Policy Forum
Global Pharmacovigilance for Antiretroviral Drugs:
Overcoming Contrasting Priorities
Nyasha Bakare1¤, Ivor Ralph Edwards2, Andy Stergachis3, Shanthi Pal4, Charles B. Holmes5, Marie
Lindquist6, Chris Duncombe7, Alex Dodoo8, Joel Novendstern9, Jude Nwokike10, Ricardo
Kuchenbecker11, Judith A. Aberg12, Veronica Miller13, Jur Strobos13*
1 Forum for Collaborative HIV Research and Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America, 2 WHO Collaborating
Centre for International Drug Monitoring, Uppsala, Sweden, 3 School of Public Health, University of Washington, Seattle, Washington, United States of America, 4 Quality
Assurance and Safety: Medicines, Department of Essential Medicines and Pharmaceutical Policies, World Health Organization, Geneva, Switzerland, 5 Office of the US
Global AIDS Coordinator, US Department of State, Washington, D.C., United States of America, 6 WHO Collaborating Centre for International Drug Monitoring, Uppsala,
Sweden, 7 Department of HIV/AIDS, World Health Organization, Geneva, Switzerland, 8 WHO Collaborating Centre for Advocacy and Training in Pharmacovigilance,
University of Ghana Medical School, Accra, Ghana, 9 Ranbaxy Inc., Princeton, New Jersey, United States of America, 10 Management Sciences for Health, Strengthening
Pharmaceutical Systems (SPS) Programs, Arlington, Virginia, United States of America, 11 Graduate Studies Program in Epidemiology, Federal University of Rio Grande do
Sul, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil, and Brazilian National Institute of Science and Technology for Health Technology Assessment (IATS CNPq),
Porto Alegre, Brazil, 12 New York University School of Medicine, New York, New York, United States of America, 13 Forum for Collaborative HIV Research, Washington,
D.C., United States of America
Background but with varying success. The Forum for academia, multilateral organizations, and
Collaborative HIV Research (Forum) was implementers to discuss the creation of a
As of 2010, over 5 million people asked to use its neutral setting for key sustainable global pharmacovigilance sys-
worldwide have access to antiretroviral stakeholders from the United Nations and tem for ARVs that would be applicable in
drugs (ARVs) [1]. With increased access government agencies, donors, industry, RLS. A meeting was convened by the
comes a greater need to monitor and
promote the safety and effectiveness of
these essential medicines. Few resource- Citation: Bakare N, Edwards IR, Stergachis A, Pal S, Holmes CB, et al. (2011) Global Pharmacovigilance for
limited countries have all the structures, Antiretroviral Drugs: Overcoming Contrasting Priorities. PLoS Med 8(7): e1001054. doi:10.1371/journal.pmed.1001054
systems, or resources necessary to support Published July 5, 2011
medicines safety activities [2,3]. Diverse
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted,
international efforts to provide optimal modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under
treatment could be compromised by the the Creative Commons CC0 public domain dedication.
absence of robust strategies and frame- Funding: The Bill & Melinda Gates Foundation were the funders. The funders had no role in study design, data
works for monitoring of inappropriate use, collection and analysis, decision to publish, or preparation of the manuscript.
toxicity, drug-drug interactions, diversion, Competing Interests: The Forum for Collaborative HIV Research is part of the University of California
and substandard medicines [4]. While Berkeley, where VM and JS are employees. This project was supported by the Bill & Melinda Gates Foundation.
The Forum also receives unrestricted grants from the Glazer Pediatric AIDS Foundation, the National Institutes
isolated episodes of substandard medica- of Health, the Centers for Disease Control, amFAR, Kaiser Permanente, the HAART Oversight Committee, Merck,
tion distribution have been identified and Johnson & Johnson, Gilead, Viiv, Pharmasset, Abbott, Vertex, Bristol Myers Squibb, Boehringer Ingelheim,
handled through the involvement of the Idenix, Incyte, Monogram, Tobira, and BD. Over the last year, the Forum for Collaborative HIV Research has also
received grants from Becton-Dickinson, Intermune, Roche, and Virco. NB has accepted a position with Johnson
World Health Organization (WHO), glob- & Johnson. IRE and ML are employed by the Uppsala Monitoring Center of WHO, which has received grants for
al pharmacovigilance is needed to fully two projects from the European Union FP7:Monitoring Medicines and PROTECT. AS is an employee of the
understand the extent of the issue. Loss of University of Washington and is supported in part by the Bill & Melinda Gates Foundation and indirect grants
from USAID. CBH is an employee of the US Government. AD has received funding for undertaking
confidence in the safety of ARVs could pharmacovigilance, including a grant in 2009 from the Global Fund to Fight AIDS, Tuberculosis and Malaria to
lead to poor adherence and the emergence develop a pharmacovigilance toolkit and a sub-grant (main grantee Swiss Tropical and Public Health Institute)
of drug resistance, reduced demand for in 2010 to develop a malaria pharmacovigilance toolkit. J. Novendstern is employed by Ranbaxy, a
pharmaceutical company that makes antiretroviral medications. J. Nwokike works for the USAID-funded
therapy, or inappropriate switching to Strengthening Pharmaceutical Systems program. RK is an employee of the University of Rio Grande do Sul and
more toxic or expensive medicines. A advisor to the National STD/AIDS Program of the Brazilian Ministry of Health. JAA is an employee of New York
sustainable pharmacovigilance system can University Medical Center, and serves or has served in past 2 years as a scientific advisor for BMS, Gilead, Merck,
Theratech, Tibotec, and Viiv. Her university also receives research support for her participation as an
help achieve comprehensive, safe, and investigator on multicenter clinical trials from Gilead, GSK, Merck, Pfizer and Tibotec. She is funded by the NIH
effective healthcare. Efforts to date have supported AIDS Clinical Trials Group Grant # AI069532. All other authors have declared that no competing
attempted to address the need for respon- interests exist. The findings and conclusions in this paper are those of the authors and do not necessarily
represent the views of the US Department of State.
sive drug safety monitoring systems for
Abbreviations: ARV, antiretroviral drug; EU, European Union; Global Fund, Global Fund to Fight AIDS,
ARVs in resource-limited settings (RLS)
Tuberculosis and Malaria; PEPFAR, President’s Emergency Program for AIDS Relief; RLS, resource-limited
settings; SPS, Strengthening Pharmaceutical Systems; UMC, Uppsala Monitoring Center/WHO Collaborating
Centre for International Drug Monitoring; WHO, World Health Organization.
The Policy Forum allows health policy makers * E-mail: jur@berkeley.edu
around the world to discuss challenges and
opportunities for improving health care in their ¤ Current address: J&J Pharmaceuticals Research and Development, Titusville, New Jersey, United States of
societies. America
Provenance: Not commissioned; externally peer reviewed.
PLoS Medicine | www.plosmedicine.org 1 July 2011 | Volume 8 | Issue 7 | e1001054
Summary Points covigilance systems, the need to develop
systems that may differ from well-estab-
N lished models, and the need to assess theWith increasing numbers of people worldwide on antiretroviral drugs, the need
for improved and sustained global drug safety monitoring or pharmacovigi- feasibility of novel models offer opportu-
lance is critical. nities for innovation. Barriers among these
N channels of funding in established systemsPharmacovigilance includes monitoring for substandard products, diversion, are not applicable in RLS. Sustainable
inappropriate use, and toxicity and is an essential component of safe and
global pharmacovigilance must derive
effective drug usage.
N support from operational, research, andThe Forum for Collaborative HIV Research was asked to use its neutral setting programmatic funds as programs, such as
for key stakeholders from the UN and government agencies, donors, industry,
health care delivery and pharmacovigi-
academia, multilateral organizations, and implementers to discuss the creation
lance, are inextricably intertwined in this
of a sustainable global pharmacovigilance system for ARVs.
N setting with the need for epidemiologicalImportant but contrasting priorities and values among stakeholders—all of and implementation research [5].
whom are dedicated to establishing global pharmacovigilance—were identified
4. Active versus spontaneous surveillance
as barriers to progress.
N Active surveillance with intensive dataRecognition, understanding, and respect for these contrasts is a pathway for collection is one proven method of sys-
increased collaboration and cooperation that will then lead to a sustainable
tematically identifying and assessing med-
system involving all stakeholders including industry and experienced regulatory
ication use and patient outcomes. Sponta-
agencies.
neous surveillance collects reporters’
concerns about an event seen during
treatment, assesses clinical causality, and
Forum on June 11, 2010, that included national Drug Monitoring (UMC) all
provides timely information on low inci-
relevant stakeholders to discuss barriers to value national sovereignty. Their remit
dence adverse events that manifest upon
progress. Stakeholder participants other has been to work with national systems
exposure of large numbers of patients to
than the authors are identified in the wherever possible. They also recognize
drug products. Spontaneous reporting can
Acknowledgments. that the need for data sharing and
be time consuming and adds to the
resource efficiency in some cases is best
workload of already overburdened health-
The Issue: Contrasting done through collaboration among region-
care professionals in RLS. In these in-
Priorities, Values, and Ideas al and international stakeholders who stances, monitoring through a sentinel site
provide systems, expert personnel, and
The Forum meeting participants dis- might be a viable alternative. Activeother resources.
cussed their approaches to establishing an surveillance of cohorts [6] or through the2. The value of pharmacovigilance versus the
acceptable and sustainable global pharma- use of registries (e.g., the establishedneeds for care delivery
covigilance framework for ARVs and how Antiretroviral Pregnancy Registry) [7]
Optimal use of all available resources to
these efforts might be harmonized. The may be more expensive but provides a
deliver safe and effective HIV treatment
discussions revealed varieties of methods, mechanism for assessing incidence and to
and prevention is a priority. Safe and
opinions, and practices among the stake- conduct pharmacovigilance within special
effective use of medicines is only guaran-
holders. Challenges in integrating these populations. While countries with estab-
teed when access goes hand-in-hand with
different approaches and sub-optimal lished pharmacovigilance can employ both
pharmacovigilance. Many stakeholders
communication among stakeholders may systems effectively, the best mix for RLS
perceive the cost of pharmacovigilance
have impeded progress in the past. Each of still requires careful planning.
infrastructure as competing with distribu-
the values and ideas represent important 5. Confidentiality of safety data versus need for
tion of scarce human and financial re-
technical, cultural, and economic impera- transparency and public access
sources for direct care delivery. This
tives that require mutual understanding Regulatory agencies in Europe receive
and respect. The meeting participants perception may impede the devotion of confidential safety data from pharmaceu-
agreed that understanding and mutual time and resources to development of tical companies for registration purposes
respect for others’ priorities and ideas are sustainable global pharmacovigilance. and afterwards in post-marketing surveil-
the predicate to effective communication, 3. Research, pharmacovigilance, and program- lance. Confidentiality may be important to
then follows collaboration, leading to matic funding assure that adverse event relationships that
resolution or compromise and eventual Scarce funds are distributed through are later understood to be associative
success. At the Forum meeting, some of diverse channels whose distinctions may rather than causative do not create undue
these contrasting values were highlighted: be artificial in the resource-limited world. public confusion or alarm. But, interna-
1. National sovereignty versus regional and Established health care systems have tional data sharing is necessary to support
international collaboration separate channels for funding for research, global pharmacovigilance, particularly giv-
Sovereignty, country ownership, and pharmacovigilance, and operations. Re- en international trade and traffic in
building national infrastructure are values search monies are mainly derived from pharmaceuticals.
that have governed international collabo- national scientific or medical agencies, 6. Industry support versus global enforcement of
ration since the founding of the United industry research, and foundations. Phar- reliable reporting
Nations. The WHO, the President’s macovigilance is largely funded by the The pharmaceutical industry plays an
Emergency Program for AIDS Relief operational side of the pharmaceutical active role in funding pharmacovigilance
(PEPFAR), the Global Fund to Fight industry and by health ministries. Health in many nations. In respect of national
AIDS, Tuberculosis and Malaria (Global care operations are funded by insurance sovereignty and, possibly, to avoid indus-
Fund), and the Uppsala Monitoring Cen- companies, donors, and national health try conflicts of interest in reporting events
ter/WHO Collaborating Centre for Inter- systems. The absence of global pharma- that may undermine investor confidence,
PLoS Medicine | www.plosmedicine.org 2 July 2011 | Volume 8 | Issue 7 | e1001054
global pharmacovigilance systems have macovigilance Systems: Ensuring the Safe cines safety, performing statistical and data
not drawn upon industry funding and Use of Medicines,’’ on the implementation analyses, and training practitioners.
collaboration. In countries with estab- of pharmacovigilance systems from a
lished drug regulation, the conflict is partly country-centered perspective. The confer- Much Remains to Be Done
controlled by audit, laws, regulations, and ees discussed a framework for pharmacov-
enforcement—a system not necessarily igilance and the need for performance More can be achieved. Principally,
available globally. A global system that metrics—the Indicator-based Pharmacov- there is hope for more inclusion of non-
enjoys reliable industry engagement must igilance Assessment Tool (IPAT)—and national stakeholders and experienced
draw upon new or shared sources for experiences and best practices were shared regulators and, perhaps more importantly,
funding of enforcement. by participants from 30 countries. for assurance of financial and institutional
7. Generic versus innovator antiretroviral The first version of a Web-based sustainability. Many stakeholders with
manufacturers ‘‘Pharmacovigilance Toolkit,’’ developed substantial interests are still not routinely
Generic companies provide a significant by the WHO Collaborating Centre for at the table. Most prominently, the
proportion of ARVs distributed in RLS. Advocacy and Training in pharmacovigi- pharmaceutical industry, both innovator
The lower pricing ensures greater access lance (the WHO CC/UMC-Africa) along and generic, are not included, although
[8]. But, correspondingly, these companies with SPS and other partners, was present- both sets of institutions have substantial
may devote fewer resources for pharma- ed at the Stakeholders meeting in Accra investment in global infrastructure, per-
covigilance. Established systems rely upon [12]. sonnel, data management, databases, and
innovator companies to support pharma- More recently, WHO has initiated two other resources that could be purposed, at
covigilance on market entry, but this may major projects in pharmacovigilance with least in part, to sustaining global pharma-
not work in RLS where innovator com- the support of the Bill & Melinda Gates covigilance systems in RLS. Well-estab-
panies may not be marketing their com- Foundation (BMGF). A pilot sentinel lished national regulatory authorities, such
pounds. cohort in Tanzania established with the as the European Medicines Agency
collaboration of UMC and the national (EMA), the US Food and Drug Adminis-
Progress health ministry may be open to patient tration (FDA), and the WHO Prequalifi-
enrollment soon. Second, the US National cation Programme also have data, exper-
There has been great progress in Institute of Allergy and Infectious Diseases tise, human resources, and technical
international identification of the need for (NIAID) is working collaboratively with capacity that could be used more system-
collaboration and renewed vigor in pursu- WHO to establish spontaneous adverse atically to support pharmacovigilance in
ing a global pharmacovigilance system— event reporting in their IeDEA patient RLS. The EU has provided research and
an important outcome of the Forum cohorts in two countries with an aim of development money for pharmacovigi-
meeting. This is reflected in recent and evaluating and improving an abbreviated lance. This funding must be continued in
ongoing developments in intergovernmen- reporting system developed by UMC future rounds of EU funding. More
tal assistance programs as well as initiation (CEMFlow). The Global Fund has also transparent and proactive mechanisms
support from the WHO and allied inter- supported a start-up pharmacovigilance for drug evaluation at all national regula-
national and national entities. The Fo- program for ARVs in the Ukraine. tory agencies may also enhance support
rum’s meeting recognized ongoing efforts Monitoring Medicines, a project funded for comprehensive and sustainable phar-
for collaborative pharmacovigilance by the European Commission, brings macovigilance. Those mechanisms may
among less resource-rich nations. In No- together 11 partners, including WHO, also raise awareness of the importance of
vember 2009, a WHO-Global Fund the UMC, and the Copenhagen HIV pharmacovigilance.
Pharmacovigilance Strategy was drafted Programme, to advance pharmacovigi- Current projects need sustainable, if not
that identified the elements and roadmap lance within and outside the European growing, support. BMGF research funding
for a sustainable, global partnership for Union (EU) [13]. The 14 work packages will largely end in 2012. Round 11 of the
system-driven pharmacovigilance [9]. The within this project consider various issues Global Fund is unlikely to result in
concept paper together with the minimum such as tools to support public reporting of initiation of new pharmacovigilance pro-
pharmacovigilance requirements for coun- adverse drug reactions; an electronic grams. PEPFAR currently supports the
tries in RLS were presented for consider- platform that consolidates HIV ADR clinical care and treatment of over 3.2
ation at a Pharmacovigilance Stakeholders information from several sources (http:// million people and has funded the
Meeting in November 2010, in Accra, www.hivpv.org/); and an algorithm for strengthening of supply chains and access
Ghana. Participants included many of the detection of substandard and counter- to pharmaceuticals. PEPFAR also sup-
those present at the Forum meeting and feit medicines from pharmacovigilance ports some WHO pharmacovigilance ac-
were invited to comment. Progress was data. tivities but is also exploring ways to
made on encouraging regional systems Finally, the US National Institutes of collaboratively fund pharmacovigilance
and the inclusion of international resourc- Health, the Global Fund, UMC, and a systems to further strengthen the quality
es [10,11]. There was support for the consortium of North American universities of national HIV programs. National laws,
continued development of UMC as a led by the University of Indiana (funded remits of international agencies, and
global resource for pharmacovigilance by PEPFAR through USAID) have col- funding authorizations may need to spe-
activities. laboratively initiated a pharmacovigilance cifically address the need for funding of
The US Agency for International De- program with the Kenyan national health sustainable global pharmacovigilance.
velopment (USAID)-funded Strengthening ministry. This illustrates, as well, the Still, too little is understood about the
Pharmaceutical Systems (SPS) program growing number of academic institutions value and need for global pharmacovigi-
implemented by Management Sciences that are engaged in pharmacovigilance: lance and more must be done among
for Health sponsored a conference in advancing methods, creating an evidence- funding organizations, including national
Nairobi, Kenya, entitled ‘‘National Phar- base for assessing and improving medi- bodies in resource-rich nations with
PLoS Medicine | www.plosmedicine.org 3 July 2011 | Volume 8 | Issue 7 | e1001054
established systems. Better linkages be- generic companies. A workable system will rum for Collaborative HIV Research; Vijaya
tween disease-driven national programs not be necessarily based on each resource- Kuppa, Aurobindo Pharma Ltd.; Fabio Lie-
(e.g., HIV/AIDS) and national pharma- limited national entity or regional pro- vano, Merck & Co.; Albert Mwango, Ministry
of Health, Zambia; June M. Raine, Medicines
covigilance centers should be made. While gram developing a separate system—there
and Healthcare Products Regulatory Agency;
BMGF and NIAID have provided re- are simply insufficient technical, manage- Lulu Oguda Mwangi, Elizabeth Glaser Pediat-
search funding, barriers between the ment, and funding resources. Instead, the ric AIDS Foundation; James F. Rooney, Gilead
purpose of those funds and investigations stakeholders must collaboratively insist on Sciences; Praphan Phanuphak, Thai Red Cross
into sustainable systems and funding for broader systems that provide local value. AIDS Research Centre; Ian Sanne, Wits Health
those systems remain. Decisions on fund- These systems should be highly valued and Consortium; David H. Brown Ripin, Clinton
ing must include participation and collab- be supported by industry, governments Health Access Initiative; Andy Stergachis,
oration with academic researchers, indus- and funders of HIV programs and nation- University of Washington; Caroline Ryan,
try, donors, and well-resourced existing Office of the US Global AIDS Coordinator,al health systems, multilateral organiza-
PEPFAR; Melissa Truffa, US Food and Drug
pharmacovigilance systems. Pharmaceuti- tions, and other key stakeholders, and
Administration; Carlie Williams, Division of
cal industry resources must be more should be funded even during difficult AIDS, National Institutes of Health; Marco
effectively recruited and used in imple- economic times. Vitoria, World Health Organization; Serge
mentation, whether in terms of interna- Xueref, The Global Fund to Fight AIDS, TB
tional and national mandates or in terms
Acknowledgments and Malaria.
of in-kind technical support.
Stakeholder collaboration, communica- The Authors are grateful for input and Author Contributions
tion, and joint activity are developing insightful contributions to the planning of this
rapidly. Stakeholders must continue to project from the meeting participants: Stephen Wrote the first draft: NB JS. Contributed to the
writing of the manuscript: NB IRE JAA AD CD
work together and communicate. There Becker, Bill & Melinda Gates Foundation;
Barbara Da Silva-Tillmann, Abbott; Gerald J. CBH RK ML JN JN VM SP AS JS. ICMJE
must be a formalized process comparable
Dal Pan, FDA; Rob Dintruff, Abbott; Chris criteria for authorship read and met: NB IRE
to the Forum-initiated consortium to Duncombe, World Health Organization; Ngozi JAA AD CD CBH RK ML JN JN VM SP AS
ensure ongoing communication among Erondu, Global Alliance for TB Drug Devel- JS. Agree with the manuscript’s results and
all stakeholders that includes established opment; Robert Ferris, US Agency for Interna- conclusions: NB IRE JAA AD CD CBH RK
national regulators and the innovator and tional Development; Benjamin Hauschild, Fo- ML JN JN VM SP AS JS.
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PLoS Medicine | www.plosmedicine.org 4 July 2011 | Volume 8 | Issue 7 | e1001054