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 research 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.
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. 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.
Our medical team also includes Dr. Isabella Szeto who has 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 Facility
BioPharma conducts all early-phase clinical trials, including multiple ascending dose studies, in our state-of-the-art Phase 1 center in Toronto, Canada. Our center is 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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Multiple Ascending Dose (MAD) Studies FAQ
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What are Multiple Ascending Dose (MAD) Study?
A Multiple Ascending Dose (MAD) Study is a type of clinical trial that is used to evaluate the safety and efficacy of a drug over an extended period of time, typically involving multiple doses. The study is used to assess the drug’s pharmacokinetics, tolerability, and safety. The drug’s pharmacokinetic profile is determined by MAD studies, which also identify the recommended Phase 2 dose or the drug’s maximum tolerated dose (MTD) (RP2D).
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Where can Multiple Ascending Dose (MAD) Studies be done?
Studies involving multiple ascending doses (MAD) are frequently carried out in a clinical setting, such as a hospital or research facility. The majority of the time, they are carried out under the direction of a licensed healthcare professional, such as a doctor or a clinical researcher like those at BioPharma Services. MAD studies are frequently carried out in phases, with phase 1 studies frequently being carried out in healthy volunteers and phase 2 studies later being carried out in patients with a particular disease or condition. The location of these studies will depend on the countries regulatory requirements, the accessibility of patients, and the presence of qualified medical personnel. For instance, MAD studies are typically carried out in clinical research centres, academic medical centres, or other specialised research facilities, such as BioPharma Services.
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Why are Multiple Ascending Dose (MAD) Studies Important?
Studies using Multiple Ascending Dosing (MAD) are crucial in the creation of new medications. These studies offer important data on a drug’s efficacy, safety, and best use, which is necessary for making educated decisions about its development. The ability to assess a drug’s safety and tolerability over an extended period of time is a key component of MAD studies. This ensures that the medication is taken at the most effective and secure dose, while also determining the drug’s risk-benefit ratio. MAD studies also studies provide vital pharmacokinetic data on the drug’s absorption, distribution, metabolism, and elimination that is helpful in determining the right dosage and in understanding the drug’s physiological effects. MAD studies also offer crucial pharmacodynamic details on the drug’s mode of action and its physiological effects. MAD studies enable early detection of any potential safety or efficacy concerns that might arise with the drug, increasing the likelihood of success in later stages of development and decreasing the possibility of expensive failures.
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What Pharmacokinetic Assessments are Performed During a MAD Study?
A number of pharmacokinetic (PK) analyses are carried out during a multiple ascending dose (MAD) trial to assess the drug’s behaviour in the body, including:
- Plasma concentrations: The drug’s pharmacokinetic profile is ascertained by measuring the drug’s plasma concentration at different times after dosing.
- Bioavailability: The area under the plasma concentration-time curve (AUC) after oral dosing and the AUC after intravenous dosing are compared to estimate the drug’s bioavailability.
- Clearance: The rate at which a drug is excreted from the body is used to calculate its clearance. This includes the apparent volume of distribution (Vd/F) and apparent oral clearance (CL/F).
- Half-life: The drug’s half-life is calculated by timing how long it takes for
- Protein binding: The percentage of drug that binds to plasma proteins is determined.
- Drug-drug interactions: The potential for drug-drug interactions is evaluated by measuring the effect of concomitant medications on the pharmacokinetics of the drug.
- Metabolism: The metabolic pathways of the drug are characterized by measuring the levels of the drug and its metabolites in blood and urine.
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How are Multiple Ascending Dose (MAD) Studies Designed for Phase 1 Trials?
An extended period of time is used in multiple ascending dose (MAD) studies for phase 1 trials, a type of clinical trial that assesses a drug’s safety and effectiveness. Typically, they take the form of a dose-escalation study, in which the drug dose is progressively increased in a series of patient groups. Patients are healthy normal volunteers (HNVs) or people who have the particular illness or condition for which the drug is being developed. Throughout the study, adverse events and adjustments to laboratory parameters are closely watched. If a significant portion of patients have serious adverse events or if the medication is deemed unsafe, the study is typically stopped. MAD studies’ primary goal is to establish the maximum tolerated dose (MTD) or the recommended Phase 2 dose (RP2D) of the drug.