The Pharmacogenomics Journal (2002) 2, 83–86 2002 Nature Publishing Group All rights reserved 1470-269X/02 $25.00 www.nature.com/tpj EELS (Ethical, Economic, Legal & Social) ARTICLE to comply with all applicable federal A regulatory protocol for laws, including FDCA.2 To effectively monitor predictive pharmacogenomics services drug testing, two sets of CLIA assay standards should be considered—one LA Bristol for genomic characterization and gen- omic testing, and the second for in Arent Fox Kintner Plotkin & Kahn, PLLC, Washington DC, USA vitro protein- or cellular-based assays used to detect altered drug metaboliz- ing function. The Pharmacogenomics Journal (2002) 2, tics are labeled Class III devices. Before The European Agency for the Evalu- 83–86. DOI: 10.1038/sj/tpj/6500079 a medical device can be made available ation of Medical Products does not to the public, the developers of the currently regulate in vitro genetic test- device must apply for an Investi- Genotyping technologies have ing.3 In June of 2000, a report to the gational Device Exemption (IDE), advanced the decades-old field of Committee for Proprietary Medical which is analogous to the Investi- pharmacogenetics whereby drug ther- products (CRMP) was presented on the gational New Drug Application (IND) apies are designed to be compatible use of pharmacogenetics in the drug required for new drugs. The FDA has with a patient’s specific genetic development process. No guidelines maintained that it has the authority to makeup. Pharmacogenomics com- were proposed but consensus was regulate genetic testing laboratories as bines genetic testing, protein reached as to the need for a harmon- medical devices, but it has chosen not expression analysis, and in vitro drug ized approach to pharmacogenetic to do so. The FDA does not regulate metabolism to screen patients in protocols in clinical trials small private laboratories, which per- advance for responsiveness toward (EMEA/1483/00). Under EMEA, regu- form their own genetic test methods. drugs. These technologies may be lation of pharmacogenomics test ser- Most genetic testing is done with applied to streamline clinical trials and unregulated reagents that laboratories vices would loosely fall under several to target approved drugs to patient use to build a testing system.1 guidelines, some of which are already populations scored on the basis of Even assuming, arguendo, that pre- in force and others of which have been their drug metabolism. Where predic- dictive drug testing is considered an proposed. CPMP/ICH/378/95 sets tive drug testing is successful, results aspect of drug research and develop- forth the guidelines for dose response from such studies may be used to ment, then pharmacogenomics would determinations, but does not determine how drugs can be pre- fall within the realm of preclinical test- encompass a technology where predic- scribed for the general population. ing, and would remain unregulated tive drug testing is a core feature. One of the core platform techno- under current FDA guidelines for new CPMP/ICH/141/95 discusses the in logies of pharmacogenomics is genetic drug development. vitro and in vivo standards for evaluat- screening and diagnostics for gene- Under the Clinical Laboratory ing pharmaceuticals for genetic tox- based polymorphisms or mutations. Improvements Act (CLIA), genetic test- icity but does not address genetic test- The genetic screening and diagnostics ing falls within the statutory meaning ing. A draft consensus guideline technology should reach the level at of cytogenetics (42 U.S.C. §263). How- submitted to the ICH in July of 2000, which it can accurately and consist- ever, under that classification, CLIA deals with harmonization for good ently detect genetic mutations or poly- does not require a genetic testing ser- manufacturing practice for active morphisms before the technology is vice to be proven proficient. As a pharmaceutical ingredients, but does integrated with proteomics and pre- whole, CLIA lacks any category not relate to diagnostic services per se. dictive drug testing. At the very mini- devoted to genetic testing much less CPMP/ICH/137/95 provides guid- mum, DNA-based tests should sub- predictive drug testing on the scale of ance on clinical study reports and the scribe to current regulations in both pharmacogenomics. CLIA imposes contents of the reports as they relate the US and Europe, for assay perform- requirements on assay performance to patients involved in clinical trials, ance standards for diagnostic pro- for accuracy, sensitivity/specificity, but the guidelines are specifically cedures. reproducibility, reportable ranges of silent as to preclinical evaluation for Currently, the US FDA regulates any patient results and reference range of drug responsiveness as encompassed type of medical testing kit, including assay. Notably, CLIA does not preempt by pharmacogenomics. genetic testing kits, as a medical device the FDA’s authority to regulate a clini- Molecular assays should be compa- (Medical Device Amendments Act, 21 cal laboratory’s devices used in testing. rable to a single, known standard, U.S.C. §360). Genetics-based diagnos- CLIA regulations require laboratories which is not cross-reactive with con- A regulatory protocol for pharmacogenomics services LA Bristol 84 taminants. Accuracy, in terms of mol- of a given polymorphic gene and In the matter of the predictive drug ecular testing, would be determined by assignment of the protein to a bio- testing procedure (steps 1–4, or 9(b)), whether an assay has the ability to chemical drug-metabolizing path- any firm providing this type of service quantitate equally across different way; should guarantee both analytical and genotypes. Sensitivity at a molecular (4) Investigation of drug metabolism clinical validity of the genetic and in level means the ability to detect a sin- in vitro with: vitro tests, which comprise the diag- gle copy of a messenger RNA tran- (a) human microsomal liver nostic assay. This would include firms script. For the reproducibility of mol- preparations of known pheno- linked to medical research institutions ecular assays it is important that an types/genotypes from a patient but more particularly those that com- assay include a multiple-point cali- with a given polymorphism; mercialize pharmacogenomic diagnos- bration curve, which is sensitive to the (b) human erythrocytes of tics to the public sector. linearity (or the sensitivity of the high known phenotypes/genotypes A patient’s phenotype for a single and low ranges of results) and from a patient with a given poly- given polymorphism, as determined dynamic range (or the breadth of the morphism; by in vitro methods, may not strictly high and low ranges of results).4 (c) eukaryotic cells carrying correlate with that patient’s metab- Accuracy, sensitivity and reproduci- expression vectors incorporating olism of a particular targeted drug bility are equally important in any known human genes compared to when administered in vivo. Pharmaco- methodologies that serve as platform cells carrying expression vectors genomic testing neither negates nor technologies from which other diag- incorporating the polymorphic reduces responsible drug monitoring nostic procedures are based such as homologues of the normal gene; for those patients who are later predictive drug testing. In developing (d) as (c) with inhibitors or pre- grouped or stratified according to their genetic test methods, firms should be viously recognized polymorphic ability to metabolize a drug in vitro. certified in their testing capabilities for substrates; and The patient, consumer, physician and detecting a genotypic variant or a (e) as (c) with antibodies to the service provider must be aware nucleotide polymorphism from any known polymorphic enzymes; that pharmacogenomics yields only given patient sample. Firms should (5) Perform animal studies (in more predictive and not definitive infor- also be held to a standard, which than one species) to identify the mation on drug metabolizing requires that the data be reproduced in main routes of metabolism and efficiency in patients prior to treat- at least three separate experiments. toxicological aspects; ment. Only after confirmation of the identity (6) Investigation in a few humans in Another complexity of the system of the polymorphism, should a firm be vivo to confirm results of animal lies in the evaluation of the drug allowed to proceed to the next step of studies; metabolism data. For this step, it is the analysis, which involves proteo- (7) If the existence of biotransform- fundamental that the laboratory per- mics or analysis of protein expression ation polymorphism is substan- sonnel are familiar with the limi- of the genotypic variant. tiated, begin testing on typed tations of various techniques, and that The identification of a polymor- panels of healthy individuals of they have the ability to evaluate how phism in a pharmacologic effect (a) at different genetic backgrounds, test results are going to be used. In an early stage in the development of a who represent the different pheno- either case, the clinician will need test new drug, (b) in re-evaluating a failed types of the main polymorphisms; results that can be used to compare a drug candidate or (c) in evaluating (8) If the polymorphism is confirmed, patient’s disease status over time. patient responsiveness to a market- investigate single dose and mul- Consequently, this kind of compara- approved drug may now be possible tiple dose kinetics in relation to tive information is problematic where through careful pharmacogenomic the pharmacological effect: the overall pharmacogenomic test pro- testing. A predictive drug-testing (a) in phenotyped healthy per- tocol has not met the standards for scheme based on the supposition that sons of different backgrounds; and accuracy or sensitivity. Improperly there is a genetic polymorphism of (b) in phenotyped patients suf- performed laboratory tests or misinter- drug metabolism might include the fering from the conditions for pretation of predictive drug test data following steps:5 which the drug is being may result in increased health care developed; and costs.