Early phase clinical trials are becoming increasingly complex, potentially leading to a higher risk of failure. But careful planning and attention to some key areas in the early phase can mitigate the challenges.
Improving experimental drug success rate and accelerating clinical development are top priorities for pharmaceutical and biotech companies, and careful decision making is essential to minimize development time, manage costs and improve the probability of commercial success. There are a number of areas where clear focus and attention to detail can optimize the clinical development process.
The principal aim of early phase clinical trials, known as human pharmacology studies, is to collect information on the safety and tolerability of the drug product.
When planning a first-in-human (FIH) trial, a carefully tailored design is essential for safety and further decision making. This is also the first opportunity to assess the pharmacokinetics (PK), and potentially the pharmacodynamics (PD), of a compound in humans. Most FIH trials are randomized, double-blind and placebo controlled, but many other decisions about major practical aspects of the protocol are based only on pre-clinical data. These decisions may include whether the compound should be tested in healthy volunteers or patients; how many dose groups and subjects are needed and whether these should be run sequentially, or in cross-over; what the safe starting dose should be and how it should be escalated; how long the follow-up should be; and whether there is added value in using an integrated protocol testing a food effect, drug interaction or special populations.
Modeling and Simulation
Modeling and simulation can help drug developers to better plan and design their clinical trials by exploring and quantifying potential risks prior to the start of a study. Modeling and simulation allows for the study of a drug’s effects in a ‘virtual patient population’, using mathematical models that incorporate information on physiological systems. Simulations can be used to test assumptions, improve predictability, better characterize risk and identify opportunities to optimize outcomes by observing the effects of different model inputs, thus helping drug developers to improve the planning and design of clinical trials. Physiologically-based pharmacokinetic (PBPK) modeling and simulation integrates prior knowledge and data generated through the prior research and development stages.
The US FDA, European Medicines Agency (EMA), Japanese Pharmaceuticals and Medical Devices Agency, and other global regulatory agencies encourage the use of modeling and simulation. They consider it an important drug development tool, which enhances product and process understanding, with the ultimate goal of ensuring consistent performance once the drug is placed on the market.
Working with Regulators
Working closely with regulators is a key element for successful drug development. Building regulatory advice into a trial program is an effective strategy to mitigate the regulatory risk inherent in product development and improve the likelihood of early product approval.
Regulators in Europe and the United States have created tools to help developers to ensure research and development programs can meet regulatory needs. Requesting scientific advice from the correct regulatory body at the appropriate time has become an essential tool to guide product development and to obtain answers on many aspects of a development program. Requests for advice – and responses – can be multidisciplinary and focus on a broad range of questions, such as product quality, acceptance of novel study designs, pharmacokinetic and pharmacodynamics modeling, biomarkers, and hard versus surrogate endpoints.
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The clear message from regulators in both Europe and the United States is that it is never too early to seek scientific advice. Whether the questions deal with broad issues of study design (for example population, dose selection, statistical aspects) and appropriate indication and study population, or issues of chemistry manufacturing controls (CMC) for a new product class, earlier agency consultation is better.
Human Challenge Models
Human challenge models are designed to generate symptoms and mimic a disease state in an otherwise controlled environment. Testing an investigational compound in such a setting generates the first evidence of efficacy, and in general, similar planning rules apply to all: safety, in-house expertise and necessary equipment are crucial. Viral challenge studies present additional challenges because of the risk of potential contagion and these more challenging and complex phase 1 trials require a facility that is adequately equipped and a team with the required expertise, experience and accountability.
If a challenge study is being considered, the research question must be clearly justified, the proposed methods must be appropriate and provide a meaningful, valid answer and must be as safe as possible with appropriate management of possible risks in place. The selection of study participants must be justified and also safe, with rigorous consent procedures established to ensure full understanding. The clinical site (challenge unit) needs to be adequately equipped and the team experienced.
Protocol and Design
The protocol is a detailed outline of a clinical study that describes the objective(s), design, methodology, statistical considerations and organization of a trial. It should be designed in such a way that it simultaneously ensures the safety of the participants and solid scientific answers. Flaws in the protocol will lead to deviations, violations, amendments and even to missing, invalid or uninterpretable data.
Although a “perfect” protocol may have been created on paper, many study aspects need to be evaluated from a practical point of view. These include: the feasibility of recruiting the exact study population; Investigational Medicinal Product (IMP) preparation steps; the use of sentinel dosing groups; sample-handling processes; decision making process and the frequency and types of assessments. Despite timeline pressures, clear communication on content and operational feasibility is essential if potential issues are to be avoided, and all worst-case scenarios need to be considered.
There is a tendency for early phase clinical trial protocols to become increasingly complex. The focus on gaining as much scientific insight as possible can lead to multiple objectives being embedded into one single design. In these “umbrella” studies some decisions can be made only after analysis of the collected data. To avoid the need for protocol amendments after every decision, adaptive features, such as exact dose levels, the number of cohorts, the regimen for multiple dosing, and assessments to be added or omitted, can be described in a flexible way. As long as the changes follow what is written in the protocol, substantial amendments are not warranted. To meet regulatory requirements, adaptations must be described in detail, clear boundaries must be set and the decision-making process, including rules for stopping, must be clear.
Once the clinical trial protocol has been finalized it must be followed rigorously by the clinical trial team, not only for regulatory reasons, but also to avoid harm to participants and prevent erroneous results and conclusions.
Enrollment and Recruitment
Subject enrollment is a key driver of clinical trial success but remains one of its biggest challenges. Recruitment and retention issues result in trial delays and increased costs and could potentially undermine trial results.
Each clinical trial phase presents specific hurdles in terms of recruitment. Most early phase trials do not offer therapeutic benefit for the subjects and are typically performed in healthy volunteers, for whom the incentive to participate remains mainly a financial one. Conversely, from phase 2 onwards, patient populations are needed. Confronted with disease, study participants tend to be willing to help innovation, but may be deterred by the fear of side effects and of receiving placebo, thereby losing time to get treated.
Early phase studies typically require frequent visits to medical facilities and a number of clinical assessments, so the overall burden and time spent also becomes a decisive factor. In addition, eligibility criteria are more restrictive in early phase, making the search for participants that match the requirements difficult. Identifying factors that affect recruitment, both positively and negatively, simplifying the protocol if possible, to reduce the burden on patients and physicians, and identifying overly restrictive eligibility criteria can all aid recruitment and retention of participants. From a practical point of view, having a realistic recruitment period, using various recruitment tools/activities as well as motivated principal investigators and an experienced site with demonstrated subject access are the critical measures to evaluate to assure recruitment in a timely manner.
Managing a Clinical Trial Facility
The principles of Good Clinical Practice (GCP) ensure the protection of trial participants and the integrity of the data recorded, and all clinical trials must be designed, conducted and reported in accordance with GCP guidelines to be acceptable upon submission for marketing approval.
Any site involved in a clinical trial, including the investigator sites, laboratories, the sponsor’s premises, and any contract research organization, may be subject to GCP inspection by regulatory authorities with or without notice. These may be conducted on a routine basis or occur in response to a specific trigger, and can be related to ongoing or completed studies.
During an inspection, an inspector must be able to wholly reconstruct the clinical trial to confirm that all steps have been performed in accordance with the guidelines, that patients’ rights and safety were protected at all times, and that all data is reliable.
A solid Quality Management system, consisting of robust standard operating procedures that cover the required measures to maintain high quality standards, should be developed, together with a proactive Quality Control process, which not only checks activities but also aims for continuous improvement. Internal mock audits and inspections are good tools to evaluate whether the quality system is working as intended, and if the team is indeed inspection ready. These types of self-compliance checks provide valuable opportunities for the identification of deficiencies in documentation or processes and lead to a culture of “inspection readiness”.
Handling Data
High-quality data are needed in all clinical studies, including exploratory FIH, and should meet the protocol-specified parameters and comply with the protocol requirements. By their nature, FIH and most phase 1 trials are exploratory, without a statistical hypothesis. But despite this, the data need to be relevant, accurate and appropriately analyzed to obtain meaningful results that are useful for future clinical development. There are four main steps in clinical data processing: planning, collection, management and analysis.
When developing the study design/protocol, planning of data at an early stage should consider which measurements to foresee, exactly when, for how long and how frequently. Often, planning is not very targeted in phase 1/FIH protocols because the only supporting information available at this stage is preclinical data and there is no precise statistical endpoint.
Once the study starts, data are collected on an ongoing basis. Any inappropriate methodology and non-adherence to the protocol may adversely affect data reliability and introduce bias. A consequence of the relatively high-risk nature of FIH studies and the absence of therapeutic benefit is an ethical obligation to limit the number of exposed subjects, stressing even more the need for good quality data capture and handling.
Clinical data management is the process of collecting, cleaning, coding and managing subject data in compliance with regulatory standards. The primary objective is to provide good quality data and gather the maximum data for analysis. To meet this objective, best practices (software, standard automatic process, electronic case report forms, electronic data review) should be adopted.
If, at the end of the trial, appropriate methods of analysis are used with the appropriate data, it will be possible to interpret results and come to a conclusion. In the case of FIH studies, the conclusion should enable a decision as to whether to continue or not to the next phase of development and to give initial indications on how to design the next study. Scientifically-sound bridges should therefore be established linking human pharmacology studies to initial exploratory studies and later confirmatory studies.
Planning to Succeed
The ultimate objective of any drug development program is to bring to market a drug product that is safe, and shows positive benefit-risk balance for treatment of the target patient population. The more attention is paid to key areas in the design, planning and execution of the early phase clinical trials, the greater the chances of successfully bringing the product to market.