One person’s medicine is another person’s poison. It is estimated that prescription drugs are the fourth leading cause of death in the US, accounting for over 100,000 fatalities annually. Even though rigorous safety checks are carried out during clinical trials prior to marketing, they don’t always spot potential adverse reactions in the subset of volunteers participating in the study.

That’s why pharmacovigilance, the activities relating to the collection, detection, assessment, monitoring and prevention of side effects, is so important. It plays a vital role in ensuring doctors and patients have enough information when it comes to choosing a drug for treatment.

"The problem is that a clinical trial isn’t designed to catch rare adverse events," explains Dr Albert Wertheimer, professor of pharmacy at Temple University in Philadelphia, US. "It’s set up so you can look at the difference between the drug that’s being tested and either a placebo or an existing drug.

"If the drug is tested on 3,000 people and it shows that it lowers blood pressure better than the existing therapy or sugar pill, the drug is approved. And it shows basic safety in that group of 3,000 people. But what if, in fact, there’s one horrible interaction and it occurs in a ratio of 1:4,000, you probably won’t even see the first one in a clinical trial."

Risk management and signal detection

Most people are aware that a clinical trial isn’t good for spotting things that could be serious or debilitating in a tiny minority of patients, but it still took the US food and Drug Administration (FDA) until 2002, when Congress reauthorised the Prescription Drug User Fee Act, to start publishing rules dictating what pharmaceutical companies needed to do to monitor the rare side effects of new chemical entities.

The regulatory agency issued three concept papers, each focusing on one aspect of risk management including conducting premarketing risk assessments, developing and implementing risk minimisation tools, and performing post-marketing pharmacovigilance and pharmacoepidemiologic assessments.

Before and after a product is approved, pharmaceutical companies have to look for potential risk factors, and if the risk is deemed significant an application must be published, together with a mediation plan.

"Risk management plans might include something about changing the labelling or they’ll focus on educating physicians to be on the lookout for this or that – or maybe they’ll do some laboratory testing to make sure some enzyme isn’t being elevated or depleted which might lead to disease," says Wertheimer.

The biggest change in the last decade with regards to drug safety, he says, is that there’s now a sincere and significant endeavour post-marketing. After the drug is approved and on the market, there are specific rules the company that owns the therapeutic must follow concerning the reports that come in from doctors, nurses and patients about side effects that have cropped up. All the reports must be aggregated.

"Every now and then a report will come in and it’s something that is unexpected," says Wertheimer. "Those need to be turned into FDA every month, which acts as the cleanhouse.

If one of those comes from Portland, Oregon, the other one from New Mexico and the third one from New Jersey, and they were isolated, no one would have paid any attention before just because one doctor had one adverse event.

"But now, when FDA can look at the total and see that there’s a pattern developing, they can research that and get the information out there before any more people are injured."

By investing in an activity called signal detection, the regulatory agency has made arrangements with healthcare insurance companies. It buys data from them and looks for any hint of problems with drugs prescribed by patients on the insurer’s books.

"About six or seven years ago, large defence contractor Martin Marietta was hired by FDA to help design a means of picking up these kind of things from insurance company databases," reveals Wertheimer. "So pharmacovigilance is now a huge growth area. A company may have had two or three people in the department answering the phone or receiving requests; now they’ve got epidemiologists, statisticians and data entry people, who will evaluate every report when they come in."

A focus on transparency

"As electronic health records become ubiquitous, signals and patterns will be identified more rapidly, allowing pharmacovigilance professionals to report in greater depth about adverse events."

There’s also been a major drive in recent years to make sure doctors are actually reporting occurrences of adverse events to medication in their patients.

"Before, physicians didn’t want to give any ammunition to patients, so many of the adverse drug events went unreported," says Wertheimer. "But now people are assured that’s not the case and they can even be turned in anonymously."

Pharmaceutical companies in particular stand to lose their reputation if they don’t acknowledge concerns about a drug on the market. Take Vioxx (Rofecobix). Merck & Co’s non-steroidal anti-inflammatory drug was used for the treatment of osteoarthritis, acute pain conditions and dysmenorrhoea, and was approved by FDA in 1999. Worldwide, over 80 million patients were prescribed the medication at some point. But in 2004, the company was forced to withdraw Rofecobix from the market after concerns about increased risk of heart attack and stroke.

There were disclosures that the organisation had withheld information about risks from doctors and patients over the five years it had been on the market, resulting in up to 140,000 cases of serious heart disease.

"Look at the lawsuits that ensued from that, and what it did to the profitability and the stock price," says Wertheimer. "I don’t think anybody was happy with that."

Pharmacovigilance is clearly here to stay. And, with the regulators demanding ever more detailed information and risk management plans, it’s becoming a more resource-intensive role. Consequently, pharmaceutical companies are increasingly turning to contractors to do the work for them. According to Transparency Market Research, the global pharmacovigilance market, valued at $2,15 billion in 2012, is estimated to reach a market worth of $5 billion in 2019 at a compound annual growth rate of 12.9% between these two time periods.

However, Wertheimer has reason to believe that new developments in the area of personalised medicine could change this expected progression. This is because many adverse events related to medications occur due to various metabolic pathways that differ in both group populations as well as within individuals.

"It’s not commonplace today, but probably in the next five to ten years, every newborn will be genotyped," he opines. "And probably, when somebody signs up to a new GP practice, when they’re getting a physical examination, the doctor will order lab work which would include at least some genotype information."

This data would ensure that, in some circumstances, there would be the information and ability to select medications for the individual, meaning that many potential adverse drug effects would be avoided, and the patient would receive the most effective and least risky treatment.

"There are some things you just can’t know until you have a lot more people on the drug," says Wertheimer. "But once you’ve figured out that there’s a problem, you don’t want to wait three years afterwards, you want to deal with it immediately. So that’s where pharmacovigilance has huge benefits."

Personalised medicine

We now know that a number of drugs are metabolised or handled by the body through different systems. The cytochrome P450 family of enzymes, for example, are responsible for the oxidation of almost 90% of the drugs currently on the market. But single nucleotide polymorphism variations in human CYP450 genes can cause different effects. Therefore, knowing a person’s genotype could predict not only drug efficacy and adverse drug effects but drug-drug interactions.

"If someone is taking three drugs that all need that enzyme in order to process the drug and metabolise it, all three are competing for that limited amount of enzyme that the body makes," explains Wertheimer. "The levels of one, two or all three of them are going to increase because the enzyme can’t process all of that. One or two could get to a toxic level and cause some kind of adverse event.

"If we know the characteristics of a person and what drugs they’re taking, the physician has the opportunity to prevent a potential problem by using personalised medicine techniques."

While there may be fewer reports submitted each year, as personalised medicine evolves to give us improved clinical outcomes and economic savings – as opposed to the current, rather hit and miss system used to prescribe drugs to patients – pharmacovigilance will be needed more than ever.

As electronic health records become ubiquitous, signals and patterns will be identified more rapidly, allowing pharmacovigilance professionals to report in greater depth about adverse events, and which subpopulation groups are more at risk. It is likely that more precise and detailed reporting requirements will be demanded by FDA, with the standards for drug safety increasing.

Wertheimer believes the time a company is granted to report serious adverse events to the regulators will also shorten.

"There will be as much if not more need for pharmacovigilance activity in the future," he concludes. "And as we become more and more quantitative, have better access to databases and can do more tests, again there will be more need. The sooner we can catch things before they happen, the better."