On Biostatistics and Clinical Trials: SAD and MAD: Single Ascending Dose and Multiple Ascending Dose first-in-human studies

Friday, November 03, 2017

SAD and MAD: Single Ascending Dose and Multiple Ascending Dose first-in-human studies

The acronym is everywhere in clinical trials. Previously I mentioned that in 21st Century Cure Act, an acronym RAT was used for Regnerative Advanced Therapy designation – the term ‘RAT’ was criticized and later was changed to MRAT(Regenerative Medicine Advanced Therapy) in FDA’s implementations.

Now we have a pair of names SAD and MAD commonly used in early phase clinical trials. It does not mean anybody will be sad or mad. A sponsor should be happy (not SAD or MAD) when its development program can progress into the clinical trial stage.

SAD stands for single ascending dose and MAD stands for multiple ascending dose. SAD and MAD studies are typically the first-in-human (FIH) studies. They seek to gain information on safety and tolerability, general pharmacokinetic (PK), and pharmacodynamic (PD) characteristics, and identify the maximum tolerated dose (MTD). SAD/MAD study can also be used to test the cardiac safety and evaluate QT/QTc prolongations.

There may be a lot of dose escalation studies that belong to SAD and MAD studies even though the SAD/MAD terms are not used. For example, the popular 3+3 design is one type of the SAD/MAD study with focuses on safety and tolerability.

SAD/MAD studies are usually conducted in healthy volunteers in clinical research unit (CRU) or phase I unit. But they can be conducted in patients when it is unethical to test the experimental drug (for example, the oncology drugs and plasma-derived drugs) in healthy volunteers. SAD/MAD studies can be combined into one study within the same study protocol or conducted as two separate studies.

For SAD studies, the starting dose is based on the pre-clinical and animal studies. For MAD studies, the starting dose is usually based on results from the SAD study.

From the PK assessment standpoint, in SAD studies, each subject receives a single dose and the series PK samples can be taken to evaluate the PK profiles after single dose. The study will be conducted on cohort basis. Subjects within each cohort receive the same level of dose. In MAD studies, each subject receives multiple doses. After the steady state is achieved, the series PK samples will be taken to evaluate the PK profiles at the steady state. The study is conducted on cohort basis. Subjects within each cohort will receive the same level of dose. With the PK results from SAD/MAD studies, dose linearity and dose proportionality can be evaluated.

From the safety assessment standpoint, in both SAD/MAD situations, the first cohort of subjects receive the lowest dose (starting dose). Subjects are usually confined in Clinical Research Unit (CRU) with close safety monitoring. After each cohort, safety and tolerability will be assessed to determine if the next cohort with higher dose should be continued. The safety evaluation after each cohort is usually performed by the internal team within the sponsor, but can certainly be performed by the independent committee such as data and safety monitoring committee (DSMB). With the safety data, the maximum tolerated dose (MTD) may be identified.

In SAD/MAD studies, within each cohort, placebo control can be added. Depending on whether there is a concurrent placebo control group, the SAD/MAD studies could have the following types.

SAD without placebo control
SAD with placebo control
MAD without placebo control
MAD with placebo control

When placebo group is added to the SAD/MAD study, to avoid too many subjects in placebo group for the final analysis, it is very common to use a n:1 randomization ratio within each cohort, For the final analysis, subjects in placebo group across all cohorts are pooled together.

Here are a couple of examples for SAD/MAD study designs – they are extracted from a presentation slide I made almost 20 years ago, but is still relevant: