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The Science of Drug Safety

Searching for a genetic basis for differences in response to drugs:

“Patients respond differently to medicines and all medicines can have side effects in some people. The SAEC’s work is based on the hypothesis that these differences have a genetic basis, and its research studies will examine the impact genes can have on how individuals respond to medicines.... The most efficient way to study drug-related SAEs is to create a global, publicly available ‘knowledge base’ that will help identify the genetic variations that may predict SAEs.” (from the SAEC Press Release of September, 2007).

The US FDA has an active interest in the application of genomics to the understanding of the varying reactions of individuals to drugs - pharmacogenomics.

Examples of severe adverse drug reactions.  

A number of severe adverse drug reactions are known.  These include the conditions which are the initial focus of the Consortium's efforts:

  • Serious Skin Rashes: Stevens-Johnson Syndrom (SJS) and Toxic Epidermal Necrosis (TEN) - related, rare, severe, mucocutaneous blistering disorders that are associated with over 200 medicines.
  • Drug Induced Liver Injury (DILI) - Hepatotoxicity caused by more than 30 different drugs in more than seven different classes, including NSAIDS, various antibiotics, analgesics and anti-depressants.

as well as others such as:

What are SNPs?

SNPs are Single Nucelotide Polymorphisms - variations in the an organism's DNA sequence. Such variations may have no effect, or may have direct or indirect effects on the functioning of cells, tissues or organs. Even if a SNP has no direct effect, it may be physically close enough on the DNA strand to a causative mutation (this closeness is called being in Linkage Disequilibrium, or LD) that it can serve as a reliable marker for that mutation's presence.

At any given location in an individual's DNA, there are four possible nucleotide bases that can occur (called A, C, G, and T). However, most individuals in a population will have identical bases at any particular position. The variations from the prevalent bases are SNPs. For further information see the SNP Fact Sheet and What is the HapMap?

In some cases particular mutations or SNPs can predispose an individual to a certain condition or disease. Scientists try to detect such effects using association studies.

What is an association study?

Association studies are used to determine if a particular genetic feature, for example a SNP, is linked to the occurence of a particular condition or disease. The nucleotide bases actually present at particular known SNP locations are measured in a number of individuals, both affecteds and controls. Statisticians then attempt to determine if any of the variations (the SNPs) are associated with the condition. Again, a SNP may not be causitive, it may only be "linked" to the actual causitive mutation. But that is enough to give scientists clues as to where to look for the true causitive mutation.

The International HapMap Project is currently identifying SNPs in a number of human populations that can be used to find genes associated with human disease and response to pharmaceuticals.

Government documents concerning serious adverse events

Investigational New Drug Applications: FedReg_21CFR312.32_IND_safety_reports.pdf includes definitions of the various categories of severe drug events and lays out the reporting requirements relevant to Investigational New Drug Applications.

Postmarketing Reporting: FedReg_21CFR314.80_postmarketing_reporting.pdf also includes definitions of the various categories of severe drug events and lays out the requirements for postmarketing reporting of adverse drug experiences.