Pharmacovigilance: more than ever, an overall responsibility

EDITORIAL

Pharmacovigilance: more than ever, an overall responsibility

Sonia Mansoldo Dainesi

Hospital das Clínicas, Faculty of Medicine, University os São Paulo - São Paulo/SP, Brazil. E-mail: [e-mail]

All medicines have side effects and, hence, should be followed up after they are introduced into the market. This is the simplest way to define and start talking about Pharmacovigilance. Another way would be to say that "First, do no harm", a medical principle first put forward by Hipocrates and followed throughout the centuries by all physicians and others working with medical sciences. A third way of looking at this would be to remember that absence of evidence is not evidence of absence.¹ It is well known that a long time can be required to identify a problem with a new drug. Aspirin is certainly a good example but thalidomide is definitely a better one. An extensive and in depth review on this very controversial drug, published in 1999, shows an analysis of the historical context of the thalidomide disaster, and its revival for the treatment for some serious clinical conditions where no better therapeutic option is available.² More than 30 years after the disaster, the drug is back indeed, with new indications, but with very precise and restritive prescribing information.³

In September 2004, Merck & Co. announced the voluntary withdrawal from the market of rofecoxib (Vioxx^®), a widely used non-steroidal anti-inflammatory drug, due to safety concerns. This episode and some other subsequent related issues raised many questions concerning drug policy, scientific evidence and the role of postmarketing surveillance.⁴ An uncorfortable consequence of this episode was doubtlessly the erosion of the public confidence in the development, approval, and follow-up of medicines. And, surprisingly, not only the pharmaceutical industries, but also the regulatory agencies - such as the American FDA (Food and Drug Administration) - as well as the investigators who participated in the studies, none of them have escaped criticism.^5,6 The final question, which will not go away, is how can public trust be recovered.

When a new medicine is first marketed, the efficacy and safety data are commonly based on the experience of several thousand patients who were included in the pre-marketing clinical trials. Even after the most rigorous clinical development plan, some rare adverse events can not be detected, nor can all the drug interactions or coexisting clinical conditions be well assessed.^7,8 The classical criticism which applies to the clinical trials approach is that they do not reflect the real world. In fact, only clinical practice, after launching, will really do the job.

There is an important message behind all this. The spontaneous reporting systems we have in place to track adverse drug reactions enable detection of any increased incidence of rare events, such as fulminant liver failure or rhabdomyolysis, after the introduction of a new drug into the market. But detection of increased incidence of a common event, such as a myocardial infarct, or a stroke, is a much more difficult proposition. And the real problem is that the latter entails far more impact on public health than the former. Taking into account that epidemiological studies with cardiovascular end-points, for instance, are subject to somewhat confusing interpretations, determination of true risks associated with treatment requires randomized controlled trials specifically designed to look for such risks.⁹ This is one of the challenges for drug development and surveillance in the new century. Some successful strategies are already in place in the most countries such as the voluntary report of Suspected Adverse Drug Reactions. Other strategies used to increase reporting can be listed: emphasis on educating junior doctors and medical students; a broadening of the reporting base by involving pharmacists and nurses; the introduction of user-friendly reporting using eletronic links; the provision of feedback by personalising communications or through periodic bulletins, the tracking of early signals, the implementation of the so called "sentinel hospitals", etc.¹⁰ The challenge for those working in pharmacovigilance will therefore be to investigate and document, in epidemiological and health economic terms, whether drug safety profiles obtained from clinical trials in narrowly selected populations still hold true when drugs are used in clinical practice.¹¹

An extended approach is already applied by the agencies, including the Brazilian ANVISA, regarding the concept of safety issues: firstly, instead of focusing only in the detection of adverse events, we shall also focus on their prevention; secondly, apart from tracking drug adverse events, regulatory agencies must take care of product quality; finally, agencies should not rely exclusively on traditional safety and efficacy data, as they usually did in the past, but concentrate in the rational use of medicines as well.

What does the recent COX-2 inhibitors controversy mean to all of us? First, it has shown that post marketing drug surveillance is an important task, and that improvements can be introduced at the FDA, and certainly all over the world. Second, physicians may be aware that there is always a trade-off between a drug's risk and its benefits; but the public expects perfection when a new drug comes to the market. When something like Vioxx^® happens, it throws the risk-benefit analysis into disarray. Third, the regulatory hurdles for bringing drugs to market are likely to increase. Usually, it takes ten to fifteen years to carry a drug to market, from the scientist's discovery to the regulator's approval. The FDA appears poised to impose much tougher standards on the authorization of new drugs, making it more difficult for the R&D-oriented pharmaceuticals companies to deliver products to the market.

Although efficient regulatory systems are indeed necessary to protect patients, they will always depend on the active participation of all health professionals. Such systems must make it clear that what is really needed is a culture that encourages the sharing rather than the hiding of errors.¹² Additionally, the difficulties faced by the regulatory agencies probably reflects the great complexity of the theme, more than a possible fragility in the regulatory systems.

Putting together some factors such as: more trials required by the agencies before approval, more people taking more drugs and more combinations of drugs and for longer periods of time (partly because of the greater longevity we fortunately enjoy), it should be expected that more adverse events may be reported.¹³ In addition, public awareness of the potential for drugs to cause adverse reactions is on the increase. One of the messages to be taken home from recent events is that doctors must to be more aware of the very preliminary nature of data, both in termos of safety and efficacy, which come with newly licensed drugs. Clearly, this is an immensely complicated equation involving, among other factors, the nature of the condition being treated, the therapeutic strategies already available, and the perceived benefit-risk of the new treatment.⁵ Regulatory decisions are necessarily based on scientific knowledge that balances benefits and risks. But, doubtlessly, we need to be sure that we don't deny access to patients who really need a given medication.

No medicine is risk-free. All have side effects which must be weighed against the potential benefits. That is why medical judgment is so critical. Additionally, the effort for improving adverse reaction reporting should deserve special attention of all in health professional community. This is the only way to guarantee the quality and the safety of the drugs we and our patients usually take.

REFERENCES

1. Fitzgerald GA. Coxibs and cardiovascular disease. New England J Med. 2004;351:1709-11.

2. Oliveira MA, Bermudez JAZ, Souza ACM. Talidomida no Brasil: vigilância com responsabilidade compartilhada? Cadernos de Saúde Pública. 1999;15(1):99-112.

3. Thalomid^® (thalidomide). Draft/Proposed prescribing information. Available at: http://www.fda.gov/cder/foi/label/2003/20785slr022,023,024_thalomid_lbl.pdf, accessed on May 4^th, 2005.

4. Coxibs, science and the public trust. Editorial. Arch Intern Med. 2005;165:158-160.

5. Horton R. Vioxx, the implosion of Merck, and aftershocks at the FDA. The Lancet. 2004;364:1995-96.

6. Topol EJ. Failing the public health - Rofecoxib, Merck and the FDA. New England J Med. 2004;351:1707-09.

7. Trontell A. Expecting the unexpected - Drug safety, pharmacovigilance and the prepared mind. New England J Med. 2004;351(14):1385-87.

8. Dainesi SM, Juquiram AB, Biazetti L. Farmacovigilância. Um dever de todos. Parte I. Rev Soc Bras Cancerologia. 2001;anoIV(13):33-37.

9. Drazen JM. COX-2 inhibitors - A lesson in unexpected problems. New Engl J Med. 2005;352(11):1131-1132.

10. Barnes J. Challenges for pharmacovigilance in ther new millenium. Inpharma. 1999;1211: 20-21.

11. Talbot JCC, Nilsson BS. Pharmacovigilance in the pharmaceutical industry. Br. J Clin Pharmacol. 1998;45:427-431.

12. Altman OF, Clancy C, Blendon RJ. Improving patient safety - Five years after the IOM Report. New Engl J Med. 2004;351(20):2041-43.

13. Peachey J. From pharmacovigilance to pharmacoperformance. Drug Safety. 2002;25(6):399-405.

Publication Dates

• Publication in this collection
  29 Aug 2005
• Date of issue
  Aug 2005