Phase 1 clinical studies are the initial step in drug development, designed to assess the safety and tolerability of a new molecule in humans. Traditionally investigational medicinal products (IMP) were tested in multiple Phase 1 clinical trials that enrolled large numbers of healthy participants before a first patient was randomized. To accelerate development of novel therapeutics, there is a need to streamline drug development processes by integrating early clinical studies in healthy subjects as well as patients. Integrated study protocols may offer a more efficient way of exploring safety and a preliminary clinical effect of an IMP at an early stage of clinical development. The aim of obtaining information about pharmacodynamics (PD) in healthy subjects and/or patients is to consolidate decisions about the next developmental steps. According to the Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products of the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) early clinical trials with integrated protocols should allow that the information generated in previous parts needs to be analyzed and integrated into an assessment in a limited timeframe prior to proceed to the next part of the clinical study. All parts, and the criteria to move from one part to the next one, should be clearly explained within the clinical study protocol. These criteria should integrate data from previous study parts.
Accordingly, healthy subjects and patients may be enrolled in different parts of an early clinical study if different study parts are integrated into a single study protocol. Yet, unforeseen study events that may lead to changes in trial design still require substantial modification of the protocol and approval of these modifications by the responsible authority. Importantly, the total number of patients included in a multi part FTIH study is limited, and the primary endpoint (safety/tolerability) should not change between study parts.
An interesting alternative to the multi-part single protocol approach is to plan and conduct an early Proof of Concept (PoC) patient study semi parallel to an ongoing first-in-human (FIH) study. Essential documents of the PoC patient study can be finalized and submitted as soon clinical safety data of an ongoing phase 1 trial emerge.
The two-protocol strategy also offers larger flexibility regarding number of patients to be included, entry criteria and endpoints when compared to a multi-part phase 1 study and is particularly attractive if a single dose administration suffices for an early readout in a patient study (e.g., acute disease indications). In that case the single dose phase 2a patient study can be activated while the MAD part in the phase 1 trial is ongoing. The approach can accelerate your development timelines, reduce costs, and may provide a solid basis to take the right decision for further developmental steps.
How to plan, initiate and execute the integrated approach
Begin with a small cohort of healthy volunteers to establish the safety profile of the investigational drug. The maximum recommended starting dose (MRSD) should be established based on the minimally anticipated biological effect level (MABEL) in human tissue assessed in the preclinical testing. Employ a classic dose-escalation design to determine potential safety signals along with pharmacokinetic parameters in a healthy population. If many dose groups are anticipated the number of subjects per group may be reduced in the lower dose ranges. Study protocols should specify adequate time intervals between individual IP administrations (sentinel and subsequent subjects) within a dose group to react to upcoming safety findings. In addition, data needs to be acquired and evaluated timely before a dose can be escalated or adapted. This includes pharmacokinetic (PK) data but ideally also pharmacodynamic (PD) effects if feasible. Dose escalation should be proceeded until the pharmacological active dose (PAD) and/or anticipated therapeutic dose (ATD) in your target disease population. Once a pharmacologically active dose range is reached the number of healthy participants may be expanded to further explore PD. If possible, biomarker or surrogate parameters should be analyzed to identify potential indicators of drug response in healthy subjects.
Integrate monitored safety data of the phase 1 SAD study in study documents (CIP, IB) to be submitted in the relevant countries for the PoC phase 2a study. The PoC study documents may also be submitted to regulatory authorities in different countries (EMA and non-EMA) within Europe to decrease risk and further accelerate development. Doses to be tested in patients may also exceed the highest dose that was deemed to be safe in healthy volunteers in certain cases (e.g. target mediated drug disposition, etc.).
It is important to note that coordinating activities involving this integrated research requires meticulous planning and collaboration among various stakeholders that include investigational sites (Phase 1 units as well as hospitals / clinics), regulatory agencies and ethical committees as well as third party vendors.
Conclusion:
Integrating Phase 1 clinical studies in healthy volunteers and patients with cardiovascular disease represents an intriguing option for acceleration of early drug development. This innovative approach enhances the efficiency, cost-effectiveness, and overall robustness of early-phase trials. By bridging the gap between a healthy and a patient population with the semi parallel approach, researchers can accelerate the translation of promising compounds into effective treatments for cardiovascular diseases. As therapeutics and disease entities are highly diverse, the individual assets need to go on an individual path. By partnering with Scirent you will be provided with a tailored approach according to not only the state-of-the-art science expertise but also a vast experience in the cardiovascular therapeutic area. We will help you to connect with the most relevant clinical experts, key opinion leaders, statisticians, and capable investigational sites from our network.
