By the clinical operations and medical affairs experts at drug development consultancy Boyds
Early phase clinical trials can be complicated and time-consuming, with their success dependent on several different factors. The outcome of these early phase clinical trials will determine the future of your drug development project, and so ensuring safety and efficiency at every step since the start is vital for its overall success.
The clinical operations and medical affairs experts at drug development consultancy Boyds share their ten top tips for how to start and promote the success of early phase clinical trials.
1. Engage with regulators early on to start your clinical trial successfully
Working closely with regulators and regulatory specialists is key to successful drug development. Early expert advice and guidance can shape appropriate clinical development plans and identify potential weaknesses in the clinical development program, enabling the study to be carried out effectively.
Specific forms of scientific advice may be available at different stages of clinical trial conduct. Early regulatory engagement with agencies and regulatory specialists is a good way to access various incentives that will facilitate additional interactions such as protocol advice and breakthrough designation with the FDA. To achieve this, pharma/biotechs may choose to reach out to the appropriate agency themselves. Each agency has systems in place for companies to engage with them in study planning discussions. Companies can also incorporate the expertise of a third-party to support them, which may be preferable if the sponsor does not have the experience of submitting to that agency themselves.
In order to deliver high-quality data, regulatory compliance is key. Ensure studies are compliant with local, national, and international regulations, including ethical and privacy requirements.
2. Consider trial design
Efficient and effective clinical trial starts are enabled by thorough planning from the outset, including determining the number of patients required, identifying potential sites, and a detailed review of study protocol.
Numerous types of clinical trials exist, depending on the design of the individual study. Trials can be adapted to overcome potential problems as sponsors can work to predict these issues and mitigate the risks through a flexible clinical protocol without having to pause the study and resubmit for regulatory and ethical approval. Input from key opinion leaders could also be invaluable for the quality of your trial design.
Adaptive clinical trial design builds in flexibility and can provide advantages both to patients, in terms of facilitating patient access, as well as quick generation of data to enable sponsors to make rapid decisions, such as whether to continue with, or halt, clinical development. This flexibility means that if certain criteria is met, the approach as documented in the protocol can be changed without having to re-submit the change to the regulators and wait for new approvals.
3. Think about dose escalation
Dose escalation is a core component of many First-in-Human (FIH), early phase clinical trials: correct identification of optimal safe and efficacious doses for later phase trials is often critical for the success of the clinical trial start and development program. Clever dose selection and escalation avoid undue costs and delays.
During the dose escalation phase, consider adding additional dosing levels to a protocol in order to provide additional flexibility to the trial, often as a type of flexible or adaptive clinical trial design.
4. Determine the starting dose of the clinical trial
Determining the starting and subsequent dose range is an important component when designing a FIH trial: generally, this is based on using the most sensitive preclinical results from pharmacology, toxicology, and PK studies as well as other therapies with a similar mechanism of action.
Regulatory agencies provide excellent guidelines for determining the appropriate starting dose, based on either a no observed adverse effect level (NOAEL) or a minimal active biological effect level (MABEL). Careful consideration of all suitable approaches is important for appropriate dose selection.
5. Utilise digital tech
Leveraging technology effectively, for example, by using electronic data capture, enables processes to be streamlined and improves data quality.
Multiple digitalized clinical trial platforms are available which facilitate the decentralized recruitment of clinical trials through initiatives including remote consent and tele-visits. Other similar digitalization innovation includes the use of electronic diaries (e-diaries) to facilitate symptomology and treatment recording.
These tools can be exceptionally useful to facilitate efficient engagement with patients, to improve patient relationships and thus foster subject loyalty and reduce dropout rates.
6. Engage with service providers early on to start your clinical trial successfully
Communication and strong relationships are the foundations of a successful study. Encouraging open communication between study sites, investigators, vendors, and sponsors to address issues and facilitate problem-solving ensures mitigation strategies are put in place prior to issues escalating.
It is important to engage early on with a variety of service providers to select the one that best meets the sponsor’s requirements. Consider prioritizing a service providers with relevant therapeutic and delivery modality experience, as well as one with the most appropriate facilities, expertise, and staff.
When considering third-party vendors, ask for an itemized cost proposal to be prepared to ensure that like-for-like costs are being compared between prospective parties. It is also vital that vendors are prioritizing the safety and wellbeing of subjects in addition to ensuring high-quality data collection.
7. Introduce strong data management
The primary objective of data management processes is to provide high-quality data by keeping the number of data entry errors and missing data points as low as possible and accumulating maximum data for analysis. Clinical data management ensures the collection, integration, and availability of data at the appropriate quality required. This is managed through a robust data management plan that details the required vendors and processes to be adhered to throughout the duration of the trial.
CROs can provide data management services as part of their package of running a clinical trial on behalf of drug companies. There are also standalone data management companies that specialise in just performing the data management component of a clinical trial. Drug companies themselves can also create an internal data management department within their organisation to perform this task. Whilst many people are involved, the process is managed by the study data manager. An experienced and flexible data management team with be able to get your data cleaned efficiently, preventing delays to getting your cleaned data analysed.
8. Prioritise quality oversight
Clinical trial oversight is a critical element that ensures the protection of research participants and the scientific integrity of the data collected. Maintaining high data quality standards is crucial to ensure patient safety, maintain regulatory and legislative compliance, and guarantee the integrity and validity of trial data. Establishing strict quality control measures enables data accuracy and consistency across study sites. This is achieved through the generation and implementation of robust Standard Operating Procedures and applicable manuals, which is managed by the quality assurance (QA) professionals involved, who may also contribute to ensuring the quality of particular trials through targeted audits.
In addition, clear issue and escalation pathways ensure any issues are addressed at the source and do not escalate into a larger risk and significantly impact the study.
9. Adhere to ethical principles
It is important to adhere to ethical principles in order to protect the dignity, rights, and welfare of research participants. As such, all research involving human beings should be reviewed by an ethics committee to ensure that the appropriate ethical standards are being upheld and that all participants provide their consent to be included in the study. Ethics committees are made up of a diverse mix of individuals from the community who apply to be a member. In the US, these committees are called Institutional Review Boards (IRBs). As part of keeping participants well-informed, a detailed Patient Information Sheet (approved by the national ethics committee) is provided to study participants which details the study informing the participants of what is required, enabling them to make informed decisions about participation.
10. Maintain safety oversight
Continuous monitoring of patient safety throughout a study is imperative. This is managed through a detailed Safety Management Plan which includes the management and processing of adverse events.
Sponsors may also be required to appoint individuals and groups to Data and Safety Monitoring Boards (DSMBs), otherwise known as a Data Monitoring Committee (DMC). DSMBs form an important part of study setup and monitoring. DSMB members are a group of individuals with expertise who review the accumulating data and advise the sponsor regarding the continuing safety of trial subjects.
Careful selection of DSMB members is critical – choosing a balance of individuals with the relevant expertise but balancing this with team member availability is key to avoiding delays to ongoing clinical trial conduct, such as general clinical trial pauses or recruitment holds.
Summary: how to start an early phase clinical trial
There are many areas to focus on when starting, planning, and executing an early phase clinical trial. A strong, overarching approach to take is to ensure you discuss, question, and involve as many stakeholders as you can, as early on as possible, so that you get their perspective and understand what is important to each stakeholder. Then take the time to properly consider this information at each stage of setting up the study and be prepared to compromise when necessary. In such a highly regulated industry, ensuring discussions, issues, mitigations and actions are well-documented could prove invaluable for your next project.