are proved beyond a shadow of a doubt. The attitude that the “drug is innocent until proven guilty” and those safety warnings should not be issued to the health agency or the public until this point is reached is not at all appropriate in the world of safety. Rather, each safety issue must be evaluated and acted on because of its own merit and criticality in a timely fashion to evaluate and minimize risk. This can become quite challenging because risk must be considered in the context of benefit and alternatives. Some problems must be addressed on Friday at 5 p.m. and over the weekend.
In the corporate world, this attitude runs contrary to the prevailing fiduciary obligation of a corporation (“to increase stockholder value by making more profit”). The personnel in the drug safety department needs a fairly thick skin to work in this non-glorious field, unlike the world of clinical research or sales where there are congratulations (and monetary rewards and bonuses) for completing a study, getting drugs approved, or selling more product. Rather, drug safety personnel need strong backbones to be able to say to management that a product has a safety problem that must be acted on immediately or tracked until more data are in. Sometimes expensive studies are required and the outcome may merely strengthen the evidence of a problem. Good and wise corporate management understands this and welcomes “straight talk” from the safety unit. Bad management buries or delays. This is becoming more dangerous as the penalties (commercial, regulatory, and legal) are becoming more severe and bad behavior goes viral on the internet overnight.
It should be noted that the concept of drug safety is often less well understood and less well developed in small start-up companies with only a small number of employees. Their primary task is to develop one or a few drugs and their goal is to complete trials rapidly and either sell the product to another company for further development (e.g., large phase III trials) or get rapid FDA approval with the goal of getting positive cash flow. These companies usually do not have a safety department and sometimes do not even have anyone specifically handling safety or tracking regulations and new requirements. They usually rely on their partners or CROs. They often do not handle safety well and when safety issues or crises occur they have significant problems often requiring external “emergency” assistance to help resolve the issues.
It is hoped that corporate executives will realize that a safety problem hidden in the short run may, in the long run, appear on the front page of the New York Times, on TV or the Internet, or the six o’clock news. They may need to explain their actions to governmental investigation panels and to the multiple lawsuits — class action, civil, and criminal — that are frequent in the US and, increasingly, now pop up elsewhere in the world on any safety-related issue.
Similarly, the role of drug safety in the health agency is difficult. The primary mission is similar to the corporate safety role: to protect the public health. However, the profit-making motive is not present. Instead, there are always intense budget pressures to save money as well as the need to answer to multiple demanding constituencies: in the US, the FDA answers in one way or another to the Secretary of Health and Human Services, the US Congress, the public, the press, patient advocacy groups, the Internet blogosphere, the health professions, and the companies (and lobbies) the HA regulates. Similar political pressures exist for other agencies around the world.
Q: Why would anyone want to work in drug safety?
A: Good question. Once the decision is made by a healthcare professional to move out of the clinical world and into industrial/pharmaceutical medicine, it is noted that certain personality types tend to go to drug safety. Unlike the “glamour” of clinical research, where new and exciting drugs are tested, drug safety tends to have a different atmosphere, dealing with the problems of the new and exciting (and old and dull) drugs.
There is much more detective work and medical analysis in working hard to obtain all the clinical facts available, perform a defensible medical analysis, and come to a medically sound conclusion often based on incomplete (or even misleading) data. The work can be quite academic when one is working up a complex signal or risk evaluation/mitigation plan. And as always in medicine, one never has enough information. There is always one more test or examination one could do to get closer to the truth. Like the clinician, the drug safety worker is usually dealing with uncertainty and must still make rapid and often irreversible decisions. Yet given the data available, one must come to the medically proper and defensible conclusion and convey this in a cogent way to both medical and non-medical people. The work is challenging and fulfilling when done well.
The ethical issues come up when clear, compelling safety arguments calling for action are made and no action is forthcoming from management. This puts drug safety personnel in awkward and sometimes legally risky positions.
There is also much drama and excitement. Much can be routine, but the next e-mail or Tweet may bring a disaster with widespread consequences if the signal bears out. The adrenaline level rises and the “crisis” team mobilizes. The drug safety department is the emergency room of the company. Those who perform drug safety as a career are often passionate about it. Few decide at the outset of a pharmaceutical career that they want to “do side effects”. Rather, they want to discover new drugs or do clinical research or study the pharmacology of drugs. Many come into drug safety after trying other areas in the industry and discover they love it.
Q: Is there not an inherent conflict of interest in asking a company to police itself?
A: In a sense yes, especially when money is involved. Most regulated professions have some level of self-policing, including aviation, banking and finance, the food industry, medicine, and law. The results of self-policing have not always been happy. Thus, there must be some level of outside oversight to ensure that self-policing is done correctly. Finding the right balance is always the trick. In practice, there is far too much to do and oversee in the pharmaceutical industry to have total outside oversight from health agencies. Rather, practicalities force the system to police itself with regulations, periodic reports, monitoring, reviews, audits, and other mechanisms looking over the industry’s shoulder to “keep it honest”. In recent times, following terrible banking and investment scandals, there is a strong tendency toward risk aversion and the demand that there be more regulation and control “to prevent another (fill in your own crisis: Vioxx, AIG, Madoff, earthquake, etc.)”. Thus, we are likely to see more regulation and perhaps less risk-taking. Whether or not more regulation will lead to better outcomes (i.e., “safer” drugs) remains to be seen.
CHAPTER
5
The Mathematics of Adverse Events and a Brief Note on Pharmacoepidemiology
This chapter is not intended to be a reference on statistics, epidemiology, or the technical mathematical aspects of data analysis. Rather, it is meant to give a very elementary and selective overview of some of the “numbers” and quantitative methods used in pharmacovigilance and to show why, in our view, they have not been 100% effective yet in clinical medicine, pharmacovigilance, and regulatory decision-making.
When a new adverse event (AE) begins to be reported in association with a product, the two fundamental questions raised in the eyes of the regulator and the manufacturer are about frequency (How often will it happen?) and causality (Can it happen?).
Suppose that one or two spontaneous reports of liver injury with drug X are received at the safety department or health authority shortly after the first approval and use of the drug. First, what is the likely causality link between the liver problem and that suspect drug in those reports? Was the patient exposed to only the suspect drug X or were they concomitantly taking other drugs, including over-the-counter (OTC) medicines, “natural” or homeopathic or “traditional” products,