working methods for the adverse drug reaction monitoring program in ...

Drug Information Journal, Vol. 32, pp. 85–92, 1998 Printed in the USA. All rights reserved.

0092-8615/98 Copyright  1998 Drug Information Association Inc.

WORKING METHODS FOR THE ADVERSE DRUG REACTION MONITORING PROGRAM IN THE PHILIPPINES KENNETH HARTIGAN-GO, MD, FPCP, FPSECP Project Leader, Adverse Drug Reaction Monitoring Programme, and Associate Professor, Department of Pharmacology, College of Medicine, University of the Philippines, Manila, Philippines

Initiatives to monitor adverse drug reactions (ADRs) exist in many countries. Information about ADRs assists in policy changes and interventions toward the safer use of medicines. The Philippines ADR monitoring program began in August 1994 with assistance from the Australian Agency for International Development (AusAID) and the Philippines Department of Health (DOH). This program is entrusted to an academic institution for implementation. The objective of this program is to promote drug safety through ADR monitoring nationally. The methods include training courses, establishing notification systems through hospital therapeutics committees, and advising DOH about problem drugs and their usage. A few hospitals started in-house notification schemes and are part of the program’s network. Reports received by the program are processed and sent to the World Health Organization (WHO) Uppsala Monitoring Centre. The program has received over 400 ADR reports; produced training videos, manuals, and newsletters for health professionals; and collaborated with health professional associations. Future plans include addressing the needs of general practitioners and consumers. Key Words: Adverse drug reactions; Philippines; AusAID; WHO; Therapeutic committees

INTRODUCTION

pine Adverse Drug Reaction Monitoring Programme (ADRMP) is presented in this paper. An adverse drug reaction is defined as: “any response to a drug that is noxious and unintended and which occurs in doses used in man for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function” (1). This is a strong statement often indicating a strong causality between the use of a drug and the resultant adverse reaction. The term adverse drug event (ADE) (2) is softer and denotes an adverse experience which develops following the intake of a medicine though not necessarily shown to have a strong causal link. ADE is the term advocated for use in the Philippines although it is often interchanged with ADR.

MEDICINES ARE AN INDISPENSABLE part of people’s daily lives, yet they might be considered a two-edged sword in the sense that they save lives but at the same time cause adverse drug reactions. Initiatives to monitor ADRs exist in many countries and use different methods. The experience of the Philip-

Presented at the DIA 33rd Annual Meeting “Optimizing Pharmaceutical Development: The Global Experience,” June 22–26, 1997, Montreal, Canada. Reprint address: Dr. Kenneth Hartigan-Go, Department of Pharmacology, University of the Philippines College of Medicine, 547 Pedro Gil St., Manila 1000, Philippines.

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A NEW BEGINNING FOR THE PHILIPPINES Initiatives to start a national system in the Philippines 30 years ago met with poor response to reporting; the different reasons were discussed (3). A new program was created in August of 1994 with the technical and financial assistance of the Australian Agency for International Development in collaboration with the Bureau of Food and Drugs and the Philippine National Drug Policy Office of the Philippine Department of Health. Republic Act 3970 provided the medico-legal mandate for the Bureau of Food and Drugs to carry out the implementation of drug safety assurance in the country. This program was initially entrusted to an academic institution (University of the Philippines) for implementation and started with three pilot hospitals in order to gain insight into monitoring problems. These hospitals are the Philippine General Hospital (PGH), the Santo Tomas University Hospital (STUH), and the Makati Medical Centre (MMC). PGH is a stateowned university affiliated hospital while STUH is a privately owned university affiliated hospital. MMC is a privately owned medical center without a university affiliation. At the start of the program, a technical consultant from Australia came to the Philippines to assess the situation and provide advice on methods for setting up the system. A few hospitals previously started inhouse notification schemes such as the Philippines General Hospital in the 1970s (4) and Santo Tomas University Hospital in the 1980s. It was important to elucidate issues surrounding reporting. These academically affiliated hospitals needed to have a monitoring system in order to determine safe drugs for inclusion in the hospital formulary, and provide cases for clinical teaching. Experience from the activities in these hospitals assisted in the implementation of the program. The objectives for the ADRMP were to promote the program of drug safety monitoring nationally, including not just problem drugs but also problem drug usage; and to approve the program as a viable national activity for the Bureau of Food and Drugs to

Kenneth Hartigan-Go

implement. Six months after the start of the program, the ADRMP was made an active national center member of the WHO Collaborating Centre for International Drug Monitoring. The program, therefore, had to establish a system and provide different communication packages to promote these objectives. It had to be initially conducted through hospital systems, in particular, therapeutic committees of each medical institution which have to take up this activity as part of a strengthening scheme. Hospital consultations are estimated to represent about 15% of the country’s patient population. The other 85% seek medical consultations in outpatient settings or community practice (ie, general practitioners); the potential for ADRs in the course of outpatient treatment had to be addressed at some stage by the program. WORKING METHODS Initially, the program had to address many possible groups of health practitioners: • Those who recognize an ADR and know that there is a mechanism for notification, • Those who recognize an ADR but do not know what to do, • Those who recognize an ADR but will not bother to notify, and • Those who have never seen an ADR. Health practitioners in the first group are not a problem, but this is a very small group. The program had to develop a user-friendly, nonthreatening adverse drug event form for use (see Figure 1). This form had to indicate that data will be treated confidentially and that submission of reports is not evidence of causality. For those who do not know what to do, that is, where to obtain notification forms and where to direct the forms, a system was introduced through the hospital therapeutic committees. It was necessary to implement a system of in-house training for the notification scheme within each hospital. For this activity, the program encouraged hospital therapeutic committees or adverse drug reaction subcommittees to play a significant role

The Adverse Drug Monitoring Program in the Philippines

FIGURE 1. The ADE form.

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in initially analyzing the ADR reports. Questions commonly asked during committee evaluation (4) included: • Was there a temporal relationship between the adverse event and the drug given in the appropriate manner? • Is the reaction a known response? • Can the reaction be explained by the disease? • What happened during rechallenge (in the event this was done)? • Is a toxic drug level associated with the response? This simple approach was taken to assess developments and where applicable, standardize methods within the hospital while sacrificing the time for these reports to be channeled to the program office for further collation and analysis. The introduction of a system was not difficult once WHO guidelines and reporting systems were introduced into the operation. These guidelines provided a formal reference for newcomers and support for their training. The use of the guidelines also helped overcome certain aspects of the resistance to “breaking new ground.” There were a number of opportunities for technical support through the Uppsala Monitoring Centre for which the program is thankful. This support included validation of local training packages, early warnings of unsafe medicines, citations in newsletters, and utilizing WHO posters (Figure 2). The opportunity for local Philippines medical practitioners to actively participate in a global activity elevated their interest and enthusiasm. It was apparent to all contributors that they were providing assistance and contributing to an important international drug safety monitoring program. This in turn consolidated and enhanced the national monitoring program. The Philippines Index of Medical Specialties (PIMS) is the local drug reference handbook. This publication now carries the program’s ADE report form. As a result of the publicity the program should now be regarded as a national program.

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As indicated at the beginning, there are also physicians who may have seen an ADR but will not notify. There are many reasons for this. The most difficult to overcome is the fear that a report may reflect on perceived incompetence and may also lead to possible litigation. To address this problem, the program provided clinical protocols on the recognition and management of ADRs. This initiative was an attempt to build confidence in the reporting system and the underlying rationale. It also provides information on each case and therefore assessed improvement in reporting rates and the quality of information obtained. To establish and enhance a sense of moral and ethical responsibility among doctors to report ADRs, a local promotional and instructional videotape was produced. This was of necessity a low budget production using real cases and dramatization of events. The presentation emphasized the consequences of ignoring an ADR; it also highlighted how to recognize and report ADRs. Cost was contained by contracting the services of university students from De La Salle University in Manila who made this film as part of their communication course thesis requirement. This tape is now a regular program aired on cable television for medical doctors for free. It represents one of the important achievements of this program. To further encourage voluntary reporting from health professionals, the relevant officials of the DOH had to be persuaded not to issue a departmental order compelling hospitals to report ADRs. It was recognized by the manager of the ADR program that regulation and compulsion would be perceived in a negative light by the medical profession. It was generally accepted that reporting would be improved by providing feedback to the participants in the ADR program, hence a desktop newsletter called “SIGNALS” was designed. This publication highlights program progress and ADR reports. This newsletter featured achievements of in-hospital ADR monitoring and drugs of current interest as a way to promote ongoing enthusiasm in the notification scheme.


FIGURE 2. WHO poster.

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TEACHING AND TRAINING ACTIVITIES It is important to note that in many medical, dental, pharmacy, and nursing schools, the concept and rationale for ADRs is never taught. Extensive consultations through the Association of Philippine Medical Colleges and the Philippine Society of Experimental and Clinical Pharmacologists were undertaken in order to introduce the concepts of ADR recognition and management to students. During postgraduate training and seminars/workshops on rational drug use, the ADRMP is often called upon to give talks about ADRs. In these lectures, emphasis is placed on the reporting scheme, where reports are turned over to the program and later encoded reports are sent to WHO. It was necessary to show the audience and potential reporters that the program, and that of the Uppsala Monitoring Centre (formerly, the WHO Collaborating Centre for International Drug Monitoring), were not simply an institution but a group of people with friendly faces. This made it possible for the reporters to relate with ease to the program, its aims and objectives, and the reporting center as a whole. Small scale seminars/workshops are regularly conducted to address the three groups of health care providers: doctors, nurses, and pharmacists. Collaboration with health professional associations such as the Philippine Medical Association, the Philippine Academy of Family Physicians, and the Philippine Dermatological Society often involve provision of training packages and lectures. Two national ADR training courses have been conducted. The first in May of 1996 emphasized the development of provincial ADR coordinators in various hospitals and was conducted to strengthen therapeutics committees within the hospitals and to assist them in strategies and information. The result of the course was that attendees could take responsibility to promote drug safety by training fellow health professionals in ADR recognition and reporting. The program provided the participants with lecture slides to facilitate the echo training seminars they con-

ducted in their respective institutions. Following this training course, 15 participating hospitals developed in-house notification schemes and have used local ADR data to rationalize prescribing and improve their hospital formularies. The second national ADR training was held in May 1997. The main thrust of this course was to train community practitioners, a strategy to reach the 85% of the patient population seeking medical consults with general practitioners. This course had the benefit of having a WHO external consultant to assist in the training. Training and instructions in communication skills and in running meetings were successfully completed. These two skills are deemed important in promoting advocacy in pharmacovigilance. Following the lead provided in the 19th Annual National Centers Meeting organized by the World Health Organization in Lisbon, this course also initiated a management workshop in an attempt to demonstrate to the participants the difficulty, and the need, to translate ADR signals into health policies. Because participation in decision making was necessary to conduct the workshop, the participants appreciated the actual cases provided and their involvement in decision making and how their reports paved the way to make drugs and their use safer in the country. A group of Bureau of Food and Drugs (BFAD) pharmacists have undergone intensive training as part of the intended transfer of ADR monitoring activities to the BFAD, the national regulatory body responsible for the monitoring of therapeutic products. Lastly, in every educational and promotional activity of the ADR program, emphasis has been placed on the fact that ADR reporting helps save lives, increases the confidence of medical practitioners as end users of drugs, and makes them better healers and important contributors to the program for improving public health. A NEW CATEGORY IN ADR CLASSIFICATION There are a number of important categories of ADRs. These categories can easily be re-


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FIGURE 3. Reporting scheme.

membered as A (augmented), B (bizarre), C (chronic/continuous), D (delayed), and E (ending of use) reactions (5,6). The Philippines program introduced a new category, F, to mean failure of treatment. This step was necessary to address the multiple causes and real problems of therapeutic inefficacy in the Philippines. These problems can be attributed to counterfeit drugs, substandard pharmaceuticals, irrational drug use leading to antimicrobial resistance, expired or poorly stored medicines, and improper dosing and routes of administration. THE REPORTING SCHEME AND THE ROLE OF THE NATIONAL ADVERSE DRUG REACTION ADVISORY COMMITTEE The reporting scheme is presented in Figure 3. The National Adverse Drug Reaction Advisory Committee (NADRAC) was created by the Department of Health in 1994 to assist the program by providing guidance, and to advise the BFAD on drug safety and policy issues. The committee deliberates the final evaluation of ADE reports using the WHO causality assessment definitions. EXAMPLES OF SAFETY APPLICATION OF ADR CASE REPORTS Since the establishment of the program, over 400 ADR reports have been received, many of which have been translated into policy recommendations to make drugs and drug use safer. A few examples are:

• Detection of steroid compounds adulterated in certain herbal products and natural health supplements, • Detection of intravenous drug-drug incompatibility and drug-drug interactions, • Detection of misuse of misoprostol as abortifacients, • Reported numerous drug reactions following the use of parenteral antimicrobial which led to the detection of uncertified batches of medicines, • Detection of defective devices such as needles, • Warnings about weight reduction preparations and their hazards, • Warnings against self-medication, and • Warnings about the presence of metabisulfite in anesthetic preparations.

CONCLUSIONS ADR monitoring is an important task in every country in the promotion of drug safety and rational drug use. The activities of the Philippines program were presented as a model utilizing hospital therapeutics committees; the future plan is to involve community practitioners. Emphasis on drug safety through knowledge, information, and education have been the guiding principles for the Philippine program.

Acknowledgment—The Adverse Drug Reaction Monitoring Programme is a project under the assistance of the Australian Agency for International Development and the Department of Health in the Philippines.

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REFERENCES 1. WHO Collaborating Centre for International Drug Monitoring Guide to Participating Countries. World Health Organization: Uppsala, Sweden; Sept 1993. 2. Finney DJ. The design and logic of a monitor of drug use. J Chron Dis. 1965;18:77. 3. Ines-Cuyekeng E. Adverse drug reaction reporting, Philippine experience. Med Toxicol. 1986;1(suppl 1): 99–104.

4. Hartigan-Go K. Adverse drug reaction monitoring: experiences in the Philippine General Hospital. Acta Medica Philippina. 1992;28(3):164–166. 5. Rawlins MD, Thompson JW. Pathogenesis of adverse drug reactions. In: Textbook of adverse drug reactions. Davies DM ed. Oxford, England: Oxford University Press; 1985;12–38. 6. Ferner R. Forensic Pharmacology. Oxford, England: Oxford University Press; 1996;28–33.