The Brighton Collaboration A Global Vaccine Safety Effort

The Brighton Collaboration: A Global Vaccine Safety Effort Jane Gidudu, MD, MPH April Compingbutra, MPH Brighton Collaboration, Immunization Safety Office of the Chief Science Officer CDC-Atlanta National Immunization Conference March 17 -20, 2008

Learning Objectives • Describe the need for standardized case definitions and guidelines in the assessment of adverse events following immunization (AEFI) • Access the Brighton Collaboration website to download standardized case definitions • Describe the usefulness of using standardized case definitions and guidelines.

Mission The Brighton Collaboration is an international voluntary collaboration with a mission to facilitate the development, evaluation, and dissemination of highquality information about the safety of human vaccines

Global Standardization • Vaccines are used worldwide • Standardization of Adverse Events Following Immunization (AEFI) • Facilitates comparability and communication of safety data • Enhancement of trust in current immunization programs

Existing Definitions • Case definitions for adverse events lack a common format • CIOMS and ICH mainly focus on drug AE • WHO definitions are not graded or evaluated • Companies have a wide range of definitions but no comparability CIOMS: Council for International Organizations of Medical Sciences ICH: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use

Background The Need: § Safety can not be measured directly, only inferred from the relative absence of AEFIs § Assessing safety requires standardized terminology of AEFI § Lack of a standard “vocabulary” (i. e. , case definitions & guidelines) for AEFI has hindered comparability of vaccine safety data The Solution: § A global collaboration to address this “missed opportunity” § Development of standardized case definitions and guidelines § Case definitions categorized by levels of evidence - Clinical trials vs. post marketing surveillance - Developed vs. developing countries

Goal To enable comparability of vaccine safety data across clinical trials, surveillance systems, and epidemiologic studies within different geographic regions

www. brightoncollaboration. org secretariat@brightoncollaboration. org

Brighton Structure Brighton Steering Committee • Michael Blum, Industry-USA (Wyeth) • Miles Braun, Regulatory-USA (FDA) • Najwa Khuri-Bulos, Clinical & Academia-Jordan (University Children’s Hospital) • Brigitte Keller-Stanislawski, Regulatory-Germany (Paul Ehrlich Institut) • Katrin Kohl, Public Health-USA (CDC) • Odile Leroy, Public Health-Netherlands (European Malaria Vaccine Initiative) • Michael Marcy, Clinical & Academia-USA (Center for Vaccine Research, University of Southern California and Kaiser Foundation Hospital) Brighton CDC Secretariat • Jane Gidudu, MD MPH (CDC-Atlanta, USA) • April Compingbutra, MPH (CDC-Atlanta) • Paige Lewis, MPH (CDC-Atlanta)

Brighton Process • Select or prioritize an adverse event to be defined • Initiate a 6 -step process – – – Review literature for available evidence Form working groups Develop draft definitions and guidelines Review and evaluate draft Review and receive endorsement from the CIOMS and WHO vaccine pharmaco-vigilance committee – Finalize and disseminate documents

Case Definition Format (5 Categories) • Level 1 of diagnostic certainty [most specific least sensitive] • Level 2 of diagnostic certainty [intermediate] • Level 3 of diagnostic certainty [least specific, most sensitive] • 2 Additional categories for data analysis Reported [AEFI] with insufficient evidence Not a case of [AEFI]

Example: Intussusception Level 1 – Surgical criteria AND/OR – Radiological criteria AND/OR – Autopsy criteria Level 2 – Clinical criteria – 2 Major* OR I major & 3 minor¥ criteria Level 3 – Clinical criteria – >4 minor¥ criteria • *Major criteria include: evidence of intestinal obstruction, features if intestinal invagination, evidence of intestinal vascular compromise or venous congestion • ¥ Minor criteria include: predisposing factors such as abdominal pain, vomiting lethargy, pallor, hypovolemic shock, plain abdominal radiograph

Guidelines Data Collection – Includes the minimum data collection elements for adverse event reporting recommended by CIOMS and ICH [an identifiable reporter and patient, immunization history, and a detailed description of the event] Data Analysis – Categorization of event as appropriate, – Predetermined increments as appropriate Data Presentation – Brighton vaccine standards analogue to CONSORT statement for RCTs

Highlighted Achievements “Success is the progressive realization of a predetermined worthwhile goal” Paul J Meyer

Case Definitions • • • • Anaphylaxis Aseptic meningitis Encephalitis, myelitis, and ADEM Fever Fatigue Hypotonic-hyporesponsive episode Intussusception Local reactions – abscess – cellulitis – nodule – induration – swelling Persistent crying Rash Seizure Thrombocytopenia Unexplained sudden infant death including SIDS Vaccinia – eczema vaccinatum – inadvertent inoculation – generalized vaccinia – progressive vaccinia – robust take

How to Access the Brighton Case Definitions “Today knowledge has power. It controls access to opportunity and advancement” Peter F. Drucker 1909

Online Collaboration Platform

Download published definitions & Guidelines

Enter E-mail Address

Old Brightonians Log in here

Current Projects • Case definitions – – • • • Guillain-Barré Syndrome (GBS) Local reactions Bell’s Palsy Diarrhea Guidelines for surveillance systems and clinical trials Neonatal and maternal guidelines Implementation Working Group - Formed to better address needs of developing countries • • Evaluation studies CIOMS & WHO working group on vaccine pharmacovigilance - Exploring mapping of select Brighton case definitions to Med. DRA coding

Network of Participants (N=1697) January 2008 69 countries with > 2 participants 24 countries with 1 participant www. brightoncollaboration. org secretariat@brightoncollaboration. org

Professional Background of Active Participants • Regulatory • Industry • Public Health • Patient care/ Scientific /Prof.

• Use of Brighton Case Definitions in Studies Mortality and Morbidity Weekly Report (MMWR). Postmarketing monitoring of intussusception after Rota. Teq vaccination---United States, February, 2006 -February 15, 2007. March 16, 2007/56(10); 218 -222. • Ruiz-Palacios GM, Perez-Sachael I, Velazquez RF et al. safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med 2006; 354: 11 -22. • Mortality and Morbidity Weekly Report (MMWR). Update: Guillain-Barre Syndrome among recipients of Menactra meningococcal conjugate vaccine United States June 2005 -September 2006. October 20, 2006 /55(41); 1120 -1124. • Bines JE, Ivanoff B, Justice F et al. Clinical case definition for the diagnosis of acute intussusception. J Pediatric Gastroenterol Nutr 2004; 39: 511 -518. • Babl FE, Lewena S, Brown L. Vaccination related adverse events. 2006. Pediatr Emerg Care 22(7): 514 -522. • Tapiainen T. Heininger U. Fever following immunization. 2005. Expert Rev Vaccines 4(3): 419 -427.

Applicability in Surveillance Systems • Check list for active follow-up • Validation of data – Report & signal generated • Standardized safety assessment – Comparability with other studies Improved value of surveillance data

Applicability in Clinical Trials • CRF design – relevant data collection – check list for follow-up • Data analysis – clearly defined outcomes • Standardized safety assessment – comparability with other studies Improved value of individual study

Global Recognition and Recommendation – World Health Organization (WHO) – US Centers for Disease Control and Prevention (CDC) – European Centers for Disease Control and Prevention (ECDC) – US Food and Drug Administration (FDA) – Council for International Organization of Medical Sciences (CIOMS) – European Agency for the Evaluation of Medicinal Product (EMEA) – American Academy of Pediatrics (AAP) – Council for International Medical Sciences (CIOMS)

Summary • The Brighton Collaboration is a growing global network of experts and scientists concerned with vaccine safety. • The common goal is to facilitate data comparability across studies in different settings. • We have a voluntary platform for almost 1700 participants. • The collaboration consists of various disciplines (academia, patient care, industry, regulatory, public health organizations and donor agencies) • We use a systematic approach and transparent, scientific process. • Our products are suitable as a global standard. • Case Definitions can be accessed freely online.

Many Thanks!