Phase 4 Trials and Postapproval Pharmacovigilance Methodologies
In science, ‘fact’ can only mean ‘confirmed to such a degree that it would be perverse to withhold provisional assent.’ I suppose that apples might start to rise tomorrow, but the possibility does not merit equal time in physics classrooms.
–Stephen Jay Gould
INTRODUCTION TO POSTAPPROVAL METHODOLOGIES
Over the past decade, there have been steadily increasing expectations for companies to conduct more postmarketing trials (referred to as Phase 4 trials), primarily to assess the nature and incidence of adverse events from newly approved drugs as used in real-world populations. For example, some member states within the European Union require postauthorization safety studies as a condition of approval. Also, in many parts of the world, especially in the United States, European Union, and Japan, a new “risk management” paradigm has emerged that requires companies to specify any shortcomings of their Phase 1 to 3 database (e.g., suspicion of liver impairment in certain types of patients, or insufficient data on women, elderly, organ-impaired patients) and to plan and implement postapproval trials and other techniques for obtaining new and clarifying information, primarily on safety, but ultimately on the benefit-risk relationship. Even though risk management plans may have to remain country or region specific, there is a considerable amount of standardization that has influenced local regulations of Phase 4 through an International Conference on Harmonisation (ICH) guideline, “Pharmacovigilance Planning” (see ICH Guideline E2E; http://www.ich.org/).
Requirements for submission to regulators of spontaneous reports that companies receive have become largely standardized through the ICH process under ICH Guideline E2D. Although some country regulations require submission of such reports on customized forms and in the local language, the majority of countries
now accept a standard form in English [the Council for International Organizations of Medical Sciences (CIOMS)-1 form] that has been in use for many years. Certain countries and regions are now beginning to require that spontaneous individual case safety reports are submitted electronically under an ICH standard specification and transmission scheme (ICH Guideline E2B).
now accept a standard form in English [the Council for International Organizations of Medical Sciences (CIOMS)-1 form] that has been in use for many years. Certain countries and regions are now beginning to require that spontaneous individual case safety reports are submitted electronically under an ICH standard specification and transmission scheme (ICH Guideline E2B).
Many countries around the world now require periodic safety update reports for marketed products that are meant to summarize the latest key information from all sources and to indicate whether the safety profile has changed since the last report. If it has, then depending on the nature of the changes, modifications would have to be made to product information (i.e., labeling). Such periodic reports have become standardized under yet another ICH guideline, E2C. The frequency required of such reports may differ between countries, but the European Union standard of reports every six months for two years, annual reports for three years, and reports every three years thereafter may become more widely used. ICH periodic safety update report-type reports are not yet required in the United States, but the Food and Drug Administration (FDA) will accept them in place of currently required New Drug Application safety reports under a waiver program.
This chapter does not discuss the reporting of safety and other data to regulatory agencies and the many activities involved in the interactions within pharmacovigilance departments and between these professionals and the medical community, some of which are discussed in Chapter 66. Rather, it reviews the numerous methodologies that are available to study a product during the postapproval period and the collection of data by both passive and active means. It concludes with Best Practices of Industry.
There are several ways to describe all of the various types of clinical activities in the postapproval period, and no agreement exists in the field that one approach or series of names is better than the others. Academics, the FDA, the industry, and others each have certain preferences in how they wish to describe the methods used in this period. The following discussion generally reflects how the postapproval period is viewed by professionals in the pharmaceutical industry. The methods used to obtain data are described as a spectrum from the totally passive to totally active, and this is illustrated in Fig. 67.1.
 Figure 67.1 Spectrum of how data are acquired in Phase 4. These activities range from purely passive collection of unsolicited data to various types of active surveillance and clinical trials. |
Pharmacovigilance
There is no agreement on either the definition or the scope of what constitutes pharmacovigilance. The very first sentence in the textbook by Stephens, Talbot, and Routledge (1998) presents the broadest definition possible: “Pharmacovigilance has been defined as ‘All methods of assessment and prevention of adverse drug reactions.’” They go on to state that it covers both the preclinical period and clinical period, a view that is supported by CIOMS Working Group VI (2005). They then quote an European Union directive that includes the phrase “under normal conditions of use,” which implies it is limited to the postmarketing period. The editors state that they cannot take a position on this issue as the industry itself will establish its correct and appropriate use and definition. Nine aims and functions of pharmacovigilance are then indicated by Stephens, Talbot, and Routledge (1998) and are shown in Table 67.1.
One of the major activities of pharmacovigilance is to identify new adverse events from large databases. This often involves data mining techniques and these are discussed for pharmacovigilance in Chapter 100.
MARKETING TRIALS
The methods described in this chapter are within the research and development area of postmarketing surveillance or Phase 4 with one major exception. This exception is the marketing trials that are conducted in Phase 4. While all trials conducted in Phase 4 may represent research that is useful to marketing in terms of the reprints, new label claims, and removal of parts of the label that were not desired, there are some trials that are directly under the marketing group’s control. These may be conducted by a clinical group within marketing, the company’s primary clinical group, or an external vendor (e.g., contract research organization) that the marketing group hires for this purpose.
Table 67.1 Aims of pharmacovigilance | ||||||||||||||||||||||
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One of the most common marketing-oriented types of trials is to compare the company’s drug with that of standard therapy or the competition. These trials may be conducted during the investigational period (Phases 1 to 3) but often are left for Phase 4 because of the urgency to bring the drug to market and because the appropriate comparator products may differ in different countries.
Another commonly conducted type of trial is to conduct well-designed trials to hopefully obtain modest changes to the product’s labeling. In order to gain regulatory approval for new indications, new dosage forms, or uses in new patient populations, a sponsor must conduct such trials under an Investigational New Drug Application for Phase 2 and 3 trials. However, longer duration of treatment, new target organisms for an approved drug used in an infectious disease, and modification to dosing regimens are examples of possible allowable labeling changes that may result from Phase 4 trial results.
If patient-reported outcome trials (quality of life) or pharmacoeconomic trials have not been conducted or have not been completed during Phases 2 and 3, they will be completed during this period.
“Seeding” studies of new drugs are those that are presented to physicians as a way of merely inducing them to use the new drug. These have acquired a bad reputation and are highly inappropriate. All studies should have a legitimate scientific objective.
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