DRUG REPURPOSING AND REPO4EU
In recent years, there has been a recognized need to improve the efficiency and effectiveness of drug development. A strategy with great potential in achieving this is drug repurposing. Drug repurposing is the process of identifying a new use for an existing medicine or active substance outside the scope of the original indication(s). It has the potential to make drug development more efficient, using the knowledge that has already accumulated on a drug such as safety and pharmacokinetics. This allows repurposing to occur in a more efficient manner beginning with Phase II clinical trials, since preclinical and clinical safety have already been established. The primary objectives of Phase II trials include efficacy assessments and confirmation of the safety and tolerability.
REPO4EU, The Euro-Global Platform for Mechanism-based Drug Repurposing, has the vision of creating an EU industry-level online platform for validated precision drug repurposing with a global reach. Given the importance of Phase II clinical trials in drug repurposing, one aim of the REPO4EU project is to develop comprehensive resources for investigators to conduct high-quality Phase II clinical trials, particularly with repurposed drugs and innovative clinical trial designs. In line with REPO4EU’s high precision and mechanism-based approach, innovative trial design options are described to increase the efficiency and cost-effectiveness of drug development by requiring a lower number of patients and reducing trial costs.
These resources, which are currently under development through collaboration of many different partners, will eventually be presented in the form of an online platform.
REGULATORY CONTEXT
The conduct of clinical trials, including repurposing trials, is governed by a comprehensive regulatory framework to ensure patient safety, ethical conduct, and reliable data generation. Understanding the key laws, regulations, and guidelines is essential for investigators.
The ICH E6 GCP guideline is a vital document that provides internationally recognized ethical and scientific quality standards for the design, conduct, monitoring, and reporting of clinical trials. It establishes the essential principles that have their origin in the Declaration of Helsinki to ensure the rights, safety, and well-being of trial participants as well as the reliability of trial data. The guideline emphasizes the importance of ethical considerations, informed consent, and the need for appropriate trial documentation. It outlines the responsibilities of investigators, sponsors, and ethics committees, emphasizing the importance of qualified personnel and effective communication. Familiarity with the guideline enables investigators to maintain high-quality standards throughout the trial process, ultimately contributing to the generation of robust evidence to support the repurposing of drugs for new indications.
SPECIFIC CONSIDERATIONS IN DRUG REPURPOSING TRIALS
When conducting a drug repurposing trial, there are considerations that an investigator may need to take into account during the design and preparation of the trial.
A Strong Scientific Rationale
This is crucial for drug repurposing trials. The trial program should be based on robust preclinical and clinical evidence supporting the potential effectiveness of the repurposed drug for the new indication. It is important to have a strong focus on the mechanisms of action, pharmacokinetics and pharmacodynamics (especially when another formulation or route of administration is being tested), and safety profile of the drug or the combination of drugs in the context of the new therapeutic indication.
Combinations of Drugs
REPO4EU prefers combining therapies as it becomes more and more clear that hardly any disease can be explained or cured via one single target. Testing combinations of drugs potentially improves the overall efficacy and/or more rapidly achieves effectiveness than monotherapy. In symptom-based combination therapy, different drugs are combined targeting symptom phenotypes, independently of the causal disease mechanism. In curative mechanism-based network pharmacology approaches, low-dose drug combinations target the causal disease mechanism and reach a synergistic effect. 1 The safety profile could be improved due to counteracting of adverse reactions between the active substances, and/or a subtherapeutic dose could be used in combination compared with monotherapy.
The Safety Profile
The safety profile of the repurposed drug(s) is an essential consideration. Although the drug may have an established safety profile for its original indication, the safety profile in the new indication needs to be thoroughly evaluated, especially when drugs are combined. Therefore, drug–drug interactions need to be considered. The benefit–risk evaluation in the new indication may put a different light on the safety data that is already available for the existing indication. Close monitoring of adverse events and potential drug interactions is necessary.
Dose
A new indication could require dose adjustments. Pharmacokinetics and pharmacodynamics of the drug in the new patient population and potentially in combination with other drugs need to be evaluated carefully to determine the appropriate dose regimen. As a result of a network pharmacology approach, low or even lower than marketed dosages may be used in trials with repurposed drugs. This might reduce the number of side effects associated with the used drugs.
Inclusion and Exclusion Criteria
Inclusion and exclusion criteria should be carefully defined to ensure patient safety and trial validity. Phase IIa studies are typically pilot studies designed to demonstrate clinical efficacy or biological activity (proof-of-concept studies). Phase IIb studies determine the optimal dose at which the drug shows biological activity with minimal side effects (“definite dose finding studies”). Definition of success criteria should be based on the specific characteristics of the new indication and the mechanism of action of the drug(s). The implementation of precision clinical trials requires careful consideration of various factors, such as patient selection criteria, biomarker validation, and statistical analysis methods to assess treatment response in different subgroups. By identifying subgroups of patients who are more likely to benefit from a treatment, patient outcomes can be improved, adverse effects can be minimized, and overall treatment efficacy can be improved.
Endpoints
The choice of endpoints should align with the new indication and the expected clinical benefits of the repurposed drug(s) and will likely differ from those used for the original indication. Endpoints in Phase IIa may differ from Phase IIb. In Phase IIa, early inclusion of quality-adjusted life-year measures and front-loading endpoints to detect multiple signals to demonstrate activity is recommended. The endpoints should be patient-centered and demonstrate efficacy in the context of the new indication. Including a sufficiently large dose range to establish the right dose and/or dose range can be beneficial.
Intellectual Property Rights
Intellectual property rights for the repurposed use of the drug(s) should be considered. If the new indication is not covered by existing patents, additional intellectual property possibilities may need to be explored. It should be noted that there can be country-by-country differences in this as well.
Collaborations
Collaborations with other research groups, pharmaceutical companies, or academic institutions can facilitate sharing of resources, expertise, and data. Collaboration can be particularly valuable and, in some cases, unavoidable in Phase II drug repurposing trials, particularly in the case of combination therapies, in which multiple parties may have an interest in the new indication.
MAKING EXPERTISE WIDELY AVAILABLE
As a part of the REPO4EU project, comprehensive resources are under development for investigators to conduct high-quality Phase II clinical trials. Shown in Figure 1 is an overview of the resources that will be made available in the form of an online platform, containing tools, services, case studies, and information.
Online platform structure for Phase II clinical trial resources. HFpEF, Heart failure with preserved ejection fraction; PK, Pharmacokinetics; PD, Pharmacodynamics; PoC, Proof of Concept; WP3, Work Package 3.
A wide range of resources will be made available, and several of these are highlighted.
Trial Design Tool
Innovative clinical trial designs have the potential to make trials more efficient. In order to help investigators in selecting an innovative design that will work best for their study, a trial design tool in the form of a decision tree is under development to guide investigators to recommended designs and connect them to more in-depth information about trial designs of interest.
Phase II Trial Center Registry
In order to connect investigators with Phase II trial centers, a matchmaking service was created. Trial centers can self-register by filling out a questionnaire, which collects information on the centers and acts as a quality check. Then, the trial centers are listed on the platform, where investigators can easily sort, filter, and select from a list to determine potential centers that are a good fit for their study’s needs.
INNOVATIVE TRIAL DESIGNS
Innovative trial designs have the potential to reduce patient burden and improve operational efficiency. Because of this, innovative designs will be emphasized on the REPO4EU platform.
In the past, a clinical Phase II trial usually included two or more treatment arms, of which one arm is a control arm with placebo and/or standard of care and the other arms are one or more different dose regimens of the therapy of interest. In this way, limited safety and/or efficacy data can be collected for only one therapy and the success rate of clinical trials is low. In addition, the burden for patients participating in clinical trials is high, and the time, costs, and number of patients that are necessary to develop one good therapy are significant.
There are a number of different innovative clinical trial designs in existence:
Enrichment Designs and Precision Trials
The Food and Drug Administration defines enrichment as “the prospective use of any patient characteristic to select a study population in which detection of a drug effect (if one is in fact present) is more likely than it would be in an unselected population.” 2 The purpose of using an enrichment design is to select a subset of patients in which the potential effect of a new drug can be demonstrated more readily:
By decreasing the variability; the selection of patients is based on predefined criteria, like biomarkers or baseline measurements.
By using a prognostic enrichment strategy; the selection of patients from whom it is expected that they will have a certain disease-related disease progression.
By using a predictive enrichment strategy; the selection of patients who are more likely to respond to a treatment.
Precision clinical trials aim to determine whether a treatment is more effective in a particular patient subgroup, allowing for more targeted and personalized approaches to healthcare. These trials always apply an enrichment design. The use of biomarkers, baseline measurements, and historical patient information can all support the selection of patients either at screening or during the run-in period of a trial.
Adaptive Trial Design
These allow for modifications in the trial based on interim analysis or predefined criteria. Adaptive designs enable the adjustment of sample size, treatment arms, or statistical methods during the trial. This flexibility facilitates the efficient utilization of resources, increases the probability of success, and maximizes the chances of identifying effective treatments.
Master Protocols
A master protocol is a single, blanket design that is intended to evaluate multiple hypotheses and is mostly implemented in Phase II and III trials. Master protocols include basket trials, umbrella trials, and platform trials.
A basket trial evaluates the effectiveness of one or a combination of targeted therapy in multiple diseases sharing a common biomarker or clinical characteristics.
An umbrella trial is designed to evaluate multiple investigational drugs administered as individual drugs or as drug combinations in a single disease population.
Platform trials allow simultaneous evaluation of multiple treatments and/or treatment combinations with a shared control group. It can also be used to test multiple hypotheses in patient subpopulations with the same indication.
Pragmatic Trials
These specifically aim to evaluate treatments in a real-world setting by applying broad inclusion criteria and minimal interference with routine clinical practice. It has already been in existence for many decades, if not longer. Pragmatic trials focus on measuring relevant outcomes for patients and clinicians.
N-of-1 Trials
These focus on the treatment of an individual patient, also known as a single-patient trial. It could be assessing the response to different treatment sequences within an individual with a chronic and complex disease, or in the case of very rare diseases, the response to a treatment designed specifically for a genetic variation presented in the patient. It can provide personalized evidence for treatment decisions, particularly for patients with unique characteristics or when the treatment sequences are expected to have different effects.
PILOT TRIALS
Three pilot trials are currently in the preparation stages within the REPO4EU consortium, with the purpose of validating the platform content. These studies incorporate elements such as precision medicine, drug repurposing, and innovative design, and therefore they have the potential to demonstrate the ways in which these strategies can make clinical trials more efficient, and reduce burdens to patients and staff.
CONCLUSION
An online platform with extensive resources on Phase II clinical trials is under development, with emphasis on investigator-initiated, drug repurposing, and innovative design clinical trials. These resources go well beyond what is discussed in this article and aim to provide comprehensive guidance to investigators and others working within the clinical trial realm. Drug repurposing, in combination with innovative design, has the potential to make clinical trials smarter and more efficient.