By John Centofanti
Can pharmaceutical companies bring drugs to market any faster? Companies like Cetero Research think so. Cetero and its competitors operate accelerated proof-of-concept programs for pharmaceutical companies. Such programs can reduce clinical study times by as much as 50% and cut expenses up to 10%. Graham Wood, president of clinical operations for Cetero, revealed valuable benefits, as well as risks, to entering an accelerated proof-of-concept program.
Cetero Research is a CRO that began combining various parts of clinical studies more than 10 years ago. Over the past three years, the company has established a more formal process for implementing accelerated proof-of-concept programs.
In a traditional drug development program, Phase 1 begins with a first-in-human study where a single ascending dose of the drug into a small group of subjects, as few as eight. If there are no safety issues then multiple doses of the drug are given to another group of healthy subjects. If all goes well, the clinical program advances to Phase 2, patients are given the drug, often in groups up to a few hundred. In many development programs, Phase 2 is the first time the effectiveness of the drug is examined. Phase 3 involves two large studies to definitely demonstrate the drugs efficacy in a large number of patients. Accelerated proof-of-concept programs combine these first two phases into one integrated study so that earlier in development the potential efficacy of the drug can be tested. This gives the company developing the drug the data needed to decides on whether to continue drug development much faster.
A typical standard drug development program goes from first-in-human studies to POC in eight to nine months. An accelerated proof-of-concept program can be completed in as few as four to five months. The expedited process is appealing for companies wanting to introduce the drug to market as quickly as possible. The prospect of faster business is sure to interest nearly all companies.
Accelerated proof-of-concept is a desirable program for numerous indications. Cetero has run accelerated programs in allergies, diabetes, asthma, endocrinology disorders, obesity, dermatology, and ophthalmology. Wood explained that Cetero administers drugs to otherwise healthy subjects or in patients depending on the development program.
Cetero’s accelerated proof-of-concept program serves a wide range of sponsors in the pharmaceutical industry. With few exceptions, Wood believes these programs are to be preferred over standard drug development programs. He shared the following story. “We performed an accelerated proof-of-concept for an allergic rhinitis compound. The sponsor needed to verify the compound was safe and effective in humans, but also wanted to quickly get an indication if the compound might be an effective treatment. Cetero administered the single ascending doses with the last single dose cohorts overlapping with the multiple ascending dose cohorts. Once each dose proved safe, the dose was increased for the next cohort. Once the last cohort of the multidose study was complete, the proof-of-concept was established in a number of patients exposed to an allergen. The process was complete in half the time of that of a standard early development program.”
According to Murray Ducharme, chief science officer at Cetero, the use of modeling and simulations with successive learn and confirm cycles is critical to the success of the accelerated Phase 1/proof-of-concept designs. “Instead of being ‘reactive’ to the results of each cohort, when your model predicts accurately what happens, you can then adjust more quickly the successive cohorts and/or studies to make sure the correct doses are being studied. You can do this because you are confident that you fully understand the PK/PD [pharmacokinetic/pharmacodynamic] of the drug as you predicted correctly what was seen,” explains Ducharme. A large part of the modeling and simulations work is done before each study/cohort is conducted, so results can be obtained extremely quickly.
Pharmaceutical companies can save as much as 10% purely in clinical trial costs by entering an accelerated proof-of-concept program. While 10% may not sound like a staggering amount, an important consideration is the program will take 50% less time, so a company that needs $200,000 of internal resources each month for its drug development program will save $800,000 in the four months that are saved in the development program.
Some CROs do not engage in accelerated proof-of-concept programs. It can be a complicated process, and the CRO needs to have the resources to run multiple parts of the study at the same time as well as having the capabilities to recruit patients into the study.
As with any newer approach to business, accelerated proof-of-concept comes with risks and challenges. These types of studies can be fairly smooth for healthy subjects, but it becomes more complicated when subjects have other health issues for which they are taking medication. Patients are reluctant to stop taking their other medication because they would have to deal with the symptoms they are trying to avoid. Many patients are resistant to very early development drugs because the benefit has not yet been established. Still, there are pockets of willing subjects who participate in trials for altruistic reasons.
Wood stresses pharmaceutical companies should engage a CRO that has expertise in a particular indication. While recruiting can be challenging for some therapeutic areas, it’s easier to find willing subjects when the CRO is trusted in the community. Cetero is known in its region for conducting allergy trials, so the company can easily find willing subjects. It’s also recognized for conducting asthma trials, but a smaller percentage of the population has asthma compared to allergies, so asthma patients are harder to find.
In traditional clinical trials, there may be separate teams of people working in each of the four phases of the study. In accelerated proof-of-concept programs, companies such as Cetero use the same team throughout all phases of the study. Wood believes there is better communication and cooperation among the team members. When studies are run at two different clinics by different teams, there tends to be a learning curve, working against the team’s time and effectiveness.
Wood estimates about half of all pharmaceutical companies have utilized accelerated proof-of-concept. While each CRO develops its own procedures, they must still answer to the FDA and other regulatory agencies. For each study, Cetero develops the procedure based on the client and indication and works directly with clients to prepare for answering FDA questions. At times, the company has joined the client in presenting to the FDA. Wood says working with the right CRO with expertise in accelerated proof-of-concept is a key factor in receiving FDA approval and IRB approval to conduct the study
While the FDA regulates the introduction of new drugs, that does not mean it is resistant to new drugs. In fact, in 2004 the FDA introduced its Critical Path Initiative. According to the FDA website, it is “FDA’s national strategy for transforming the way FDA-regulated medical products are developed, evaluated, and manufactured.” It is the FDA’s intention to help pharmaceutical companies establish proof-of-concept faster and speed up the approval process so companies can deliver their indications to the public more quickly.
Risk Versus Reward
Accelerated proof-of-concept would seem to be the most sensible route for a new indication. However, Wood warns, “There is financial risk to accelerated proof-of-concept. If all goes well, you will establish proof-of-concept faster and at a lower cost. However, if safety concerns are found with the compound during the single or multiple dose studies, the sponsor will have already incurred the cost of recruiting the patients for the proof-of-concept part of the study. However, no patients will have been dosed, so there is no greater safety risk than a standard first-in-human program.”
Wood advises pharmaceutical companies to communicate early with the FDA and the IRB. As accelerated proof of concept programs are more complex there is often much more of a back and forth interaction, as the FDA and IRB work to ensure the safety in maintained during these accelerated programs.
To ensure a successful accelerated proof-of-concept program, Wood advises pharmaceutical companies to plan well and plan ahead. Determine there are enough resources to recruit, and screen subjects for different parts of the study at the same time. Be sure there is enough physical space to include all the subjects. These may seem to be secondary concerns to an accelerated proof-of-concept program, yet unprepared pharmaceutical companies have lost time and money from poor planning. An effective CRO will help its clients to plan properly and address some of these overlooked aspects to a successful study.
Accelerated proof-of-concept is very much a pharmaceutical fast track. As in any business, much of the value lies in saving time and money, but this must be weighed against the higher financial risk.