Pharmacovigilance in perspective: drug withdrawals, data mining and policy implications

Introduction

Pharmacovigilance (PV) has been a valuable method in identifying adverse drug reactions (ADRs) and improving the safe use of medicines¹. PV has been the backbone for many drug safety interventions, such as drug withdrawals, labelling changes and prescription restrictions^2–4. The advancement and synchronization of information technology had led to valuable contributions in signal detection and data mining processes in PV⁵. It is important to have policy framing to incorporate PV measures in every country’s drug regulatory mechanisms, so as to implement and sustain drug safety monitoring processes. In this review article, three important aspects of PV are discussed; significant examples of drug withdrawals as an outcome of PV data, data mining and its role in PV, and policy implications related to PV. In addition, PV experiences in selected countries are detailed.

Examples of drug withdrawals as a result of pharmacovigilance

Many medications have been withdrawn from the market due to their severe, harmful or life-threatening effects. Following marketing approval, once the first ADRs are reported, the reports will be analyzed and the incident will be investigated; and if post marketing surveillance indicates harmful effects for the medication, it will be withdrawn from the market⁶.

Rofecoxib (Vioxx), manufactured by Merck & Co. in 1999, was indicated as an NSAID in the treatment of “osteoarthritis, rheumatoid arthritis, acute pain and menstrual pain”. In the marketing stages, the company did not mention any cardiovascular disorders. Between 2000 and 2002, reports started to emerge on the hazards of Vioxx, but it took a 3-year clinical trial, “APPROVe” (Adenomatous Polyp Prevention of Vioxx), executed by Merck Frosst Canada, which lead to participants experiencing cardiovascular events such as heart attacks and strokes, for the drug to be withdrawn from the market⁷. In 2004, during a US Senate hearing concerning rofecoxib issues, Dr. David Graham, who was the associate director in the U.S. Department of Food and Drug Administration (FDA)’s Office of Drug Safety, stated: “The approval of rofecoxib (Vioxx) by the US FDA has led to the single greatest drug safety catastrophe in the history of this country or the history of the world”. It has been estimated that 88,000 to 139,000 Americans have had heart attacks or strokes due to Vioxx. The drug was finally discontinued in 2004⁸.

Lysergic acid diethylamide (LSD), was discovered in 1938 by Dr. Hofmann, who was in Sandoz Laboratories in Switzerland⁹. After five years, it became evident that the drug was causing hallucinations, euphoria, delusions, depression, as well as suicidal thoughts^10,11. In 1970, LSD was placed in Schedule 1 category of drugs; the most restricted category, following passage of the Controlled Substances Act. This category indicates “a high potential for abuse, no recognized medical use, and no safety when used by a physician”⁹.

Benfluorex (Mediator) was first manufactured and marketed by Servier in 1976 in France as an add-on therapy for hyperlipidemia and diabetes associated with obesity. In 1998, an official PV investigation was opened regarding the drug in France due to its “potential danger”, and Italian regulators expressed apprehension to the European Medicines Agency (EMA). In 1999, two cardiovascular complications were reported in France. In 2003, Spanish regulators reported a cardiac valvulopathy case to the EMA¹². Servier decided to withdraw the drug from Spain and Italy through not renewing their expired license¹³. In 2009, AFSSAPS (Agence Française de Sécurité Sanitaire des Produits de Santé), the regulatory authority of France¹⁴, suspended benfluorex marketing due to “efficacy and safety issues” especially after a case control study that was done by a chest physician, Irene Frachon, in which she discovered that drug-induced valvular heart disease is associated with benfluorex. Servier withdrew the medication worldwide after earning 20 million Euros each year for the previous 15 years¹². EMA fully withdrew the drug in 2010¹³.

Sibutramine (Meridia, US; Reductil, UK)⁸, a weight management and weigh loss agent, was approved in Europe in 1999¹⁵, and in other parts of the world. Since 2002, many cardiovascular events were reported, including hypertension, tachycardia, arrhythmia and myocardial infarction (MI). In Sibutramine Cardiovascular Outcomes Trial (SCOUT), results demonstrated that patients with preexisting cardiovascular disease who had taken sibutramine had an increased likelihood of developing MI or stroke¹⁶. David Graham - in his testimony before the Senate committee about medications that may harm the patients - included Meridia as one of them⁸. Sibutramine was withdrawn from the US and European markets in 2010^15,16.

Pergolide (Permax) was developed by Eli Lilly & Co., and approved in 1988 for the management of Parkinson’s disease symptoms (Reuters, 2007)¹⁷. It was then withdrawn from the US market in 2007 due to “increased rates of cardiac valvular dysfunction (cardiac valvulopathy)”⁶.

Pemoline (Cylert) was approved in Europe in the sixties, and in the US in 1975, for the treatment of attention deficit hyperactivity disorder (ADHD). Between 1975 and 1989, the FDA received reports of “12 cases of jaundice and 6 deaths in youths ascribed to pemoline hepatotoxicity”. Serious hepatotoxicity was unveiled only in 1996. Pemoline hepatotoxicity reporting was not sufficient in the 1980s to stir an action, due to the poor post marketing surveillance and reporting systems¹⁸. Following those incidences, the FDA mandated a black box warning to highlight the risk of hepatotoxicity. Afterwards, another case of liver failure was reported, forcing the manufacturer of Cylert (Abbott Laboratories) to cease production in May 2005, and the FDA notified healthcare professionals about the discontinuation of all pemoline products¹⁹.

The Contergan scandal took place in early 1960s. Contergan had thalidomide as the active ingredient, a product of a German company “Chemie-Grünenthal”, having sedative effects, apparently non-toxic, with few side effects²⁰. It was used as a sedative, hypnotic and antiemetic for pregnant women²¹. Mothers who used thalidomide in their early pregnancy had horrific results, as over 10,000 children were born with birth defects such as phocomelia²². It was withdrawn from most markets between 1961 and 1962²¹.

Valdecoxib (Bextra) was an NSAID used for arthritis and joint pain²³. According to The New England Journal of Medicine, increased cardiovascular events occurred after coronary artery bypass grafting surgery associated with valdecoxib usage²⁴. Cardiovascular complications were reported, as well as “Stevens–Johnson syndrome, erythema multiforme, and toxic epidermal necrolysis”. These reports led to valdecoxib’s withdrawal from the market in 2005²³.

Levamisole (Ergamisol) is an immunomodulatory agent used as an adjunct chemotherapeutic drug. It was manufactured by Janssen Pharmaceutica in 1966. Serious side effects were discovered, including: “neutropenia, agranulocytosis, cutaneous vasculopathy, and leukoencephalopathy”²⁵. Levamisole was withdrawn from the US market in 2000. However, it is currently being used as an antihelminthic in veterinary medicine and can be found in street drugs as a cocaine adulterant²⁶.

Hydromorphone hydrochloride extended release (Palladone) manufactured by Purdue Pharma and launched in the USA in January 2005, was used as a narcotic analgesic²⁷. The FDA withdrew the drug in July of the same year due to dose dumping with alcohol, which leads to accidental overdosing^27,28. Dose dumping is the release of large amount of hydromorphone drug from the extended release form leading to toxicity²⁸.

Cisapride (Propulsid), manufactured by Janssen Pharmaceutica²⁹, was indicated as a prokinetic for severe heartburn associated with gastroesophageal reflux disease. Post marketing studies showed patients experiencing “palpitations, unusual tachyarrhythmia, torsades de pointes, ventricular fibrillation, QT prolongation, and sudden death”³⁰. Cisapride was associated with 341 heart rhythm abnormalities cases and 80 deaths. Most of these cases involved patients taking other medications or have medical conditions that increased cardiac arrhythmia risk²⁹. It was later withdrawn in 2000³⁰.

Drotrecogin alfa (Xigris) is a recombinant human activated protein C that has anti-thrombotic, profibrinolytic and anti-inflammatory activity³¹. It was indicated for treatment of severe sepsis. Xigris was marketed by Eli Lilly; the FDA approved it in 2001^31,32, while the EMA approved it in 2002³². Following a study (PROWESS-SHOCK) that included 1696 patients and concluded that Drotrecogin alfa did not reduce mortality within 28 days, Eli Lilly voluntarily withdrew Xigris from the market in October 2011, and the FDA and EMA communicated the decision to healthcare professionals^33,34.

Aprotinin (Trasylol), manufactured by Bayer in 1993, was indicated as antifibrinolytic to reduce blood loss during heart surgery³⁵. By the end of 2007, aprotinin was discontinued globally, following Blood Conservation using Antifibrinolytics Trial (BART) findings that suggested an increase in 30-day mortality with aprotinin³⁶. However, in 2012, the EMA recommended that the suspension be lifted³⁷. However, these claims were disputed in another study in 2013, which found that aprotinin may increase the likelihood of mortality in low and intermediate cardiac surgery patients. The study suggested that the decision by the EMA to reinstate the drug for lower risk patients should be debated³⁶.

Data mining in pharmacovigilance

Data mining is the process of collecting and analyzing data from sources of information that may be raw and complicated (such as data sets or databases) and extracting patterns of links and relationships between these data, to be translated into useful information³⁸. Data mining has been used in many aspects; most importantly it has contributed to drug discoveries, prediction³⁹, diagnosis of diseases (such as diabetes)⁴⁰ in addition to drug complications and ADRs⁴¹. According to Wilson et al.⁴² “Data mining encompasses a number of statistical techniques including cluster analysis, link analysis, deviation detection and disproportionality assessment which can be utilized to determine the presence of and to assess the strength of ADR signals”. Whenever we predict these ADRs, we can reduce the morbidity and mortality rates⁴³.

Policies and procedures for implementing pharmacovigilance

The WHO considers the monitoring of safety and effectiveness of medicines in any country as the responsibility of national governments. The fulfillment of this responsibility can be achieved by establishing national PV centers with well-defined PV systems. The foundation of the launch of PV centers is the establishment of policies regarding the costs, budget and the financial requirements of running the centers⁵⁶. Financing for a PV center must be secured and given official approval, in order to guarantee the progress of work. The costs incurred depend on the size of population that is serviced by the center and the rate of reports generated. Possible sources of funding may be: insurance companies, academic institutions, and governmental bodies that are interested in the safety of medicinal products⁵⁷. The location of the center may initially be within a country’s main hospital and, over time, be extended to multiple hospitals all over the country. Each smaller center would then send its reports to the main national center, which would be responsible for gathering the information and communicating and coordinating between the multiple centers. Finally, the main center would conduct and transfer the gathered information to the global PV institutions, such as Uppsala Monitoring Centre (UMC) in Sweden⁵⁷.

However, this will not be achieved unless the center has a sufficient number of qualified and trained personnel. The WHO determined that the minimum requirement of manpower to work in the PV center is at least one full-time employee⁵⁸. Staff should give support and be involved in the PV process depending on their assigned tasks and responsibilities. However, these tasks and all organization resources should be structured and arranged to assist in the proper conduct of PV activities. Besides, the presence of qualified leadership is one of the most important factors in order to implement PV techniques and to motivate all staff to achieve the objectives. A good PV system must have excellent data collection methods to gather evidence on the risk/benefit balance and all criteria related to the safety of medicinal products, which will affect decision making. The system must include preparedness plans with appropriate instructions for urgent cases. The center should contain appropriate facilities and equipment which include office space and information technology systems⁵⁹. Each center should have a database and a standard individual case safety report (ICSR) form and be connected with the national database. The national PV center should recruit an advisory committee, which will help and support the local PV centers in risk assessment and management, and most importantly in crisis⁵⁸.

As the core of the PV system is to report any ADRs, reports must utilize a specific ADR reporting form and should be unique to each country. The forms should be distributed to all healthcare professionals in all areas, and all healthcare institutions; hospitals, pharmacies, medical centers⁶⁰. These forms are known as standard ICSR forms⁵⁸. ICSR is defined in PV as “a notification relating to a patient with an adverse medical event or laboratory test abnormality suspected to be induced by a medicine. It is an essential source of information for the achievement of the main objectives of PV and can involve several ADRs”⁶¹. Forms should then be gathered and collected or posted to the center by fax or email to ensure an easy flow of data. The minimum information in these forms should be general information about the patient (such as age, gender, race), a detailed description of the ADR, severity, lab tests (if any), date of appearance of ADR, the suspected medication causing the reported ADR (product information such as brand name, dosage form, the ingredients, and concentration), manufacturer related information, dose of medicine and date of initiation and withdrawal (if applicable), a brief medical history of the patient, the risk factors may be present in the patient like other medical problems or diseases (such as liver or renal problems and allergies), and the name of medical practitioner who detected and observed the ADR⁵⁷.

For the reporting procedure to be complete, communication of ADR reports to VigiBase, the WHO global database that receives contributions from national PV centers in different countries, is essential for the success of the WHO’s International Drug Monitoring Programme⁵⁶. The startup of the WHO’s Programme for International Drug Monitoring was in 1968 as a pilot project, with 10 countries already having established national systems for reporting of ADRs. The project then expanded to include more countries all over the world. New member countries developed PV centers to report the ADRs and coordinate with the WHO center in Uppsala, where VigiBase is based. VigiBase contains more than 8 million ADR reports from more than 110 countries⁶². VigiFlow is an internet-based system that offers free access to all member countries to see all information and reports in VigiBase, and their analysis from all over the world⁶³. In April 2015, the WHO launched VigiAccess, a web application that allows anyone to access information. This is a significant step, which encourages reporting ADRs⁶⁴.

PV programs and drug regulatory authorities must be linked together so that the regulatory authority is continuously updated about any emerging safety issue, and at the same time regulatory authorities should know the critical need for the PV concept, leading to a focus not only on the approval of new medicines, but on their safety as well⁵⁶.

In order to assure reliable PV program, it is crucial to periodically train staff on gathering and analyzing information related to ADRs, risk management, signal detection, data mining and possible actions in cases of a serious or fatal ADRs⁶⁰. Today’s quick-paced advancing world implies that PV personnel may require training on new skills, technologies and concepts, like artificial intelligence and machine-learning.

Moreover, training should be directed not only for the staff with specific PV tasks but also those with activities that have impact on the PV system, including clinical trials, and regulatory affairs⁵⁹. As the training and education of healthcare professionals in the services of PV increases, patient safety will improve, quality of ADR reports will be enhanced, and the development of policies to prevent them will occur.

A non-randomized study was conducted in a hospital in Brazil in 2012 on a multidisciplinary group of healthcare providers. Educational intervention involved different methods such as: lectures on PV, a practical class about reporting ADRs, and distribution of written materials about PV to healthcare providers. In order to assess the level of information about PV among the participants, a questionnaire was given before and after the intervention. The results showed that the educational intervention was successful in the understanding of PV concepts, and improving skills to effectively complete reports related to ADRs. Directly after the educational intervention, the number of reports increased; however, four months after the educational intervention the number decreased, which implies that the education has to be continuous or periodic to keep the motivation among healthcare practitioners toward reporting ADRs⁶⁵.

Implementation of pharmacovigilance regulations: country experiences

Conclusions

In the past, PV has contributed to identifying the safety of medications at an earlier stage and thus preventing harmful effects of medicines affecting much larger populations. Several drugs have been banned based on the safety findings obtained during PV programs. Data mining is a powerful method of early detection of ADR signals and can provide valuable contribution to PV if properly integrated with modern information technology tools. Several countries have implemented policies governing PV that offered them substantial benefits in terms of ensuring patient safety.

Data availability

No data is associated with this article.