Modern study protocols for phase I or phase I/IIa clinical trials (‘early phase clinical trials’) often include several classic phase I clinical trials in the form of integrated, consecutive sub-studies. Typical examples include consecutive sub-studies with single ascending dosing (SAD), multiple ascending dosing (MAD) and interaction studies with food and other drugs, which are sometimes followed by a pharmacodynamics (PD) study in patients. However, these complex study protocols can only offer an advantage in time if the individual sub-studies do not require the submission of a substantial modification subject to authorisation before they can be carried out.

To this end, BfArM and PEI recommend the implementation of a ‘guard rail concept’, which describes the safety corridor within which the trial participants or patients would remain during the conduct of these integrated studies. As long as this ‘corridor’ in mono-national clinical trials is adequately described in the approved trial protocol and is not left during the course of the integrated trial, the single parts of the trial can generally be carried out consecutively without prior Substantial Modification, provided the following basic principles are followed:

1. The study objectives are clearly specified in the protocol and are comprehensible in their overall form to the investigator.

2. In the event that the transition from one study part to the next is to take place without a Substantial Modification, this must be clearly indicated in the protocol and clear definitions are required for the criteria in the protocol as to when a Substantial Modification will be submitted by the sponsor:

   • a) Clear cut-off values for still acceptable laboratory values must be defined, which adequately take into account the fact that healthy subjects are usually involved. The criteria for the determination of Recommended Phase 2 Dose (RP2D) must be clearly described.
   • b) Additional dose levels may be added without requiring a Substantial Modification as long as the maximum dose and the maximum exposure described in the protocol that is considered tolerable is not exceeded. When transitioning from the SAD to the MAD part or from the i.v. to the s.c. part, the initial exposure should be in the range of what is considered safe based on previous clinical data.
   • c) Thresholds should be defined for the frequency of adverse events of all degrees of severity that are considered acceptable without Substantial Modification (‘guard rail concept’).
   • d) Furthermore, depending on the nonclinical results and the postulated mechanism of action, pharmacologically justified limits for adverse events in particular should be defined that take these pharmacological aspects into account appropriately. For example, a grouping according to system organ class can be considered.
   • e) Even in the case of mild or moderate adverse events, if there is an unexpected increase in frequency, e.g. in an organ system, adequate information should be provided in the trial protocol and informed consent form (ICF) if this could have a relevant influence on the participant's decision to take part in the trial.
     In this case, a modified informed consent form and the trial protocol with a revised
     section on the benefit/risk ratio have to be submitted for approval.

   • f) If prospectively defined safety measures are to be established in the event of certain events, clear escalation criteria must also be defined in the trial protocol. For example, in the event of the occurrence of certain cardiological events, a cardiological consultation can be made mandatory before re-exposure of affected participants and before the transition to a subsequent part of the study.

   • Appropriate stopping criteria (and criteria for Dose Limiting Toxicities (DLT)) must be derived from the aspects mentioned in points a and c-f and specified in the trial protocol.
   • As a general rule, no Data Safety Monitoring Boards (DSMB) need to be established in Phase I/I-IIa studies (see GUIDELINE ON DATA MONITORING COMMITTEES, EMEA/CHMP/EWP/5872/03 Corr, 2006). In certain cases, however, they can be supportive and can be set up. The involvement of such a DSMB or an internal safety review committee or a comparable body in the ongoing assessment of the safety of participants can be seen as an additional aspect of the continuous monitoring of participants and should then also be described in the protocol. In this context, it can also be stipulated, for example, that a transition to the next study phase will only take place if this committee votes in favour. (This vote does not have to be submitted as a Substantial Modification).
3. A Substantial Modification is always required if the benefit-risk assessment changes significantly in the course of the trial. The same applies to relevant changes in the sample size (more than +/- 10%) or the inclusion, exclusion or discontinuation criteria. This must be adequately assessed and decided by the sponsor based on the data of the respective completed cohorts and study arms. This procedure must already be described in the trial protocol. Criteria that are used, for example, for dose escalation decisions in the SAD or MAD study part without Substantial Modification can be used as guidance for the applicant.

4. The switch from healthy subjects to patients in an ‘integrated’ early phase protocol can be useful if no appropriate PD response can be expected in healthy subjects for the establishment of an adequate PK/PD correlation for the subsequent development steps. This step from healthy subjects to patients is possible without Substantial Modification, as long as this is previously described in the protocol and the following criteria are met:

   • a) The patients' state of health is stable, usually only slightly or moderately impaired, which allows this population to participate with an acceptable risk.
   • b) The sub-studies in healthy subjects are fully analysed, with scientifically appropriate follow-up (duration of PK and PD dependent).
   • c) Clear criteria for the switch from healthy subjects to patients must be defined in the trial protocol, based on the general approach outlined above.
   • d) If target-specific toxicities are possible that cannot be observed in healthy subjects (e.g. because the target is not present in healthy subjects), this must be adequately taken into account. This may include, for example, higher requirements for safety monitoring, a dose reduction of the starting dose and/or a slower dose escalation in patients.
   • e) The trial participation and the intervention within the trial must not result in any clinically relevant foreseeable disadvantages for the intended patient population. This must be adequately outlined in the protocol.
   • f) Applicants/sponsors are required to take into account the relevant guidelines and recommendations of the European authorities (e.g. EMEA/CHMP/SWP/28367/07 Rev. 1 ‘Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products’ and ‘CTCG Q&A on submission Complex Clinical Trials in CTIS’, in the current version). In particular, the sentinel approach may be of particular importance and should be described for the various study phases. In addition, complex, multi-centre trials should have a communication strategy that describes the early detection and forwarding of safety signals to all trial stakeholders.