Postmarketing controls

In our efforts to bring safe and effective products to market as quickly as possible, CDRH needs to be able to rely on a variety of postmarket controls that will assure continuing safety and effectiveness after a medical device is widely distributed. We believe that data and information gathered in the postmarket setting are critical to our continued confidence in the safety and effectiveness of the marketed device. Annual reports are one of the important tools that the FDA relies upon to gather information about the device in its postapproval setting. 

Postmarketing controls include estabUshment registration, device listing, quality system compliance inspection, and medical device reporting (MDR). 

Loss of insurance coverage (in a postmarketing case control study)... 

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. 

From 1978 through 1990, the Centers for Disease Control and Prevention (CDC) and the Food and Drag Administration divided the responsibility for postmarketing surveillance of vaccines in the United States. FDA received reports of adverse events after vaccines were administered in the private sector events occurring after the administration of vaccines purchased with public funds were reported to the Monitoring System for Adverse Events Following Immunization. 

Phase IV. Studies or trials conducted after a medicine is marketed to provide additional details about the medicine s efficacy or safety profile. Different formulations, dosages, durations of treatment, medicine interactions, and other medicine comparisons may be evaluated. New age groups, races, and other types of patients can be studied. Detection and definition of previously unknown or inadequately quantified adverse reactions and related risk factors are an important aspect of many Phase IV studies. If a marketed medicine is to be evaluated for another (i.e., new) indication, then those clinical trials are considered Phase II clinical trials. The term postmarketing surveillance is frequently used to describe those clinical studies in Phase IV (i.e., the period following marketing) that are primarily observational or nonexperimental in nature, to distinguish them from well-controlled Phase IV clinical trials or marketing studies. 

Class II devices are those for which general controls alone are insufficient to provide reasonable assurance of safety and effectiveness and for which sufficient information is available to establish special controls to provide this assurance. Special controls may include performance standards, postmarket surveillance, and guidance for analytical/clinical data. Examples of class II IVDs are automated differential cell counters, fetal hemoglobin test systems, sickle-cell tests, and Toxoplasma gondii serological reagents. 

Hepatotoxicity. Duloxetine is rarely associated with increases in serum transaminase levels, typically in the first 2 months of treatment. In controlled trials in major depressive disorder, elevations of alanine aminotransferase (ALT) to greater than three times the upper limit of normal occurred in 0.9% (8 of 930) of the duloxetine-treated patients and in 0.3% (2 of 652) of the placebo-treated patients. Current product labeling contains a caution regarding the use of duloxetine in patients with significant alcohol use or chronic liver disease. Postmarketing reports have indicated that increases in transaminases have occurred in some patients with chronic liver disease (Cymbalta 2005). 

It is appropriate to recognize that some medications are more susceptible to abuse than others. If two medications are equally effective for a given indication, the one with lower abuse liability would obviously be preferred. Information on abuse liability is necessary for the appropriate regulation of medications and provides a basis for education of physicians, patients, and the public. In this chapter we describe the control of marketed medications, abuse-liability assessment procedures for premarketing testing in laboratory animals and humans, considerations of the formulation properties, and postmarketing surveillance of abuse. Finally, we provide three case studies of marketed medications that have been abused. 

The information on safety provided by the controlled trials are of course valuable, but the populations are highly selected and the administration of SLIT is usually supervised this situation is profoundly different from that occurring in the clinical reality. Therefore, more consistent information on the safety should be obtained when SLIT is prescribed and administered in the everyday clinical practice, i.e. in postmarketing surveillance studies. 

In addition to the three more recent withdrawals of Merital, Serzone, and Cylert, I have also reviewed the entire list of serious adverse reactions to psychiatric drugs detected during the postmarketing period in the GAO (1990) study. It seems probable that every one of them was discovered and confirmed through a combination of the SRS, individual case reports, and general clinical experience. As far as I can ascertain, not one of these adverse reactions was primarily, if at all, identified by means of a controlled clinical trial. As a result of postmarket discoveries, alprazolam (Xanax) had rage added to the label as a paradoxical reaction, and amoxapine (Asendin) had NMS added. 

The authors recognized that mirtazapine alone could have caused the hypertensive event. In postmarketing surveillance of mirtazapine, hypertension occurred in at least 1% of patients. However, it is likely that the patient lost antihypertensive control because mirtazapine antagonized the antihypertensive effect of clonidine. Mirtazapine, a tetracyclic antidepressant, stimulates the noradrenergic system through antagonism at central alpha2 inhibitory receptors, which is precisely opposite to the effect of clonidine. 

Observational studies, where the drug is observed epidemiologically under conditions of normal use in the community, i.e. pharmacoepidemiology. Techniques used for postmarketing (Phase 4) studies include the observational cohort study and the case-control study. The systems are described on page 69. 

Coulter DM. Eye pain with nifedipine and disturbance of taste with captopril a mutually controlled study showing a method of postmarketing surveillance. BMJ (Chn Res Ed) 1988 296(6629) 1086-8. 

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