Sound responses to the changing late-phase game

By Dipti Amin, Quintiles

Safety concerns in drug development, both from the public and regulators, have clearly intensified – and there will be no let up.

As a result, FDA, through the FDA Amendments Act of 2007, has new authority to require post-marketing studies, and the EMEA in 2005 made the submission of risk management plans mandatory in the European Union.

New regulatory requirements mean that pharmaceutical companies must allocate additional resources for large-scale patient safety studies that assess adverse events in real-world patient use. Getting a drug to registration, therefore, is becoming just a step along a long and winding road. 
 
Meanwhile, payers are also demanding more health economics and comparative outcomes data – the layer behind the safety and efficacy data – to determine if one drug is better than others for a particular indication. The growing significance of comparative effectiveness research opens the door to new types of Phase IV trials and to a reconsideration of how clinical research is conducted to maximize service delivery.
 
At Quintiles, we believe in starting the conversation about late-phase study design during Phase II. What will it take to get the work done effectively? What have we seen with other drugs in this class? What are the data requirements? With a choice of possible study designs, we can decide what truly distinguishes the evolution of Phase IV, with a consideration of everything from global lifecycle benefit-risk management to prospective and retrospective epidemiology studies.  These opportunities introduce a new view of large-scale Phase IV studies that can make the entire research effort more efficient.

The thinking goes like this: If large-scale phase IV studies are going to be built, they also can be used cost effectively as the backbone for any subset studies, since shared systems, sites, trained personnel, data management platforms and contracts are already in place.  Such sub-studies could include comparative, side-by-side studies, treatment satisfaction studies, target biomarker investigations, burden of illness assessments, randomized clinical trials, patient-reported outcome studies, observational/non-interventional studies and registries and new indication studies, among others.

This use of an existing Phase IV research infrastructure also calls for changes in the research methodology and the use of certain procedures and tools. Such as central monitoring and controlled sampling of source data (both authorized by the ICH E6 GCP Guideline, Section 5.18.3). Central monitoring – monitoring techniques from a remote monitoring resource – can be done successfully, especially when there is a solid understanding of the efficacy and risks of a product. Controlled sampling of source data using statistical sampling methodology can be used for certain criteria and risk-based studies.

The introduction of risk identification and triggered monitoring techniques. These are used to measure risk to subjects or risk to data, such as sampling methods, source data, query rates or even such qualitative risks as site communications. Triggered monitoring is a planned methodology for timing on-site monitoring and source data selection based on on-site workloads or other quality triggers.

Greater incorporation and/or access to electronic health record information. The use of EHR would help identify subjects qualified for trials in any phase, abbreviate the process of moving data or complete entire studies using only electronic health records, such as a retrospective examination of a control element of a previous study.

With existing large-scale phase IV studies, we can step away from a single use approach to study design and use the existing infrastructure or portions of it for additional, specific research. As such, the infrastructure is available not only for basic safety and exposure data, but also for focused investigations to meet either regulatory demand or strategic, post-marketing needs. 

We believe this new model produces both the service delivery efficiency and cost advantages to do all.
 
Dipti Amin is the Senior Vice President and Global Head of Quintiles Late Phase and Safety Services unit. Educated in the United Kingdom, Amin earned professional degrees through GKT Medical School of the University of London. She earned graduate degrees or certificates in medicine, surgery, family planning, obstetrics and gynecology, child health and clinical pharmacology. She is licensed to practice medicine in the US as well as the UK.