What is Pharmacovigilance?

Corresponding Member of the Russian Academy of Medical Sciences, Professor Vladimir Konstantinovich Lepakhin

Pharmacovigilance, or drug-safety control, is a new direction of clinical pharmacology that has emerged in recent years and is rapidly developing around the world. According to the WHO definition, pharmacovigilance is the science and activity of detecting, assessing and preventing adverse drug reactions (ADRs) or any other possible drug-related problems.

At one time the USSR had an All-Union Center for the Study of Side Effects of Drugs (VTsPDL). Information and educational work were relatively well organized. The center published a specialized abstract journal called “Adverse Effects of Medicinal Substances,” distributed free to practically every medical institution in the country. Most articles were translated from foreign sources — but even that was important: if your own system does not work, you should at least know what is going on in the world.

Another important part of pharmacovigilance is collecting and analyzing drug-safety information. The center received 1,000–1,500 reports per year from physicians. With the collapse of the USSR the center disappeared. When the Russian Ministry of Health succeeded the Soviet Ministry of Health, no comparable structure was organized. Doctors who did not read foreign journals — most did not — were left in an information vacuum.

In 1994, on the initiative of our Department of General and Clinical Pharmacology at the Peoples’ Friendship University of Russia, the International Foundation for Drug Efficacy and Safety Research was created. It began publishing a bulletin called “Drug Safety” — again largely translations from foreign journals. The foundation’s resources were limited and the work rested on enthusiasm. The main editor and chief enthusiast was Associate Professor Alla V. Astakhova of our department, who practically single-handedly prepared the bulletin. The first issues were typed and stapled; later issues were sent to central research institutes and regional health authorities for further distribution. Given the strong demand, the Ministry started funding the bulletin; it became more substantial and reached a print run of 10,000 copies — though Russia has more than 600,000 doctors. Funding later ceased, and publication continues through voluntary efforts.

We regularly publish ADR reporting forms and urge doctors to report pharmacotherapy complications. In 1997 (again on our initiative) the Russian Ministry of Health issued an order establishing the Federal Center for the Study of Adverse Drug Effects on the basis of our department; I was appointed director. Regional health authorities were instructed to create regional centers. By the end of 1997 more than 20 regional centers had been established. The Federal Center was set up on a functional basis — it received no funding, as the year’s budget had already been allocated. Everything again rested on enthusiasts.

The reports received were processed, entered into the database and analyzed. The most important were sent to the WHO Uppsala Drug Monitoring Centre in Sweden, because in December 1997 WHO officially admitted Russia into the international drug-safety program after positively evaluating the Federal Center. At the time the center was receiving reports from 47 countries; Russia became the 48th member, followed by China. Russia could now access a WHO database with over 3 million ADR reports and establish working contacts with drug-safety centers in nearly 50 countries.

In April 1998 the Ministry of Health and the Ministry of Foreign Affairs assigned me to WHO headquarters as Deputy Director-General. Meanwhile in Russia the Federal Center was renamed a scientific-practical center — still without funding — and a year later it was reorganized again into a small laboratory within one department of the Institute of Preclinical and Clinical Drug Examination. The Federal Center was effectively destroyed and its role as the coordinator of this work in the country was lost. Some regional centers, however, continue to function today.

As Deputy Director-General of WHO I oversaw the drug departments and the medical-technologies department. The WHO Drug Monitoring Centre was part of the pharmaceutical department, and it was painfully embarrassing that reports from Russia to WHO numbered in the tens, not tens of thousands: sometimes 39, sometimes 18 per year. By the WHO “gold standard” of 200–300 reports per 10 million people (accounting for the fact that only about 10% of doctors report), Russia should have at least 60,000 reports a year. It had 400 last year, 200 the year before. Abroad, participants include doctors, manufacturers, distributors, pharmacists, nurses and even patients.

Unfortunately the Russian Ministry of Health gave pharmacovigilance little attention for many years. In the first 5 years I worked at WHO HQ, Russia had 5 different health ministers — each time a new team, starting anew, and no one was thinking about drug side effects.

Another issue is the lack of specialists. Pharmacovigilance must be done by professionals, but Russia does not teach this work. The Ministry of Health’s order introducing a clinical-pharmacologist position in large hospitals helped somewhat — work on detecting, preventing and treating ADRs began. Today the situation is paradoxical: some regions work hard on it, while there is no federal center. We continue to do everything we can, chiefly publishing the journal “Drug Safety and Pharmacovigilance” at the department’s expense in very small print runs.

The thalidomide tragedy was the trigger for creating pharmacovigilance and post-marketing drug-safety observation systems. Tens of thousands of pregnant women took thalidomide as a sedative, sleep aid and anti-emetic; children were born with severe congenital malformations. The link was identified only after several years of use. At first, the malformations were attributed to viruses, environmental factors, etc. Recognizing a drug-reaction causal link is not easy — and becomes especially hard with polypharmacy.

Everyone — doctors, healthcare administrators — understands the need for drug-safety work, but in practice pharmacovigilance is not supported. Yet it is about saving the health and lives of thousands of people. Preventing side effects is possible only if we receive information about them in time.

Abroad, the law obliges drug manufacturers to list every known side effect in the product information. Most of the safety information seen in package inserts comes from clinical trial results. But trials are limited in number and duration; they do not include people with comorbidities, the elderly, children or pregnant women. Yet the elderly are most often the ones who fall ill, and most ADRs occur in them. These limitations prevent clinical trials from revealing all possible ADRs across populations. Trials detect frequent ADRs; rare (but potentially very dangerous) ADRs are usually found only during widespread use.

That is why pharmacovigilance is needed — to detect complications of new drugs in broad medical practice. A more accurate name would be “pharmaco-vigilance,” which better conveys the meaning. The better the service works, the faster side effects are detected. When new reactions are identified, these services can require manufacturers to update the product information — and even ban the drug.

Globally there has been “liberalization” of the registration process. The goal is clear — drugs should reach patients quickly; progress should benefit people. But insufficiently studied drugs are also being registered. Some are withdrawn within 1–2 years — some with scandals, some quietly — because serious adverse effects are discovered. It is obvious that the role of pharmacovigilance grows with registration liberalization.

Today 97 countries participate in the WHO drug-monitoring program. Drug-safety structures around the world are expanding. They are usually state-run and government-funded, although some are run by medical associations or foundations to which the state has delegated this work. For example, in the Netherlands the Lareb Foundation is a non-governmental professional association to which the Dutch Ministry of Health has fully delegated pharmacovigilance; it sends the ministry already analyzed information with its proposals.

Pharmacovigilance and pharma manufacturers are not enemies, but their interests do conflict. For a serious pharma company, the earlier undetected serious ADRs are discovered the better — warnings can be added, recommendations updated or the drug withdrawn in time, avoiding multi-million-dollar lawsuits. In recent years there have been several such high-profile cases — Vioxx and others were banned.

In the short term, less-reputable pharma companies are not interested in a well-functioning pharmacovigilance system; reputable ones that are not planning to close tomorrow are. In countries with well-established pharmacovigilance, companies (required by law) are major suppliers of reports. In Russia this is not the case. The severity of our laws is offset by the possibility of ignoring them. Our drug law has two special articles obliging everyone in the drug-circulation chain to report side effects — but no one does.

Experience shows laws and orders alone will not get the work done. Forcing a doctor to report an ADR is practically impossible — you must convince them of their professional and civic duty, of the fact that they can save thousands of lives by reporting a case. Doctors should report even cases where they are not sure, where only suspicion exists. When one center gathers dozens or hundreds of such “suspicions” it becomes clear there is a real link.

Decisions about a drug’s further fate are difficult and require weighing risk against benefit. It is one thing for a drug that makes life more comfortable, another for a drug treating a serious, life-threatening disease.

Once, as Chairman of the Pharmacological Committee under the USSR Ministry of Health, we had a special commission on product information, including leading specialists from all branches of medicine. There were separate instructions for doctors and adapted inserts for patients. Scaring patients with rare side effects is pointless — they will stop treatment. Today the global trend is to give patients all the information and shift responsibility for the choice of drug to them. Of course, patients must be educated about their health and pharmacotherapy. More than half of pharmacotherapy problems stem from incorrect drug use (by the doctor or the patient).

Unfortunately most of the public is illiterate on drugs. Many believe more vitamins is always better and have never heard of severe hypervitaminosis. Vitamin A in large doses is teratogenic, yet doctors prescribe Aevit to pregnant women — with ten times the dose the international teratology society considers safe. Both doctors and patients need education.

Finally, I hope that a modern pharmacovigilance service meeting international standards will soon be created in Russia. The preconditions exist. As far as I know, the new head of Roszdravnadzor, Nikolai Viktorovich Yurgel, has already issued an order to create such a structure. Incidentally, in 1997 when regional ADR-study centers were being set up, he — then one of the healthcare leaders in Omsk — signed the order creating the Omsk regional center, which still operates and is one of the best. With political will, funding and trained specialists the work will be established.

I am sure clinical pharmacologists and practitioners will enthusiastically support this initiative, and Russia will take its rightful place in the international drug-monitoring program — and most importantly, tens of thousands of patients will be spared severe pharmacotherapy complications.