Fast-tracking proof of concept

September 17, 2010 – 10:46 am by Michael Christel

In this month’s issue of R&D Directions, we talk about the need for contract research organizations to truly differentiate their services for a pharma client base that, given various circumstances, has become increasingly selective. For the clinical outsourcing provider, that means coming up with inventive and lasting solutions to help speed up drug development, while lessening the cost burden for sponsors. One area where CROs are putting that responsibility to the test is in early-stage development, particularly around smoothing the patches between first-in-human and proof-of concept studies, an admitted stumbling block for drugmakers now much more under gun to generate go/no-go decisions on their products sooner.

Early-stage CRO Cetero Research, for example, recently proclaimed success in using an innovative accelerated proof-of-concept design approach in Phase I and II trials. By combining single ascending dose, multiple ascending dose, and preliminary food effect trials into one study, Cetero says it cut study times by 50% and reduced costs by more than 10%.

The all-in-one design paid off in a recent allergy study Cetero conducted for a major pharmaceutical company. The program went from first patient, first visit, to top-line proof-of-concept results in just 16 weeks, instead of the 32-week average to run the trials separately, according to Cetero executives. In an accelerated proof-of-concept study for an obesity treatment, the time to top-line results was 12 weeks.

This week, Cetero kicked off a series of scientific seminars called “An Accelerated Path to Proof-of-Concept in Drug Development,� where researchers will learn about new innovations in Phase I and IIa clinical trial designs. The series started Wednesday in Princeton and will wrap up in San Diego Oct. 21, with stops in between in Raleigh, Chicago, Boston, Philadelphia, and San Francisco. Cetero experts will discuss lessons gained from conducting more than 10,000 clinical pharmacology studies in a range of therapeutic areas.

I spoke recently with one of the speakers, Graham Wood, Ph.D., president of clinical operations for Cetero’s Toronto and Miami facilities, to learn more about the advantages and challenges of the accelerated proof-of-concept model.

R&D Directions: Accelerated POC studies sound difficult to pull off on the surface. Can you explain how this approach works?

Dr. Wood: At Cetero, we’ve been working for years to do what we can to really improve the efficiencies and add value for sponsors. This is kind of the culmination of that, putting a lot of different things we’ve learned through the years together.

What the accelerated proof of concept allows us to do is to take all those studies from your first-in-human study all the way to your first proof–of-concept study and put them together. In some examples, it’s going to be four studies put together; it could be five studies, it could be three. It really depends on the products. Each time the design is going to be different, because in each therapeutic area and each product, we’re going to have to approach it a little bit differently.

The key overriding protocol is really the adaptive protocol. So, as you go, you learn from what happened in Phase I of the protocol and you apply it to what you do in parts B, C, and D. It’s really learning as you go. The key last step is establishing that proof of concept to show, is this compound going to have success when it goes out into patients?

R&D Directions: What prompted Cetero to explore this approach?

Dr. Wood: We’re a bit unique in the industry in that we do a lot of clinical pharmacology studies, but we also do a lot of patient studies with efficacy measures. There’s clinics out there that really focus on clinical pharmacology, but when it comes to doing the efficacy measures and the uniqueness of them, they’re not as familiar.

Some of our units were specifically built looking at therapeutic areas – either allergy, asthma, or endocrinology and diabetes. We used the knowledge gained from those centers, and paired it with our general clinical pharmacology experience to help sponsors get through to the proof-of-concept studies much faster.

R&D Directions: Are sponsors, who clearly want to establish POC earlier in development, embracing this approach in their Phase I and II trials?

Dr. Wood: Yes. Almost every sponsor that comes into us – even if they’re not doing the full extent of accelerated proof of concept – are trying to add in some biomarkers for their first-in-human studies and really get as much data as they possibly can out of those. The ideal scenario is when you have a good validated biomarker, or you can go into patients with a really sound model to assess the symptoms.

In allergy and asthma, for example, we use environment exposure chambers. They kind of look like a movie theater – the patients go in, we fill the room with an allergen, and then we assess their symptoms right then and there. Because the variability is so much lower, you can with small sample sizes get a good, significant result. If we do what’s called a field study, you need hundreds of people, because subject A may work in an office space, while subject B works outside. Their allergen exposures are going to be totally different.

What kind of holds [sponsors] back is not having those models and being able to work with the experts to help them understand how they can use those models to get that proof of concept.

R&D Directions: Are challenges in recruitment another factor that may be holding some companies back in pursuing the accelerated proof-of-concept approach?

Dr. Wood: It’s definitely going to be more difficult to recruit a patient, versus a healthy normal subject. That’s kind of how we got in there. We have the experience of recruiting the patient and running them through studies and doing the often more subjective measures. We were able to use that patient recruitment experience to really help drive our accelerated proof-of-concept studies.

R&D Directions: How challenging is it to collect the key data in these all-in-one trials, while being mindful of speed and quality?

Dr. Wood: The quality part, we don’t diminish that at all. We really focus so that the QC, the QA process that goes into these studies is as robust as the hundreds of other studies that we run each year. Because we’re running so many of the different studies, we’ve really learnt and built systems that allow us to go faster.

One of the keys is we use electronic case report forms for these studies. Our staff enters the information into the report forms and sponsors can actually review them remotely on the Web. They can, as the data is coming in from the different groups, start looking at it right away to help them make decisions.

These are adaptive designs – you are going to maybe change your dose, change different things about it before you go to the next [stage]. The sooner you can look at the data, the better informed your decision is. The electronic case report forms help us tremendously in doing that without affecting quality at all. It’s still QC’d, it still goes through the queries. It just gives that kind of instant access that the sponsors need.

R&D Directions: Do you need strong training in place to capture the symptoms correctly in these cases as well?

Dr. Wood: That’s a very important point. Taking someone’s blood and having our bioanalytical lab measure it to see the level of the stain is very different than sitting someone down and saying, “I need you to rate your congestion on a scale of 1 to 5.� We definitely put our staff through a lot of training to make sure that they can speak to the subjects clearly so that the subjects will rate their symptoms as consistently as possible.

On the other side, we do a lot of studies in the allergy field with eye retinas. We make sure that our staff is consistent in how everyone is scoring it. We have training sessions where everyone has to score some red eyes, and we make sure that there’s minimum variability between all our different scores.

R&D Directions: Can you elaborate a bit on your trial successes so far in using the accelerated POC design?

Dr. Wood: In some cases, the studies actually ended in the safety phase because it was shown that the drug was really not going to be a safe product in the market. For sponsors, that truly is a success because now they’ve been able to stop it and kill it before going too far in development. That’s where the adaptive part of the design plays in well.

The allergy treatment is finishing up the proof-of-concept part. It’s gone through single ascending dose – we established that as a single dose, it was very safe. It went into the multiple dose – we established that was very safe. The single and multiple-dose studies actually overlapped a fair bit. So, as we were going to the top doses in single dose, lower multiple ascending doses were starting.

We also did the food effect study at the same time as the single ascending dose and multiple ascending dose studies were continuing. Everything looked good, and we were able to go into proof of concept. Hopefully, fairly shortly the sponsor is going to have really solid data to decide whether they should go into the late Phase II studies with this product.

Tags: CROs, proof of concept