Surveillance, post-marketing

Spontaneous ADR reporting is conceptually simple. Reports are submitted on a voluntary basis and information from them is entered onto a database which is screened regularly for signals. The main elements of a scheme which are essential to its success may be summarised as follows  

If busy health professionals are to submit reports voluntarily, they are only likely to do so if the process is straightforward. Reporting 

Reporters may be contacted for follow-up - i.e. provision of additional detailed clinical information (e.g. results of investigations, autopsy reports, etc.) or ascertainment of the outcome subsequent to initial submission. In most schemes follow-up is selective, dependent on the perceived importance of a report and the extent to which information important for its evaluation has already been provided. A simple principle is that all serious reports should be followed-up. 

In the past decade there have been major advances in the application of analytical methods to detect to signals from spontaneously reported ADRs (see Chapter 4). The general view is that these tools are now sufficiently well-established to be regarded as an essential component of the method but there are some sceptics. 

In order to complete a feedback loop, information must also flow back to reporters through acknowledgement, provision of data and bulletins describing evaluated signals. 

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The requirements for market vigilance and oversight in the US are set out in 21 CFR 803, Medical Device Reporting, 21 CFR 806, Reports of Corrections and Removals and 21 CFR 822 Post market Surveillance. 

The FDA may also require manufacturers to conduct post-market surveillance studies for Class II and III devices that meet the following criteria ... 

Several areas in dmg regulation receive relatively little attention in the implementation process. The informal sector, post-marketing surveillance and control of dmg information were the most important of these. 

Post-marketing surveillance of product quality is carried out by means of a QC system. The quality of products available on the market is therefore an important indication of the effectiveness (or otherwise) of the dmg regulatory system. 

Monitoring, violation and sanction spheres For post-marketing surveillance of product safety, ADR monitoring systems exist in all the countries, with the exception of Uganda. But it is difficult to evaluate the effectiveness of these systems in monitoring product safety. Only the Adverse Dmg Reactions Advisory Committee in Australia... 

Human studies (including estimations of occupational and environmental exposure, epidemiological investigations, post-marketing surveillance for medicines, cosmetics and household and agricultural products, and the ethical and properly controlled use of human volunteers) [6]. 

Post-marketing surveillance for medicines, cosmetics and household or agricultural products... 

Post-authorization evaluation of medicines for human use. This regulatory affairs unit is responsible for issues such as post-marketing surveillance of drugs. 

Food and Drug Administration (FDA) (2002) Report to Congress on Post-Marketing Surveillance of Drugs, March 13, 2002, available at www.fda.gov/cber/fdama/pstmrktfdamal30.htm (accessed May 30, 2002.)... 

FIGURE 20.1. The pharmaceutical development process, viewed as four stages (discovery, preclinical development, clinical development, and NDA review) as well as the important post-market surveillance phase. 

ROCK C L, THORNQUIST M D, KRISTAL A R, PATTERSON R E, COOPER D A, NEUHOUSER M L, neumark-sztainer D and cheskin l j (1999), Demographic, dietary and lifestyle factors differentially explain variability in serum carotenoids and fat-soluble vitamins baseline results from the sentinel site of the Olestra Post-Marketing Surveillance Study , J Nutr, 129(4), 855-64. rodale (1996), The Prevention Index - a report card on the nation s health, 1996 summary report. Rodale Press, Inc, Emmaus, Pennsylvania. SANDLER R S, ZORICH N L, FILLOON T G, WISEMAN H B, LIETZ D J, BROCK M H, ROYER M G and MIDAY R K (1999), Gastrointestinal symptoms in 3181 volunteers ingesting snack foods containing olestra or triglycerides , Annals Internal Med, 130, 253-61. 

A review of case reports, clinical trials, post-marketing surveillance, and drug monitoring studies concurrently showed that the most common side effects were gastrointestinal, dizziness/confusion, and sedation (Ernst et al. 1998). Importantly, the side effects of hypericum in this study were comparable to placebo levels. A pharmacokinetic study showed that plasma levels of up to 300 ng/ml were well tolerated. Headache occured in one subject who was taking 1200 mg extract (59 mg hyperforin, plasma cone. >400 ng/ml) (Biber et al. 1998). 

Phase III Extended large-scale trials to obtain additional evidence of efficacy and safety, and definition of adverse effects. Humans exposed several hundred to several thousand Phase IV Post-marketing surveillance occurs after the chnical trials programme is complete. It is used to collect adverse event data from a large patient population. Humans exposed 10 000+... 

The need for monitoring long-term followup in post-marketing surveillance (PMS) and safety assessment of marketed medicines studies to determine effects of the drug on physical functions and development, such as bone maturation, growth and sexual development. 

Some large, multicentre post-marketing surveillance studies, in which a comparison of the newly marketed drug and standard therapy is made... 

These deliberations may result in several outcomes. Clinical development may continue as planned, but additional vigilance with more frequent visits and special tests may be added. The dose may be reduced or certain at-risk subjects may be excluded from further trials. The drug may proceed to registration, but the authorities may stipulate that a post-marketing surveillance study be conducted. The drug may even be withdrawn from further clinical development. 

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 ... 

The pharmaceutical industry presents many new challenges to such a person which include the interface with pharmacy and pharmacology, toxicological research, human volunteer studies, clinical trials and post-marketing surveillance to name just a few. Product safety is a factor which impacts on all of those endeavours and the pharmaceutical physician will be expected to work and provide advice within that framework. It will be clear to anyone that evidence of lack of safety in a medical product is not good news for the company concerned and that some level of protective action will often be required which in extreme circumstances may involve product withdrawal. It is, therefore, essential that the pharmaceutical physician should be absolutely clear what constitutes lack of safety in relation to the intended use of the product. 

In the United States, there are several computerised healthcare systems, sometimes referred to as multipurpose databases, which have been used for post-marketing surveillance purposes. The best-known include Group Health Cooperative of Puget Sound, Kaiser-Permanente, Medicaid, Rhode Island and the Saskatchewan database in Canada. ... 

There has never been any incentive for the pharmaceutical industry to pursue research along these lines even though, as in the case of Vioxx, the end results of neglecting adverse effects may be very costly. The aim of the industry has usually been to extend the market size irrespective of potential risk and attempts to implement effective post-marketing surveillance has received little enthusiasm. It is to be hoped that company medical departments and pharmaceutical physicians will continue to support the need for a broad range of safety evaluation studies to be conducted on new medicinal products. 

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