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International Clinical Trials

Managing Drug Safety

On behalf of the Safe-T consortium, Joe Keenan from Argutus Medical Ltd gives an insight into the first European collaborative project looking at the qualification of translational biomarkers

The development of new medicines is associated with high levels of development attrition, it is well known that less than 10 per cent of all drug candidates entering preclinical studies will complete clinical development and be submitted for regulatory approval. The full drug development process is a lengthy and complicated one, which generally takes more than 10 years.

Drug toxicity is a major cause of costly late-stage development failures and devastating market withdrawals. Traditional preclinical toxicology approaches have limited power to detect adverse events and to evaluate the relevance of preclinical findings to the clinical setting. Species differences in drug toxicity in preclinical safety tests, the lack of sensitive translational biomarkers and the non-representative patient population in clinical trials are probable reasons for the failures in predicting human drug toxicity. However, changes in drug discovery practices and the development of specific and sensitive safety biomarkers, more predictive models (in silico and in vitro), ‘omics’ approaches, translational methods and studies are expected to reduce these drug development failures considerably.

A EUROPEAN INITIATIVE

On 15th June 2009, the Safer and Faster Evidence-Based Translation (SAFE-T) consortium was launched as the first project to start under the EU Innovative Medicines Initiative- Joint Undertaking (IMI-JU), a unique public-privatepartnership between the European Communities (represented by the European Commission) and the pharmaceutical industry (represented by the European Federation of Pharmaceutical Industries and Associations (EFPIA)) in Stockholm. The IMI-JU’s objective is to support projects that address the main causes of delay, or ‘bottlenecks’, in the pharmaceutical research and development process.

SAFE-T CONSORTIUM

The SAFE-T consortium will work to qualify biomarkers for drug-induced kidney, liver and vascular injury in translational studies and to seek regulatory acceptance in translational and clinical contexts. The consortium is a public-private-partnership between 20 participants from the pharmaceutical industry, small- to medium-sized enterprises, academic institutions and clinical units of excellence with representatives from the health authorities EMEA and FDA as external observers and advisors (see Table 1).

Table 1: SAFE-T consortium stakeholders

SMEs

  • Argutus Medical Limited (Ireland)
  • EDI Gmbh (Germany)
  • Firalis (France)
  • Interface Europe (Belgium)

Academic

  • Barcelona Cardiovascular Research Center (Spain)
  • Charite Hospital (Germany)
  • Groupe Hospitalier Pitie Salpetriere (France)
  • NMI, Natural and Medical Sciences Institute (Germany)
  • Tel Aviv (Souraski) Medical Center (Israel)

EFPIA Members Pharma

  • Almirall
  • Amgen
  • AstraZeneca
  • Bayer Schering Pharma AG
  • Boehringer Ingelheim
  • Eli Lilly
  • GlaxoSmithKline
  • Hoffmann La Roche
  • Novartis
  • Pfizer
  • Sanofi Aventis

 External Advisors

  • European Medicines Agency
  • FDA (proposed)

OBJECTIVES

SAFE-T is working to address the current lack of sensitive and specific clinical tests to diagnose and monitor druginduced injury to the kidney, liver and vascular systems in humans, which is a major hurdle in drug development. Therefore, many promising candidate drugs with preclinical toxicity signals of unknown relevance do not enter the clinical phase, as no sensitive tests exist to allow timely detection of patient safety signs before irreversible injury occurs. New tests based on biomarkers will enable studies to assess whether these drugs are safe to ‘translate’ into clinical use. Furthermore, the new translational safety biomarkers will allow the identification and management of side effects of drugs throughout drug development, helping to reduce the risk of developing medicines and improving the safety management of patients.

The consortium will develop promising biomarkers to detect drug-induced kidney, liver and vascular injury in humans using peripheral samples such as blood and urine. In preclinical and clinical studies, evidence about the utility and limitations of these biomarkers will be collected in order for health authorities to approve their use in drug development. Daily care in clinical units will also benefit from this biomarker qualification project, as these safety biomarkers are expected to support the diagnosis of liver, vascular and kidney diseases and to help clinical management of patients susceptible to organ injury. In summary the objectives are:

  • To evaluate the use of safety biomarkers for monitoring organ safety in humans
  • To develop assays and devices for clinical application of safety biomarkers
  • To compile sufficient evidence to qualify safety biomarkers for regulatory decision making in clinical drug development and in a translational context in cooperation with the health authorities
  • To gain evidence on how safety markers may also be used in the diagnosis of diseases and in clinical practice

CONSORTIUM STRUCTURE

A project this size demands considerable commitment and resource from all parties. To simplify the process, the project work is split into a number of groups or ‘work packages’ numbered from 1-9. Each of these work packages has an EFPIA and non-EFPIA team leader with the responsibility of driving the group to achieving its own milestone objectives within a defined timeline. The work packages are divided thus:

  • WP1 – Development of generic scientific qualification strategy for translational safety biomarkers
  • WP2 – Drug-induced kidney injury
  • WP3 – Drug-induced liver injury
  • WP4 – Drug-induced vascular injury
  • WP5 – Assay development
  • WP6 – Integrative data analysis
  • WP7 – Bio-banking
  • WP8 – Dissemination, communication and training
  • WP9 – Consortium management

KEY ORGAN AREAS OF FOCUS

Drug-Induced Kidney Injury (DIKI)

Commonly used tests to monitor renal function, such as serum creatinine and blood urea nitrogen (BUN), are unsuitable for sensitive nephrotoxicity monitoring as they reflect compromised glomerular function, while most nephrotoxins tend to affect the renal tubules. WP2 will develop a list of candidate biomarkers and assess them to qualify biomarkers of DIKI for use in man that are earlier and more sensitive than SCR and BUN, and to gain regulatory approval for their use in certain clinical contexts.

Drug-Induced Liver Injury (DILI)

This work package will shortlist promising liver biomarkers and assess them to develop and qualify biomarkers of human DILI that are predictive and more sensitive/specific than the current standards for the pathologies and mechanisms that are relevant to drug development. It will also work towards gaining scientific acceptance and ultimately regulatory approval for the use of these biomarkers in defined clinical contexts.

Drug-Induced Vascular Injury (DIVI)

WP4 will test novel vascular injury biomarkers to develop and qualify translational DIVI biomarkers of preclinical DIVI and to gain regulatory approval for the use of these biomarkers in related clinical contexts.

ASSAY DEVELOPMENT

Key to the success of this project is initially in the selection of promising candidate biomarkers that can potentially show greater value in organ injury detection than the currently used battery of tests in drug development and the clinic (there being an historical connection in similar assay utility). Following on from this is the importance of presentation of these candidate biomarkers in assay formats that can be assessed by the consortium. WP5 (assay development) was instated by SAFE-T to develop immunoassays for the quantitation of individual biomarkers and panels of biomarkers (the estimated number is between 60 and 100 assays) for DIKI, DILI and DIVI. The process runs as follows:

  • Selection of commercially available antibodies and/or kits for candidate biomarkers of DIKI, DILI and DIVI 
  • Antibody generation and/or management of this activity
  • Immunoassay development (single-plex assays on microtitre plate based technology and multiplex assays on Luminex and Mesoscale technologies)
  • Validation of these immunoassays
  • PoT studies for DILI, DIKI and DIVI (sample processing)
  • Validated biomarker assays that satisfy regulatory requirements for clinical application
  • PoP studies for DILI, DIKI and DIVI (sample processing)

CANDIDATE BIOMARKER UTILITY

Biomarkers with probable translational utility for DIKI, DILI and DIVI, and their assays will be qualified for human applications first, in exploratory biomarker proof of translation (PoT) studies conducted in a small series of healthy volunteers and in patients for proving the translational value of the selected candidate biomarkers. They are then in confirmatory biomarker proof of performance (PoP) studies, conducted for biomarker performance testing in large patient populations with drug- and non-drug-induced pathologies and with common disorders. Integrative data analysis will be carried out to demonstrate the performance and the added-translational-value of biomarkers in comparison to current gold standards. In addition, the consortium will investigate biologic/ mechanistic understanding of DIKI, DILI and DIVIbiomarkers that will reinforce the translational capacities of the qualified biomarkers.

The Consortium will establish a database of human biomarker profiles and a biobank for supporting future biomarker R&D. A specific taskforce involving all partners will communicate the key results and make them available for identified target audiences via knowledge dissemination at workshops, training sessions and media briefings.

CONSORTIUM FINANCING

The total budget of the consortium will be €35.8 million ($51.1 million), over a total duration of five years, with combined financing from the participating European pharmaceutical companies and the IMI-JU for academic partners and SMEs (the completion and signature of the grant agreement with the IMI-JU is pending).

CONCLUSION

After finalisation of the project agreement, work started on 15th June 2009 with an inaugural meeting in Stockholm. The SAFE-T consortium is the first project to start under the EU IMI-JU. The SAFE-T project is ambitious and only possible through the partnership of the SMEs, academics, hospitals and EFPIA members. Significant progress has been made in the first five months of the project.

The SAFE-T concept is based on the application of advances in biomarkers, new technologies and in the better understanding of injury mechanisms to the drug development process, for the predictivity of safety evaluation and benefit-risk assessments, and thereby bringing safer medicines to patients quickly. This will be achieved by selecting specific and sensitive candidate safety biomarkers based on their potential for translational use and proceeding to their qualification in clinical settings for supporting early clinical regulatory decision making, as well as optimising the drug development process by accelerating it and decreasing its cost.


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Joe Keenan studied Medical Virology at University College Dublin, conducting extensive research in hepatitis C in the 1990s. Having a major interest in clinical assay development, he joined a major diagnostics company as Product Manager and Technical Sales Manager. Based in Dublin, Ireland, Joe joined Biotrin International in 2005 as Head of Sales and Marketing and ran the biomarker business unit. In 2008 Joe and other Biotrin senior management spun out the biomarker division of Biotrin into a new company Argutus Medical Ltd. Over the last five years, Joe has been involved in a number of cross industry biomarker consortia, including the ILSI HESI Nephrotoxicity working group, which recently submitted a panel of preclinical markers fro qualification to the FDA. Currently, he is acting as joint leader of the kidney injury work package of the SAFE-T consortium.
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