Making the Link - Pharmaceutical Executive

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Making the Link
Post-marketing safety studies have one big problem: They're too slow. That's why companies are turning increasingly to databases that link prescribing data with patient outcomes.


Pharmaceutical Executive


Pharmacoepidemiology (PE) studies the use and effects of drugs in large populations and has been used for drug safety assessment for decades. PV is designed to detect safety signals across all organ systems. PE, on he other hand, compares two or more groups of patients to answer specific research questions. For example, pharmacoepidemiological studies were used to quantify the risk of gastric or duodenal ulcer among users of non-steroidal anti-inflammatory drugs (NSAIDs).


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Prospective epidemiologic studies require prohibitive amounts of time and resources. As a result, many researchers have turned to large databases that link prescription information to patient outcomes, such as the databases maintained by state Medicaid programs and various health insurers. To date, PE studies have been conducted mostly in reaction to safety signals detected through pre-marketing trials or PV, rather than as a matter of course.

Registries In addition to PV and PE, some drug safety programs use techniques such as monitored release, but the methodology is not feasible for all drugs, and there are few examples. The most striking of these is the recently initiated registry of all patients taking Accutane (isotretinoin), Roche's product for severe acne. Other registries also have been established for specific drugs or populations.

Problems With the Status Quo

PV systems, including FDA's MedWatch, generate tens of thousands of reports each year from healthcare providers and patients. But it is impossible to expect overworked healthcare providers to report all adverse events. It is estimated that no more than 10 percent of adverse events find their way into MedWatch. There may be duplicate reports, and many of the reports received by PV systems lack crucial information. The reports certainly do not represent a random sample of adverse events, which limits their usefulness.

It has been proposed that the Adverse Event Reporting System use automated signal detection and statistical algorithms to screen for safety signals. The problem is that mathematical models may not produce valid answers when applied to data of haphazard origins. In addition, these models have not been tested in a controlled setting. In April 2005 the Pharmaceutical Research and Manufacturers Association (PhRMA) issued a Request for Proposal to call for more rigorous evaluation of these statistical methods.

There are other limitations to the post-marketing spontaneous reporting system:

Common adverse events can be hard to spot Spontaneous reports are valuable in linking drug exposure to certain adverse events such as liver failure, agranulocytosis, or Stevens-Johnson syndrome—events that are both serious and rare in the general population. But the reporting system may not be sensitive enough to identify events that are common among high-risk groups. For example, myocardial infarction is not rare, and there are several well-known risk factors. Even if the use of a drug raises the risk of acute myocardial infarction by 50 percent, medical care providers may not recognize the increase among limited numbers of individual cases. Take Vioxx (rofecoxib) for example. Typically adverse events first come to light through case reports in the FDA system or clinical literature. In the case of Vioxx, cardiovascular safety signals were first detected in a clinical trial—and at the time there was not a single case report in the peer-reviewed literature that suspected an association between myocardial infarction and use of rofecoxib.

Post-marketing trials are slow—and single-purpose Studies can take several years to complete, and though they can answer a specific question ("Does this drug cause liver toxicity"), they probably won't provide much help when the next question ("Does it cause cardiac problems?") emerges.

Safety signals detected in pre-marketing trials may have limited utility in predicting post-marketing events For example, some drugs that subsequently proved hepatotoxic, such as troglitazone, showed increased incidence of elevation of transaminase in pre-marketing trials. But simvastatin, which also raised concerns during clinical trials because of elevated transaminase, has proven to be relatively safe after many years of post-marketing experience; in fact, low-dose simvastatin is now sold over the counter in the United Kingdom.


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