Baycol, Vioxx, Bextra, and now Celebrex. Who's responsible for these unsafe drugs? Well, there's more than enough blame to go around. Here's an overview . . .

Unsafe Drugs?

Robert W. Griffith, MD
January 7, 2005

Introduction

Having worked for 25 years in the research arm of the pharmaceutical industry, I haven't been very surprised by the recent reports of side effects with some best- seller drugs. As I was taught early on, "there are no therapeutic roses without thorns". It all depends, of course, on how big the thorns are! Every effective drug has side effects, and the secret lies in balancing the benefits the drug can bring against the risks it may carry. It's in everyone's interest that this risk-to-benefit ratio is calculated as carefully as possible.

The withdrawal of Vioxx and the subsequent disclosures about the safety of Bextra and Celebrex have led people to blame the pharmaceutical industry (Big-Pharma) and the FDA (the US Food and Drug Administration) for putting unsafe drugs on the market. But it's a little more complicated than that. There's plenty of blame to go around, and I'll try to apportion some of it.

Big-Pharma

The role of the pharmaceutical industry is to discover, develop and market new medications. It has a duty to its stockholders to sell marketable products at a profit -in this it's no different from a company like McDonald's selling cheeseburgers. Obviously it should not knowingly put an unsafe drug on the market. Like any other manufacturer, Big-Pharma faces wrath and litigation from consumers if a product causes injury. This possibility forces drug companies to try to ensure that their products are safe, by any reasonable standard. In this they are helped, to some extent, by the FDA (see below).

Companies like Bayer and Merck have been nearly brought to their knees by the discovery that their blockbuster drugs (Baycol, Vioxx) are unsafe. These discoveries were made months or years after marketing. Obviously such companies wish they'd been more diligent in researching the safety of their products after they'd been introduced - a process known as Post-Marketing Surveillance. In future we can expect that Big-Pharma will pay much more attention to reports of adverse drug effects during the early marketing years, and react accordingly, with appropriate warnings or even withdrawal of the product.

Mention must also be made of direct-to-consumer advertising, that has allowed Big-Pharma to bombard potential patients with drug information promoting the claims of effectiveness to the absolute limits allowed, using all the invasive and seductive techniques at Madison Avenue's disposal.

The FDA

The FDA is responsible for approving the effectiveness and safety of new drugs before they are marketed, reviewing their safety subsequently, and, if necessary, ordering their removal from the marketplace. Much has been made of the fees that are charged to Big-Pharma for the FDA's review of new drug applications. It's been suggested that the FDA is thereby in the drug companies' pockets. In fact, however, a collegial but adversarial relationship exists between these parties. The company wants to have its drug approved as quickly as possible (before the competition arrives), while the FDA wants to ensure effectiveness and safety.

However, safety of a new drug (or almost anything else - food, drink, planes, autos) is not an absolute. The FDA must use the concept of relative safety, and compare that with the benefit the new drug can bring. Relative safety is based on the likelihood of an injury not happening; for instance, it's relatively safe to take an airplane trip, as your chances of being killed are less than one in 800 million. An adverse drug effect can occur in one in 10, one in a thousand, or one in several million patients exposed to the drug. The effect may be mild (a headache), in which case a likelihood of one in 50 cases is acceptable to just about anyone - the FDA, the patient, and the pharmaceutical company - provided the drug has the desired therapeutic effect.

The FDA evaluates the probable frequency of adverse effects with a new drug, based on documentation from one or two thousand patients. So they can only assess those effects having a likelihood of occurring in more than one in a thousand patients. When they are unsure of the actual risk of an adverse effect, they can demand that the drug company conducts post-marketing studies to establish this.

After the new drug is approved, many more patients are exposed to it, in less well-monitored circumstances then those used in the clinical trials. Spontaneous adverse effect reporting to the FDA or to the company should provide databases that would allow evaluation of the likely frequency of comparatively rare effects. Unfortunately, the mechanisms for this post-marketing surveillance are weak, both at the FDA and in individual companies. It is here that the main criticisms are aimed (correctly).

There are now cries for clinical studies in several thousands of patients before a drug can be approved. This would obviously add years to the new drug approval process, delaying the introduction of possibly life-saving medications. At the same time, patient-groups battle for earlier approval of new drugs in their particular diseases. This potential trade-off needs to be resolved, quickly.

The doctor

Doctors are bombarded by advertisements and information on new drugs. The FDA attempts to monitor the ads to ensure a fair balance between claims and warnings, but often by the time they demand a correction or retraction, the ad series has run its course. Small wonder, therefore, that possible known adverse effects are not communicated to the doctor as forcibly as information on the likely benefits.

Adding to the pressure for the doctor to prescribe a new drug are the demands from some patients, who want the latest advance in treatment for their condition, regardless of possible risks; they've seen the ads on TV and hope to experience the benefits offered. One must remember, too, that a family practitioner is unlikely to have personal experience of an adverse event that only occurs in one in a thousand patients exposed to a particular drug. How much more unlikely are they to recognize a doubling in the frequency of heart attack, for instance?

The patient

Patients expect their doctors to prescribe safe drugs, and are naturally distressed to learn about the withdrawal of a drug that has been widely used for some years. They are angry at Big-Pharma for making so-called "obscene profits" with disregard for safety, the FDA for failing in their duty to only approve safe drugs, and at their doctors for prescribing unsafe medications. It's no surprise that they turn to alternative medicines (herbs, supplements, etc), little realizing that many of these have not been proven safe or effective at all. Patients should educate themselves as to the know benefits and risks of both traditional medications and alternative medicines.

The unknown

What makes one patient develop a side effect and not the next ten (or thousand) patients? The studies and reports leading to the withdrawal of Baycol and Vioxx were clearly not in a position to say. Is there a genetic factor, an interaction with a nutritional item, or an unrecognized environmental issue? It will take years until we have answers to these types of questions. In the meantime, people should realize that the world is a risky place (see the first link, below). They should educate themselves about the medications they take (read the label), be suitably reluctant to try the latest drug just because it's new (and probably expensive), report to their doctor any unexpected or severe side effects, and steer clear of alternative medicines that don't have any evidence of effectiveness or warnings about possible adverse effects.

Source

• Robert W Griffith -- Personal Experience

Related Links
Risk Analysis Center (you must register, but it's free)
Risk Assessment - The Illusion of Certainty
A New Risk with an Older Drug