Meeting Report Immune-Mediated Drug Hypersensitivity Reactions (IDHR) Workshop

Abstract

Immune-mediated drug hypersensitivity reactions (IDHR) are relatively rare reactions to drugs that can be observed in a limited population of patients, yet these reactions can have significant impacts on public health, clinical practice, and drug development. Despite the potentially significant impact of IDHR, research into the causes and mechanisms of action of these reactions has been limited. In order to identify and enhance potential research opportunities in IDHR, the Health and Environmental Sciences Institute (HESI) hosted a two-day workshop involving stakeholders from government, academia, and industry. Discussions focused on ways to increase IDHR research opportunities within both presently existing collaborative structures and new networks. Based on these discussions, workshop participants concluded that a volunteer organization of interested stakeholders could be established to provide for ongoing advocacy and coordination of efforts related to IDHR research. The primary objectives of such an organization would be to increase public awareness of the impact of IDHR, encourage multidisciplinary IDHR research and training, encourage the development and funding of IDHR research network and seed grants, and to establish a framework for the further exchange and dissemination of IDHR information.

BACKGROUND

Immune-mediated drug hypersensitivity reactions (IDHR), although relatively rare events, can have significant impact on public health, clinical practice and drug development. Despite these potential consequences, research aimed at addressing the causes, mechanisms, and predisposing factors for IDHR has been limited. As well, little progress has been made in the development of diagnostic and predictive tests for IDHR. In 2002, the Health and Environmental Sciences Institute (HESI) Immunotoxicology Technical Committee (ITC) issued a task force report identifying data gaps and offering recommendations to increase research in this important field (Health and Environmental Sciences Institute Task Force, 2002). As a follow-up to its task force report, the ITC hosted an interactive workshop in Washington, DC, on November 17–18, 2003. This workshop was planned by representatives from industry, academia, and government (Table 1). Approximately 65 participants from various disciplines (allergists, dermatologists, immunotoxicologists, toxicologists, immunologists, regulatory scientists) and organizations (medical schools, hospitals, U.S. FDA, industry, CROs, NIH) attended this meeting. The goals of this workshop were to:

• Bring together key stakeholders in government, academia, and industry to exchange information on the impact of IDHR,

• Identify and enhance potential mechanisms to increase research opportunities in IDHR, and

• Determine pathways forward to implement these approaches.

TABLE Workshop planning committee

Name	Organization
N. Franklin Adkinson	Johns Hopkins Medical School
Ellen Evans	Schering Plough, Inc.
Sylvia Furst	Pfizer Global Research and Development
Dori Germolec	NIH, National Institute of Environmental Health Sciences
Rebecca Gruchalla	University of Texas, Southwestern Medical Center
Helen Haggerty	Bristol Myers Squibb Company
Kenneth Hastings	U.S. FDA, Center for Drug Evaluation and Research
Norbert Kaminski	Michigan State University
Thomas Kawabata	Pfizer Global Research and Development
Amy Lavin	ILSI Health and Environmental Sciences Institute
Richard Okita	NIH, National Institute for General Medical Sciences
Marshall Plaut	NIH, National Institute of Allergy and Infectious Disease
Neil Shear	Sunnybrook & Women's College Health Sciences Center
James Weaver	U.S. FDA, Center for Drug Evaluation and Research
Thasia Woodworth	Novartis

MEETING SUMMARY

The meeting format was designed for information-sharing between stakeholders and to stimulate discussion and idea generation. Three research presentations by Professors Neil Shear (Sunnybrook and Women's College, Toronto, Canada), Kevin Park (University of Liverpool, UK) and Werner Pichler (Inselspital, Switzerland) were added to initiate each session by highlighting cutting-edge IDHR research programs.

Stakeholders' Perspectives

The overall theme for the discussion session was “Fostering Collaboration Among Stakeholders.” Representatives from academia, industry, FDA and NIH presented their perspectives on what is needed in the area of IDHR research and how opportunities for new interactions in this area of research can be increased.

Professor N. Franklin Adkinson (Johns Hopkins Medical School) presented examples of successful IDHR research programs conducted over the past 30 years related to beta lactam antibiotics and industry supported studies, and noted the common features of such programs. These features include industry support and expertise, the availability of reactive patients, appropriately accessible testing reagents and available immunochemical background information. Dr. Adkinson also described several attractive research programs that could not be conducted due to a variety of problems (Table 2). He concluded by outlining changes that could promote IDHR research in academic centers (Table 3).

Examples of research projects that could not be consummated

Project description	Reasons
Familial aggregations of drug allergies and multiple drug allergy syndromes	Lack of markers, inadequate historical data sets on exposures and reactions
Genetics of reactions to anti-seizure medications	Lack of understanding of epitopes and the role of drug metabolism, few accessible patients
Sulfonamide reactions and cross-reactions	Lack of systematic data sets and diagnostic methods
Industry sponsored research of drug development candidates	Unwillingness of industry sponsors to publish findings

What would promote IDHR research in academic centers?

Collaborative networks Shared cases and samples Shared capability for diagnosis Shared ability to evaluate drug metabolism More sophisticated genetic approaches Common access to shared datasets Registries of multiple drug reactors and families Systematic data collection on drugs of interest Ability to train and engage multidisciplinary teams Ability to publish research on drugs in pharmaceuticaldevelopment Public access to data from Phase IV drug studies andadverse event reporting systems Access to funding sources with a clear commitment to fund IDHR research

Dr. Thomas Kawabata (Pfizer Global Research and Development) focused his discussion on the specific types of hypersensitivity issues that pharmaceutical companies face during preclinical and clinical studies and the types of questions that arise from these issues. As an example, he indicated that when a compound (or its metabolite) is found to covalently bind to proteins or when an allergic-like reaction is observed during preclinical or clinical studies or with a marketed drug, several questions arise. Some of the issues that must be addressed include (1) the clinical significance of the covalent binding, (2) the human predictivity of allergic reactions in general toxicity studies, (3) the potential use of animal models to predict sensitization potential, (4) the availability of diagnostic methods and (5) the potential of mild reactions to lead to more serious reactions with continued treatment. Dr. Kawabata concluded by stating the needs of pharmaceutical companies with respect to addressing IDHR risks. These needs include preclinical methods to detect potential hypersensitivity reactions, diagnostic methods to differentiate immune from non-immune mediated reactions, an understanding of the risk factors for development of hypersensitivity reactions, effective treatments and a worldwide reporting database to track the incidence of IDHR.

Similarly, Ken Hastings (CDER, U.S. FDA) reviewed the types of issues and questions that arise during the different stages of drug development (discovery, development and marketing) and the types of assays currently available to possibly address these. He concluded that IDHR remains a difficult problem from the regulatory point of view and that tracking IDHR during the post marketing stage is especially difficult. He emphasized the need for predictive models and methods that can be used to identify drugs during the hazard identification process with the potential to produce IDHR.

Richard Okita (National Institute of General Medical Sciences, NIH) reviewed the history of IDHR grants funded by the NIH using the CRISP (Computer Retrieval of Information on Scientific Projects) database. He indicated that only three RO1 research grants in the area of IDHR were funded by the NIH in 2003. Similar numbers of IDHR grants were funded in 2001 and 2002. These grants focused on drug metabolism/activation and it relationship to IDHR, pharmacogenetics of IDHR, IDHR in AIDS patients, pediatric drug allergy and incidence of IDHR associated with the use of anesthetics. Dr. Okita indicated that the lack of significant funding in the area of IDHR research is due to a number of reasons, including lack of demand from public stakeholders, lack of funding applications directed at IDHR research, and the lack of specific training in IDHR scientific approaches.

Examples of Successful Collaborations

To build upon other successful collaborations, several examples were presented to stimulate discussion on how to increase IDHR research opportunities. Dr. Scott Loveless (DuPont Haskell Laboratory for Health and Environmental Sciences) discussed the industry funded research portfolio being coordinated by the American Chemistry Council (ACC). A Long-Range Research Initiative (LRI) was started to promote research across the chemical industry to develop new methods that could be used to support the development of science-based regulatory policies. Based on input from ACC member companies, the LRI was launched in 1999 with $100 million in funding over 5 years. Several guiding principles were used to develop this program—many of which could be applied to future initiatives in IDHR research: (1) the research process must be open and transparent with the results made public and published in peer-reviewed journals, (2) individual researchers must be allowed to determine their own course of research, including their choice of model compounds, (3) experts provide guidance regarding the quality and value of conducted research, and (4) research is leveraged to complement existing programs and further enhance collaborations. Dr. Loveless indicated that monies for the LRI were committed to specific research focus areas, with each subgroup preparing Request for Proposals, which were subsequently reviewed by an ad hoc panel of expert scientists. Dr. Loveless emphasized that the key to success for effective research has been extensive communication between team members and funded investigators, with an emphasis on publishing and presenting results at scientific meetings.

One of the recommendations of the Task Force Report (Health and Environmental Sciences Institute Task Force, 2002) was to develop a network of researchers that would share case information, samples and expertise. A similar network is now being established by the National Institutes of Allergy and Infectious Diseases (NIAID) of the NIH for the study of primary immune deficiency diseases. Research in IDHR and primary immunodeficiency diseases share similar problems regarding the limited number of cases, limited access to clinical cases and samples, and the small number of investigators. Dr. Josiah Wedgwood of the NIAID provided an overview of the recently formed Primary Immunodeficiency Disease Consortium. The goal of the program is to develop a patient registry and sample repository, and to foster collaborative research. The consortium oversees the registry and repository in addition to providing seed grants, mentoring young investigators and developing collaborations between investigators. A similar approach to foster IDHR-related research could be taken in the future.

Professor Werner Pichler (Rheumatology and Clinical Immunology/Allergology, Inselspital, Bern, Switzerland) presented information on the European Network of Drug Allergy (ENDA), a research interest group of the European Academy of Allergology and Clinical Immunology (EAACI) with approximately 30 active members. These members are primarily clinicians and a few research scientists. ENDA's main aim is to increase knowledge in the area of drug allergy and to foster collaborative research in this area among European researchers. Through ENDA, scientists can pool their resources, have greater accessibility to patients, and discuss procedures and concepts. Dr. Pichler noted that although they have a formal group, ENDA still requires more funding to accomplish some of its larger goals. Dr. Pichler observed that, for a U.S.-based group to be successful, it needs to have a balance of clinicians and research scientists, and substantial funding to support research efforts. He concluded by suggesting that ENDA could assist in the establishment of a similar U.S.-based IDHR alliance group.

Dr. David W. Kaufman (Slone Epidemiology Center, Boston University) presented information on the coordination of multicenter epidemiological studies of IDHR. Dr. Kaufman mentioned some of the obstacles faced in conducting these types of studies and offered some solutions aimed at addressing these difficulties. He indicated that epidemiological studies can contribute significantly to the study of IDHR by helping to identify associated drugs, quantifying risk factors of IDHR, characterizing exposed cases, and providing genetic materials for laboratory evaluation. To illustrate, Dr. Kaufman provided an overview of the International Study of Severe Cutaneous Adverse Reactions and the International Collaborative Study of Severe Anaphylaxis. To conduct such studies, he stressed the importance of: (1) large populations for study, (2) active case ascertainment by study staff, (3) established definitions and case confirmation processes that are independent of exposure, (4) rigorous data collection processes with access to patients, (5) continuous monitoring by the coordinating center, and (6) a large commitment of funds to ensure study needs are addressed.

DISCUSSION SESSIONS

Various discussion sessions on how to foster collaborative IDHR research were led by Drs. Neil Shear (University of Toronto) and Thasia Woodworth (Novartis), Norbert Kaminski (Michigan State University) and Richard Okita (National Institutes of Health, James Weaver (U.S. Food and Drug Administration) and David Kaufman (Boston University), and Franklin Adkinson (Johns Hopkins University), Rebecca Gruchalla (University of Texas), and Marshall Plaut (National Institutes of Health).

Collaborations not Requiring New Organizations

For this session, discussions were focused on collaborations between industry and academia, potential external funding mechanisms, and the development of databases. During the discussion on collaborations between industry and academia, it was noted that companies generally only provide funding for research when under pressure to deal with an immediate problem. It was suggested that industry needs to develop a long-term strategy to solve common problems with IDHR. Industry representatives also noted that, contrary to the beliefs of many people outside of industry, IDHR reactions are not very common during drug development. Thus, there are a limited number of compounds that could be used to better understand mechanisms and develop diagnostic methods. In addition, more detailed studies to understand IDHR mechanisms are difficult to conduct during drug development due to the urgent need to immediately move forward with the current compound or focus on the development of alternative candidate compounds. Furthermore, legal and intellectual property issues are also barriers to establishing collaborations. Discussion participants noted that the impact of IDHR on drug development and public health needs to be further documented. Greater awareness of IDHR impacts on drug development will result in additional support from industry to provide the needed efforts and funds to foster IDHR research.

In discussions on external funding mechanisms, discussants noted that the primary reasons for limited IDHR research funding were the lack of pressure from the public to increase research, competition with other high priority research needs, limited models to apply new technologies, and the lack of break-through findings that could stimulate the generation of new hypotheses on IDHR. Concerns about the lack of grant reviewers with expertise and/or awareness of IDHR was also expressed. It was suggested that the pharmaceutical industry could implement a model similar to that of the ACC (an industry consortium), whereby projects of common interest, such as IDHR, would be prioritized and funded.

During the discussion on the development of IDHR databases, the types of data currently available in existing databases, the spectrum of data needed, access to these databases and the types of new databases or improvements of existing databases that should be developed were discussed. In general, it was noted that there is a limited amount of IDHR-related data available and that significant improvements in data collection are needed. Increased public accessibility to these databases is also necessary to open up new opportunities in IDHR research.

Collaborations Requiring New Organization Structures

Discussants agreed that a new organization with representatives from the various stakeholders and disciplines needs to be developed. Such an organization should use various other organizations as models for its initiation, structure, and function. A key role of this new collaborative research organization would be to facilitate the development of a global multi-center IDHR research network. Because IDHR are relatively rare, a collaborative research network would help foster greater access to case information from individual investigators, increased access to samples, and the ability to study multiple drugs in the same category. Such a network would be able to provide administrative infrastructure, a steering committee, research agenda, shared technical resources and samples, and interdisciplinary training. Funding of such a network could be shared by government and industry.

It was suggested that the pharmaceutical industry could implement a model similar to that of the ACC (an industry consortium), whereby projects of common interest, such as IDHR, would be prioritized and funded. Funding from this consortium could be a source for seed grants.

Because hypersensitivity reactions may be caused by immune and nonimmune mechanisms, it may be often difficult to determine which mechanism is involved. Thus, the group discussed how to define “immune-mediated” reactions and whether the new organizations proposed at this workshop should also concentrate on understanding nonimmune-mediated mechanisms as well. There was general agreement that the organization should primarily focus on immune-mediated reactions. More specifically, it will be necessary to study the precise immune mechanisms of action (e.g., those mediated by IgE antibodies, IgG1 antibodies, cytotoxic T-cells, etc.). However, it was also recognized that the development of new approaches to differentiate immune from non-immune mediated mechanisms and reactions will be important. The understanding of mechanisms of hypersensitivity reactions is expected have a significant impact on the risk management plan for newly developed or marketed drugs.

CONSENSUS AGREEMENT

Based on the input regarding the needs from the various stakeholders (academia, industry, government) and examples of collaborations and organizations that have been successful in other research areas, a list of objectives to increase IDHR research opportunities was developed by the workshop participants. There was a strong consensus on establishing a volunteer organization for all interested stakeholders that could provide ongoing advocacy and coordination of efforts to enhance IDHR research in the United States. Working groups from this volunteer organization will address the following high priority objectives:

• Increase public awareness of the impact of IDHR on public health and drug development and publish these findings;

• Encourage the NIH to establish multidisciplinary networks for IDHR research and training;

• Encourage industry to develop and fund seed grants for IDHR research; and,

• Establish a framework for exchange and dissemination of existing and future IDHR data sets to facilitate research.

ACKNOWLEDGMENTS

The authors thank the Immunotoxicology Technical Committee (ITC) of the ILSI Health and Environmental Sciences Institute (HESI) for hosting the November 2003 Immune-mediated Drug Hypersensitivity Reactions (IDHR) Workshop: Mechanisms to Increase IDHR Research Opportunities in Washington, DC, and for supporting the preparation of this manuscript. The authors acknowledge the hard work of their fellow workshop planning subcommittee members (listed in Table 1) in putting together this workshop. As well, the authors thank Drs. Stephen Pruett and Scott Loveless for their careful review of the document before its submission for publication. For more information on HESI or the ITC, please call 202-659-3306 or e-mail [email protected]. The opinions expressed herein are those of the authors and do not necessarily represent the views of HESI.