First-In-Human (FIH) & Single Ascending Dose (SAD) Studies
First-In-Human Studies include the first administration of a chemical or a biological product, designated as a New Chemical Entity (NCE) or a New Investigational Medicinal Product (IMP), in humans. First-in-Human studies identify a dose range that is both safe to administer in further trials and capable of exerting a pharmacological activity. These studies are commonly associated with Single Ascending Dose (SAD) design, and with Multiple Ascending Dose (MAD) studies which are carried out subsequently or in parallel.
Prior to the initiation of a first-in-human trial, comprehensive preclinical studies are carried out to assess the safety and efficacy of an investigational drug. However, since preclinical models generally cannot encompass the complexity of medical conditions affecting humans, first-in-human studies are associated with inherent safety risks.
Participant safety should be the utmost priority of investigators designing and conducting first-in-human trials. Moreover, there are significant challenges associated with selecting the optimal first dose and dosing schedule for single ascending dose studies, and appropriate observation periods should be maintained between the dosing of individual participants to ensure their safety.
Strategies for Risk Assessment, Mitigation and Study Monitoring
A comprehensive strategy for risk assessment and mitigation and study monitoring is critical for first-in-human studies and should be in place prior to their initiation. BioPharma Services Inc.’s expert team of physicians and Ph.D.-level pharmacologists have developed a standard baseline set of safety assessments that are implemented in the safety monitoring of all investigational drugs entering first-in-human studies.
Based on the preclinical data of our clients and the characteristics of the investigational drug, our team proposes and implements additional safety measures to specifically evaluate any safety signals detected in the preclinical program or relevant for the pharmacology, drug target, or therapeutic target of the drug.
Our risk mitigation strategy is not only well-defined, but also adaptive and responsive to the data collected in the course of first-in-human and single ascending dose studies. In designing the first-in-human study, we can assess the information that researchers will later need for their Phase 2 trial.
Capabilities in Expanding Complexity of First-in-Human Studies
The complexity of clinical trial design and conduct has markedly increased in recent years, including a higher number of more frequently performed procedures and more substantial time commitment for study participants. The complexity of early-phase clinical trials, including first-in-human studies, is also enhanced by the need for extensive safety monitoring and correlative testing.
BioPharma’s expert multidisciplinary team and dedicated, state-of-the-art Phase 1 centers enable us to efficiently design and conduct even the most challenging and complex first-in-human and single ascending dose studies in healthy normal volunteers (HNVs).
An Unparalleled Expert Multidisciplinary Team
The extensive expertise of BioPharma’s medical and scientific teams in designing and conducting first-in-human and single ascending dose studies enables us to successfully manage the studies’ inherent risks and complexity. Our multidisciplinary team consists of physicians, pharmacologists, laboratory scientists, statisticians, and regulatory affair specialists who collaborate closely in the design and conduct of all aspects of the study.
Dr. John Oldenhof
Chief Scientific Officer
Dr. John Oldenhof has extensive senior management experience in Phase 1 clinical pharmacology, product development, biostatistics, clinical trial data management, and regulatory and scientific affairs.
Dr. Janice Faulknor
Medical Director & Principal Investigator
Dr. Janice Faulknor has over 15 years of experience as a PI or sub-investigator of over 100 clinical trials in various therapeutic areas.
State-of-the-Art Facility for Early-Phase Clinical Trials
To ensure the safety of participants in first-in-human and single ascending dose studies, the BioPharma Services’ team relies on our state-of-the-art Phase 1 center, located in Toronto, Canada. Our facility has all necessary infrastructure and equipment for comprehensive safety monitoring, including dedicated Phase 1 clinical trial intensive monitoring units.
The capabilities of our clinical center include a limited number of beds, a nursing station in the rooms, 24-hour monitoring, a telemetric option, a crash cart, ALCS-trained staff, and PIs with extensive experience, including ER physicians and anesthesiologists.
Comprehensive Support for Starting Dose Selection and Dose Acceleration Schedule
The starting dose selection for first-in-human studies is a complex process due to the challenges associated with extrapolating preclinical findings to humans and selecting a dose that minimizes the toxicity risk but is still relevant as a starting point for subsequent dose acceleration studies.
At BioPharma Services, we thoroughly review our clients’ preclinical data and provide feedback and suggestions regarding all safety aspects of the study. Moreover, we help our clients with the starting dose selection for first-in-human studies in an individualized manner, based on the specific needs of their studies and the extent of their previous experience.
Our expert team also helps clients with the pharmacokinetic design of single ascending dose studies. We start with a sufficiently low dose to ensure patient safety, and then escalate the dose at a safe rate. Moreover, we ensure that the acceleration schedule covers doses expected to exert pharmacological effects in future trials.
BioPharma Services’ pharmacokinetic team plays a key role in the selection of appropriate pharmacokinetic time points for the trial. We use pharmacokinetic modeling to examine the preclinical data and to model the dosing for the subsequent multiple ascending dose study.
Our team can also help with the selection of pharmacodynamic endpoints of a trial in order to provide a better understanding of the drug. This may include biomarkers or cognitive endpoints that evaluate the effects of the drug in HNVs. Moreover, we can work with various early formulations selected by the study sponsors. Our team has extensive pharmacy capabilities and can perform complex compounding and sterile preparations.
Experience With Challenging Routes of Administration
Our multidisciplinary team has designed and conducted studies with various administration routes, including oral, intravenous, intraperitoneal, and topical skin administration. Moreover, we have experience conducting clinical trials with medical devices. Notably, we collaborate with a network of experts with experience in challenging administration routes that help us accommodate the unique needs of our clients.
Multidisciplinary Management of First-in-Human
and Single Ascending Dose Studies
BioPharma Services has established a large database of study volunteers, including over 18,000 HNVs and individuals from special populations. The strong rapport that we have established with our study volunteers greatly facilitates the recruitment for our clients’ clinical trials. Moreover, our recruitment procedure is comprehensive and sets participants’ safety as our top priority.
Our in-house bioanalytical laboratory analyzes biological samples from bioequivalence and bioavailability bioequivalence/bioavailability and clinical pharmacokinetic studies. Our bioanalytical team performs state-of-the-art liquid chromatography with tandem mass spectrometry (LC/MS/MS) analysis to confirm and quantify low-abundance analytes in a variety of matrices.
Dr. Nicki Hughes, who has over 20 years of experience in bioanalytical research, oversees our R&D, validation, and production groups. Our good laboratory practice (GLP) of our bioanalytical services laboratory has been certified by the Standards Council of Canada (SCC).
Exhaustive Statistical Design & Analysis
Our biostatisticians’ team has expertise in the development of statistical analysis plans (SAPs), safety clinical trial data management, and medical coding for first-in-human studies. Moreover, all statistical analysis aspects of the first-in-human studies designed by our team strictly comply with the requirements of the Clinical Data Interchange Standards Consortium (CDISC).
Expert Team of Regulatory Support
BioPharma Services’ team of regulatory experts ensures that all study aspects comply with the requirements of regulatory agencies. The expertise of our team has been confirmed by over 30 successful regulatory inspections by a number of regulatory agencies, including the United States FDA, United Kingdom MHRA, French ANSM, Danish Medicines Agency, Brazilian ANVISA, Health Canada, and the World Health Organization.
First-in-human and single ascending dose studies present significant challenges, especially in regard to participants’ safety. Partnering with an experienced and innovative full-service clinical research organization (CRO) like BioPharma Services will ensure all aspects of your studies are designed and performed with participants’ safety as a top priority and in compliance with all regulatory guidelines.
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First-in-Human & Single Ascending Dose (SAD) FAQ
What is a first-in-human clinical trial, and why is it important?
A first-in-human (FIH) clinical trial, which involves testing an experimental drug, procedure or treatment that will be tested in humans for the first time. A FIH trial are typically conducted after extensive in-vitro and in-vivo preclinical testing in animals to ensure safety and efficacy. FIH trials mark an important milestone in the drug development process when a scientific discovery is being transferred to clinical therapeutic applications. The FIH is expected to provide crucial initial information about the safety and tolerability dose range of new drugs or treatments, as well as the basic pharmacology characteristics in humans
What is a Single Ascending Dose (SAD) study, and how are they designed?
A study with Single Ascending Dose (SAD) design or SAD study is a clinical trial in which participants will be assigned to multiple small groups to receive a single dose of an experimental drug or treatment subsequently, the provided dose for each of the groups and will be gradually increased until a maximum tolerated dose (MTD) is reached. This design is used to evaluate the safety and tolerability of single-dose of a new medicinal entity at different dose-levels.
On the contrary, a study with Multiple Ascending Dose (MAD) design or MAD study, is similar to the SAD study in which the dose provided for all groups will be increased gradually. However, each group in MAD study will receive multiple-dose of the investigational product instead single-dose as in SAD study.
Dose escalation is a key component of SAD and MAD studies. Subsequent doses are escalated in a stepwise manner, which allows researchers to determine MTD. The goal of this dosing strategy is to identify the MTD as quickly and safely as possible, so that subsequent clinical trials can be designed with an appropriate dose range.
SAD (and MAD) designs belong to dose-ranging studies type, which the most common design types for first-in-human (FIH) trials.
How is data from FIH clinical trials used to inform further drug development and clinical research?
The data from first-in-human (FIH) clinical trials is used to inform further drug development and clinical research in a number of ways. If the drug is found to be safe and tolerable within the evaluated dose range, further clinical trials can be conducted to evaluate its efficacy and optimal dosing regimen. If safety concerns arise, modifications to the drug, doses or dosing regimen may be made. The data can also be used to guide further preclinical research and to inform the regulatory review process for the drug. Ultimately, the data from FIH clinical trials is the critical links for advancing new drugs and treatments through the drug development process and into clinical practice.
What Pharmacokinetic assessments are performed during a first-in-human (FIH) clinical trial?
Besides the primary objective of evaluating the safety and tolerability, pharmacokinetics of the investigational drug in humans is often investigated at the early phase clinical trials:
Systemic Pharmacokinetic Profiling: Although the pharmacokinetics (PK) of investigational products should be evaluated during the pre-clinic stage, evaluating the systemic PK in human is critical to confirm the previous findings and/or establishing the bridge between the animal and human PK. In majority cases, systemic PK can be estimated from the blood samples, which are collected at regular intervals after dosing to measure drug concentrations in the bloodstream. In rare cases, samples from different matrices (e.g. urine, synovial fluid, cerebrospinal fluid) can be obtained to provide further PK information.
Pharmacokinetic Modeling/Simulation and other related models: Pharmacokinetic models, simulations and other related models are mathematical tools that can be applied as clinical support tools to interpret, extrapolate and/or visualize the quantitative analysis of investigational agents distributions in the body and its relation to the drug absorption, distribution, metabolism and excretion. With sufficient data and suitable model, we can establish the correlations between PK data and the physiological characteristics (PBPK model), PK and PD profiles (PD/PK model) which allows further predictions of the PK or PD data for the targeted population from known physiological and PK information obtained from other trials. This approach has been supported by many regulatory and innovator as it can significantly reduce the cost for clinical stage but still provide reliable predicted information for safety and efficacy assessment.
Food Effect Assessment: Food effect studies are conducted to evaluate the effect of food on the drug’s pharmacokinetics. Although this type of study could be done at late stage, if the investigation drugs are intended for specific administration conditions or there is known risk at higher exposure associated with or without food during the pre-clinic trial, assessment of food effect can be performed as a separate study or as a cohort in a bigger study combined with other evaluation such as SAD/MAD cohorts.
Drug-Drug Interaction Assessment: Drug-drug interaction studies are conducted to evaluate the potential for the investigational drug to interact with other drugs that may be co-administered in clinical practice. This is an essential assessment for drug that are prone for drug-drug interaction (e.g. substrates, strong inhibitors or inducers of P450, p-protein) and drug that is intended for clinical indication in co-administration with other drug. This assessment can be performed at both the early and late clinical phase.
What other assessments can be evaluated during first-in-human clinical trials?
Drug Effectiveness: In addition to other pharmacokinetic assessments, early signs of drug effectiveness can also be evaluated in early phase of clinical trials, e.g. SAD/MAD studies. Such preliminary evidence of the drug’s effectiveness are helpful for optimizing dosing regimen to achieve the desired effect and support for the drug development decision.