An accelerated path to proof-of-concept in drug development – new innovations in Phase I and IIa clinical trial designs

A recent issue of R&D Directions highlights 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.

An editor of R&D Directions recently spoke with Cetero’s president of clinical operations, Graham Wood, Ph.D.

Accelerated POC studies sound difficult to pull off on the surface, so he explained how this approach works.  “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,” says Dr. Wood. “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.”

Dr. Wood says 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?” he says.

One of the keys in speed is the use electronic case report forms for these studies. Dr. Wood says, “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.”

For research sponsors who clearly want to establish POC earlier in development, this approach to Phase I and II trials may be one avenue to consider.  And beyond that, trying to add biomarkers for first-in-human studies and really get as much data as possible 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.