What Are SAD MAD Studies? A Guide to First-in-Human Clinical Trials

Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) studies are complementary Phase 1 designs. SAD establishes initial human safety and pharmacokinetics after single exposure; MAD characterises repeated‑dose safety, accumulation, and steady‑state PK/PD. Many sponsors integrate both in one protocol to accelerate decisions while maintaining robust safety oversight.

Why combine SAD and MAD?

Combining parts streamlines start‑up, reuses site infrastructure, and lets teams apply real‑time learning from SAD to optimise MAD (e.g., dose levels, sampling windows). This integrated approach has become common among CROs and sponsors aiming for faster Phase 2 readiness without compromising safety governance.

Benefits

• Operational continuity and faster cycle times between parts.
• Earlier visibility into steady‑state safety and PK accumulation.
• Flexible addition of food‑effect or special‑population sub‑studies.
  

Pre-Requisites

• Robust nonclinical package (NOAEL, TK, safety margins) and MABEL/PK predictions.
• Clear stopping rules and Safety Review Committee (SRC) cadence.
• Logistics and bioanalytical capacity aligned to review timelines.
  
  

How are cohorts designed and escalated safely?

SAD typically uses small cohorts with sentinel dosing in the first group, ascending by predefined increments after SRC review of blinded safety/PK. MAD mirrors the structure but repeats dosing to steady state. Dose increases are gated by exposure margins and predefined toxicity thresholds to protect participants.

Core Elements

• Randomised, placebo‑controlled cohorts; first cohort with sentinel pair.
• Escalation based on emerging safety, PK (C_max, AUC), and exposure vs. nonclinical limits.
• Washouts between cohorts in SAD; steady‑state confirmation in MAD.

Stopping Rules & Governance

• Protocol‑defined stopping criteria with SRC/IDMC review cadence.
• Unblinded safety physician access under firewalled procedures.
• Expedited reporting pathways for SAEs and DLTs.
  
  

What PK/PD assessments are typical?

SAD focuses on single‑dose PK (absorption, exposure, half‑life) and tolerability signals. MAD characterises trough/peak, accumulation ratio, time‑to‑steady‑state, and any time‑dependent PK. Biomarker or PD readouts can de‑risk dose selection for later phases when scientifically justified.

• Dense early sampling around T_max; sparse later windows based on SAD learnings.
• Food‑effect and drug–drug interaction sub‑studies where relevant.
• Exploratory PD/biomarker panels to link exposure to pharmacology.
  
  

Which adaptive options can accelerate timelines?

Pre‑specified adaptations—cohort size changes, dose‑increment adjustments, optional arms (food effect), or sampling tweaks—reduce idle time while preserving control via SRC governance and documented decision rules. Adaptive early‑phase designs are widely used to increase efficiency.

• Response‑adapted dose increments driven by emerging exposure margins.
• Seamless SAD→MAD transitions using interim PK to refine targets.
• Operational adaptations (randomisation ratios, windowing) with clear bounds.
  
  

What operational practices reduce risk?

Plan for rapid data flow to the SRC (near‑real‑time safety lab reads, expedited PK), maintain pharmacy checks for blinded dose prep, and align bioanalytical capacity with cohort cadence. Proactive recruitment and standby alternates minimise delays between dose escalations.

Data & Safety

• Near‑real‑time safety dashboards for AEs/SAEs and labs.
• PK bioanalysis SLAs aligned to SRC meetings.
• Deviation control on dosing windows and vitals timing.

Sites & Staffing

• Sentinel dosing SOP execution and documentation.
• Recruitment funnels for HVs/patients depending on indication.
• 24/7 medical coverage during first cohorts.
  
  

What common pitfalls should teams avoid?

Avoid over‑ambitious escalation steps, under‑powered safety reviews, and rigid sampling schedules that ignore early PK learning. Ensure the protocol permits pauses for exposure margins, introduces food‑effect only when justified, and defines clear rescue and unblinding pathways.

• Escalation without integrating nonclinical exposure limits → specify exposure‑guided gates.
• Operational bottlenecks in bioanalysis → align capacity and SRC cadence.
• Insufficient PD planning → miss early signals that inform Phase 2 dosing.
  
  

FAQs

How many subjects per cohort are typical?

Small cohorts (e.g., 6–10 with placebo) are common in SAD; MAD cohorts may be similar but powered to characterise steady‑state PK and safety over multiple days. Exact numbers depend on modality, risk, and biomarker plans.

Do all FIH programs need both SAD and MAD?

No. Some modalities progress with SAD plus targeted PD readouts; others require MAD for accumulation or safety at repeat exposure. Integrated protocols allow optional activation of MAD after review of SAD data.

When is a food-effect assessment performed?

When absorption is likely impacted by food or to match intended clinical use. It can be a separate arm or nested crossover, often triggered after early PK is reviewed in SAD.

What governance is expected?

Predefined stopping rules, a Safety Review Committee with rapid access to safety/PK summaries, sentinel dosing for first exposure, and clear unblinding pathways under medical oversight.

Quanticate’s statistical consultancy team design and oversee SAD MAD studies with robust governance, PK/PD insight, and adaptive trial strategies. Submit an RFI today.