clinical study reports. And we also get involved with some consulting and clinical development plans, the regulatory submissions for IND studies, and so on.

G Fishbein: I’m a medical oncologist and I’ve been with PharmaNet for about six years. And I get involved with all aspects of pharmacology, clinical development plans. We’ll get new compounds going to FDA for pre-IND discussions, all the way through to pivotal Phase Three and Phase Four studies, you know, further defining the indications for oncology products.

Pharma IQ: And Gary, how would you define adaptive trial?

G Fishbein: I would define adaptive trial as clinical trials that they’re able to use accumulating evidence to modify aspects of the trial with the idea that the ongoing conduct of the trial, the ability to look at the data as they’re being obtained, can help to adjust patient populations and to refine the treatment arms that might be most effective in the population that’s being studied.

Pharma IQ: And Surya, would you have anything else to add to that?

S Chitra: The key word in the adaptive trials is how to modify the aspects of the study. So, the study aspects, they all depend on the type of, which stage of the product development, drug development, we are in. If we’re, particularly in oncology, what we are looking at in adaptive designs, is how they can help us to, as Gary pointed out, some of the endpoints, biomarkers, and the doses we need for the early stage so that it’ll be much more successful in the later stages of the development, where the success rate in Phase Three is going to be improved as you go through these adaptive designs and learn more and more about the patient population, the drug indications, how the drug is efficacious, and what dose and what biomarkers are giving a good endpoint.

Pharma IQ: Why do you think adaptive designs have become such popular tools in oncological research?

S Chitra: Yes, oncology research is becoming very popular because they provide the opportunity for us to, as I said, improve the patient care within the adaptive design trial, so that we can specifically see how this drug is efficacious in certain populations, and what doses it is good at. And also, it gives us early stopping rules. If the drug is not efficacious for certain populations, we can stop treatment, and then they can go with their standard treatment. This gives us more flexibility in that way, and also, at the same time, it is enhancing the drug development cycle as well as the learnings as we go into the later stages of the development.

G Fishbein: You know, especially within oncology, we’re observing across falters in many pivotal Phase Three studies. The failure rate at Phase Three is probably 70% or greater, and it’s really quite tragic when you think of the patient resources, the amount of money that’s invested in a drug that looks promising and then it fails at Phase Three. I think what adaptive trials really provides is the ability to predict more accurately what populations, what drugs are likely to see that success at Phase Three, so that you’re making the best use of the patient resources and the investment in the drugs, and that you’ve really got the patient population defined, as Surya had mentioned.

Pharma IQ: And Gary, what practical considerations do you think need to be addressed for early versus late phase adaptive designs in oncology?

G Fishbein: Well, what comes to mind there is the issue of the biomarker. In other words, how are we going to really be able to sort out these populations? You know, certainly within oncology, we’ve got much better at looking at these molecular markers, understanding, you know, for example, what biological targets are active, what molecular systems are driving a particular tumour. So, that science has really put us in a position to find the targets and develop drugs that are specifically addressing those targets. I think the practical issue is, how do you then go ahead and validate the biomarker itself? You know, making sure that there is a standardised clinical way, a clinical laboratory technique, for identifying that biomarker, making sure that a biomarker that’s measured in London is done the same way in Los Angeles. I think that’s where the challenge… I think that’s sort of the practical issue that the industry is facing right now. Because developing the biomarker could cost, you know, upwards of a billion dollars, and certainly that’s the challenge. If you invest as much in the drug, you know, you may actually need to have an equal investment in the biomarker. And again, I think that’s going to be a challenge for the industry, for the scientific community, to really have these tools, but I think it is essential.

Pharma IQ: Surya, do you think there are any other key practicalities that need to be addressed?

S Chitra: Gary brought up a very good point about the biomarkers. What the adaptive designs are going to do for us is that the earlier we learn about these biomarkers and get a handle on what all this is going to be monitored during the later phases of the development, I think that the adaptive designs will reduce our number of patients we need. And also, if the biomarkers are not working, we can stop monitoring those and reduce the cost there. So, it is a very key thing for us to look in the early phases – Phase One, Phase Two – and understand all these patient populations, biomarkers at those levels, and that will enhance our success in the later phase of the studies.

Pharma IQ: Surya, what would be your top three tips for incorporating adaptive trials into your oncological development plans?

S Chitra: The key, as we’ve been pointing out and as the industry is now facing, is that, what are the good biomarkers? How do we define the endpoints for these studies so that we’ll have a good success rate to demonstrate the drug in the later phase, and also the target dose. That is the first thing, is the endpoints and the target dose, and what populations we need. And the second one is the planning success for later phase development through clear go no-go decisions. I think that’s where the adaptive designs can help too in Phase One and Phase Two. The earlier we know whether this thing is working or not, and that will save quite a bit of time and money for the industry. And I think the… and also we need to involve all the regulators and patient advocacy groups and the other key stakeholders in this when we are doing these adaptive trials for oncology.

G Fishbein: Again, as Surya mentioned, I think the number one is identifying the relevant biomarkers and really having validated methods for, you know, validating those biomarkers. And the second would be support for the research sites, support for the research community in general, for developing the biomarkers, for having this profiling done to the patient’s tumour at the time of diagnosis. And in that way, we can move more towards a personalised medicine approach such that a patient’s tumour is really the driving factor as to what clinical trial they’ll go on, as opposed to the patient, let’s say, coming to a research site and sort of having to themselves adapt to whatever trials are available. With the tumours being defined [unclear] their characteristics, the trial that the patient goes on can really be much more personally tailored to the characteristics of the tumour.  And I think the third would be the enlistment of, again, advocacy groups to really promote these kinds of clinical trials, to really keep patient groups informed as to how the research directions are going. I think patients are really asking and demanding for this. They really want to see clinical benefit at earlier stages in the development of oncology products.

Pharma IQ: Apart from a rise in personalised medicine, are there any other industry changes that you’ve observed?

G Fishbein: Well, yes. I mean, again, we have the opportunity at PharmaNet to work with a number of companies that are in early stage development with their oncology products and we’ve certainly seen these ideas, these correlative methods of getting tissue, of really understanding the nature of the responses, making sure there are drugs that are targeted, are actually mediating their effect through their target. So, we really are seeing that these methods are being incorporated in earlier stages of trials with the idea that patient populations can be enriched based on the groups that appear to be responding. You know, again, it really takes a lot of input from many scientific experts to make sure that the drugs are being developed in the proper way. On the one hand, you want to be able to pursue all of the observations that you make that show the positive impacts of the drug, and at the same time you want to be able to keep an open mind that you’re not missing other targets or other patient populations who can benefit. So, you know, we really are seeing this translation of the clinical and the scientific groups coming together for the benefit of clinical trials and improvement in patient care for these new products.

Pharma IQ: And Surya, are there any changes that you’re excited about?

S Chitra: Yes. I think the exciting thing about this oncology drug development is, I think, we are more and more about the personalised medicine and then defining the target patient populations and what can benefit them. What are the biomarkers? What are the endpoints? How we can provide efficacious drugs, as Gary pointed out, at earlier stages of the development, and so we can have more patients enrol into these studies and that that way we can expedite this development process. I think that’s exciting in what’s going on right now.

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Interview conducted by Andrea Charles

IQPC

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