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IMPs for immunotherapeutics require a different mindset, effective strategies, and meticulous planning, among other things, says KCR Trial Execution and Consulting.
Over the years KCR Trial Execution and Consulting, has assisted in conducting and executing clinical trials in immuno-oncology around the globe for biopharmaceutical and biotechnology clients. Valuable and useful perspective and insights have been gained through these interactions with regulatory authorities in the European and U.S. market which are corroborated by reviewing current and relevant guidance and literatures and we would like to share these experiences with our drug development and clinical researcher, as well as industry peers.
1. Study formulation and concept
2. Modeling for Simulation
Design features and associated parameters can be simulated to optimize the study design configurations by using a variety of parameters and combinations to estimate a design for its operation characteristics. The Input parameters could include the accrual rate, event rate, time to event and effect size. Thereby to provide the clinical investigators with some fundamental understanding with respect to the potential trial results. The computational approach is usually carried out with Monte Carlo simulations leading to possible optimization of the study design in dose finding for early stages of clinical studies. Furthermore, modeling and simulations could also facilitate enrollment planning in feasibility study. 25
3. Master protocol for adaptive trial design
Current business models of cytotoxic drug development have been outdated for IMP development in immunotherapy. Traditionally the drug is following a trajectory path of sequential testing scheme, from Phase I to II, and efficacy and toxicity, later if data are supportive to Phase III trials. However, the biologicals in immunotherapy are highly complex and less predictable in PK/PD as the cytotoxic agents. This requires the trial planning and protocol designs being more flexible and agitative which could respond to and integrate new data and new information from interim analysis, and therefore, help to meet the challenges in biological complexity, restraints in study time, and requirements in cost containments.5,10
Immuno-oncology trials are an appropriate setting to adopt an adaptive design with a master protocol for multiple arms because of the complexities and uncertainties associated with I/o therapeutic agents. The mater protocols are of three types depending on the clinical trials, i.e. platform, basket, and umbrella. The platform master protocol is for trials of multiple immunotherapeutic biologicals of a single disease entity. The basket mater protocol is employed in a trial for multiple diseases. The umbrella trial, while on the other hand is also a protocol for multiple therapies in a single disease, is used usually for biomarker-driven trials and enrolled patients of certain biological characteristic in a specific trial with further randomization.26-28
Of note, master protocol is appropriate for clinical studies with adaptive designs and biomarker-defined subgroups. Thereby it should be applicable in I/o agent development. Other potential and major advantages of the adaptive study designs are possibility of integrating new information continuously such as that derived from real-world data, for dose selection and sample size re-estimates, and thereby would be more appropriate in IMP development with an iterative development process, particularly in immunotherapy. The master protocols are also support the trial designs of combining the early phase trials such as Phase I/II trials for early efficacy determination through controlling for Type 1 error. Both EMA and FDA recognize that the adaptive design has the potential to shorten the development time and to allocate limited resources more efficiently and meeting the requirements in scientific and regulatory guidelines.25, 29-31
Other elements of master protocol should be taken into consideration include common control, success or failure criteria, study configurations, sample size, timeline, success and failure criteria, combination, endpoints, statistical analysis plan, etc. (Fig. 1)
4. Planning, qualification process and regulatory interactions
Medicine is a regulated business. To increase the odds of successful clinical development, it is imperative to keep the end in mind which requires well-planned process development and open and transparent communications with the regulatory agencies. Both the EMA and FDA have established early interaction programs for the biopharmaceutical industries. The EMA qualification process addresses innovative drug development methods and tools including pre-submission consultation and advice; review by the Scientific Advice Working Party on novel methodologies of biomarkers, preclinical models, clinical outcome, modelling and statistics, etc. Similarly, the FDA has also instituted the same qualification process tools to facilitate clinical development which has three programs i.e. animal model, biomarker, and clinical outcome assessment. 32-34
Although the qualifying is not mandatory, it is advisable that sponsors interact with the regulatory agencies early if there are issues in study designs that require regulatory opinions and feedbacks and/or in case of further clarifications on agency guidance documents are warranted.
Biosafety is a major concern in planning and conducting gene therapy and vaccine clinical studies which may involve viral vectors especially if they are replication competent. The environmental and health impact should be carefully evaluated following biosafety guidelines in handling the sampling, storage, disposal, administration of the recombinant nuclear acid materials and developing appropriate protocol in management of the patients in such a clinical trial.
Institutional Biosafety Committee (IBC) review and approval are required as per recent released guideline by the National Institutions of Health (NIH) in the U.S. The institutions and respective IBCs subject to the NIH Guidelines are expected to establish policies and procedures to ensure that the research is conducted in full conformity with the provisions of the NIH Guidelines. But any required documentation for approval is at the discretion of the institution and IBC. Sponsor should contact for IBC review and approval or a central IBC before or at the same time the clinical trial protocol is submitted to Intuitional Review Board (IRB).35-36
In the EU, the Advanced Technology Medicinal Products (ATMPs) are under the purview of the EMA and follow ATMP legislations and relevant regulations. Under the current GMO regulations, ATMPs are required to be evaluated of environmental and health risk either in the framework of deliberate release (Directive 2001/18/EC) or contained use (Directive 2009/41/EC) before or in parallel with the clinical trial application. The contained use is defined by the risk class of the GMOs and protective barriers by design to limit the unexpected exposure of the potentially infective agents and harmful effects. The deliberate release is, in contrast, in consideration of no or less restrictive measures to protect or limit the public from exposure in the general environment.37-40
IMPs in immunotherapy are different biochemical entities and highly complex in mechanistic dynamics leading to less predictable behaviors in PK/PD, affecting their efficacy and toxicity profiles in vivo. Accordingly, the clinical developments of IMPs for immunotherapeutics require a different mindset, fresh perspective, effective strategies, meticulous planning, innovative designs, and precise execution in order to accelerate the process of the biological drug development in a timely and manageable manner to bring state-of-the-art science to patient care.
Dave Li, MD, PhD, is a Principal Consultant; and Anna Baran, MD is the Chief Medical Officer both of KCR Trial Execution Consulting