Drug induced serious adverse events (SAEs) are a significant issue for patients, providers regulators, industry, and payors; and an important element contributing to healthcare cost inflation. They are a major cause of drug development failures, and block box warnings on marketed drugs. The rarity of drug induced SAEs and the absence of efficient surveillance/research networks, makes it extremely difficult for any one company/research entity to accrue enough SAE cases and controls to conduct effective whole genome studies and follow on hypothesis driven molecular research. To date, the iSAEC has partnered with “academic investigators” to build a variety of SAE “research cohorts”. To obtain the research subjects for SAE research in the scale and diversity required, new collaborations with large integrated researcher groups and health networks (with electronic health records) will need to be developed. In order to expand drug induced SAE research in this direction, standardized phenotypes for Electronic Medical Record (EMR) identification of potential cases must be developed and published. To date, the published literature is variable on such definitions and related assessment models.
The PSP is being executed through the efforts and financial support of the US FDA (CDER), the iSAEC and the Wellcome Trust.
Objectives of the PSP
The objective of this project is to produce standard phenotypic definitions for four (4) major drug induced SAEs, which can then be adopted and widely used by the clinical/scientific/biomedical research communities to better standardize research into the genetic base of SAEs and to leverage EMRs in the process.
The PSP
The primary object of the PSP is to develop and publish a set of common phenotypic definitions and associated “diagnostic criteria” to characterize and the clinical features required for the identifications of each of the following phenotypes:
- Serious skin rash (SSR)
- Acute Hypersensitivity syndrome (AHSS)
- Drug-induced liver injury (DILI)
- Drug-induced renal injury (DIRI) (2012-2013)
- LQT/Torsades de Pointes (TdP)
Simple flow diagrams outlining the clinical diagnostic criteria will be developed to aid in phenotyping for each of the above SAEs. These flow diagrams will assist researchers when recruiting patients or for general clinical diagnosis. These phenotypic standards, their scientific underpinnings and related “diagnostic flow charts” will be published in a top peer reviewed journals, and also posted on the SAEC website for widespread use within the clinical and scientific communities.
In order to deliver the PSP four expert working groups (EWGs) were established for the initial four phenotypes of interest. (SSR and AHSS will be supported by one integrated EWG.) It is the responsibility of the EWGs to develop and reach a consensus position for definition for their respective phenotypes.
The EWGs have the following chairmanships:
- Serious skin rash (SSR)/Acute Hypersensitivity syndrome (AHSS) EWG – Munir Pirmohamed
- Drug-induced liver injury (DILI) – Ann Daly and Guru Aithal
- Prolonged QT/Torsades de Pointes (TdP) – Dan Roden and Elijah Behr
- Drug-induced renal injury (DIRI) – Ravi Mahta, UCSD
The overall PSP program is being chaired by:
Prof Munir Pirmohamed
MB ChB (Hons), PhD, FRCP, FRCP(E)
NHS Chair of Pharmacogenetics
Deputy Director, MRC Centre for Drug Safety Science
Department of Pharmacology
The University of Liverpool
Ashton Street, Liverpool, L69 3GE
UK
The PSP project leader will be Julian Arbuckle, consultant to the iSAEC, and supported by an Organizing Committee which includes Arthur Holden (iSAEC), Michael Dunn (Wellcome Trust), Munir Pirmohamed (Clinical Chairman), and ShaAvhree Buckman (FDA)
Expert Working Groups Composition
Each EWG is comprised of between 4-5 disease experts (Munir Pirmohamed (Liverpool), Ann Daly (Newcastle), Paul Watkins (UNC), Guru Aithal (Nottingham), Dan Roden (Nashville) & Dr. Elijah Behr (London), Ravi Mehta (UCSD), plus participation from other interested parties such as the FDA, the Wellcome Trust and the SAEC pharmaceutical members.
PSP Timelines
Phase 1 -- Commenced in the Q2`09 and was completed in Q4`10.
Phase 2 – (DIRI) commenced in Q3`12 and will be completed by Q4`13