FDA Guidance for Industry Clinical Pharmacogenomics: Premarketing Evaluation in Early Phase Clinical Studies

Pharmacogenomics (PGx) broadly refers to the study of variations of DNA and RNA characteristics as related to drug response. Drug exposure refers to the administered dose, drug levels, or the pharmacokinetic (PK) profile following administration.  Drug response refers to the pharmacodynamics (PD) of the drug (i.e., all of the effects of the drug on various physiologic and pathologic processes, including effectiveness and adverse effects). Genetic variations can also influence the exposure-response (E/R) relationship of drugs, including both the shape of the E/R curve and the maximum effect. 

Consequently, drug product labeling has increasingly included preapproval information on the likelihood of treatment response based on genetic/genomic status or the need to genotype before a specified dose can be prescribed. Drug product labeling has also been revised after approval to include PGx information that can alter the benefit/risk (B/R) relationship, or allow dosing of the medicine to be adjusted for individuals. 

Examples of these product label revisions have involved dose adjustments needed to address drug safety issues or effectiveness or identification of high risk people. Because these recent postmarketing examples have, in most cases, been based on data from postmarketing experience, their discoveries were relatively late. It is hoped that full ascertainment of genomic information on all subjects during early development will allow early discovery of clinically important genomic differences. 

As a result, the Food and Drug Administration (FDA) recently released a “Guidance for Industry Clinical Pharmacogenomics: Premarketing Evaluation in Early Phase Clinical Studies.” The purpose of the guidance is to suggest approaches to improve the quality of the data collected and the ability to assess genomic relationships.

The guidance is also intended to assist the pharmaceutical industry and other investigators engaged in new drug development in evaluating how variations in the human genome could affect the clinical pharmacology and clinical responses of drugs. The guidance provides recommendations on when genomic information should be considered to address questions arising during drug development, and in some cases, during regulatory review. 

While the application of pharmacogenomic approaches during drug development is an evolutionary process that begins with discovery and continues through confirmation of clinical efficacy and safety outcomes, the guidance provides advice on general principles of study design, data collection, and data analysis.

The guidance does not address statistical considerations for later phase randomized controlled clinical trials for which genomic hypotheses are prospectively planned, and that are intended to draw definitive conclusions from genomic subgroup effects (e.g., enrichment designs, adaptive enrichment designs, simultaneous hypothesis testing overall and within subgroup(s)). The statistical considerations in this guidance are more relevant for exploratory and observational studies. For instance, FDA noted that early phase data on genomic-dependent dosing, where not definitive, can provide guidance on dose selection in later phase studies or inform the strategy for further collection of genetic and related biomarker data in a larger number of patients in controlled trials.

Prospective DNA Sample Collection

An important prerequisite to successful use of genetic information in drug development is the appropriate collection and storage of DNA samples from all clinical trials, both exploratory studies and the adequate and well-controlled trials intended to support effectiveness and safety. 

Potential PGx differences in efficacy and/or safety can arise from gene variants not yet as well characterized as the metabolism or transporter genes.  Therefore, FDA recommended that plans for general DNA sample collection should be prespecified at the time of randomization or initiation of a study to minimize the potential for sample selection bias, even if these samples are studied only at a later time during or after a study. It then becomes possible to seek explanations for differences in exposure, efficacy, tolerability, or safety not anticipated prior to beginning the study, noting, of course, potential multiplicity and bias issues.

Ideally, FDA also recommended that consent for DNA collection should be obtained from all participants in clinical trials and an effort should be made to collect genetic samples at enrollment and/or at baseline to avoid potential bias associated with delayed collection. FDA also stated that samples should be collected in all arms of the trial and DNA should be retained in the event that new genomic issues arise after the completion of the studies.

Routine collection of DNA samples should provide applicants with an opportunity to investigate  the causes of lack of efficacy or the occurrence of toxicity in different individuals, using such approaches as exploratory genome-wide association investigations, and candidate gene or targeted pathway analyses. The need for genomic tests and possible relationship to clinical phenotypes of efficacy or safety may not be suspected at the time of initiating a study and will become of interest only at a later time. Therefore, where possible, FDA recommended that informed consent procedures should anticipate this possibility, and attention should be given to the appropriate sample handling, storage, and sample retention duration so that exploring these genotype-phenotype relationships can be performed after completion of the study. 

The value of DNA sample collection and the information that analysis of these samples can provide will vary for different drugs and indications. FDA asserted that considering known PGx factors during preclinical assessment is critical because these data inform decisions as to whether subsequent clinical studies need to take PGx  differences into account (e.g., in dose-response studies).

Principles of Including Pharmacogenomic Information in Labeling

In general, information on PGx in labeling is intended to inform prescribers about the impact, or lack of impact, of genotype on phenotype, and indicate whether a genomic test is available and if so, whether testing should be considered, recommended, or necessary.  Accordingly, FDA recommended that a “Pharmacogenomics” subsection should be created in the “Clinical Pharmacology” section and should include details on the clinically relevant information on the effect of genetic variations affecting drug  therapy. Pharmacogenomic information can include, but is not limited to, the following:

• Description of polymorphic enzymes (for example, genetic-based differences in enzyme activity such as reduced cytochrome P450 enzyme activity attributable to polymorphisms in a CYP gene).
• Subpopulation-based information on the prevalence or frequencies of alleles, genotypes, haplotypes, or other genomic markers.
• Positive and negative predictive values associated with the use of the genomic marker for safety and/or efficacy purposes.
• Effect of genotype on important PK parameters, such as clearance, half-life, and AUC
• The pharmacogenomic studies that provided evidence of genetically based differences in drug benefit or risk.
• Changes in dose based on genotype

FDA also recommended that when the information has important implications for the safe and effective use of the drug and the consequences of the genetic variations result in recommendations for restricted use, dosage adjustments, contraindications, or warnings, this information should be included in the appropriate other sections, such as:

–       The boxed warning

–       Indications and usage

–       Dosage and administration

–       Contraindications

–       Warnings and Precautions; and/or

–       Drug Interactions

FDA noted that the detailed information will most often appear in the Pharmacogenomics subsection of Clinical Pharmacology  or Clinical Studies. In addition, FDA recommended that PGx information conveyed to patients should be summarized in the Patient Counseling Information Section.

FDA also noted that the following are types of PGx information that would be appropriate to include in the specified labeling section or sections.  

• PGx information related to proper patient selection (e.g., the need for PGx testing) — Indications and Usage
• Different dosing recommendations for subgroups of patients based on genetic makeup — Dosage and Administration
• PGx information affecting drug safety — Boxed Warning, Contraindiciations, Warnings and Precautions, and/or Adverse Reactions
• Relevant information concerning the role of genetic variations in drug-drug interactions and the clinical consequences of the combination of genetic polymorphisms in protein(s) in the context of the drug’s metabolism, transport and action — Drug Interactions 
• PGx impact on PK or PD (if not included in another section) — Clinical Pharmacology
• Efficacy differences related to PGx — Clinical Studies (if studied and the evidence is substantial)
• Genotype(s) that are known to be associated with an adverse reaction in a specific population  — Warnings and Precautions and Use in Specific Populations