Clinical Development
Once pre-clinical development has reached a promising stage, the clinical stage of development can follow. All clinical studies must follow standards developed by the International Conference on Harmonisation of Good Clinical Practice (GCP). GCP standards guide the overall conduct of clinical trials, including the reporting of results that are credible and accurate, and ensure that all rights of study subjects are protected.
Clinical trials are generally categorized into four phases. Phase I trials represent the initial in-human studies during drug development. Achieving this step does not guarantee that the drug will be approved(2). The primary aim of Phase I studies is to determine tolerability, pharmacokinetics, and pharmacodynamics in humans to find the appropriate dose range for safety and toxicity. Initial dosing and dose ranges are based on pre-clinical animal studies; the results of Phase I studies identify the dose range that is anticipated to be safe in future clinical studies. Depending on the molecule, pre-clinical results, and mode of delivery (e.g., oral or inhaled), absorption, distribution, metabolism, and/or excretion (ADME) are evaluated. In orphan diseases like CF, some information on efficacy may be sought as a secondary endpoint in Phase I studies. Obtaining some efficacy data may be beneficial to pharmaceutical companies if the data can inform a “go-no-go” decision prior to proceeding to increasingly costly Phase II and III studies. Phase I studies may cost up to $5 million, Phase II and Phase III costs may range between $10 and $16 million and $10 and $30 million, respectively (https://aspe.hhs.gov/system/files/pdf/77166/rpt_erg.pdf, accessed June 11, 2020).
Phase I studies are most often conducted in a small number, e.g., 20-30, healthy adult volunteers, who are typically male. These studies are very short (a participant may receive the candidate drug for days to weeks), open label, uncontrolled, and are usually conducted at centers that specialize in Phase I trials. Some studies may be conducted in people with the target disease if the mechanism of action is specific to the condition, e.g., chronic endobronchial infection with Pseudomonas aeruginosa in people with CF(16). Up to 75% of drug candidates move on to Phase II trials(17).