Emerging Safety Science Workshop Summary (2008) / Chapter Skim
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9 Integration
9 Integration
Pages 93-105
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From page 93... ...
An integration tool at GLAXOSMITHKLINE Almenoff noted that although the FDA receives about 400,000 adverse event reports each year for marketed products, there is very limited systematic feedback of that clinical safety information to the discovery pipeline. And while there is likely a great deal of information embedded in This section is based on the presentation of Dr.
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From page 94... ...
Molecular Clinical Safety Program GSK developed the Molecular Clinical Safety Program (MCSP) as a way of closing the knowledge gap among various disciplines and helping to minimize both safety risks and attrition in the drug pipeline.
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From page 95... ...
Almenoff offered an example of how the MCSP tool was used to model toxicity data by linking human clinical safety data with molecular targets. GSK researchers examined tardive dyskinesia (TD)
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From page 96... ...
In 1999 he was the principal investigator in a cooperative research and development agreement between Elsevier and the FDA to predict toxicological and adverse event end points. Leveraging historical data, the researchers sought to establish a comprehensive database comprising well-organized and integrated preclinical, clinical, and postmarket data using FDA approval packages.
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From page 97... ...
Another barrier involved hierarchical terms. For example, if one is interested in retrieving data about ventricular arrhythmias from the database, it will be important for the database to recognize that there are many different types of ventricular arrhythmias: premature ventricular contraction, multifocal ventricular tachycardia, wide complex ventricular tachycardia, ventricular flutter, etc.
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From page 98... ...
FIGURE 9-1 Example of hierarchical thesauruses for adverse events, drugs, and targets. NOTE: MedDRA = Medical Dictionary for Regulatory Activities.
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From page 99... ...
• The lack of standardized terminology throughout the drug development industry and the health care community is a major barrier. • Using this database, it is possible to look at preclinical, clinical, and postmarket data simultaneously; identify all compounds with a certain substructure and a certain target; and list all the toxicological effects of a particular type.
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From page 100... ...
The Need for Bridging Biomarkers While it is important to create feedback loops that enable data from later in the process to inform technologies and decisions in earlier stages, it is also important to create forward connections. Frueh stressed the importance of having bridged biomarkers from the preclinical to the clinical stage in the event that preclinical information could predict what might happen in the clinical stage (see Figure 9-2)
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From page 101... ...
Predictive Safety Testing Consortium, a partnership between the FDA's Critical Path Initiative and a number of large pharmaceutical companies that is aimed at predicting the safety of new treatments before their use in humans, is investigating the analytical validation of a set of nephrotoxicity markers, and in the near future it will consider methods for establishing clinical qualification. Such bridging biomarkers would likely be highly useful in exploratory IND (investigational new drug)
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From page 102... ...
Dealing with Idiosyncratic Events Frueh explained that in addition to developing biomarkers to predict preclinical and clinical events, it is necessary to establish biomarkers for dealing with idiosyncratic events -- random, unexpected, often doseindependent adverse drug reactions -- that occur during clinical testing and once a drug is on the market. These events are generally caused by an interplay between the properties of a drug and the predispositions -- genetic and otherwise -- of the patient.
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From page 103... ...
The main problem is that the safety databases generated during drug development are generally too small to highlight rare events successfully. The largest amount of safety data is actually produced once a drug is on the market, but current tools do not allow scientists to capture this information effectively and capitalize on its potential.
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From page 104... ...
Figure 9 -3 to identify at-risk patients and remove them from the population being prescribed that drug, the drug could proceed to final approval. Summary Frueh summarized the potential of these emerging technologies and some of the future barriers scientists must overcome: • The emergence of new molecular biomarkers for drug safety will make it possible to better bridge the safety gap between the preclinical and clinical stages; the hope is that eventually, having true translational biomarkers will transform the process into a continuum.
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From page 105... ...
have the potential to identify markers for rare adverse events, but access to well-characterized samples remains a problem. • New mechanisms and processes for studying clinical and postmarket safety need to be explored.
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