Applied Clinical Trials
The adoption of new, consistent definitions are needed to help demystify late phase trials.
In the biopharmaceutical industry, research terminology largely reflects the phased regulatory drug development process. Around the time of product approval, there are many descriptors—late phase or late-phase research, registration/pre-registration research, peri/post approval research, postmarket research, Phase IIIb/IV research—but no formal definition exists, and the ones available are used inconsistently.
Louise Parmenter, PhD
These phase labels have served us well for many years, but they increasingly feel out of step with the new healthcare environment. Designed with the regulatory approval process in mind, the phase descriptions do not always fit with a broader stakeholder setting that includes physicians, payers, patients, and policy makers. For example, phase descriptions offer no insights into whether a product will be paid for by any healthcare payer.
Late phase (with or without the hyphen) research is one of the most widely used terms, but it can be confused with late stage research which commences in Phase II of product development.
Registration/pre-registration and peri-/post approval research are terms directly related to dossier submission and approval. In the pre-registration phase, all the necessary clinical trials have been completed and the drug is waiting for registration or approval for use by a governing body. Registered drugs are those registered or approved for use in a particular country, or group of countries. Approved drugs have received regulatory approval in an individual country or region, but are not yet on the market. Launched drugs are marketed in one or more countries.
Postmarket research is a term favored by some divisions of the FDA, simply meaning in-label research on marketed products, while the term post-approval studies is used by the Centers for Devices and Radiological Health.
One emerging construct is to use the term late phase to denote research on products following regulatory submission for at least one indication, and dividing this into Phase IIIb for trials occurring subsequent to that submission pre-approval or for new indications post-approval. Phase IV is utilized for studies conducted post approval that are not designed specifically to obtain a new labeling indication.
Phase IIIb. Pre-approval Phase IIIb trials occur while the regulatory agency is reviewing the submission (Phase III pivotal data submitted) and usually focus on gathering additional data to support the product's anticipated launch, or commence long-term safety monitoring. Post-approval Phase IIIb trials investigate the use of an already approved product, outside the terms of their approved label, to expand the product indications.
Phase IV. Interventional designs test specific hypotheses (generally safety, effectiveness) relating to treatments for marketed products in existing indications. Observational designs examine actual use and often in more representative populations. Inclusion/exclusion criteria generally reflect an existing product label, although these may be based simply on product use in some observational studies.
Bringing even more complexity to this confusing situation, many organizations are augmenting the drug development phase descriptions with new terms such as real-world, value demonstration, and comparative effectiveness research.
There's no doubt that regulatory terms will continue to form the backbone of research terminology, yet adoption of new, consistent definitions are needed to help demystify late phase trials, and to facilitate a focus on research objectives to meet multiple healthcare stakeholder perspectives.
Louise Parmenter, PhD Senior Director, Strategic Operations Quintiles Outcome E-mail: Louise.Parmenter@quintiles.com