Achieving Regulatory Success in Phases IIIb and IV

Well-planned studies designed to pinpoint additional data are increasingly important as a result of the EU's emphasis on added therapeutic value.
Jul 31, 2004

The explosive costs associated with today's clinical trials require a very high level of scrutiny to weigh their scientific and regulatory merits prior to their commencement. However, passing the regulatory hurdles in order to obtain a marketing license does not always fully coincide with providing the necessary clinical information to place a new product in its intended context. Phase IIIa studies are therefore often not sufficient from a public health viewpoint, and additional Phase IIIb and IV trials need to be considered. This article gives a review of some of the regulatory challenges associated with later-phase development and highlights opportunities to participate in the formation of guidelines.

DefinitionsWhile various definitions of what Phase IIIa, IIIb, and IV constitute are in use between various agencies, academic centers, and companies, the following definitions are used in this article for the purpose of clarity:

Phase III: The efficacy and safety trials that are conducted with the primary purpose of filing for a marketing authorization (MA) of a particular product with the relevant authorities.

Phase IIIa: The efficacy and safety trials that support the initial claims made by the future marketing authorization holder.

Phase IIIb: Additional studies that are conducted to increase patient exposure; these additional data are either provided to the authorities at the time of approval or, because the studies are typically not completed at the time of initial filing, will be submitted as a postapproval commitment.

Phase IV: Studies with focus on new indications, new comparators, new efficacy endpoints, efficacy assessed by new methods, etc. after MA has been obtained.

These definitions are not universally recognized. Most regulatory agencies do not make a distinction between Phase IIIa and IIIb, and some companies use the concept of a Phase V that would fit under the definition of Phase IV above. There is also considerable overlap. Some studies are conducted to provide information that can be used to promote a drug at the time that a license is granted, such as a study in a special population or under special circumstances. When studies are initiated before the filing for a license, they are to be considered Phase IIIb studies, but there is often clear similarity in objectives or design to Phase IV studies.

The results of a Phase IIIb study are, as previously stated, typically not available at the time of initial filing for a license. The results must be presented to the regulatory authorities when available. Furthermore, the authorities must be informed of the status and kind of all additional ongoing incomplete studies at the time of application submission.

Challenges in drug developmentIt is estimated that out of every 10,000 molecules discovered, synthesized, and screened, only about 50 are found to have potential as a drug and progress to preclinical in vitro and animal testing. Further, only 10 make it to Phase I and just three make it to Phase II, leading hopefully to one product that can get licensed as a human medicine. As Figure 1 illustrates, the basic research takes on average 3 to 7 years, the clinical development an additional 4 to 8 years, and registration another 1 to 2 years for an accumulated average of 10 to 14 years on a product that is granted a 20-year patent.1

This long lag time between the development of a concept to roll-out of a new product is exceptionally long compared to other industries; in the car industry this is typically in the range of 2 years, in the software industry less than 18 months. This lag time adds to the investment burden.