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FDA Draft PGx Guidance Urges Early Planning to Anticipate Pre-market Gene-Drug Issues

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By Turna Ray

In a draft guidance to help drug developers incorporate pharmacogenomics data in early clinical trials, the US Food and Drug Administration urges industry to collect DNA samples from patients or at least have a plan for pre-specified DNA collection before starting a study.

The agency is hoping that the recently issued guidance can help lay out a path for drug developers to identify PGx issues before the drug enters the market, instead of after. The guidance notes several examples in which the FDA has updated drug labels with genomic information in the post-market setting, after PGx data has emerged to change the treatment's risk/benefit profile (i.e. Warfarin, Plavix, and Abacavir).

"Because these recent postmarketing examples have, in most cases, been based on data from postmarketing experience, their discoveries were relatively late," the FDA states in the document. "It is hoped that full ascertainment of genomic information on all subjects during early development will allow early discovery of clinical important genomic differences."

FDA will accept public comments on the draft guidance until April 19. The recommendations in FDA guidance documents are not legal requirements for sponsors, and are meant to inform industry standards and best practices.

In this preliminary document, FDA advises drug companies to obtain consent for DNA collection from all study participants and make an effort to collect genetic samples at the time participants are enrolled for a study or at baseline, in order to avoid bias that can taint the study if samples are collected later in the trial.

According to the agency, DNA sample collection from all enrolled patients is "particularly important … where many patients do not complete the study, do not comply with the protocol, or withdraw from the trials before experiencing a clinical outcome.

"In cases of incomplete sample acquisition, the specific reasons should be described and any potential bias estimated where possible," the FDA states. "Samples should be collected in all arms of the trial. DNA should be retained in the event that new genomic issues arise after the completion of the studies."

The agency has been pondering how to present its stance on DNA sample collection to industry for some time. In March 2010, the FDA's Advisory Committee for Pharmaceutical Science and Clinical Pharmacology discussed the circumstances under which the agency should encourage DNA data collection by drug companies. They ultimately advised that while the agency could not "require" sponsors to collect DNA samples from all study subjects, they could through guidance "strongly urge" this practice (PGx Reporter 03/2/10).

Earlier this year, Issam Zineh, associate director of genomics at FDA's Office of Clinical Pharmacology, told PGx Reporter that sponsors are still struggling with sample acquisition in drug development trials. Most sponsors make sample donation voluntary for study participants. However, if a gene marker is identified later in clinical trials — thus requiring a stratified trial — companies may find they don't have enough samples to conduct such analysis. In trying to collect DNA samples in later phases of development with out a pre-specified plan, there is a possibility sample collection from patients can be biased (PGx Reporter 01/05/11).

Anticipating PK/PD Effects

Routine collection of DNA samples is one way the agency suggests drug companies can prepare for anticipated and unanticipated gene-drug associations that arise during the development program of a drug. According to the FDA, while some genomic impact on a drug's pharmacokinetic profile can be anticipated, the interplay of genes on an agent's pharmacodynamic characteristics is often harder to gauge.

Genes linked to a drug's pharmacokinetics impact how that drug is absorbed, distributed, metabolized, and excreted, and may explain how the drug forms into active metabolites. Genes linked to the PD characteristics of the drug may impact its effectiveness and adverse effects.

The FDA advises sponsors to keep an early lookout for potential PGx issues that might impact PK/PD of the drug and require changes to the development plan later on. For example, in vitro studies can sometimes show that a molecule's metabolism is dependent on a well-understood polymorphic gene, such as CYP2C19. In such a case, "it would almost always be important to determine the contribution of genomic factors to variability in PK and subsequently to dose or dosing regimen selection," the FDA notes.

"These data inform decisions as to whether subsequent clinical studies need to take PGx differences into account (e.g., in dose-response studies)," the agency states in the draft guidance. The FDA suggests the use of "available technology platforms" to characterize allelic variations metabolism and transporter genes to gain a "thorough understanding of PK and/or PD related to genomics."

In order to scan for response variability, even before understanding the specific underlying genetic causes, the FDA suggests routinely screening study participants in early phase trials using a gene chip containing a large number of possible candidate metabolism and transporter genes, some of which may influence the drugs PK or PD. Another suggestion in the draft guidance is for sponsors to develop high-density SNP arrays to explore SNP profiles that could influence PK, PD, or patient outcomes.

Preparing for Later PGx Studies

Once in vitro exploration suggests the need for a human PGx study, many of those studies are not prospectively designed randomized trials, the agency reports.

However, FDA would like to change this trend: "In later-stage clinical trials intended to support efficacy and safety conclusions in genomic subsets, stratified randomization or planned subset assessment would generally be expected," the agency states.

The first time the FDA accepted retrospective PGx analysis to change drug [missing word?] was in the case of two metastatic colorectal cancer drugs: Amgen's Vectibix and Merck/ImClone/Bristol-Myers Squibb's Erbitux. In order to inform doctors and patients that those who had tumors with mutated KRAS genes should not receive these drugs, the agency reviewed retrospective PGx analysis from seven clinical trials, two involving Vectibix and five with Erbitux (PGx Reporter 07/22/09).

In an effort to better understand the circumstances under which the FDA would accept retrospective data to narrow the indication of a drug for a particular subpopulation, the agency convened an advisory committee meeting last fall to discuss Amgen and BMS/ImClone's submissions for the labeling changes (PGx Reporter 12/17/08).

Other advice provided in the guidance revolves around the types of genomic testing companies can conduct to capture early PGx signals. For example, the agency advises that when in vitro studies suggest that a drug is metabolized in a polymorphic pathway, companies should conduct PK studies in healthy volunteers "representing various common genotypes to determine the extent of variability and the maximal differences in systemic exposure between genotypes."

The agency also asks sponsors to "pay special attention" to drugs that are converted to an active metabolite from an inactive form through a polymorphic pathway. "It is advisable to characterize the metabolism of the drug and study the biological activity of the relevant metabolites early in drug development," FDA says in the draft guidance.

"Where drug metabolites have important clinical effects (e.g., tamoxifen, clopidogrel), failure to form the active metabolite may have profound effects on disease recurrence and/or sequelae," the agency notes. "It is particularly critical from the beginning of development in these cases to include subgroups of subjects with genetic variants of metabolic or transporter pathways."

Ultimately, the takeaway for sponsors reading the draft guidance should be that the agency wants them to plan early for PGx issues that might crop up in later trials. Early planning for stratifying clinical trials becomes even more critical as genetic tests enter the picture, and the agency has to coordinate a joint review of a drug/diagnostic combination product by its drug division and its diagnostics division.

"Analytical validation of genotyping and phenotyping methods should be established before initiating a clinical PGx study," according to the draft guidance. "Appropriate quality control materials, standards, and calibrators (where applicable), as well as validated protocols, should be established to provide assurance of continuing analytical performance over time and across testing sites." The guidance directs companies seeking more advice on the analytical and clinical validity requirements related to the regulatory approval of a genomic assay to consult the Office of In Vitro Diagnostic Device Evaluation and Safety in Center for Devices and Radiological Health.

The FDA has also been working on a draft guidance for drug/diagnostic codevelopment. Combination Rx/Dx products are thought to be a mainstay of individualized medicine. According to CDRH, a draft guidance on companion diagnostics will most likely be released in early 2011; and a separate co-development guidance focusing on the simultaneous, multi-FDA center review of combination products will be out by the end of next year (PGx Reporter 12/08/10).


Have topics you'd like to see covered in Pharmacogenomics Reporter? Contact the editor at tray [at] genomeweb [.] com.

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