New Medicines and Vaccines

– Monitor Safety in Emergency Situations?

Rebecca Chandler, Uppsala Monitoring Centre,

Emerging infectious diseases disproportionally impact the poorest countries in the world. They typically break out in places where both the healthcare and research infrastructure are limited and inadequate. New medicines and vaccines are being deployed for treatment and prevention efforts in regions where there is a considerable concern about pharmacovigilance resources. Will those countries be able to meet the challenges of monitoring the safety of these medicinal products upon wide-spread use?

This workshop will discuss whether the current WHO guidelines are sufficient to ensure that new medicines and vaccines used in the treatment and prevention of emerging infectious disease threats in resource-poor settings are adequately monitored for safety. If not, we will define the elements required in the establishment of a “reasonable minimum” pharmacovigilance system for the rational and safe use of medicines in these circumstances.

This workshop will address the following topics:

•    Should we reconsider our approach to the monitoring for adverse events? Are resources and efforts best focussed on active surveillance or should we prioritize the support of a passive surveillance infrastructure?
•    How can safety problems known at the time a new medicinal product is introduced be more effectively dealt with? How can risk minimization best be carried out on a limited budget?
•    Would resources be better allocated to the development of cost-effective ways of identifying individuals known to be at risk of harm from medicines within the context of public health programmes?
•    Is there a way to move beyond collecting and analysing adverse event data to ensure that new medicines and vaccines are used in rational and safe ways? How can a culture of drug safety awareness be created and then sustained?
•    In what way could better collaboration be established among the multiple stake-holders involved in the development and deployment of new medicines and vaccines in these circumstances? How do we ensure that resources are rationally distributed among stakeholders with different roles?


Surveillance of new medicines under “normal” circumstances is a long process

Currently, the practice of pharmacovigilance in the setting of the treatment and prevention of emerging infectious diseases has been limited to the monitoring of adverse events from new medicines and vaccines. However, there is evidence to suggest that short-lived programmes of active surveillance may not be adequate to draw strong conclusions on safety and that the level of reporting from public health programmes into passive surveillance systems, most notably the database of the WHO Programme for International Drug Monitoring (PIDM) remains low.

Even under “routine” circumstances, the amount of knowledge about new medicinal products at the time of introduction to public use is limited. Clinical trials, designed to investigate both the efficacy and safety of products, are performed using a relatively small sample of participants, include specific inclusion and exclusion criteria, and have limited participant follow-up times. Spontaneous case reporting is central to the safety surveillance of medicines in the post-marketing period, as it allows for the early detection of rare, unexpected or suspected adverse drug reactions. Risk management plans/risk evaluation and mitigation strategies are implemented by marketing authorization holders at the time of approval. This is done in order to minimize the risk from known safety concerns, to collect important missing information on populations not included in clinical trials, and to further characterize effectiveness and safety through observational studies.

It is common practice for new medicinal products to be developed and first introduced into high-income countries, allowing drug manufacturers the opportunity to recover the cost of the research and development of their products. Consequently, there are typically several years of post-marketing experience in these countries, which contributes to the knowledge base regarding both effectiveness and safety prior to their introduction in lower- and middle-income countries.

Emerging infectious disease threats, however, typically do not offer the luxury of “routine cir-cumstances”. The knowledge base at the time a new medicine or vaccine is introduced may vary from fully completed clinical trial programmes to only “proof of concept” data. Furthermore, given that such diseases disproportionately affect lower- and middle-income countries, new medic-inal products are directly introduced into countries with limited pharmacovigilance resources and less advanced health care systems.

Are the current approaches to surveillance adequate?

New medicines and vaccines against emerging infectious diseases are typically developed through governmental, academic and industry partnerships. Public health programmes orches-trate the implementation of such campaigns, often with the additional support of international public health and non-governmental organizations. The practice of pharmacovigilance in these situations has been largely limited to the collection of adverse event data, using active surveillance methodologies for limited periods at the initiation of the campaign. Furthermore, pharmacovigilance data from public health programmes is not often shared, and results are not always communicated.

There are examples to suggest that the current approaches to the practice of pharmacovigilance in the treatment and/or prevention of emerging infectious disease threats are not adequate. It is imperative that efforts should focus on the establishment of sustainable pharmacovigilance systems to ensure an overall rational and safe use of medicines. The absence of such a system may not only cause great harm to individual patients but also lead to a detrimental effect on public confidence in the public health campaigns required for the treatment, prevention, and/or control of emerging infectious diseases.

The use of LapDap in malaria treatment

Chlorproguanil-dapsone or “Lapdap” was a new medicine introduced directly into Africa for the treatment of malaria. It was developed in a collaboration between GlaxoSmithKline (GSK) and the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR). It was approved by the UK national regulatory authority, the MHRA, for the treatment of uncomplicated Plasmodium falciparum malaria in children, adolescents and adults in July 2003 based upon a clinical trial database of less than 3000 persons. Within a relatively short amount of time after MHRA approval, the drug was registered in more than 20 African countries.

A known safety concern for Lapdap, which in-terferes with folate metabolism, is haemolytic anaemia. This well-characterized adverse drug reaction (ADR) is more severe in persons with inherited glucose 6-phosphate dehydrogenase (G6PD) deficiency. Formal clinical trials of Lap-Dap were undertaken in Africa; however, no G6PD testing was done during a key trial. Anaemia was found to be more common in patients given LapDap, which the investigators termed as a “possible” ADR. In the regulatory approval of LapDap, its use was to be contraindicated in patients with G6PD deficiency; however, there were no further recommendations described to minimize this risk (1).

WHO assessment leads to questions about safety of LapDap

Given the known high prevalence of G6PD deficiency in sub-Saharan Africa in addition to the limited availability of screening tests for this condition, WHO undertook a safety assessment of the product in 2004 to provide recommendations on the safe use of LapDap in Africa. The WHO committee determined that there was a lack of sufficient information to substantiate its safe and efficacious administration in the circumstances under which it was to be used in Africa; it therefore provided guidance for use as well as priorities for further research (2).

A retrospective analysis of clinical trial data revealed that 35 % of children in whom there was a notable drop in haemoglobin were G6PD deficient. The number of events that happened outside of controlled trials is unknown.

LapDap remained on the market in many African countries until February 2008, at which time it was withdrawn by GSK because of “significant reductions in haemoglobin levels of patients with G6PD deficiency” (1).

Use of MenAfriVac in Africa’s “meningitis belt”

MenAfriVac is a meningococcal A conjugate vaccine directly introduced into several countries included in Africa’s “meningitis belt”, which stretches from Gambia in the west to Eritrea in the east. The conjugated vaccine, PsA-TT, was developed in a collaboration between the Meningitis Vaccine Project (a partnership between the WHO and the non-governmental organization PATH) and the Serum Institute of India and underwent clinical trials in Africa and India in 2005. It was licensed in India in January 2010 and prequali-fied by the WHO in June 2010.


Upon the recommendation of the WHO Global Advisory Committee on Vaccine Safety, the vac-cine introduction began with an initial phased approach to collect additional safety information; this approach was meant also to serve as an opportunity for capacity building in vaccine pharmacovigilance. The vaccine was then ini-tially introduced into three countries (Burkina Faso, Mali, and Niger) and subsequently offered to all countries in the meningitis belt (3).

Problems of adequate surveillance

There are several papers which report on the incidence and types of adverse events following immunization collected from both passive and active forms of surveillance at the time of vacci-nation campaigns in various African countries (4–7). Two publications have also highlighted the challenges and difficulties in the collection of safety information in both the clinical trial as well as early post-marketing use of MenAfriVac (8, 3). Collection of safety data in the clinical trial setting was complicated by a lack of uniformity in collection methodology and medical practice among clinical study sites, communication challenges, and local endemic diseases which made safety evaluations of vaccinations difficult (malaria, rotavirus). Challenges in the safety surveillance in the initial phases of the vaccination campaign included limited resources which impacted on the sustainability of data quality and the establishment of national expert committees for investigation and causality assessments of serious Adverse Events Following  Immunization, AEFIs; difficulties in the establishment of collaboration and an unequal distribution of resources among healthcare systems, immunization programmes and national regulatory (pharmacovigilance) centres; and an inability of the less sophisticated local healthcare systems to detect, diagnose and register conditions of interest likely to be reported after vaccination.

Conclusions on the safety of the vaccine, especially as it relates to less frequently and/or later occurring adverse effects following immuniza-tion therefore remain limited.

WHO guidance and resources

The WHO has issued guidance in various forms intended to promote safe use of specific medi-cines and vaccines being used in public health programmes.

An overall guide, “The Safety of Medicines in Public Health Programmes: Pharmacovigilance an  essential tool”, aims to encourage the integration of pharmacovigilance as an essential component of public health programmes that use medicines. It highlights the importance of collaboration and communication among public health programmes and pharmacovigilance systems/drug regulatory authorities, both locally and internationally (9).

The WHO additionally offers disease-specific guidance in various forms. Examples include a practical handbook on the pharmacovigilance of antimalarial medicines (10), interim guidance on the use of bedaquiline for multi-drug resistant tuberculosis (MDR-TB) (11), and a position paper on dengue vaccine (12).

Specifically available for vaccines is a manual: “Active Vaccine Safety Surveillance” by the Council for International Organizations of Medical Sciences (CIOMS) Working Group on Vaccine Safety. Developed to address objective #8 of the WHO Global Vaccine Safety Initiative, it is intended as a practical approach to aid immunization professionals and decision-makers in determining the best course of action if additional vaccine safety data is needed when a new vaccine is being introduced into lower- and middle-income countries (13).

WHO Programme for International Drug Monitoring and Vigibase

In 1968, after the thalidomide experience, Resolution 16.36, passed during the 16th World Assembly, called for “a systematic collection of information on serious adverse drug reactions during development and particularly after medicines have been made available for public use”. The WHO Programme for International Drug Monitoring (PIDM) was subsequently formed with an initial composition of 10 countries. Today the programme has grown to include 127 countries as full members. In addition, there are 28 associate members who are in the early stages of establishing their pharmacovigilance systems. Many lower- and middle-income countries which have been targets for public health programmes, such as LapDap and MenAfriVac, have joined the programme in recent years.

VigiBase aids reporting of anomalies

A harmonized system of vigilance is found in local and national pharmacovigilance centres, in regional organizations, as well as in the WHO PIDM. Member countries record incidents of medicinal harm suffered by patients and submit them to the WHO global database, VigiBase. Data within VigiBase are recorded in a structured and comprehensive way to allow for the detection of potential medicinal safety hazards.

An integral part of pharmacovigilance is the sharing of data and/or knowledge among relevant stakeholders. Members of the WHO PIDM have access to the data collected within Vigibase so that when an ADR is reported in their country, they are quickly and easily able to see if it has been reported in other countries and to understand their reports in a global context.

Many of the countries in which public health programmes for the treatment and prevention of infectious disease threats are ongoing are members of the WHO programme; however, there remains a relative paucity of reports on the new medicines and vaccines in VigiBase.

Towards a robust pharmacovigilance system

There are many aspects to a sustainable, robust pharmacovigilance system. Far more than sim-ply the collection and analysis of adverse event reports, it also develops and relies upon a public awareness of drug safety and nurtures a culture of reporting suspected adverse drug reactions. In addition, it encourages communication within the local context along with the sharing of safety data on a global scale. The absence of such a system may not only cause great harm to individual patients but also lead to a detrimental effect on public confidence in the public health campaigns required for the treatment, prevention, and/or control of emerging infectious diseases.

Currently, the practice of pharmacovigilance in the setting of the treatment and prevention of emerging infectious diseases has been limited to the monitoring of adverse events from new medicines and vaccines.  However, there is evidence to suggest that short-lived programmes of active surveillance may not be adequate to draw strong conclusions on safety and that the level of report-ing from public health programmes into passive surveillance systems, most notably the database of the WHO PIDM, remains low.  Furthermore, sustainable pharmacovigilance systems do not simply monitor reported adverse events from medicines or vaccines; they also promote an awareness of medicine safety and aim to ensure the rational and safe use of medicines in specific context.


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