Multiple Ascending Dose (MAD) Studies
Multiple Ascending Dose (MAD) studies include the administration of multiple doses of a New Chemical Entity (NCE) or a New Investigational Medicinal Product (IMP) to evaluate their safety and tolerability and to analyze their pharmacokinetic and pharmacodynamic profiles. Typically, first-in-human trials start with a single ascending dose (SAD) study based on the preclinical toxicological results. A multiple ascending dose study can then be conducted following or simultaneously with the single ascending dose study.
Expertise in Design and Conduct of MAD Studies
BioPharma Services, Inc. (BioPharma) is a full-service clinical research organization (CRO) with extensive expertise in all aspects of the design and conduct of early-phase clinical trials, including multiple ascending dose studies. Our scientific and clinical team has successfully completed over 2,000 early-phase clinical trials, including numerous multiple ascending dose studies. BioPharma’s accomplishments in clinical research have been acknowledged with more than 20 awards and recognitions.
At BioPharma, the design and conduct of MAD studies are performed by our multidisciplinary team, including clinical pharmacology scientists, pharmacokinetics scientists, clinicians, medical writers, biostatisticians, data managers, analytical laboratory scientists, recruitment and screening specialists, and pharmacists.
Industry Leading Leadership Team
We draw on the know-how of BioPharma’s over 250 multidisciplinary experts, including at least 8 Ph.D. graduates. The overall cumulative experience of our principal investigators (PIs) exceeds 50 years. The company’s medical and scientific leadership team includes BioPharma’s chief scientific officer (CSO), Dr. John Oldenhof and chief medical officer (CMO), Dr. Fathi Abuzgaya.
Dr. John Oldenhof
Chief Scientific Officer & Executive VP of Scientific Affairs
Dr. Oldenhof has over 18 years of senior management experience in Phase 1 clinical pharmacology, product development, biostatistics, data management, and regulatory and scientific affairs.
Dr. Fathi Abuzgaya
Chief Medical Officer & Principal Investigator
Dr. Fathi Abuzgaya has over 15 years of experience as a PI or sub-investigator of over 100 clinical trials in various therapeutic areas.
Our medical team also includes Dr. Isabella Szeto and Dr. Artan Markollari, both of whom have served as PIs in a number of clinical trials.
Efficient Multiple Ascending Dose Study Design
A key component of multiple ascending dose study design is the careful selection of dose levels and dosing intervals. The BioPharma team often designs MAD studies in conjunction with SAD studies to streamline the drug development process and optimize costs. We usually derive the planned doses from the preclinical data, with the dose levels falling between the anticipated safe starting dose and the maximum planned dose for the single ascending dose study.
In addition, our team commonly establishes the maximum tolerated single dose and then proceeds with the multiple ascending dose portion of the study. Multiple ascending dose studies are usually designed and conducted as randomized, double-blind, placebo-controlled, parallel-group, time-lagged studies.
Safe and Reliable Dose Escalation Schedule
The selection of dose levels and dosing frequency for MAD studies should be considered carefully to safely achieve therapeutic drug levels and a steady state of study drugs. This, in turn, enables the determination of key pharmacokinetic parameters and safety aspects. The pharmacokinetics and safety data are carefully examined before each dose escalation. Particular attention should be paid if the preclinical data are limited or indicate a narrow therapeutic window, or if there are concerns regarding the toxicity of the drug candidate.
BioPharma’s pharmacometrics group can model the expected concentrations and pharmacokinetic profile of the drug candidate based on the single ascending dose study results. We use a flexible and adaptive approach that enables us to adjust the dose levels for the single and multiple ascending dose studies according to the emerging pharmacokinetic and safety data. Based on this strategy, we can identify the potential maximum dose. If the incoming clinical results indicate a need to move beyond the protocol-defined parameters, we can prepare a protocol amendment and help our clients obtain regulatory approval for the protocol change.
In addition to the pharmacokinetic assessments, BioPharma’s team can also select pharmacodynamic endpoints to gain further insight into the study drug, including biomarkers and cognitive endpoints. Notably, we can perform all bioanalytical assessments in our in-house, state-of-the-art bioanalytical laboratory, which is equipped with liquid chromatography with tandem mass spectrometry (LC/MS/MS) and has been certified by the Standards Council of Canada (SCC).
Unparalleled Recruitment Process
Generally, MAD studies are performed in normal healthy volunteers (NHVs) unless the toxicity profile of a drug candidate raises safety concerns, in which case a patient population may be recruited. Even though the timely recruitment of study participants is a prerequisite to ensure sufficient power and timely completion of the study, the recruitment process is often challenging.
BioPharma’s recruitment process is spearheaded by an experienced recruitment and screening specialists who efficiently recruit volunteers from BioPharma’s database of potential study participants. Our database includes more than 18,000 NHVs and individuals from special populations.
Comprehensive & Responsive Safety Monitoring Strategy
BioPharma’s strategy for the safety monitoring of a multiple ascending dose study is comprehensive, well planned, and adaptive. It includes a standard baseline set of safety assessments and additional measures to specifically evaluate any safety signals detected in the preclinical program or relevant for the pharmacology and targets of the drug candidate.
However, our safety strategy is also responsive to the emerging data collected during the course of the clinical study.
Carefully Considered Safety Aspects
The safety aspects of every multiple ascending dose study should be considered carefully already during the planning phase. The development of predictable and unpredictable toxicities, the pharmacokinetic profile and mechanism of action of drug candidates, the quality of drug formulations, and the route of administration should be reviewed.
Predictable & Unpredictable Toxicities
Both predictable and unpredictable toxicities and hypersensitivity reactions may occur in the course of MAD studies and should be closely monitored. BioPharma’s expert medical and scientific team has the expertise to assess all toxicity risks and promptly intervene if necessary.
Monitoring of Pharmacokinetic Profiles
During a multiple ascending dose study, unexpected pharmacokinetic profiles may be observed, resulting in higher than anticipated doses.
Drug Candidate Mechanism of Action
The mechanism of action of the drug candidate should also be considered. If a novel mechanism with poorly characterized adverse effects is expected, intensive safety monitoring is required. Drug candidates that are associated with multiple signaling pathways or modulate biological cascades require special attention.
Quality of the Drug Formulation
The highest quality of the investigational drug formulation should be used in terms of its purity, potency, sterility, and stability. BioPharma’s team can work with various early formulations and perform complex compounding and sterile preparations. This enables us to select the most suitable drug formulation for our clients’ studies.
Drug Candidates Appropriate Route Administration
The possibility for a fast interruption of drug administration may be a consideration in certain instances. BioPharma has experience designing and conducting studies with various routes of administration, such as oral, intravenous, intraperitoneal, and topical skin administration, enabling us to select the most appropriate administration route for drug candidates.
Modern Clinical Facilities
BioPharma conducts all early-phase clinical trials, including multiple ascending dose studies, in our state-of-the-art Phase 1 centers in Toronto, Canada, and St. Louis, Missouri. Both centers are equipped to enable comprehensive safety monitoring, including dedicated Phase 1 intensive monitoring units. Our clinical team is highly qualified and includes PLS with broad experience, ER physicians, anesthesiologists, and ALCS-trained staff. The safety infrastructure and equipment include a limited number of beds, a nursing station in the rooms, 24-hour monitoring, a telemetric option, and a crash cart.
Streamlined Clinical Drug Development Process
Multiple ascending dose studies provide key information for further drug development. Thus, they collect data on the drug candidate’s safety, tolerability, maximum tolerated dose, general pharmacokinetic characteristics, steady-state parameters, accumulation, elimination, variability, linearity, and dose proportionality. This information can then be used in designing future Phase 2 trials. BioPharma has vast experience in the design of MAD studies and offers a high-quality, full-service solution. Moreover, we commonly combine single and multiple ascending dose studies into single, flexible protocols that streamline the drug development process and reduce the associated costs.
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