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Moving Early Phase Trials Forward

Graham Wood of Cetero Research discusses ways to remove the speed bumps between first-in-human (FIH) and proof-of-concept (POC)

The need to accelerate drug development to establish proof-of-concept (POC) is becoming increasingly vital for both small biotechnology and large pharmaceutical companies. Small and mid-sized biotech companies need to establish POC to secure the next round of financing or hit the next milestone payment. Pharmaceutical companies need to replace the large number of drug patents that are set to expire in 2012 and manage the uncertainty caused by the US healthcare reform bill, while still providing the public with safe, effective treatments.

First-in-human (FIH) studies are an important step in the drug development process. These studies determine the safety and tolerability of the drug in humans for the first time, but do not address the efficacy of the treatment. The first glimpse of efficacy is found when POC studies are conducted.

The good news is that there is a way to cut the time it takes to go from FIH to POC by 50 per cent and cut costs by more than 10 per cent. The standard development plan takes a drug from single ascending dose (SAD) to multiple ascending dose (MAD) to food effect study and then POC. Running these studies sequentially can take between 28 and 36 weeks using standard study designs. However, several studies have proven that it is possible to use an accelerated POC approach to combine all four of these studies using an all-in-one design that takes between 14 and 18 weeks.

To use a real example, in one accelerated POC allergy treatment trial for a major pharmaceutical company, the time from first patient, first visit (FPFV) to top-line results for a POC study was 16 weeks. This included SAD, MAD, definitive food effect and POC. The average time to run these as four separate studies is 32 weeks. In a different all-in-one study for an obesity treatment, the time from FPFV to top-line results was 12 weeks to conduct the full range of SAD, MAD, food effect and POC.

From a cost perspective, combining these four studies can save organisations more than 10 per cent, on average, due to improved efficiencies in a number of areas of the study.

At a time when it is more important than ever for pharmaceutical companies to know early on whether or not they should continue to study a particular drug candidate, obtaining results earlier and for less cost are huge benefits.

HOW THE ACCELERATED PROOF-OFCONCEPT APPROACH WORKS

Figure 1 illustrates the typical design to run SAD, MAD, food effect and POC as four separate studies. Figure 2 shows one approach for structuring an accelerated proof-of-concept (AcPOC) study that combines these four studies into one.

SINGLE-ASCENDING DOSE

The first step is a single-ascending dose study. Depending on the target and indication of the compound, this can be a double-blind, randomised, placebocontrolled design in healthy subjects or patients.

The primary goal of the SAD study is to examine the safety and tolerability of the compound after a single dose. A secondary goal is to examine the pharmacokinetics (PK) to determine the Cmax, Tmax, t1/2, AUC and dose proportionality of the compound. This is very important as the PK seen in humans often differs from that seen in animals.

Using the study design in Figure 2 as an example, randomised subjects receive either the test substance or a placebo after an overnight fast. The planned doses will be escalated in steps if the safety, tolerability and PK profile are found acceptable.

MULTIPLE-ASCENDING DOSE

The second phase is a MAD study. Again, this can be a double-blind, randomised, placebo-controlled design of healthy subjects, or it can include patients. While Figure 2 shows five cohorts, the numbers can vary depending on the study design.

With MAD studies, the primary goal is to examine the safety of the compound after multiple doses. A secondary goal is to examine the PK to determine the time dependence linearity, the dose proportionality and the peak and trough values after reaching steady-state, and assess the potential accumulation at the dosing regimen selected.

The first point where time savings are realised in the AcPOC design comes from the fact that the MAD study can be started while the SAD study is ongoing. As Figure 2 illustrates, after the third cohort of the SAD study is complete, the first cohort of the MAD study can begin.

FOOD EFFECT

The goal of the food effect study is to examine how the relative bioavailability of the compound changes when given with a high fat meal compared to the fasting state. These safety studies are needed before the POC study whenever it will be conducted under fed conditions. This study can start once the SAD study is finished, as illustrated in Figure 2, or it can take place concurrently with the SAD as long as the safety dosage with a higher dose given in fed conditions has already been established in the SAD.

PROOF-OF-CONCEPT

The final phase in the AcPOC model is the POC, which can take many forms depending on what therapeutic treatment is being investigated. For example, if the treatment is a single-dose allergy remedy, the study design might include an environmental exposure chamber session, which can reliably reproduce peak allergy season all year round. In these allergy models, subjects are continuously monitored within the custom-built facilities by highly-trained staff, which means maximum compliance in symptom recording.

The goal of POC studies is to establish whether the compound is acting at its intended target or having its intended effect. Ideally this is accomplished by measuring signs or symptoms, as is done in the environmental exposure chamber for anti-allergic or anti-asthma compounds. For other indications, this is accomplished by measuring a biomarker that can be related to the efficacy of the drug or to its mechanism of action.

In the study illustrated in Figure 2, the POC was done using a double-blind, randomised, placebo-controlled, multipledose, parallel-group study with patients who have a history of the condition relevant to the treatment being studied. Dosing in terms of number of days dosed, actual dose levels, and food requirements and regimens were calculated based on the results of the SAD, MAD and food effect studies.

ACCELERATED POC MODEL OFFERS CLEAR BENEFITS

In an AcPOC study, timelines are condensed as several parts of the studies overlap. Another saving not illustrated in Figure 2 is in staff training time and time to implement the study. Instead of having to train four groups of employees to administer four separate studies, the same group administers the combined study from start to finish.

If a sponsor wants to be on-site for dosing of the various phases, the AcPOC approach also offers advantages. Due to the overlapping sections of the study components, sponsors may have the opportunity to see several phases in the same visit without making as many trips to the study facility.

In addition, there is one comprehensive study protocol instead of four separate protocols, helping to streamline the process. From a regulatory perspective, there is only one document for regulatory approval, instead of four separate protocols to be reviewed. It is key to write the protocol so that there is flexibility in designs of the MAD, food effect and POC, and so the lessons learnt in each step can be applied to the subsequent cohorts.

Another advantage for the study sponsor is that, since with the AcPOC model all of the studies are performed at the same facility by the same organisation, the sponsor is assured that that the data will be in the same format, from the same source and housed in the same database.

WHAT KINDS OF STUDIES WORK BEST?

Based on information from previous studies, while this streamlined approach can be used for virtually any compound, to date the AcPOC has been used primarily for treatments of diabetes, obesity, dermatological conditions, allergies and asthma.

Study data also suggests that the AcPOC approach is more appropriate for short-term treatments, such as single-dose or fourweek cycles. For treatments that are being investigated for recommended durations of six months or more, some of the advantages of the AcPOC approach may not be as pronounced, but even if the programme takes 52 weeks, a potential savings of 16 weeks is still a big advantage.

THE IMPORTANCE OF RECRUITING

Accelerated proof-of-concept studies are extremely complex. While they offer many advantages in terms of reducing costs and shortening timelines, it is important to work with experienced partners to get the full benefit of this approach. As with any study, select a CRO with a proven track record in recruiting. For some studies, it is necessary to recruit both normal healthy participants and patients, so the CRO partner needs to have a proven track record recruiting both.

Questions to ask a CRO when assessing its recruiting capabilities include:

  • Do your studies start on time with the full panel of patients more than 95 per cent of the time?
  • Do you collaborate with physician networks to have wider access to patients?
  • Do you use proactive strategies to ensure your recruitment databases are well maintained?
  • How do you foster a positive relationship with participants so that they feel safe and welcome?

EXPERIENCE MATTERS

Recruiting participants is just the start; there are other competencies a CRO must have. One of the most critical is experience conducting POC studies. While some CROs may have extensive experience of recording adverse events in healthy populations, it is much more difficult to conduct complex studies and collect efficacy measures, especially when the symptoms are subjective.

The best CROs for conducting AcPOC studies are those with proven expertise in therapeutic areas who understand how to work with a range of populations and conditions. A CRO whose experience is concentrated in only one area such as with a normal, healthy population is not as well-suited as one that studies both healthy and patient populations.

Questions to ask a CRO in order to assess its experience include:

  • How many POC studies have you done?
  • What type of POC studies have you done?
  • For the indication, what efficacy measures would you suggest, and how will you control the variability?
  • What percentage of your studies involve collecting symptoms?
  • Do you have training programmes for staff and subjects to ensure symptoms are captured correctly?
  • Do you have a scientific affairs team that can perform sophisticated modelling and simulations of the study data to determine the minimum effective dose and ensure the right dosages will be studied for Phase II and III?

EMBRACING INNOVATION

The pharmaceutical industry has felt the pressure to safely expedite viable drugs through the drug development process and know earlier in the development process if the drug performs as intended in the target patient populations. Accelerated proof-of-concept studies are a giant leap in moving early phase clinical trials forward. This all-in-one approach can safely shorten early stage clinical trial time by up to 50 per cent, while also reducing costs. These advantages are important for pharmaceutical companies who want to continue to produce high-quality, safe and effective treatments, while containing internal costs. Outsourcing to an experienced CRO that has proven success with these types of trials offers even more benefits in the development process.


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Graham Wood is President of Clinical Operations in the Toronto facility of Cetero Research. Graham heads the operations team, providing clinical pharmacology, clinical efficacy, site management and clinical monitoring services to both international pharmaceutical companies and small and mid-sized biotech companies. He earned his BSc from McMaster University and a PhD in Neurology and Neurosurgery from McGill University.
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