4.1.6 Basic principles of drug development

Basic Principles of Drug Development and Evaluation

Drug development is the process of discovering, testing, and producing new medications to treat various medical conditions. The process of drug development is long, complex, and requires substantial resources. It is estimated that it takes approximately 10 to 15 years and costs billions of dollars to bring a new drug to market. The goal of the drug development process is to produce safe and effective medications that can be used to treat patients (WHO, 2021).

The drug development process is divided into several phases, each with its own specific goals and objectives. The three main phases of drug development are Phase 1, Phase 2, and Phase 3.

(MHRA, 2021)

Once a drug has successfully completed the Phase 3 trials, the drug’s manufacturer can submit a New Drug Application (NDA) to the FDA for approval to market the drug. The NDA must include data from the pre-clinical and clinical trials, as well as information about the drug’s manufacturing and labelling. The FDA reviews the NDA and determines whether the drug is safe and effective for its intended use.

In conclusion, the drug development process is a long and complex process, but it is essential to ensure that new medications are safe and effective for patients. The three main phases of drug development (Phase 1, Phase 2, and Phase 3) have specific goals and objectives, and each phase builds on the previous one to provide a comprehensive understanding of the drug’s safety, efficacy, and optimal use.

Phase I:

Phase 1 is the first stage in the drug development process and is designed to evaluate the safety and pharmacokinetics of a new drug in humans. It is usually the first time that a drug has been tested in human subjects and is therefore considered a critical stage in the development process. Phase 1 trials typically involve a small number of healthy volunteers (20 to 80) and are usually conducted in a controlled clinical setting, such as a hospital or research centre. The study participants receive a single dose or multiple doses of the drug over a short period of time, usually several days to a few weeks. The primary goal of Phase 1 is to determine the safe dose range of the drug, as well as its pharmacokinetic profile, including how the drug is absorbed, distributed, metabolized, and excreted by the body. In addition, Phase 1 trials may also provide initial information about the drug’s efficacy, although this is not the primary focus of the phase. The results of Phase 1 trials are critical in determining whether the drug should advance to Phase 2 and provide important information to guide future studies.

Phase II:

Phase 2 is the second stage in the drug development process and is designed to evaluate the efficacy and further assess the safety of a new drug in a larger group of patients. Phase 2 trials typically involve several hundred patients who have the medical condition that the drug is intended to treat. The study participants are randomly assigned to receive either the experimental drug or an established treatment, or sometimes a placebo, for a defined period of time, usually several months to a year. The primary goal of Phase 2 is to determine whether the drug is effective in treating the medical condition and to further evaluate its safety profile. The results of Phase 2 trials provide important information about the drug’s effectiveness, optimal dosing, and potential side effects, which helps to guide the design of future studies, including Phase 3 trials. Phase 2 trials are also used to gather data on the drug’s efficacy and safety in specific patient populations, including those with comorbid conditions, and to determine whether the drug has a favourable risk-benefit ratio. If the results of Phase 2 are positive, the drug may advance to Phase 3, otherwise, the development process may be terminated.

Phase III:

In the UK, Phase 3 is the final stage in the drug development process and is designed to confirm the efficacy and safety of a new drug in a large, well-controlled, randomized clinical trial involving several thousand patients with the medical condition that the drug is intended to treat. Phase 3 trials are conducted at multiple clinical sites and provide a comprehensive evaluation of the drug’s efficacy, safety, and side effect profile in a diverse patient population. Participants are randomly assigned to receive either the experimental drug, an established treatment or sometimes a placebo, for a defined period of time, usually several months to a year. The primary goal of Phase 3 is to provide sufficient evidence to support a regulatory submission, such as a Marketing Authorization Application (MAA), and to demonstrate the drug’s superiority to the established treatment, if applicable. The results of Phase 3 trials are crucial in determining whether the drug can be approved by regulatory agencies and made available to the public in the UK.

The RCT in Psychiatry

Randomized Controlled Trials (RCTs) are considered the gold standard for evaluating the efficacy and safety of treatments in psychiatry. An RCT is a type of clinical trial in which participants are randomly assigned to receive either an experimental treatment or a comparator, such as a placebo or an established treatment. The use of randomization helps to control for any extraneous factors that might affect the outcome and reduce the risk of bias in the study.

RCTs in psychiatry typically involve large groups of patients who have been diagnosed with a specific psychiatric disorder, such as depression, anxiety, or schizophrenia. Participants receive the experimental treatment or the comparator for a defined period of time, usually several weeks to several months, and are closely monitored for changes in symptoms, side effects, and overall functioning.

The primary goal of RCTs in psychiatry is to determine the efficacy and safety of the experimental treatment in treating specific psychiatric disorders. The results of the RCT are compared to those of the comparator to determine whether the experimental treatment is more effective, equally effective, or less effective.

RCTs in psychiatry play a critical role in advancing the field by providing evidence-based information on the best treatments for specific psychiatric disorders. They are used to support regulatory approval and reimbursement decisions and guide clinical practice.

Randomisation:

Randomization is a key aspect of Randomized Controlled Trials (RCTs) in psychiatry as it helps to control for any extraneous factors that might affect the outcome of the trial. In an RCT, participants are randomly assigned to receive either an experimental treatment or a comparator, such as a placebo or an established treatment, to ensure that any differences in outcome between the two groups can be attributed to the treatment being studied.

Endpoints (primary/secondary):

Endpoints, both primary and secondary, are specific outcomes that are measured in an RCT to determine the efficacy and safety of the experimental treatment. The primary endpoint is the main outcome that is being studied, and the secondary endpoint is a secondary outcome that is being measured to provide additional information about the experimental treatment.

Superiority and non-inferiority:

In RCTs, the experimental treatment may be compared to the comparator to determine superiority, where the experimental treatment is shown to be better than the comparator, or non-inferiority, where the experimental treatment is shown to be at least as good as the comparator.

Accounting for missing data:

Accounting for missing data is an important consideration in RCTs as it can impact the validity of the results. There are various methods for handling missing data, such as imputation, which involves filling in missing values with estimated values based on the available data or using statistical methods such as maximum likelihood estimation. The method chosen will depend on the specific design of the RCT and the nature of the missing data.

References:

(1) Medicines and Healthcare products Regulatory Agency (MHRA). (2021). Clinical Trials. Retrieved from https://www.gov.uk/guidance/clinical-trials

(2) World Health Organization (WHO). (2021). Clinical Trials. Retrieved from https://www.who.int/medicines/services/inn/clinical_trials/en/