The transition of a drug, medical device, or biopharmaceutical from the laboratory bench to bedside involves a long series of steps starting from drug discovery, computational chemistry, in vitro and ex vivo studies, preclinical and in vivo animal studies that finally culminates with clinical trials in human subjects. The clinical trial process is most often the lengthy and expensive and is fraught with several roadblocks such as recruitment and retention challenges, data analysis issues, patient safety and confidentiality, and informed consent to name a few. In addition to operational issues, it is important to ensure that the trial is started properly taking all measures to ensure that the trial results are accurate and reliable.

The importance of proper trial conduct is critical when it comes to biopharmaceuticals which are drugs made from living cells or organisms in contrast to small molecule drugs that are chemically synthesized. Variability in starting materials due to their natural origin, complexity of the manufacturing process, immunogenicity issues, invasive routs of drug administration, longer duration of persistence in the body, increased safety monitoring, and choice of suitable biomarkers and other endpoints is extremely critical when dealing with biological products and all these aspects must be considered when starting trials in human subjects.

First-in-human (FIH) studies are early phase I trials in which involve the first time a drug or biopharmaceutical is administered to human subjects. Since prior knowledge of the safety issues of the product, target populations, and sample sizes with endpoints are not known, FIH studies require careful planning and execution to protect the safety and well-being of patients. Typically, FIH studies involve characterization of a molecule’s pharmacokinetics, safety, tolerability, and potential effective concentration and dose. They are usually conducted in
20-80 healthy participants and aim to identify dose range(s), metabolism and excretion routes for the drug, and side effects/adverse effects of the drug or biopharmaceutical. Since FIH studies are critical as they involve the first time that human subjects are exposed to the drug, it is necessary to have a suite of information that adequately captures the drug characteristics from preclinical and in vitro studies as well as regulatory documents that allow for administration of drugs to humans.

The following are the prerequisites for FIH studies that ensure that the study is carried out in a manner that is safe and ethical:

In vitro studies:

extensive research in laboratories involving microorganisms and cultures, human cells and tissues, and computational modelling is important to understand drug pharmacodynamics and target chemistry. Drug-drug interaction studies and toxicology assessments are also important to understand maximum doses and dose selection.

Preclinical studies:

In vivo proof-of-concept studies in animals which include pharmacology, toxicology, and pharmacokinetics are necessary to obtain data prior to exposure of the biopharmaceutical in humans. It is important that data is obtained from suitable animal species and models with similar biological responses as humans so that data can be extrapolated to human subjects. This is challenging particularly for biopharmaceuticals as traditional pharmacokinetic studies may not be suitable.

Product characteristics:

A well-defined profile of the biopharmaceutical such as its physicochemical characteristics, impurity and degradation profile, route of administration, potency, immunogenicity risk, systemic persistence, and manufacturing processes and controls.

Clinical Trial Protocol:

Comprehensive trial protocol that describes the target population, primary and secondary endpoints, objectives, dose and dosing schedule, inclusion/exclusion criteria, study duration, study assessments, study tests and visit schedules, study endpoints and biomarkers, stoppage rules, etc. should be clearly stated.

General Investigation Plan (GIP) and Investigator’s Brochure (IB):

These form part of the Investigational New Drug (IND) application and include complete information on preclinical studies, clinical data (if available), risk management plan, safety information, and profile of the biopharmaceutical compound.

Toxicity data:

Single- and repeated-dose toxicity studies that help in determining the maximum tolerated dose (MTD), organ toxicity studies, genotoxicity data, immunotoxicity, and safety pharmacology data are required to guide suitable dose selection.

Risk Management Plan (RMP):

Safety monitoring plan that adequately describes the procedure for identification, reporting, and treatment of potential safety risks to participants and a streamlined process of reporting and grading adverse events to regulatory authorities is necessary.

Institutional Review Board (IRB) approval:

A thorough risk-benefit assessment, potential risks, and a safety monitoring plan is carefully reviewed by the IRB to ensure the safety and well-being of subjects.

Informed consent:

This is necessary from all participants and consent for participation in the study must be obtained after describing study details and risks including the right to withdraw from the study at any time. This ensures that the study is conducted in an ethical manner keeping patient safety at the forefront.

Study design and dose selection:

Designing the study requires a careful evaluation of the target population, sample size, control groups, blinding, and dose and regimen including dose escalation. Single ascending dose (SAD), multiple ascending dose (MAD), parallel group, or crossover designs maybe chosen depending upon patient characteristics and the type of data that is required. Data from preclinical studies and previous clinical experience is pooled together to decide the starting dose which is usually guided by the no-observed-adverse-effect-level (NOAEL). However, the selection of the starting dose varies depending upon drug characteristics and is not uniform for all drugs as interspecies dose scaling varies.

Site and Investigator selection:

It is necessary to propose the sites that the trial will be conducted at, and the investigator and staff qualifications to ensure that they meet the requirements for the trial in terms of data collection and study monitoring. It is important to choose sites where patient enrolment rates are high and the necessary equipment is available for study visits. Staff should be trained on Good Clinical Practice (GCP) guidelines and other applicable regulatory requirements and should be aware of ethical requirements.

The above-mentioned requirements ensure that FIH trials are conducted safely, ethically, and generate data that is accurate and reliable but are not a comprehensive list. For certain biopharmaceuticals, additional studies especially toxicity and immunogenicity studies may be required to support regulatory approval. A cross-functional team consisting of clinicians, statisticians, regulatory experts, data managements personnel, toxicologists, and other health care professionals is necessary for the success of FIH trials and should work collaboratively. As FIH trials shape the way that the trial progresses, it is important that they are conducted with the utmost care and appropriate risk management strategies are deployed for patient safety.

 

Read More: EMA Pharmacovigilance Regulations Updates

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