How a medicine is developed, stage by stage
A medicine is developed through a regulated sequence of stages, from a target and a candidate through laboratory and animal testing and the clinical phases to approval and use after marketing. Each clinical phase asks its own question of the candidate, and what the pharmacokinetic programme finds is carried into the dosing instructions on the label.
The stages of development
Research and development for a drug product includes many highly regulated steps required to develop a drug substance into a marketed product. The steps fall into two components. The first is chemistry, manufacturing and controls together with nonclinical testing, which covers in vitro laboratory tests and in vivo animal tests. The second is clinical testing, in which phase 1 evaluates the safety of the drug, phase 2 determines the dosage regimen to be used in phase 3, and phase 3 evaluates efficacy and safety. As a cycle, development runs from drug discovery through preclinical work, phases 1, 2 and 3 and marketing to post-marketing.
Drug discovery and development are not a one-way path. Often the first step is to identify a therapeutic target and potential routes of modifying it. Sometimes the process starts the other way round, with a molecule identified for properties that may be of clinical benefit. Cell-based laboratory research into the biochemical structures and properties of the agent then precedes the animal studies on which first-in-human trials are based. At these stages safety, pharmacokinetic and pharmacodynamic data are established and the framework for the subsequent phases of clinical trials is clarified. The whole process is fluid and dynamic, and in the vast majority of cases it is not unidirectional and straightforward: there are amendments and adaptations at each stage so that it remains efficient and meaningful. Bench-to-bedside research, also called translational research or translational medicine, encompasses everything from drug discovery and development in the laboratory through animal testing and human testing to licensing, marketing and commercial sales.
From target to candidate
Developing a novel drug is an interdisciplinary endeavour involving a multitude of competences, from biologists, chemists, computer scientists, medical staff, statisticians and regulatory experts. It starts with identifying a druggable target, and bioinformatics, genetic association studies and phenotype screening are valuable tools in discovering novel targets. To validate the target's relevance for a particular disease, studies investigate whether modulating it is disease modifying. Eventually, lead compounds are obtained and evaluated for their potential to interact with the target and for their effect on the biological system. Thousands of modifications and variations of those leads are synthesised and tested during the preclinical work. Once an optimised compound is identified, this investigational new drug becomes a candidate for clinical trials involving human subjects.
As its vice president for scientific operations described it in November 2006, Scripps Florida, the research facility the Scripps Research Institute added in Palm Beach County, Florida, focused on basic biomedical science, drug discovery, and the application of cutting-edge technology to the drug-discovery process. Three interdisciplinary teams shaped that focus: drug discovery, biomedical research and advanced technologies. Drug discovery there was primarily genomic-based, and biomedical research covered immune disorders, infectious diseases, metabolic disorders, neurobiology and cancer. Together, the advanced technologies and drug discovery teams formed a translational research institute that sought to identify and optimise new biochemical targets for drug discovery using high-throughput screening. The institute focused on cell-based screening, RNA dynamics, genetics, proteomics, medicinal chemistry, animal pharmacology, drug metabolism and pharmacokinetics, structural biology, bioinformatics, high-throughput screening and target-based programmes. Its $10 million high-throughput screening core was a highly automated robotics room that could test micro-quantities of compounds against a variety of assays for biological or biochemical activity, and the system was applicable to cDNA, RNA, proteins and antibiotics.
From candidate to drug product
Development starts with choosing a candidate, which may be called the new chemical entity, the drug substance or the active pharmaceutical ingredient. The candidate is evaluated in vitro in a laboratory to determine how it functions, and a thorough evaluation of its chemistry defines its properties and helps ensure its quality and stability. These chemistry, manufacturing and controls processes and analyses guide the development of a formulation for in vivo animal testing to determine its effects, that is, its pharmacology.
An active ingredient is rarely given alone, so before clinical development ingredients are added to support acceptable routes of administration. The resulting formulation, the drug product, may contain excipients such as substances to control release of the active ingredient or a buffer to improve the product's stability. Like the drug substance, the drug product undergoes extensive chemistry, manufacturing and controls evaluation, in part to determine appropriate manufacturing processes and container and closure systems, such as bottles or blister packages for oral tablets. Additional nonclinical studies may be conducted using the drug product to ensure that the excipients do not adversely change the pharmacokinetics, pharmacodynamics or toxicology of the active ingredient. In the regulatory world, good laboratory practice and good manufacturing practice govern all the processes that lead to drug product development. Once the sponsor has successfully formulated the drug product and can support its manufacturing process, and once the nonclinical studies show an acceptable risk profile, the programme moves on to clinical research, which good clinical practice governs.
The clinical phases
Clinical trials run in phases 1 to 4, starting from a small number of subjects and extending to large cohorts. The phases can overlap, although they are usually conducted in order. The conditions under which subjects are studied are very different in phase 1 compared with phases 2 and 3. Terminology, trial methods and standardised text are not necessarily interchangeable between them, although they do overlap.
Phase 1
In phase 1 the investigational new drug is given to humans for the first time. Phase 1 studies safety in small numbers of usually healthy individuals and the drug's distribution in humans. Preclinical work uses animal models as surrogates for humans, and phase 1 starts to make sure that humans behave in the same way as the animals in which the drug has already been extensively studied.
Early phase 1 studies, previously called phase 0, are first-in-human studies in which a small group, usually ten to fifteen individuals, receives a single sub-therapeutic dose to obtain pharmacokinetic information without inducing pharmacological effects. The goal of these exploratory studies is to investigate whether the candidate performs as expected from the preclinical studies. If they succeed, further studies assess the safety and tolerance of the investigational new drug in humans, typically in twenty to fifty healthy volunteers. They determine the maximum tolerated dose by escalating the dose until dose-limiting toxicity is reached, and they evaluate the most common and serious adverse effects alongside the pharmacological, pharmacodynamic and pharmacokinetic properties.
Phase 1 begins with testing to determine the maximum safe dosage and continues pharmacology testing in healthy human subjects. Phase 1 trials assess how well the product is tolerated, the drug's pharmacokinetic profile in humans, such as when maximum concentration occurs and how fast the drug is eliminated, and other objectives. Depending on the pharmacology, additional trials may be needed in subjects with specific characteristics, such as a specific age range, race or ethnicity, sex, or a concomitant disease such as diabetes or kidney disease. Other phase 1 trials might evaluate the effect of food or alcohol on pharmacokinetic and pharmacodynamic results, or the potential for interaction with other prescription drugs.
Phase 2
Phase 2 continues the effort to determine the optimum safe dosage and begins to assess efficacy for the target indication. Because phase 2 trials usually provide the first evidence of efficacy, they are sometimes called proof-of-concept trials. Phase 2 gathers safety and early efficacy data, begins to enrol patients with the target disease and increases the number of participants.
Phase 2 assesses therapeutic efficacy in patients, typically several hundred of them, in a population well defined by inclusion and exclusion criteria. Dose response and biological activity are evaluated on the basis of the dose or dose range determined in phase 1. Comparisons of patients before and after treatment, and of patients receiving the candidate against placebo, provide preliminary data on effectiveness. Although researchers obtain indications of the drug's benefit, phase 2 studies are not comprehensive enough to provide sufficient evidence. Subjects are carefully monitored for adverse effects to further assess safety, and these trials commonly determine the optimum dose regimen for phase 3. The main focus of both phase 1 and phase 2 is safety data to share with the agency.
Phase 3
Phase 3 trials include a much larger population with the target indication, and their data provide the most conclusive evidence of safety and efficacy. It enrols 100 to 500 patients, with the primary objective of confirming therapeutic benefit, safety and efficacy in the intended indication. Different dosages, study populations and combinations with other therapeutic agents are investigated to inform indications, contraindications, dose range and adverse effects. Because phase 3 studies have a larger cohort and a longer duration than phase 1 and 2 studies, they can potentially reveal rare and long-term side effects. Phase 3 runs larger studies, may include special populations such as patients with kidney or liver damage or elderly people, and is the final clinical trial stage before submission.
Phase 4 and use after marketing
Phase 4 studies are long-term and typically conducted after regulatory approval. They often involve more than ten thousand individuals of the relevant patient population and gather additional information on safety, efficacy and new indications. They assess the drug's real-world effectiveness in an extensive cohort and give the opportunity to detect unique adverse effects. In some cases this might result in withdrawal of the drug from the market or restriction to particular uses, and phase 4 studies may equally open up new markets by demonstrating effectiveness for new indications.
Clinical trials treat a couple of hundred, maybe up to a couple of thousand, people, while tens of thousands may take a drug once it is marketed. Its safety is still followed then, with people reporting safety signals they see, and it is not uncommon for a marketed drug to be withdrawn because a safety signal turns up when so many more people are treated.
Pharmacokinetics and the label
An understanding of pharmacokinetics was an important consideration in the posology of both abiraterone and ipilimumab, according to the European Medicines Agency's assessment reports. The European Medicines Agency granted both marketing authorisation around 2011, for metastatic advanced prostate cancer and advanced melanoma respectively.
Abiraterone is a small molecule given orally as an immediate-release tablet. Its mechanism of action is non-cytotoxic, being anti-androgenic, so it was safe to investigate its pharmacokinetics first in healthy volunteers. A critical finding from those studies was the influence of food on systemic exposure, with up to a ten-fold increase in area under the curve observed with a high-fat meal. The summary of product characteristics carried the consequent dosing recommendation: take it at least two hours after eating, and eat no food for at least an hour after taking it.
Ipilimumab is a fully human monoclonal antibody given by intravenous infusion, and its pharmacology made a healthy-volunteer study impossible. Its pharmacokinetic data came from patients with advanced melanoma, either through extensive sampling in phase 1-type single and multiple dose studies or through sparse sampling and population pharmacokinetic methods in efficacy studies. Population pharmacokinetic data from 498 patients across four phase 2 studies were instrumental in evaluating how physiologic and demographic factors influence ipilimumab's concentration–effect relationships. They found that no specific dose adjustment was necessary in patients with mild-to-moderate renal dysfunction, and that information was transferred to the final product label.
For both products, dose proportionality and systemic exposure were assessed, as was the predictability of multiple-dose pharmacokinetics from single-dose data, and the agency concluded that the pharmacokinetics of both had been adequately studied. Investigating the pharmacokinetic properties of anticancer medicines during development is in line with the European Medicines Agency's 2005 guideline on the evaluation of anticancer medicinal products in man. The guideline outlines the need to investigate pharmacokinetics in vulnerable populations and in those with organ impairment. For monoclonal antibodies, it suggests that an understanding of pharmacokinetics gives some guidance for dose-finding, because clearance may be related to target saturation.
The two programmes illustrate two important principles. In cancer as in other disease areas, it is important to understand the factors contributing to variability in pharmacokinetics and hence in pharmacodynamics, because this potentially influences the dose selected. And it is incumbent on the drug developer to investigate that variability, irrespective of whether the anticancer agent is a small molecule or a biologic.
Mass balance studies
Mass balance studies with (radio)labelled drugs are part of the clinical development programme of almost any new small molecule drug. They obtain information on the drug's absorption, distribution, metabolism and elimination (ADME) and on its absolute bioavailability in the human body. As of 2023, a variety of designs is used for them, varying in the labels used, the amount of radioactivity administered, the excreta collected, study duration, dosing sequence and the populations used. A clear description of the procedures followed, the objectives of the study design and the results obtained is challenging for clinical documents, subject-facing documents included. Mass balance studies bring specific challenges for medical writing. New developments give rise to more opportunities to collect data in wider populations and with lower exposure to radioactive material. Because these studies are increasingly complex, explaining the approach followed in a protocol, clinical study report or subject-facing document requires more guidance for medical writers.