Bringing a new drug to market is a cost and time-intensive process requiring a diverse range of professionals to come together and drive the program to the desired outcome. Clinical pharmacologists play an important role in this multidisciplinary team via the appropriate use of pharmacological principles and techniques during the clinical development cycle. This blog explores the importance of the clinical pharmacologist’s role, the various techniques employed, and the regulatory perspective – since regulatory agencies across the globe rely on clinical pharmacology data for the approval of drugs and biologics.
Clinical Pharmacology
Clinical pharmacology covers all aspects of interaction between humans and drugs, focusing on safe and effective usage. The clinical pharmacology team oversees the entire clinical development program with the aim of increasing the success rate and efficiency of the program to arrive at the right dosing regimen for the patient.
Clinical pharmacology helps overcome major scientific challenges of drug development by predicting the safety, efficacy, and drug response variability. These aspects can be appropriately understood using clinical pharmacology methods and tools before initiating and during the clinical development program, at both early and late stages. Appropriate application of the principles of pharmacokinetics (PK) and pharmacodynamics (PD), in conjunction with model-informed drug development (MIDD), can significantly reduce the failure rate, cost, and duration of the development program.
Model-Informed Drug Development
MIDD helps in clinical development by potentially reducing the size and number of clinical studies. They can also help drug developers select appropriate doses for first-in-human (FIH) clinical trials or in special populations, such as renal and hepatic impairment or pediatric patients. MIDD tools such as pharmacometric modeling, physiologically based pharmacokinetic modeling (PBPK), population pharmacokinetic (popPK) analysis, and quantitative systems pharmacology (QSP) are increasingly being used.
MIDD is a multi-disciplinary approach that uses biological, mathematical, and statistical models derived from preclinical and clinical data to inform drug development and aid in decision-making. In MIDD, a thorough understanding of PK and PD parameters of the drug is leveraged to develop mathematical models using invitro, preclinical, and clinical data obtained during the drug development program. Knowledge of biology, pharmacology, and pathophysiology is also integrated into the model to inform clinical trial design and decisions pertaining to dosage form, route of delivery, and predicting drug response in special populations. Depending on the protocol, one or more modeling approaches including PKPD, PBPK, popPK, and QSP, can be used to drive clinical development.
Safeguards for Achieving Trial Objectives
Inappropriate target selection, target validation, and inter-individual variability are a few of the main reasons for the failure of drug development programs. QSP uses mechanistic modeling to improve the selection and validation of targets. PBPK modeling can help predict the pharmacokinetics of drugs in humans and evaluate the effect of intrinsic factors (genetics, organ dysfunction, or age) and extrinsic dynamics (drug-drug interactions) on drug exposure. Population pharmacokinetic analysis helps in understanding the variability in drug exposure based on characteristics such as age, gender, disease state, concomitant medications, and the presence of renal or hepatic impairment.
Regulatory Perspective
Regulators are increasingly advocating the integration of clinical pharmacology and MIDD tools at all phases of drug development programs. Over the last two decades, FDA has engaged in a series of outreach activities and publications to reiterate the importance of MIDD. MIDD has been recognized as one of the regulatory decision-making tools under the sixth iteration of the reauthorization of the prescription drug user fee act (PDUFA VI)[1]. A major step towards a global consensus on the importance of clinical pharmacology and MIDD was the endorsement of a proposal on general considerations for MIDD by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The ICH also established an M15 informal working group[2].
Invaluable Multidimensional Insight
Clinical pharmacology teams provide inputs at multiple levels and expertise in different subdisciplines including pharmacometrics (modeling and simulation for QSP, PBPK, popPK); programming; clinical pharmacology; and pharmacokinetics. All these activities need continuous support from individuals with diverse expertise in medical writing, data management, project management, and quality assurance.
For most small and midsize firms, these skills are rarely available internally, and all or part of the clinical pharmacology program is outsourced. Allucent has an experienced team encompassing all the critical subdisciplines of clinical pharmacology. We offer critical support during the entire drug development program encompassing project management, regulatory affairs, and quality assurance. To learn more about Allucent and how we can support you, please visit our clinical pharmacology page.
[1] FDA committed to undertake additional activities for advancing MIDD during PDUFA VI.
[2] MIDD was supported and endorsed as new area of ICH harmonization under multi-disciplinary topics.