By: Lona Sheeran, SVP, Clinical Operations, Early Phase
In the dynamic world of drug development, Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) studies play a pivotal role in establishing the safety and efficacy of new therapeutics. These initial trials are critical, as they lay the groundwork for subsequent phases and can accelerate the drug discovery timeline when executed properly. But are you making the most out of your SAD/MAD protocols? This blog delves into the essential strategies for mastering SAD/MAD trial design, highlights critical insights gleaned from success stories in the field, and discusses how to optimize early phase trials to ensure rapid yet safe drug development.
Understanding SAD and MAD Studies
Single Ascending Dose (SAD) Studies focus on understanding how the body tolerates a single dose of a drug. They involve gradually increasing the dose among different groups of participants to establish the trial drug’s safety, tolerability, and pharmacokinetics.
Multiple Ascending Dose (MAD) Studies extend this evaluation to repeated dosing, assessing the effects of drug accumulation and the body’s response to prolonged exposure. This type of evaluation helps in understanding the drug’s behavior over time, which is crucial for determining suitable dosing schedules.
Challenges and Complexities of Phase 1 Protocols
Subject clinical staff burden: Designs demanding excessive or invasive procedures can deter participant cooperation and overwhelm clinical staff, jeopardizing data integrity.
Avoiding excessive data collection: Balancing thoroughness and excessive data collection is critical. Excessive data increases the chances of potentially compromised data integrity and adds unnecessary work for clinical staff.
High chance for error rates and poor data quality: Without careful protocol design, error rates could increase and overshadow your primary objective.
Unforeseen study delays can lead to delayed submissions and put the development behind schedule. While difficult to predict, having a general plan for if an unforeseen delay occurs will help foster smoother navigation and get your study back on track as soon as possible.
Strategies and Decisions for Protocol Optimization
Are timelines critical? If so, it is possible to overlap MAD and SAD cohorts, leading with SAD and then MAD. However, doing so requires additional caution, PK analysis after each cohort, and careful design.
Is your priority selling the compound right after SAD/MAD completion?
If so, consider adding Food Effect (FE) to your SAD/MAD protocol to garner useful information about your compound. If your investigational product causes GI issues, it would be good to know if dosing in a fed state would help alleviate some Adverse Events as you navigate your subsequent studies. Moreover, some scenarios benefit from incorporating an epTQT into the protocol to study the potential effect on cardiac repolarization, a critical component of early phase drug safety testing. In preclinical studies, if there are no hERG signaling abnormalities, epTQT is recommended, as it shows an increased chance for cardiac safety. This cardiac data can be helpful as you progress your compound through other studies. You can collect, store, and analyze later if needed. Some companies have successfully gotten a “waiver,” so they don’t have to run a thorough TQT study in later development.
When Is It Worthwhile to Add Patient or Population-Specific Cohorts for Early Efficacy?
Phase 1 protocols are complicated, and adding more complications may not be necessary unless targeting a specific indication. In such cases, the data could add value to the buyer and expedite the process. Including early efficacy, cohorts can complicate protocol design and study execution while significantly extending SAD/MAD timelines in your trial. You need to evaluate the balance of adding in a patient cohort and potentially extending timelines.
Lessons Learned from Previous Experiences
Sponsor A set up a SAD in a hybrid “normal healthy/ patient population” and then moved to pure patients for MAD. While the design was scientifically clean, the sponsor experienced unexpected SAD participant recruitment difficulties, delaying MAD progress. This sponsor’s experiences highlight the importance of partnering with a CRO experienced in recruitment strategies with patient populations and normal healthy volunteers with a track record of success.
Sponsor B successfully ran SAD and MAD in a normal healthy volunteer (HV) population and included the final two cohorts of MAD in patients with a specific rare disease within their protocol. This highlights the potential use case for using patient cohorts for early efficacy and makes your asset more attractive to buyers.
Sponsor C successfully ran SAD and MAD in a normal HV population and opted to run the last two MAD cohorts in a disease population, which then directly transitioned into an open-label extension (OLE) for the trial. This innovative protocol design emphasizes the use case of using OLE in a SAD/MAD. This unique strategy helped recruit a patient population.
Sponsor D ran their SAD and MAD in the full HV population without including any patient populations. However, their protocol had six primary objectives and three secondary objectives. This complexity created ambiguity as to the real aim of the study. All these objectives included many procedures that created a high subject burden resulting in subjects losing interest in this study due to the level of commitment needed.
Looking Ahead to Your Next Study
Protocol Design
When planning your next SAD/MAD study, it is important to consider some key factors that will collectively reduce friction and increase your trial’s capacity. For example, consider protocol timelines and how they are impacted by adding patient or specialized populations (obese, elderly, or post-menopausal women) to the SAD/MAD. You may also want to consider separating your SAD and MAD into two separate protocols. This allows you to database lock and unblind your SAD while your MAD is still ongoing. This may give insight and change how you want to run your MAD trial.
To ensure better odds of success, plan your design to be aligned with clinical design basics, including only two primary objectives, a maximum of two secondary, and an exploratory objective, if needed.
Selecting a CRO and Implementing the Protocol
- In general, when choosing the best CRO fit for your study, we recommend the following:
- Keep the SAD or MAD in a single protocol; if this is not possible, we highly recommend awarding both SAD and MAD to the same CRO.
- Select an experienced CRO with a successful track record of HV, patient, and specialized population recruitment.
- A CRO with an on-site manufacturing pharmacy for all your Phase 1 needs.
- Doing so avoids the need for 3rd party CGMP facility, associated costs, and increased time for production.
- The clinical Research Unit can make quick changes in dosage on-site during your study.
- If using a Clinical Research Unit with an on-site manufacturing suite, less stability time is needed. IP can be made and given to subjects within hours.
Optimizing SAD and MAD studies is about strategically enhancing every aspect of the trial from planning through execution to ensure safety, efficiency, and regulatory compliance. By understanding and implementing optimization strategies, you can significantly improve the outcomes of early phase clinical trials, paving the way for safer and more effective therapeutic solutions.
At Worldwide Clinical Trials, we have experts in Early-Phase drug development and SAD/MAD trials. We have our very own Clinical Research Unit in San Antonio, TX. We perform full doses, and our on-time metric is 95%. We owe this to our dedication to a team mentality, which drives us to work closely with sponsors and subjects as true partners, not revenue. Contact us to discuss your specific SAD/MAD trial needs today!
