Screening from the Start
by Lisa Zamosky
October 2007
Scientific advances and decreasing costs are elevating the role of pharmacogenomics in the drug development process.
The development of targeted therapies using specific patient genotypes has offered great promise in the quest for personalized medicine. Several of these drug development efforts, particularly those involving therapeutics for Alzheimer’s Disease and cancer, have demonstrated the advantages pharmacogenomics can have on a biopharmaceutical company’s ability to bring a drug to market.
At the outset of a clinical trial, most pharmaceutical companies collect blood samples that allow them to incorporate pharmacogenomics into trial designs at some point during the drug development process. Genotyping patients during the pre-trial phase is one way pharmaceutical companies can develop a database of subjects whose phenotype has been analyzed and defined.
Small Investment, Large Potential
Dr. Christopher Chamberlain, biomarker and experimental medicine leader with Roche Products Limited, in Welwyn Garden City, U.K., says that nearly all of the clinical trials Roche conducts include the collection of DNA with approximately 20 to 30 percent of the samples being analyzed immediately; the rest are held in the company’s Basel, Switzerland location for up to 15 years. This gives the company the option to use the information in the future when more may be known about a drug and patient’s potential response to it.
“In Phase I trials, we ascertain DNA resources to analyze heterogeneity,” Chamberlain says. “It’s all about anticipating what will happen and being prepared to answer the questions when they come up.” Given that the unexpected happens quite frequently in drug development, holding onto the DNA allows them to prepare for the eventual possibility of it being useful, he says.
Collecting blood samples at the outset of a clinical study amounts to about US$100, says Dr. Mark Ratain, Leon O. Jacobson professor of medicine and chairman for the committee on clinical pharmacology and pharmacogenomics clinical services at the University of Chicago, in Chicago, Ill., USA. “Phase I is expensive anyway, so why not add on an extra $100 per person to have the option of analyzing the DNA later?” he says.
Although DNA collection is routinely done early in drug development, prospectively entering patients into early clinical trials based on their characteristic molecular patterns, or polymorphisms, is not a practice that has been widely adopted. One reason for this is the complexity associated with identifying gene variations that predispose someone to disease and affect drug response.
“The human genome has tremendous variability,” says Dr. Gary Small, director of UCLA Memory and Research Center, in Los Angeles, Calif., USA. “You’re going after tens of thousands of genes, plus SNPs (single nucleotide polymorphisms). There are just so many things you can go after. If you don’t give it careful thought, you’re going to find lots of associations that are statistically significant, but spurious.”
This poses a huge challenge to investigators, but Chamberlain says they are coming to grips with it, using alternative approaches for validating and understanding gene variations once a hypothesis has been formed. The key for trial designers, Chamberlain says, is to understand precisely where pharmacogenomics has its utilization. “If we can see before starting [a trial], a way in which targeting genes will give us a clear signal of safety and efficacy, we will include it in the initial architecture of the trial.”
Greater Accessibility
Until recently, the use of pharmacogenomics has been somewhat limited due to a lack of critical information about the genome and because the process has been extremely expensive, says Dr. Christopher Austin, senior advisor for translational research with the National Institutes of Health’s National Human Genome Research Institute in Bethesda, Md., USA. “Now we have the complete reference genome sequence and the Haplotype map, which gives a catalog of most of the common polymorphisms in the human genome. In addition, the price of testing for these polymorphisms has come down 1,000- to 10,000-fold.”
According to Austin, it’s now possible to test 500,000 polymorphisms in thousands of patients whose blood previously was collected and stored, and it’s inexpensive to do so. This is a very recent development, and many groups now are starting polymorphism association projects, which will allow them to have a catalog of the common polymorphisms associated with response to a drug, Austin says.
Translating Pharmacogenomics into Clinical Practice
A drug that is adapted to individuals with a particular genetic makeup would be of tremendous value to patients and the physicians treating them, Small says. Tailored medicines would require more detailed assessments, however, and physicians need to be on board if the drug is to be of maximum use. “If the pharmaceutical companies establish the connection, doctors will use the drugs,” Small says.
Translating the use of genetics into clinical practice is “sine qua non” of pharmacogenomics, Chamberlain says. “You must predicate its use on the value you’ll offer to providers and patients, and you must have a clear message of why the patient is to take a particular medication. What will get people to adopt this is an understanding of its utility and this is what drives the whole process,” he says.
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