perspec tives
nature publishing group
opinion Is There a Need to Teach Pharmacogenetics? AK Daly1 Pharmacogenetics/pharmacogenomics has been subject to considerable development during the past 10 years and seems likely to advance even more rapidly in the next decade. Several surveys suggest that initial training for health-care professionals— particularly physicians and pharmacists—frequently includes education in this area, but equipping these professions more generally to deal with ongoing development of the field and to make best use of new knowledge remains an important challenge.
The discipline of pharmacogenetics dates from the late 1950s. Several of the investigators involved originally, including Friedrich Vogel and Arno Motulsky, were human geneticists, but progress in the subject from 1960 to 1990 came mainly from the efforts of pharmacologists. By 1990, when the Human Genome Project was launched, pharmacogenetics was essentially a specialist area of clinical pharmacology. Because of careful attention to defining phenotype, especially in relation to pharmacokinetics, the subject had been well placed to take advantage of advances in gene cloning and sequencing. By the end of the 1990s, this had resulted in an excellent understanding of genotype–phenotype relationships for most cytochromes P450, thiopurine methyltransferase, and the acetyltransferases. By 2003, when the Human Genome Project finished, newer studies on pharmacogenetic aspects of drug targets and factors affecting adverse drug reactions were in progress. However,
clinical implementation of pharmacogenetics was still very limited, despite the early promise. Use of the broader term “pharmacogenomics” also became common. The terms are frequently used interchangeably; this article refers to the entire area as pharmacogenetics. Implementation of pharmacogenetics in cancer treatment for both adults and children is a major success story, assisted by the development of new drugs whose use requires a companion diagnostic test involving pharmacogenetics. This has opened a range of educational opportunities to prescribers and others in the oncology field. However, not all progress in implementation of pharmacogenetics in oncology has involved new drugs targeting certain tumor genotypes. Prescription of older drugs, such as the thiopurines, now frequently involves genotyping of patient DNA to determine dose. The existence of well-organized regional and national cancer treatment centers with good pharmacogenetics knowledge on a
local level appears to have been a major driver for implementation of genotyping for genes such as thiopurine methyltransferase, more than for improved pharmacogenetics education generally. The toxic nature of anticancer drug treatments, and the disease generally, has also helped drive implementation of pharmacogenetics more rapidly than in other disciplines, but this relatively wide application of pharmacogenetics in oncology is exceptional. Although good examples of implementation exist in certain other specialties, such as infectious diseases and neurology, there are still major challenges in application—including in primary care, where most drugs are prescribed. The limited predictive power of some pharmacogenetic tests and the absence of randomized clinical trials showing clear benefit may be more important barriers to further application in these other specialties than inadequate pharmacogenetics education. Genomics education was the subject of a recent Commentary in this journal.1 Many of the issues raised overlap with those concerning pharmacogenetics education, but it is helpful to consider in more detail the needs of various groups with respect to pharmacogenetics education. Physicians, pharmacists, nurses, laboratory scientists, and the general public are specific groups whose members need education but whose needs differ. For example, physicians are the key target group to implement prescribing informed by pharmacogenetics because they make prescribing decisions. In 2005, recommendations from a group of pharmacogenetics researchers, most of whom were based at European medical schools, included the provision of at least 4 (preferably 8) hours of instruction in pharmacogenetics as part of the basic
1Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. Correspondence: AK Daly ([email protected])
doi:10.1038/clpt.2013.184 Clinical pharmacology & Therapeutics | VOLUME 95 NUMBER 3 | MARCH 2014
245
perspec tives pharmacology curriculum for medical students.2 They also recommended that major academic hospitals provide continuing medical education in pharmacogenetics. A survey of North American medical schools in 2010 that had 90 responses suggested that only 28% provided more than 4 hours of instruction; encouragingly, though, 82% had provision for some instruction. Importantly, 76% considered that provision of pharmacogenetics instruction at most medical schools was poor or inadequate.3 A separate survey of British medical schools provided broadly similar findings. The curriculum for an MD or similar degree is already overloaded, so inclusion of a substantial pharmacogenetics component may need to be driven by more widespread adoption of testing based on either regulatory requirement or demand by the general public. One compromise might involve ensuring that existing basic pharmacology and genetics teaching for medical students early in the degree course includes coverage of pharmacogenetics, with this teaching supplemented by 2 to 4 hours of separate, more specialized pharmacogenetics content, ideally later in the course. This content could cover the application of pharmacogenetics to various specialties. As mentioned elsewhere, most practicing physicians will have graduated from medical school more than 10 years ago.1 It seems unlikely that many will have received formal pharmacogenetics education, and the majority may also have limited genetics training. Nevertheless, physicians have a good record as “lifelong learners” and, as implementation of pharmacogenetics extends to additional specialties, are likely to be keen to take advantage of continuing education, which can increasingly be delivered in the form of “e-learning.” One other important source of education for physicians is their professional societies. With the exception of the societies relevant to oncology and clinical pharmacology, recommendations from professional societies have tended not to be particularly supportive toward pharmacogenetics. For example, in 2008 the American College of Chest Physicians published guidelines for use of warfarin 246
that advised against pharmacogenetic testing because of lack of evidence from randomized clinical trials. One interesting source of information on physicians’ experience of pharmacogenetics is a recent survey that, although having a response rate of only 3%, represented 10,303 responses.4 It revealed that, in general, the level of physician education in pharmacogenetics and of their confidence in using pharmacogenetics to inform their practice was low. Only 12.9% of respondents had used pharmacogenetic testing, which was suggested to be lower than expected.1 However, in view of the currently very limited implementation of such tests in clinical practice, this percentage seems high. Although the findings from this survey may overestimate the general penetration of pharmacogenetics into medical practice, they appear quite positive in view of the still-limited availability of testing and the small number of drugs for which pharmacogenetic testing is currently recommended. Pharmacy schools, especially in North America, have made better progress in implementing pharmacogenetics education compared with medical schools. Most appear to devote significant time to teaching the subject,5 and several employ teaching staff with research programs in the area. However, it is difficult to fully determine what is taught, and it is uncertain whether there is detailed coverage of allied subjects such as genetics and genomics. A background knowledge of the more basic aspects of these subjects is likely to be important in dealing with future developments such as genome sequencing. In general, pharmacists are very interested in both the subject and its implementation. Particularly in the United States, they have played a key role in implementing pharmacogenetics in specialist centers as well as in developing prescribing guidelines, such as those produced by the Clinical Pharmacogenetics Implementation Consortium. It seems likely that in the future pharmacists will have an important role in advising patients on individualized prescribing. Nurses form another professional group for which pharmacogenetics education is of growing interest and impor-
tance. In both the United States and the United Kingdom, there is already a commitment to educating nurses in this area, with organized programs in genetics and genomics.1 Whether this can be extended to include pharmacogenetics is currently unclear but deserves serious consideration. The final professional group to consider comprises laboratory scientists and other staff working in the general area of pharmacogenetics research—both clinical and nonclinical scientists. This group appears to be the best educated in terms of pharmacogenetics knowledge. Pharmacogenetics is included in the curricula of a number of bachelor’s, master’s, and doctoral programs worldwide. There are also a few dedicated master’s and doctoral programs in pharmacogenetics. These provide a valuable staff resource for further research in the area, and graduates of such dedicated programs should be well suited for a variety of roles in the pharmaceutical industry and regulatory agencies. However, a much larger group of scientists needs to understand pharmacogenetics and have the ability to contribute to the area, and increasing the numbers of dedicated programs may not be the most effective means of achieving this. As we enter the era of genome sequencing, a key issue is the need to bring closer together researchers whose primary interest is human genetics and those who would consider themselves pharmacogeneticists. Teaching programs should also address this need. In addition, the general public increasingly needs education in pharmacogenetics. There is growing public interest in areas such as genome sequencing, and “direct to the consumer testing” is becoming a reality, especially in North America. Press coverage of this area is generally favorable, and it appears that the public has a positive view of this type of genetic testing. The main role of education should be to manage expectations and ensure that the public view of pharmacogenetics continues to be a positive one. It is also important that pharmacogenetics education not be the preserve of genetic testing companies and that publicly funded impartial and well-presented information be available.
VOLUME 95 NUMBER 3 | MARCH 2014 | www.nature.com/cpt
perspec tives It is clear that there is a need for ongoing education in pharmacogenetics delivered by a variety of methods for a wide range of both health professionals and the general public. Although specialized courses are of value, the subject should be embedded in a variety of courses, especially in pharmacology, general medicine, and human genetics. In particular, the provision of pharmacogenetics teaching as continuing education is vital as the subject continues to develop and clinical implementation expands. CONFLICT OF INTEREST The author declared no conflict of interest.
© 2014 ASCPT
1. Passamani, E. Educational challenges in implementing genomic medicine. Clin. Pharmacol. Ther. 94, 192–195 (2013). 2. Gurwitz, D. et al. Pharmacogenomics education: International Society of Pharmacogenomics recommendations for medical, pharmaceutical, and health schools deans of education. Pharmacogenomics J. 5, 221–225 (2005). 3. Nikola, T.J., Green, J.S., Harralson, A.F. & O’Brien, T.J. The current and future state of pharmacogenomics medical education in the USA. Pharmacogenomics 13, 1419–1425 (2012). 4. Stanek, E.J. et al. Adoption of pharmacogenomic testing by US physicians: results of a nationwide survey. Clin. Pharmacol. Ther. 91, 450–458 (2012). 5. Murphy, J.E. et al. Pharmacogenomics in the curricula of colleges and schools of pharmacy in the United States. Am. J. Pharm. Educ. 74, 7 (2010).
Next-Generation Medicines: Past Regulatory Experience and Considerations for the Future MA Pacanowski1, C Leptak2 and I Zineh1 Application of personalized medicine in drug development and regulation has been limited by similar logistical, informatics, and cultural barriers that limit use of pharmacogenetics in the clinic. An additional challenge is coordinated codevelopment of new drugs and diagnostic tests. Nevertheless, the impact of personalized medicine strategies (e.g., pharmacogenomics) is being realized. We highlight some of our experiences to date and considerations for the development of the next generation of targeted therapies.
Historical regulatory application of pharmacogenomics
The US Food and Drug Administration (FDA) has sought to optimize patient selection and dosing through pharmacogenomics for drugs with “high-risk” characteristics (Figure 1). In particular, when patients may be at higher risk for toxicity or therapeutic failure because of metabolism by polymorphic enzymes,
drug labeling has provided pharmacogenetically tailored dosing instructions or warnings, analogous to what is done for drug–drug interactions. The FDA has also informed prescribers through labeling about serious safety issues if that information is deemed to be of significant public health interest, even for drugs that have been in use for decades.1 Recent labeling changes in response to new
1Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA; 2Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA. Correspondence: MA Pacanowski ([email protected])
doi:10.1038/clpt.2013.222
information for codeine, valproic acid, and pimozide reflect efforts to continually refine prescribing recommendations. The FDA recognizes that pharmacogenetic testing to lower the risk of serious but rare adverse events poses translational challenges because the numbers needed to test are typically large. How to practically translate such genotypebased risk information into labeling has many complexities. For example, in the case of codeine use following an adenotonsillectomy, CYP2D6 ultrarapid metabolizers are thought to be at excessive risk of respiratory depression and death. The drug was contraindicated in this clinical setting in lieu of recommending CYP2D6 testing because the genetic liability in some patients outweighed the benefits of its use in the larger patient population. 2 In another example, patients with disorders resulting from polymerase gamma mutations are at higher risk for valproate-induced hepatotoxicity; clinical presentation and age improve the predictive ability of testing and thus drive the labeled polymerase gamma testing strategy to minimize hepatotoxicity risk. Alternative testing approaches have also been considered, such as for pimozide, for which CYP2D6 testing is recommended only above a certain dose threshold where QT-prolongation risk is higher. Revising prescribing recommendations to reflect new pharmacogenomic interactions after approval can be nuanced. The FDA has updated labeling for some drugs before adoption of routine testing in clinical practice (e.g., warfarin, clopidogrel), but not for others (e.g., abacavir, cetuximab, panitumumab). Each case has unique challenges related to variability in postmarketing data quality (e.g., retrospective studies), consistency of findings, or limited data about alternative management strategies (e.g., whether they have similar liabilities). A risk-based evidentiary framework and community-wide acceptance criteria may be needed to foster appropriate use of pharmaco genomic information that emerges after a drug is approved. The FDA now encourages drug developers to address potential genetic liabilities before marketing, when
Clinical pharmacology & Therapeutics | VOLUME 95 NUMBER 3 | MARCH 2014
247
nature publishing group
opinion Is There a Need to Teach Pharmacogenetics? AK Daly1 Pharmacogenetics/pharmacogenomics has been subject to considerable development during the past 10 years and seems likely to advance even more rapidly in the next decade. Several surveys suggest that initial training for health-care professionals— particularly physicians and pharmacists—frequently includes education in this area, but equipping these professions more generally to deal with ongoing development of the field and to make best use of new knowledge remains an important challenge.
The discipline of pharmacogenetics dates from the late 1950s. Several of the investigators involved originally, including Friedrich Vogel and Arno Motulsky, were human geneticists, but progress in the subject from 1960 to 1990 came mainly from the efforts of pharmacologists. By 1990, when the Human Genome Project was launched, pharmacogenetics was essentially a specialist area of clinical pharmacology. Because of careful attention to defining phenotype, especially in relation to pharmacokinetics, the subject had been well placed to take advantage of advances in gene cloning and sequencing. By the end of the 1990s, this had resulted in an excellent understanding of genotype–phenotype relationships for most cytochromes P450, thiopurine methyltransferase, and the acetyltransferases. By 2003, when the Human Genome Project finished, newer studies on pharmacogenetic aspects of drug targets and factors affecting adverse drug reactions were in progress. However,
clinical implementation of pharmacogenetics was still very limited, despite the early promise. Use of the broader term “pharmacogenomics” also became common. The terms are frequently used interchangeably; this article refers to the entire area as pharmacogenetics. Implementation of pharmacogenetics in cancer treatment for both adults and children is a major success story, assisted by the development of new drugs whose use requires a companion diagnostic test involving pharmacogenetics. This has opened a range of educational opportunities to prescribers and others in the oncology field. However, not all progress in implementation of pharmacogenetics in oncology has involved new drugs targeting certain tumor genotypes. Prescription of older drugs, such as the thiopurines, now frequently involves genotyping of patient DNA to determine dose. The existence of well-organized regional and national cancer treatment centers with good pharmacogenetics knowledge on a
local level appears to have been a major driver for implementation of genotyping for genes such as thiopurine methyltransferase, more than for improved pharmacogenetics education generally. The toxic nature of anticancer drug treatments, and the disease generally, has also helped drive implementation of pharmacogenetics more rapidly than in other disciplines, but this relatively wide application of pharmacogenetics in oncology is exceptional. Although good examples of implementation exist in certain other specialties, such as infectious diseases and neurology, there are still major challenges in application—including in primary care, where most drugs are prescribed. The limited predictive power of some pharmacogenetic tests and the absence of randomized clinical trials showing clear benefit may be more important barriers to further application in these other specialties than inadequate pharmacogenetics education. Genomics education was the subject of a recent Commentary in this journal.1 Many of the issues raised overlap with those concerning pharmacogenetics education, but it is helpful to consider in more detail the needs of various groups with respect to pharmacogenetics education. Physicians, pharmacists, nurses, laboratory scientists, and the general public are specific groups whose members need education but whose needs differ. For example, physicians are the key target group to implement prescribing informed by pharmacogenetics because they make prescribing decisions. In 2005, recommendations from a group of pharmacogenetics researchers, most of whom were based at European medical schools, included the provision of at least 4 (preferably 8) hours of instruction in pharmacogenetics as part of the basic
1Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. Correspondence: AK Daly ([email protected])
doi:10.1038/clpt.2013.184 Clinical pharmacology & Therapeutics | VOLUME 95 NUMBER 3 | MARCH 2014
245
perspec tives pharmacology curriculum for medical students.2 They also recommended that major academic hospitals provide continuing medical education in pharmacogenetics. A survey of North American medical schools in 2010 that had 90 responses suggested that only 28% provided more than 4 hours of instruction; encouragingly, though, 82% had provision for some instruction. Importantly, 76% considered that provision of pharmacogenetics instruction at most medical schools was poor or inadequate.3 A separate survey of British medical schools provided broadly similar findings. The curriculum for an MD or similar degree is already overloaded, so inclusion of a substantial pharmacogenetics component may need to be driven by more widespread adoption of testing based on either regulatory requirement or demand by the general public. One compromise might involve ensuring that existing basic pharmacology and genetics teaching for medical students early in the degree course includes coverage of pharmacogenetics, with this teaching supplemented by 2 to 4 hours of separate, more specialized pharmacogenetics content, ideally later in the course. This content could cover the application of pharmacogenetics to various specialties. As mentioned elsewhere, most practicing physicians will have graduated from medical school more than 10 years ago.1 It seems unlikely that many will have received formal pharmacogenetics education, and the majority may also have limited genetics training. Nevertheless, physicians have a good record as “lifelong learners” and, as implementation of pharmacogenetics extends to additional specialties, are likely to be keen to take advantage of continuing education, which can increasingly be delivered in the form of “e-learning.” One other important source of education for physicians is their professional societies. With the exception of the societies relevant to oncology and clinical pharmacology, recommendations from professional societies have tended not to be particularly supportive toward pharmacogenetics. For example, in 2008 the American College of Chest Physicians published guidelines for use of warfarin 246
that advised against pharmacogenetic testing because of lack of evidence from randomized clinical trials. One interesting source of information on physicians’ experience of pharmacogenetics is a recent survey that, although having a response rate of only 3%, represented 10,303 responses.4 It revealed that, in general, the level of physician education in pharmacogenetics and of their confidence in using pharmacogenetics to inform their practice was low. Only 12.9% of respondents had used pharmacogenetic testing, which was suggested to be lower than expected.1 However, in view of the currently very limited implementation of such tests in clinical practice, this percentage seems high. Although the findings from this survey may overestimate the general penetration of pharmacogenetics into medical practice, they appear quite positive in view of the still-limited availability of testing and the small number of drugs for which pharmacogenetic testing is currently recommended. Pharmacy schools, especially in North America, have made better progress in implementing pharmacogenetics education compared with medical schools. Most appear to devote significant time to teaching the subject,5 and several employ teaching staff with research programs in the area. However, it is difficult to fully determine what is taught, and it is uncertain whether there is detailed coverage of allied subjects such as genetics and genomics. A background knowledge of the more basic aspects of these subjects is likely to be important in dealing with future developments such as genome sequencing. In general, pharmacists are very interested in both the subject and its implementation. Particularly in the United States, they have played a key role in implementing pharmacogenetics in specialist centers as well as in developing prescribing guidelines, such as those produced by the Clinical Pharmacogenetics Implementation Consortium. It seems likely that in the future pharmacists will have an important role in advising patients on individualized prescribing. Nurses form another professional group for which pharmacogenetics education is of growing interest and impor-
tance. In both the United States and the United Kingdom, there is already a commitment to educating nurses in this area, with organized programs in genetics and genomics.1 Whether this can be extended to include pharmacogenetics is currently unclear but deserves serious consideration. The final professional group to consider comprises laboratory scientists and other staff working in the general area of pharmacogenetics research—both clinical and nonclinical scientists. This group appears to be the best educated in terms of pharmacogenetics knowledge. Pharmacogenetics is included in the curricula of a number of bachelor’s, master’s, and doctoral programs worldwide. There are also a few dedicated master’s and doctoral programs in pharmacogenetics. These provide a valuable staff resource for further research in the area, and graduates of such dedicated programs should be well suited for a variety of roles in the pharmaceutical industry and regulatory agencies. However, a much larger group of scientists needs to understand pharmacogenetics and have the ability to contribute to the area, and increasing the numbers of dedicated programs may not be the most effective means of achieving this. As we enter the era of genome sequencing, a key issue is the need to bring closer together researchers whose primary interest is human genetics and those who would consider themselves pharmacogeneticists. Teaching programs should also address this need. In addition, the general public increasingly needs education in pharmacogenetics. There is growing public interest in areas such as genome sequencing, and “direct to the consumer testing” is becoming a reality, especially in North America. Press coverage of this area is generally favorable, and it appears that the public has a positive view of this type of genetic testing. The main role of education should be to manage expectations and ensure that the public view of pharmacogenetics continues to be a positive one. It is also important that pharmacogenetics education not be the preserve of genetic testing companies and that publicly funded impartial and well-presented information be available.
VOLUME 95 NUMBER 3 | MARCH 2014 | www.nature.com/cpt
perspec tives It is clear that there is a need for ongoing education in pharmacogenetics delivered by a variety of methods for a wide range of both health professionals and the general public. Although specialized courses are of value, the subject should be embedded in a variety of courses, especially in pharmacology, general medicine, and human genetics. In particular, the provision of pharmacogenetics teaching as continuing education is vital as the subject continues to develop and clinical implementation expands. CONFLICT OF INTEREST The author declared no conflict of interest.
© 2014 ASCPT
1. Passamani, E. Educational challenges in implementing genomic medicine. Clin. Pharmacol. Ther. 94, 192–195 (2013). 2. Gurwitz, D. et al. Pharmacogenomics education: International Society of Pharmacogenomics recommendations for medical, pharmaceutical, and health schools deans of education. Pharmacogenomics J. 5, 221–225 (2005). 3. Nikola, T.J., Green, J.S., Harralson, A.F. & O’Brien, T.J. The current and future state of pharmacogenomics medical education in the USA. Pharmacogenomics 13, 1419–1425 (2012). 4. Stanek, E.J. et al. Adoption of pharmacogenomic testing by US physicians: results of a nationwide survey. Clin. Pharmacol. Ther. 91, 450–458 (2012). 5. Murphy, J.E. et al. Pharmacogenomics in the curricula of colleges and schools of pharmacy in the United States. Am. J. Pharm. Educ. 74, 7 (2010).
Next-Generation Medicines: Past Regulatory Experience and Considerations for the Future MA Pacanowski1, C Leptak2 and I Zineh1 Application of personalized medicine in drug development and regulation has been limited by similar logistical, informatics, and cultural barriers that limit use of pharmacogenetics in the clinic. An additional challenge is coordinated codevelopment of new drugs and diagnostic tests. Nevertheless, the impact of personalized medicine strategies (e.g., pharmacogenomics) is being realized. We highlight some of our experiences to date and considerations for the development of the next generation of targeted therapies.
Historical regulatory application of pharmacogenomics
The US Food and Drug Administration (FDA) has sought to optimize patient selection and dosing through pharmacogenomics for drugs with “high-risk” characteristics (Figure 1). In particular, when patients may be at higher risk for toxicity or therapeutic failure because of metabolism by polymorphic enzymes,
drug labeling has provided pharmacogenetically tailored dosing instructions or warnings, analogous to what is done for drug–drug interactions. The FDA has also informed prescribers through labeling about serious safety issues if that information is deemed to be of significant public health interest, even for drugs that have been in use for decades.1 Recent labeling changes in response to new
1Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA; 2Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA. Correspondence: MA Pacanowski ([email protected])
doi:10.1038/clpt.2013.222
information for codeine, valproic acid, and pimozide reflect efforts to continually refine prescribing recommendations. The FDA recognizes that pharmacogenetic testing to lower the risk of serious but rare adverse events poses translational challenges because the numbers needed to test are typically large. How to practically translate such genotypebased risk information into labeling has many complexities. For example, in the case of codeine use following an adenotonsillectomy, CYP2D6 ultrarapid metabolizers are thought to be at excessive risk of respiratory depression and death. The drug was contraindicated in this clinical setting in lieu of recommending CYP2D6 testing because the genetic liability in some patients outweighed the benefits of its use in the larger patient population. 2 In another example, patients with disorders resulting from polymerase gamma mutations are at higher risk for valproate-induced hepatotoxicity; clinical presentation and age improve the predictive ability of testing and thus drive the labeled polymerase gamma testing strategy to minimize hepatotoxicity risk. Alternative testing approaches have also been considered, such as for pimozide, for which CYP2D6 testing is recommended only above a certain dose threshold where QT-prolongation risk is higher. Revising prescribing recommendations to reflect new pharmacogenomic interactions after approval can be nuanced. The FDA has updated labeling for some drugs before adoption of routine testing in clinical practice (e.g., warfarin, clopidogrel), but not for others (e.g., abacavir, cetuximab, panitumumab). Each case has unique challenges related to variability in postmarketing data quality (e.g., retrospective studies), consistency of findings, or limited data about alternative management strategies (e.g., whether they have similar liabilities). A risk-based evidentiary framework and community-wide acceptance criteria may be needed to foster appropriate use of pharmaco genomic information that emerges after a drug is approved. The FDA now encourages drug developers to address potential genetic liabilities before marketing, when
Clinical pharmacology & Therapeutics | VOLUME 95 NUMBER 3 | MARCH 2014
247
