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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 genomic 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 metabolizing 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. Still worse, patients who are (1) The chemical configuration of a (9) Formulate appropriate policies and wrongly classified in their ability to new (or known) compound may procedures: metabolize a drug in vitro may later be suggest the most probable main (a) information about the poly- subjected to unnecessary and even sources of metabolism; morphism and its implications harmful treatments. (2) Genetic testing and/or sequencing included in drug labeling; and Where a genetic polymorphism has of genetic mutations or polymor- (b) advocate phenotyping and been linked to a drug-metabolizing phisms with high correlation to DNA genotyping before starting phenotype for a given patient, the drug metabolism function; treatment with known or newly patient should be selected according to (3) Analysis of phenotypic expression approved drugs. their general phenotype for qualifi-

The Pharmacogenomics Journal A regulatory protocol for pharmacogenomics services LA Bristol 85

cation in a clinical trial (steps 6–8), or but a recommended dosage based on ally important, operators within firms the phenotype should be used to assist stratified patient groups according to and consumers/patients must be edu- the prescribing physician in selecting in vitro-based genotype/phenotype cated about both the technology’s a treatment modality. Those patients profiles. limitations and the potential respon- exhibiting a severe disability to meta- As genomics-based technologies siveness of a person to in vivo drug bolize a drug in vitro, should be tested infiltrate pharmaceutical and clinical therapy as against predictive in vitro preliminarily with the drug before laboratory testing settings, the risks of drug testing. being excluded from any clinical trial mishandling or misinterpreting data At least within the US, adoption and or before the prescribing physician from patient sample analyses becomes enforcement of the Task Force rec- elects an alternative means of treat- a significant consideration with ommendations by the FDA, in observ- ment. A corresponding failure to meta- especially dramatic consequences ance of existing CLIA standards and bolize the drug in vivo should serve as where the tests become commercially the FDA drug approval process, would the definitive indicator that the available to the public.8 In the fall of ensure greater proficiency of predictive patient is a poor responder before final 1997, the Task Force on Genetic Test- drug test services, uniformity of assay disqualification from the study. Other ing released its final recommendations standards, and most importantly, the available agents should be used to in ‘Promoting Safe and Effective Gen- promotion of consumer safety. Pharm- treat the poorly responding popu- etic Testing in the US’,9,10 but no acogenomics services should not be lation, or the polymorphism may action has ever been taken to adopt made available before a total assess- serve as a substrate on which to base this very important proposal. Clearly, ment of their benefits and risks. research for new drug designs. in view of the recent explosive growth Pharmacogenomics may be a boon The drug dose response and toxicity for this industry the proposed guide- to prescriptive medicine, but the core ranges determined from preclinical lines are now worth reconsideration. technologies essential to the design testing, should only serve as approxi- The Task Force guidelines were and interpretation of pharmacogen- mate concentrations for the treatment designed to address genetic testing omics-based diagnostics are currently regimen in the initial stages of a trial protocols for offer of service. But the under-regulated by those agencies del- (step 8). Predictive drug testing should task force report was distinctly void of egated to do so. More specifically, the not replace careful monitoring of the discussion about predictive drug test- clinical and analytical quality of gen- patient’s responsiveness to in vivo ing using genomics-based methods. etic testing and the proficiency and administration of the predetermined Overlaying predictive drug response analytical qualifications of predictive drug concentration especially where it testing on genetic testing would add drug testing services are either not may be important to modulate the even yet another level of technological covered by existing laws and regu- dose within a phenotyped/genotyped complexity to an already complex lations or the coverage is inadequate, patient group. diagnostic procedure. In addition, it given the complexity of technologies Under current FDA rules, drug labe- raises several issues concerning the underlying pharmacogenomics. Moni- ling (step 9(a)) is to provide advice on validity of drug response data in view toring of drug efficacy on individual ‘known hazards and not theoretical of the complexity of hereditary patient samples through model sys- possibilities’.6,7 In view of the predic- expression, and the interpretation tems may even require its own tailored tive nature of pharmacogenomics, thereof, by laboratory personnel and guidelines. Before considering pharm- then those drug manufacturers, who physicians.11 acogenomics a new-age health care in the future base their drug develop- Government-sponsored regulation medium, the food and drug regulatory ment programs on pharmacogenomic should reflect consumer’s expectations agencies should be prepared to take modeling, would have to subscribe to for quality care, but especially where steps to guarantee the quality of test- higher phenotyping and drug testing services are commercialized through ing and the outcome of predictive standards so as not to incur liability for unregulated independent firms or drug modeling. Oversight of predic- mislabeling of their drug products and where test results are not evaluated tion-based drug therapy services on the intended patient population. For and approved by qualified physicians. stratified human populations may consumers/patients and physicians Predictive drug tests without estab- require an altogether different set of alike, consideration should be given to lished predictive value are unaccept- standards, namely that which falls allowing supplementation of the labe- able for broad commercialization. somewhere among a diagnostic ling, for purposes of providing infor- Such tests are highly subject to misin- (device), a drug therapy and a clinical mation on the correlation between a terpretation by those who undergo service. patient genotype for a gene associated them and by the services that market with drug-metabolism in a given dis- them. DUALITY OF INTEREST The author is an Associate at the law firm of ease, and its corresponding pheno- A central premise is that regulatory Arent Fox Kintner Plotkin and Kahn PLLC type. Labeling should disclose not safeguards must be introduced to (Arent Fox) in Washington, DC and a part- only risk information on the extrapol- ensure that predictive drug testing is time faculty member of the Johns Hopkins ation of in vitro pharmacogenomic test made available only when it carries University in Baltimore, Maryland. The results to in vivo drug responsiveness, clinically valid, predictive value. Equ- author’s comments and opinions do not

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reflect those of Arent Fox or its clients or those 2 Clinical Reference Laboratory, Inc. v. Sullivan, 1995, at 14; M.J. Malinowski & R.J.R. Blatt of the Johns Hopkins University. 791 F.Supp. 1499, (D. Kan. 1992) aff’d in at 1312; and Paul H. Silverman, “Com- part, rev’d in part (21 F.3d 1026)). Also refer merce and genetic diagnostics labora Correspondence should be sent to to http://www.fda.gov/cdrh. tories”, Hastings Center Rep., May-June, L Bristol, Arent Fox Kintner Plotkin & Kahn, 3 http//www.emea.eu.int 1995, supp. at S15. 4 Genesis Report 6(4):1 (1/1/97), ‘Emerging 9 The Task Force was created by the National PLLC, 1050 Connecticut Avenue, NW Suite technologies. Are diagnostics not ready for Institutes of Health-Department of Energy 600, Washington DC 20036-5339, USA. the genetic revolution?’ Working Group on Ethical, Legal, and Social + Fax: 1 202 857 6016 5 Amended from the hypothetical scheme Implications of Human Genome Research Ȱ E-mail: Bristoll arentfox.com proposed by David A Price Evans. Genetic of the Human Genome Project factors in drug therapy: clinical and molecu- (www.hhs.gov/1993.03:Task Force on Gen- lar pharmacogenetics. pp 607–669, Cam- etic Testing). REFERENCES bridge University Press, 1993. 10 National Institutes of Health. Proposed rec- 1 Medical devices, classification/reclassification; 6 21 C.F.R. §201.57(d). ommendations of the Task Force on Gen- restricted devices; analyte specific reagents, 7 Scarlett T. The relationship among adverse etic Testing. Neil A Holtzman & Michael S 61 Fed. Reg. 10, 484 (1996) (21 C.F.R. Parts reaction reporting, drug labeling, product Watson (eds). September, 1997. Also avail- 809 & 864); FDA needs to regulate ‘home liability and federal preemption. 46 Food able at www.nhgri.nih.Elsi.TFGT, pp 1–72. brews’, Nature Biotechnology 14: 1627 Drug Cosm. L.J. 31, 32, 40 (1991). 11 Marshall A. Laying the foundation for per- (1996); and Malinowski and Blatt, 71 Tul- 8 Saltus R. Survey of labs new tests concerns sonalized medicines. Nature Biotechnol ane Law Review 1211, 1312 (1997). genetics specialists. Boston Globe, Oct. 28, 1997; 15: 954–958.

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