Historically, fewer than 10% of new chemical entities (NCEs) entering preclinical development are approved for clinical use, often because of unaccept-able toxicity in animal studies or Phase I human trials or insufficient efficacy.
THE IMPACT OF PHARMACOGENETICS
ON CLINICAL DRUG DEVELOPMENT
Historically,
fewer than 10% of new chemical entities (NCEs) entering preclinical
development are approved for clinical use, often because of unaccept-able
toxicity in animal studies or Phase I human trials or insufficient efficacy
(Kleyn and Vesell, 1998). The cost of bringing a new drug to market is
approximately $500–800 million; the costs of ADRS and treatment failures,
discussed earlier, are staggering. The appli-cation of pharmacogenetic research
and knowledge could result in streamlining and improving the clinical
development process in several ways:
• by initial toxicogenomic screening of
compounds to detect selective metabolism, disposition or action related to
known polymorphic enzymes, transporters or targets;
• by providing an ‘insurance policy’ for drug
development outcomes. If the results of pivotal trials do not show efficacy in
the whole population, subsetting the population on the basis of genetics may
enable identification of a group with positive results that were diluted in the
entire population and
• by enhancing the efficacy and safety profiles
of medicines in targeted populations to enable better penetration in the marketplace.
Many
pharmaceutical companies now routinely screen NCEs to see if they are
metabolized selectively by known polymorphic enzymes, and development is
discontinued or altered to include additional pharma-cokinetic studies for many
of those that are because of the potentially increased risk of serious ADRs or
lack of efficacy in subpopulations of patients (Zuhlsdorf, 1998).
Initially,
much of the benefits of genomics was expected to ‘rescue’ NCEs after the drug
had been ‘killed’. In reality, the value that late in the drug’s lifetime has
not been the case. In contrast, collecting and using genomic information during
drug develop-ment and at the time of launch is money and time well spent.
However,
understanding why certain drugs that have been removed from the marketplace due
to serious adverse events can help in developing follow-on compounds. For
example, terfenadine (Seldane) caused ADRs in patients who had a specific
CYP2D6 gene polymorphism and also were taking erythromycin. They were unable to
metabolize terfe-nadine in this situation, which caused toxic accumu-lation of
the drug in the body. The FDA worked with the pharmaceutical manufacturer to
distribute appro-priate warnings about the possible risks of its use with
concomitant medicines, but the company and FDA decided that the drug’s
risk–benefit ratio did not justify its continued use. If a screening test to
identify patients at risk for this problem had been available, it might have
been possible to keep the drug on the market while protecting some of those
most likely to experience toxicity from it (Bhandari et al., 1999).
Perhaps,
the most striking example was the removal of Vioxx, a COX2 inhibitor from the
marketplace. Identification of the cardiovascular risk took many years to
identify with many millions of patients exposed. It is clear that new methods
to study tens to hundreds of thousands of patients over multiple years will be
needed. These methods will likely rely on technology such as electronic data
capture that can collect data quickly and efficiently from the patients as well
as the physicians. A low cost, efficient, patient-administered DNA collection
approach will also help to identify patients at risk without compromising the
access to drugs.
Discussion
of the potential impact of pharmaco-genetics on clinical trial design is beyond
the scope of this chapter, but it is clear that many phar-maceutical companies
recognize its importance and are planning to initiate pharmacogenetic studies
in the near future (Ball and Borman, 1997). Lichter and McNamara (1995)
suggested one approach for incorporating pharmacogenetics into clinical trials:
• Perform preclinical identification of
metabolic pathways and population screening for common DNA sequence variants of
the relevant enzymes, transporters, receptors and target genes (and their
homologues), as discussed above.
• Consider the ethnicity of study populations
based on known differences in the frequency of specific polymorphisms.
• During Phase I trials, type subjects for the
genes known to control the drug’s metabolic pathway(s) to allow possible
correlation of ADRs with geno-type and use this information as a basis for
subject selection in Phase II and III studies.
• During Phase II trials, type any identified
rele-vant polymorphisms in the entire study group. Also type the gene product
and related targets in all subjects, allowing assessment of allele frequencies
in the population and in responders versus non-responders. Use these data as a
basis for subject selection in Phase III trials.
• If useful genetic markers of efficacy or ADRs
are identified during Phase II, the Phase III group could be expanded to
include a cohort prescreened to include likely responders and those at low risk
of ADRs.
This
approach is limited by its reliance on iden-tified candidate genes (genes
selected on the basis of existing knowledge or an informed guess) and molecular
pharmacology to identify drug–receptor interaction, and down-stream signalling
pathways, and unexpected associations (either causal or resulting from LD) may
not be recognized.
Another
approach that is being used already by some pharmaceutical companies has been
thought to hold even greater promise as technological advances increase the
accuracy, feasibility and cost-effectiveness of high-throughput whole-genome
scan-ning. The benefit of whole genome scanning has not yet been realized.
Regardless
of the genomic approach, collection of a single blood sample for DNA analysis
from all consenting participants in selected Phase II and clinical trials
(after approval by the appropri-ate ethics review boards and provision of
specific informed consent by subjects) enables pharmaceuti-cal companies to
have the key samples needed in case a safety or efficacy question arises. This
sample may be used to identify the occurrence of known polymorphisms affecting
drug response, to evaluate candidate genes suspected of being involved in the
disease or drug response and to assess patterns of SNP or haplotype occurrence
related to efficacy or ADRs, allowing the creation of a SNP PrintSM
to screen potential subjects or patients (post-approval) for their likely
response to the drug or determine heterogene-ity of the disease in patients
with similar phenotypes (Roses, 2000b).
Regulatory
agencies might be concerned, appropri-ately, that the smaller numbers of
patients in these streamlined clinical trials would be insufficient to detect
rare ADRs (<1:1000) and that patients who did not receive or ‘pass’ the
recommended MRT for the drug would nevertheless receive it and be at increased
risk of harm. However, rare ADRs are not likely to be detected even in the
relatively large clinical trials that are conducted now; it certainly is not
feasible to enroll the approximately 65 000 patients that would be required to
be 95% confident of detecting three or more cases of an ADR with an incidence
of 1:10 000 (Lewis, 1981). The major, albeit rare, ADRs asso-ciated with
dexfenfluramine, zomepirac, benoxapro-fen, troglitazone and terfenadine were
not detected until after they reached the market. Extensive preapproval safety
testing in even larger populations is a possible solution, although, as noted
above, it will be impractical to identify very rare ADRs in clin-ical trial
study populations, and the increased cost and delayed time to market is likely
to create signif-icant financial barriers from the perspective of the
pharmaceutical companies (and ultimately consumers and payers to whom the cost
will be passed along) (Roses, 2000a).
One
solution to this problem would be an exten-sive, regulated post-approval
surveillance system that incorporates the collection of pharmacogenetic data.
Roses (2000b) proposes that hundreds of thousands of patients receiving a
medicine would have filter paper blood spots taken (perhaps from the original
blood sample used for the MRT) and stored in a central location. As rare and/or
serious ADRs are reported and characterized, DNA from affected patients could
be compared with that of control patients, allowing ongoing refinement of the
MRT. There is increas-ing pressure to improve the inconsistent and largely
unregulated current system of post-marketing surveil-lance, and many authors
agree on the need to incorporate pharmacogenetic data in some form into a
revised system (Edwards and Aronson, 2000; Nelson, 2000).
Another approach is one that would put increas-ing control of medical data in the hands of those most directly affected by it – consumers. In this scenario, an individual could choose to have a one-time blood sample taken for DNA analysis and stored at a tightly secured central repository. As research into disease-related genes, genetic risk factors and genetic associations with medicine responses progressed, the consumer or a designated representative (such as a health care provider) could request that the sample be analyzed using relevant MRTs (including SNP PrintsSM and other markers. This ‘bank’ could serve as a central repository for the samples themselves and as a central database of information including well-established knowledge, current research and even opportunities for clinical trial subjects with specific conditions or genotypes. It could trigger genetic ‘alerts’ to consumers who chose to provide a medical and family history as new research results potentially relevant to them became available. A host of ethical, legal and social issues would need to be addressed as part of this venture, but it presents one option for an efficient, centralized and consumer-controlled bank of health-related genetic expertise and information.
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