The US Food and Drug Administration this week released a new guidance that provides recommendations on when and how pharmaceutical companies and other investigators should consider genomic information in early-phase studies of a drug’s pharmacokinetics, pharmacodynamics, efficacy, or safety.
The guidance, titled "Clinical Pharmacogenomics: Premarket Evaluation in Early-Phase Clinical Studies and Recommendations for Labeling," does not address the design or analysis of later-phase clinical trials to assess drug efficacy in specific genomic subgroups, according to the agency. Rather, the recommendations are "more relevant for exploratory and observational studies intended to generate genomic hypotheses that may then be tested in confirmatory trials."
"It is hoped that ascertainment of genomic information throughout drug development will enable earlier discovery of clinically important genomic differences (i.e., before marketing)," the FDA wrote.
The FDA has long encouraged drug developers to collect patient samples in the clinical development of a product, and begin early genomic research that can elucidate the mechanism of action of the disease and drug. It is well established that using a PGx strategy in late-stage development to rescue a drug with limited efficacy or safety issues is unadvisable as it will add to development costs and may delay commercial launch of the product, if the plan works out at all.
The FDA finalized this guidance after considering stakeholder comments to a draft guidance released in February 2011.
In the final version, the FDA has added language describing when pharmacogenomic studies are warranted, as well as elaborated on topics including sample collection, retention, dedicated prospective PGx studies, genetic sub-studies, and safety PGx.
The agency now has in recent years approved several pharmacogenomically targeted products, including Zelboraf for BRAF-mutated melanoma, Xalkori for ALK-positive non-small cell lung cancer, and a new HER2-positive breast cancer drug Perjeta. The updated guidance no doubt reflects advice the agency has gleaned from its review of these PGx drugs.
In the guidance, the agency suggests that pharmacogenomic assessment in early-phase studies can help identify subgroups that should receive lower or higher doses of a drug; separate out responder populations based on phenotypic, receptor, or genetic characteristics; as well as identify groups at high risk for adverse reactions.
Although the pharmaceutical industry is increasingly using genomic enrichment strategies to predict response to drugs, many times the link between genetic patterns and patient outcomes becomes apparent only after a drug has been available on the market.
The agency cites several examples of these post-approval pharmacogenomic discoveries — including the influence of variations in VKORC1 and CYP2C9 on warfarin dose response, variation in CYP2C19 on Plavix metabolism, and KRAS mutation on the effectiveness of Erbitux — to illustrate the value of collecting genomic information as early as possible in clinical studies to understand a range of clinical variables.
According to the guidance, the FDA's position is that "ideally, baseline DNA samples should be collected from all patients in all arms of clinical trials in all phases of drug development." But some cases may call more strongly for early genomic consideration than others.
Especially in cases where known genetic factors are likely to influence an investigational drug's efficacy, safety, or dosing, "DNA should be collected from all subjects to specifically test those genetic factors for subgroup analysis," the agency wrote.
These influences are often suggested by earlier in vitro studies, according to the FDA. "For example, if in vitro studies show that a molecule’s metabolism in human cell systems relies on a well-established polymorphic gene, such as CYP2C19, and metabolism is a major route of elimination in humans, it would almost always be important to determine the contribution of genomic factors to variability in [pharmacokinetics.]"
But even if genetic variants influencing a drug's metabolism or other factors are not yet characterized, PGx differences should still be considered, the agency said. "Therefore, general DNA sample collection for exploratory analyses should be a routine consideration, and is strongly encouraged … It then becomes possible to seek explanations for differences in PK, PD, efficacy, tolerability, or safety that were not anticipated prior to beginning the study," the agency wrote.
According to the agency, if investigators are not able to collect DNA samples from all study subjects, they should try to obtain as many as possible, focusing on those patients who are identified as pharmacokinetic or pharmacodynamic outliers, or who experience severe adverse reactions or another clinical endpoint of interest.
According to the guidance, genetic variations most likely to be relevant to drug development are those associated with genes in four categories: drug metabolism, absorption, distribution and excretion-related genes; genes that code for intended or unintended drug targets or other related pathways; genes that can predispose patients to toxic or immune reactions; and genes that influence disease susceptibility or progression.
"To design informative studies and interpret study results appropriately, careful attention should be paid in clinical pharmacology studies to differences, if known, in the prevalence of ADME-related gene variants among racial or ethnically distinct groups. [And] the genetic markers selected for analysis should be appropriate to the population being studied," the FDA wrote. "In smaller studies, it is prudent to include rarer functional alleles for evaluation so subjects are not misclassified because a particular (rare) allele was not tested. Drug-metabolizing phenotype assignment based on genotypes should be carefully considered in clinical pharmacology studies."
The FDA also lists three specific types of early pharmacology studies in which investigators have the opportunity to prospectively integrate PGx factors to inform subsequent clinical studies: pharmacodynamic and pharmacokinetic studies in healthy volunteers, the same studies in ill patients, and subsequent dose-response studies.
In pharmacology studies of healthy volunteers, genetic analysis can be performed retrospectively in most cases, according to the FDA, although "in some situations, it may be advisable to conduct dedicated clinical pharmacology studies with balanced, prospective, genotype-based enrollment, or to target enrollment of subjects with variant genotypes to permit meaningful retrospective analyses," such as "when exposures are strongly correlated with response or safety and the genetic factors expected to affect metabolism or transport are not common enough in the general population to be evaluated in an individual clinical pharmacology study."
If there is observed variability in pharmacokinetics in healthy volunteers associated with genomic variation, researchers should consider this in the design of subsequent studies in patients, the FDA suggests.
According to the agency, researchers are also responsible for validating any genotyping or phenotyping methods they plan to use before initiating a clinical PGx study.
Genomic investigation of DNA samples can vary, from rapid characterization of established variations, to candidate gene approaches for unknown polymorphisms in a drug's known target. And if pharmacology of a drug is not well known, researchers may also consider high-throughput approaches using arrays or sequencing to more broadly profile patient samples.
"Analytical validity is critical if the genomic biomarker is intended to select patients for entry into pivotal efficacy studies; if the results of the genomic test are intended to determine whether a patient is to receive the drug, the assay may require approval under an Investigational Device Exemption by [the Center for Devices and Radiological Health]."
Though the guidance is focused on early-phase studies, the FDA makes clear that PGx influences established in early research can, and often should, carry through to later-stage clinical trials.
"Phase 2 studies that suggest genomic influences can lead to Phase III trials that incorporate findings into pre-specified hypotheses. Examples might include enriching the study with genomically defined individuals, determining a dose based on demonstrated variability in earlier studies, or defining a priori hypothesis testing of a primary endpoint in a genomic subset."
The FDA continues, saying that "groups planning to apply genetic information prospectively in Phase III should plan early consultation with the FDA's Center for Drug. Evaluation and Research, Center for Biologics Evaluation and Research, and/or Center for Devices and Radiological Health.