Development postmarketing

Contracting out of activities previously only conducted in-house is already becoming quite common and will probably continue to develop. In the past a so-called full-service pharmaceutical company took direct responsibility for all the activities required for the formulation, manufacture, quality control, and regulatory approval of its drug products. Nowadays the use of specialist contract houses to perform activities such as formulation, analytical methods development, manufacture of clinical trials supplies, supervision of the assembly of an NDA, postmarketing surveillance, and even troubleshooting may be contracted for even by some of the largest companies. 

F. Premarket Notification, Investigational Device exemptions including Humanitarian Exemptions, Premarket Approval, Product Development Protocols, Classification, Device Tracking, Petitions for Reclassification, postmarket surveillance under Sections 510(k), 513, 515, 519, 520(g) and (m), and 522, and the advisory committees necessary to support these activities. 

Clinical development of NCEs is broadly divided into Phases I, II, III, and then IV (postmarketing) studies. 

In this context, a decision on whether postmarketing surveillance studies should be built into the development programme must be taken. Such an observational study may signal the occurrence of adverse events or alternatively it may signal and quantify the frequency of adverse events. At this point in the life cycle of a new medicine, post-marketing surveillance is likely to involve cohort observational studies of 10-20 000 patients. The value of these studies is likely to be three-fold ... 

In the evaluation of safety in the postmarketing phase, regulatory agencies are greatly more restricted in their enthusiasm for data derived from some of the methods available than from others. Indeed, the EC national agencies separately and the CPMP collectively have developed a legislative framework that is predominantly concerned with spontaneous adverse event monitoring and which is, for all practical purposes, silent on the matter of safety data collected by other methods. 

The clinical development of new drugs usually takes place in steps or phases conventionally described as clinical pharmacology phase I), clinical investigation (phase II), clinical trials (phase III), and postmarketing studies (phase IV). Table 1.1 summarizes the four phases of clinical evaluation. 

The most common adverse reaction to etanercept is mild to moderate erythema, pain, or pruritus at the injection site (37%). Headaches and abdominal pain can also occur. New positive autoantibodies, such as antinuclear antibodies (ANA), anti-dsDNA antibodies, and anticardiolipin antibodies, can develop in patients treated with etanercept. Although there is so far no association between this and the development of autoimmune diseases or malignancies, long-term studies have yet to be done. Rare cases of pancytopenia may be associated with this drug. Although clinical trials showed no increased risk of infection with etanercept treatment, postmarketing reports of serious infections, sepsis, and associated fatalities exist. 

In preliminary clinical trials, 2 of 2,796 mirtazapine-treated patients developed agranulocytosis, and 1 developed severe neutropenia. All 3 patients recovered after medication discontinuation, and other possible etiologies were present in at least 1 of these individuals. Thirteen patients with pretreatment neutropenia did develop more severe neutropenia or agranulocytosis. Postmarketing evaluation to date has not established a causal relation between mirtazapine and agranulocytosis. Routine laboratory monitoring is not currently recommended. 

Ocular changes. Cataracts developed in association with que-tiapine treatment in prechnical studies involving dogs, but a causal relation has not been established in humans. Postmarketing trials have not detected an increase in the incidence of cataracts with quetiapine compared with other antipsychotics. 

Hannaford P. Postmarketing surveillance study of Norplant in developing countries. Lancet 2001 357(9271) 1815-6. 

A review of Japanese patients found that of the 15 patients who had developed hematological malignancies since 1975, 6 had other risk factors for leukemia, such as Fanconi s syndrome or prior chemotherapy or radiotherapy. The incidence of leukemia in this study was 3 per 100 000, similar to that in the general population of the same age (68). The National Cooperative Growth Study (NCGS—a postmarketing database that includes 19 846 patient-years since the time of growth hormone exposure) similarly reported no increase in the incidence of new leukemia when patients with other risk factors were excluded from the analysis (96). 

The statistics of expenditure and NDA approvals can mask a major source of R D cost and frustration in the industry late-stage development and postmarketing failures. These types of failures attract significant unwanted publicity and only occur after hundreds of millions of dollars have been spent. Well-publicized examples have included the recent late-stage failure of torcetrapib (Tall et al., 2007) and the postmarketing withdrawals of fenfluramine-phentermine (Fen-Phen) and Vioxx (Embi et al., 2006). 

Annual reports that contain well-developed and meaningful information will be an important tool for the Agency and the industry to assure postmarket safety and protect the public. When manufacturers prepare the type of analysis this guidance describes and provide this information to the FDA in annual reports, industry and the FDA will be better positioned to recognize and address possible safety signals. 

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