Clinical Research: Phase 1 - Phase 4

Designing Early Stage Studies in Acute Pain Research

When it comes to analgesic drug development, it’s important to optimize design of early phase trials. The main objectives of studies at this stage are to:

  • Explore a range of doses
  • Obtain data on onset, peak effect, and duration
  • Assess relative efficacy in comparison to established analgesics

To accurately evaluate their product, sponsors need to select the most appropriate pain model, study design and outcome measures for acute pain studies. To do that, sponsors must first establish their drug’s pharmacokinetics, pharmacodynamics, target indications and intended setting for use.

Understanding the Drug’s Pharmacology

Pre-clinical, pre-human studies produce some of the most important data to be taken into account when moving forward into clinical trials. The information gathered at this stage will determine which clinical models might be best suited for early proof-of-concept studies and beyond. Investing time and resources to collect as much information as possible during pre-clinical trials is often a successful drug development strategy. Careful application of data to subsequent study designs drive efficiency and avoid costly mistakes in later clinical trials.

While establishing a new drug or formulation’s pharmacology, in vitro assays at this stage are likely to include:

  • Receptor binding
  • Human protein binding
  • Primary hepatocyte systems

Acute pain animal models are another crucial component. Through these methods, researchers determine whether a drug has anti-inflammatory properties, central or peripheral nervous system activity, or a novel mechanism of analgesic action. The pharmacokinetics of a drug also begin to be established before being later refined through clinical trials. Pre-clinical studies can provide insight into potential dosing regimens or routes of administration for use during clinical trials and in standard practice down the road.

Initiating Human Studies

Initial efficacy trials for medications intended to address acute pain are frequently single dose and use a post-surgical model. This allows for a highly controlled environment with prospective recruitment occurring many weeks or even months in advance. This is in contrast to emergency or urgent care situations, which are unpredictable and involve greater difficulty in obtaining appropriate informed consent.

Early human proof-of-concept studies should establish the drug’s dose-response relationship. At this stage, comparator analgesics should be selected for use as benchmarks for judging assay sensitivity and relative efficacy. Early human studies further define the attributes of an investigational analgesic, including elucidating its pharmacokinetics and optimal route of administration and creating an adverse event profile.

Defining Pharmacokinetics

Early studies also involve understanding a product’s pharmacokinetics and include studies on bioavailability, single ascending dose, multiple ascending dose and food effect. Pharmacokinetic data is especially useful when designing trials evaluating a new formulation of an already-approved drug: If the investigational drug has been reformulated for better bioavailability, a lower dose should be considered for use in clinical trials.

If peak serum concentration (Cmax) is significantly delayed, pre-operative dosing may be appropriate. The standard for acute pain management is that relief should occur within one hour. When administered before surgery, an investigative analgesic with a delayed Cmax can begin to work as anesthesia wears off. However, researchers must ensure that the study drug does not create surgical complications, such as bleeding, respiratory impairment or hypotension. If Cmax takes an extensive amount of time to achieve, the drug may not be appropriate for acute pain management indications.

Significant food effects may also impact the study drug’s efficacy, so limiting food close to dosing is often necessary, both within studies and as guidance for clinical use. Pharmacokinetic studies also help establish the safety profiles of different doses, possibly defining the maximum tolerated dose for proof-of-concept studies. In these cases, the tested dose range is usually extrapolated from pharmacokinetic study data as the lowest dose with measurable plasma concentration to maximum tolerated dose.

Transitioning to Later Stage Clinical Trials

Once enough preliminary data has been established, the larger efficacy trials necessary for regulatory approval can begin. Our next blog goes over factors and design considerations for these acute pain clinical studies.