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Post Haste

Late-phase studies such as post-authorisation safety studies (PASS) are typically conducted to expand understanding of a drug within a larger patient population, to ensure safety and effectiveness, or to demonstrate improved cost/benefit compared to other available therapies. These studies may be significantly varied in their design and different from earlier phase trials due to the large numbers of physicians and patients involved. Alternatively, the studies may also be very small, and focused on better understanding disease progression and the real-life environment in which the drug will be utilised.

Regardless of the size, this late-phase research is usually conducted by practising physicians under conditions of actual use and is non-interventional – no additional tests or procedures are performed and any data that is collected is purely observational.

PASS are a particular type of late-phase clinical study, which are often mandated by regulatory agencies as a condition of the product's marketing authorisation. PASS programmes provide important ongoing safety information in a real-world environment after the product has been launched. They may detect or define previously unknown or inadequately quantified adverse reactions and risk factors that have not been seen during the highly controlled environment of a clinical trial. Proactive planning of late-phase activities can support the overall launch of the product and is one of the most effective vehicles for exposing the physician population to a new drug – encouraging earlier market acceptance and use.

It is imperative that PASS are carried out in accordance with the international, national and local guidelines stipulated. The following are key factors to ensure success:

Robust Design
For PASS, it is crucial to streamline the study design and goals for data collection as laid out in the protocol. Data collection should be limited to "must-have data". This not only keeps objectives clear and simple, but also eases the burden of sites in collecting that data. In addition, follow-up with healthcare providers must be built into the design, ensuring completeness of recording adverse events and confirmation of patient-reported adverse health outcomes, as well as providing clarification to any queries surrounding entered data. Finally, study designs must be fl exible enough to enable recruitment approaches to evolve if original projections for enrolment are not met. For instance, it may be necessary to extend recruitment to outside the initially planned countries or to permit the capture of retrospective data from patients’ records.

The Right Operational Team
It is vital that a multidisciplinary operational team of highly-qualified individuals, with extensive and strong observational global operations experience, is dedicated to PASS programmes to guarantee their rapid, efficient and cost-effective completion. All project team members should have clearly defined roles and responsibilities, and they should be experienced enough to have insight into any rate-limiting factors that may adversely affect the conduct of the study.

Project planning is essential to a well-run study, and a number of related plans should be created during the start-up phase. Examples of the many plans required include: regulatory submissions, communication, site management and monitoring, data management, adverse reporting and statistical analysis. The communication plan is especially critical as it outlines all aspects of project team communication, from roles and responsibilities to issue escalation pathways. It also acts as a guideline to ensure that communication occurs on a frequent and appropriate basis among the team members, contributing to the operational delivery of the project.

Extensive Feasibility and Site Identification
A detailed feasibility assessment is the first step towards a successful clinical trial, including late-phase studies. Some critical questions can help outline a roadmap for site identification:
  • How will the epidemiology infl uence the enrolment? It is important to make sure feasibility assessments are not done in isolation. Understanding the prevalence of a disease, the patient population, and geographic dispersion, based on scientific research, can help validate site enrolment projections
  • What is the current environment? At the outset of any clinical study design, it is crucial to understand the environment in which it is going to be conducted. This should include an analysis of direct and indirect competition (studies which may be targeting a different population but will be using similar resources and sites)
  • How will geographical and cultural factors impact the research? Geographic considerations are important for any study, but they are a particularly key factor in Europe, given the language and cultural barriers that exist
  • What kind of ethical and regulatory approval will be required? Site feasibility should include a detailed assessment of local ethical and regulatory requirements
  • How will the requirements of the study play out in a real-world setting? While feasibility and site identification are different, there should be some overlap with the questions posed to sites. At the feasibility stage, there is still time to modify the study design, but this may be more difficult once site initiation has started. It is also important to consider the usual care schedule, and access to key procedures and tests proposed
Timelines and Critical Pathways
The regulatory landscape should be carefully considered before finalising any study timeline. Building the regulatory timelines and projected patient recruitment – based on detailed early feasibility feedback from participating sites – into an accurate enrolment projection and tracking tool will help initial planning and ongoing management of study progress, from first patient in, to last patient out.

Because of the variance in timelines for approvals, an understanding of the country, region and site-specific requirements can help navigate the concurrent processes necessary to obtain authorisation for international PASS. However, it is vital that the timelines include time for unforeseen delays, questions, changes and even local public holidays, in order to be realistic. A staggered start is expected in countries where the product is not already available, since the product launch and market access will not be achieved at the same time in all the participating countries.

Site Management and Tools
Well-established relationships with sites are essential to ensure a continuous connection over a number of years. Site and patient burden must be considered to minimise site fatigue over the enrolment and follow-up period. Successful conduct of observational studies in Europe is inversely related to the complexity of the study and the amount of burden placed on a site.

Sites need to be engaged in order to maintain interest specifi cally among site investigators and site staff over the long-term conduct of observational studies. Undertaking ongoing, timely site interactions can benefit and add value to keep sites motivated and the study ‘top of mind’. Issuing simple study-branded aids and materials can also assist with this – for example, easily recognisable binders containing the protocol, patient consent forms and data completion guidelines.

Deciding what technology to use to collect large volumes of data on a near real-time basis can often be difficult. Options should allow for rapid data capture, tracking, review and processing – resulting in reduced data cleaning timelines and easily understandable metrics to track progress. Although there is an increased expectation for web-based data collection – appropriate for many segments of the population – this type of data collection may not be convenient or practical for some demographics such as the elderly. Similarly, the set-up costs of such a system may not be justified in smaller studies. These variables all lead to the need for a tailored approach to how data is best captured and processed.

As sponsors continue to face increased regulatory requirements for late-phase studies, a well-qualified operations team is critical to designing the right study to meet its objectives and ensure patient safety.


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Jess Sohal, MSc, is United BioSource Corporation's Executive Director of Clinical Operations in Europe, responsible for the strategic operational oversight of all activities. She has more than 15 years of experience in the clinical research arena, holding senior management posts across multiple therapeutic areas, and leadership positions in R&D, clinical operations and business development. Jess has a Master’s degree in Biology from the University of Manchester and a Bachelor's degree in Biology and Chemistry from Lancashire University.
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