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Pharmacogenomic biomarkers in drug labels: what do they tell us? Aim: This article investigates the number of drugs on the market with pharmaco­genomics (PGx) biomarker data in their labels using two public sources – the US FDA and the PharmGKB. Methods: The article analyzes the FDA Table of Pharmacogenomic Biomarkers in Drug Labels to show the number of drugs with PGx biomarker information in their labels. Scrutinizing the language of labels, it also engages with whether this information is intended to direct clinicians to take particular actions or not, and whether biomarker information is included on grounds of drug efficacy or to improve safety. The FDA table is compared to the PharmGKB Drug Labels with PGx info database to highlight how they differ in the number of drugs that they include. Conclusion: Analysis of the FDA and the PharmGKB data show that approximately 12% of drugs licensed in the period 1998–2012 had PGx biomarker information included in their labels at the time of their approval. Of that number, labels direct clinicians to utilize PGx testing prior to prescribing treatments in only 14 cases. This clearly falls short of expectations many had in the 1990s about the transformative impact of PGx. In most cases, the inclusion of this information currently has limited or no direct clinical utility. Original submitted 23 July 2013; Revision submitted 30 September 2013 KEYWORDS: drug labeling n FDA n personalized medicine n pharmaceutical regulation n pharmacogenetics n pharmacogenomics n PharmGKB

Background In 1997, the scientific and popular press heralded the emergence of a new paradigm in drug discovery and development called pharmaco­genomics (PGx) [1]. This science would produce a new generation of ‘personalized medicines’ utilizing information about individuals’ genotypes to make more effective and safer drugs. This expectation seemed borne out by the 1998 approval of trastuzumab (Herceptin®) for the treatment of metastatic breast cancer in women with tumors that overexpress the HER2 protein, simultaneously with a companion diagnostic to identify patients suitable for treatment. Although it was not marketed as a PGx drug, trastuzumab nonetheless became a standard bearer for personalized and PGx approaches to drug discovery and delivery. Today, a number of journalists, scientists and regulators have expressed the view that PGx has not lived up to its potential [2,3]. The finger of blame is pointed in part at how regulators in the US and Europe have created uncertainties about what will gain approval. In the absence of established frameworks, regulation of PGx products has proceeded on a case-by-case basis and the US FDA has been accused of inconsistency in its approach [4]. The FDA for its part

highlights the continuing reluctance of pharmaceutical firms to share PGx data through its Voluntary Exploratory Data Submission (VGDS, now known as VXDS) initiative and others have argued that the industry as a whole has not invested seriously in this area [5]. More broadly, it has also been argued that the excitement that greeted PGx in the 1990s produced unrealistic expectations about what could be achieved and how quickly, and that many were overly optimistic about the role genes play in determining drug response [6]. For those wishing to evaluate the progress made in PGx, the number of personalized medicines on the market has become a key measure of success. For example, when the Personalized Medicine Coalition publishes a new edition of The Case for Personalized Medicine, it includes a list of personalized medicines, which not only includes drugs but also diagnostics and treatments that have been approved by the FDA [101]. Joshua Cohen at the Tufts Center for the Study of Drug Development defines a personalized medicine as one for which there are precise diagnostic tests for pharmacogenomic biomarkers, which, for the purposes of this paper, can be either measurable DNA and/or RNA characteristics in inherited

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Richard Tutton Centre for Science Studies, Department of Sociology, Lancaster University, Lancaster, UK Tel.: +44 1524 593044 [email protected]

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genotypes or proteins involved in oncogenesis that indicate a likely response to therapeutic intervention [7]. There are two sources of information about personalized medicines on the US market. The first is the FDA which, since 2009, has published a Table of Pharmacogenomic Biomarkers in Drug Labels on its website [102]. The other is the Pharmacogenomics Knowledgebase (PharmGKB) – an academic initiative based at Stanford University to disseminate information about PGx – which also publishes data on PGx in drug labels [103]. At present, the EMA does not provide a similar list of drugs on the European market but its staff are working with PharmGKB curators to produce one. Given that a thorough international comparison is therefore difficult to do at this time, this paper focuses on the US drug market and on the FDA Table of Pharmacogenomic Biomarkers in Drug Labels. This table is both the primary source of data for PharmGKB curators and is also repeatedly referred to in reviews and commentaries on the state of PGx. However, its differences with the PharmGKB table will be noted. The paper provides the first in depth ana­lysis of the FDA table on the inclusion of PGx biomarkers in its approved drug labels. It aims to answer three questions: does the FDA table help to make sense of what has been achieved in the field of PGx? What does it reveal about the clinical utility of PGx biomarkers for treatment decisions? How does it compare to the PharmGKB table and does combining the two data sources provide a different view of the progress made in PGx? Before addressing these questions, the following section sets the FDA Table of Pharmacogenomic Biomarkers in Drug Labels in the context of its efforts to promote PGx in the last decade.

Role of the FDA in pharmacogenomics In 2004, the FDA launched its Critical Path Initiative to foster interest in developing pharmaco­g enomic drugs and to reverse the pattern of decline in new drug applications since the mid-1990s [8]. This initiative aimed to encourage greater collaboration amongst government, academia and manufacturers and to improve ‘innovation’. The FDA was aware that firms had carried out ‘exploratory genomic investigations’ in the early 1990s but did not wish to share their data with the FDA because of concerns the regulator would place additional burdens on firms or ‘make inappropriate 298

Pharmacogenomics (2014) 15(3)

regulatory decisions’ based on that information [3]. In response, the FDA developed its VGDS (now known as V XDS) policy to encourage the industry to submit data informally to the FDA and to discuss with its staff current scientific issues of relevance to public health or therapeutic product development [9]. Further FDA guidance has followed on pharmacogenomic tests and on the definition, validation and standardization of genomic and other types of biomarkers [10–12]. In 2011, the FDA issued further draft guidance that sent a positive message that it encouraged where scientifically appropriate the development of ‘therapeutic products that depend on the use of approved or cleared IVD companion diagnostic devices’, which should be codeveloped through clinical testing [13]. In the past decade, however, FDA evaluation and approval has proceeded on a caseby-case basis in the absence of established and agreed frameworks [4]. Up to 2011, the FDA had only approved three ‘combination products’ of drugs and diagnostics: trastuzumab (Herceptin) in 1998 and two other cancer treatments crizotinib (Xalkori®; Pfizer) and vemurafenib (Zelboraf ®; Roche), where the FDA judged that the companion diagnostics had been codeveloped alongside the drug. In other instances, the FDA has not required a companion diagnostic to be approved formally and can remain a nonproprietary ‘laboratory-developed test’, while other drugs have been approved that depend on diagnostics that are already cleared for use in other indications [4]. Beyond the approval of new drugs, the FDA has made inserting PGx data into existing drug labels a key part of its strategy to support the development of this technology. In its 2006 guidance, the FDA aimed to revise labeling practices and encourage the avoidance of excessive descriptive language and highlighted the value of including genomic data including dosage adjustments for specific subpopulations [14]. Expert advisory committees review available evidence and then make recommendations to the FDA on what should appear in drug labels with respect to PGx biomarkers. In making these changes, the FDA’s aims have been twofold: to identify opportunities to update product labels where new data is relevant to the safe and effective use of already-marketed drugs; and to include data in labels as a means of disseminating information about pharmacogenomics even when this is not directly relevant to treatment decisions. Lawrence Lesko, future science group

future science group

www.futuremedicine.com

5 71 41 5 72

Unable to determine Safety Efficacy

Basis on which biomarker is included in label Unable to determine Advisory only Biomarker testing recommended

6 8 7 19 117

„„ Inclusion in label Of the 105 unique drugs in the December 2012 table, only three have been recognized by the FDA as ‘combination products’ codeveloped with companion diagnostics. However, there are 47 instances of the PGx biomarker data being included in drug labels at the time of their market approval. All of these drugs postdate the 1998 approval of Herceptin. In 70 cases, drugs have had this data added after

Biomarker contraindicates use of drug

Findings „„ FDA table of pharmacogenomic biomarkers in drug labels In December 2012, the FDA included 117 drugbiomarker associations between 105 unique drugs and 37 unique biomarkers (Table 1). Nine drugs appear more than once, with imatinib (Gleevec®) featuring four-times. Three discontinued drugs, protriptyline, thioridazine and nefazodone are also included in the FDA table. CYP450 polymorphisms (CYP2D6, CYP2C9 and CYP2C19) account for almost half of the total number of the drug–biomarker associations listed in the December 2012 table. This is not surprising given that CYP450 is implicated in the metabolism of 20–25% of commonly prescribed pharmaceuticals. As of April 2012, the FDA had approved diagnostics or assays for ten of the 37 individual biomarkers included in the table.

Biomarker Biomarker indicated indicated for in for in label label and testing required

Methods To analyze the FDA data a copy of the table as it appeared in December 2012 was made to extract key features of the drugs it listed using the drugs@FDA public database [104] to determine when the drug was approved, when PGx biomarker data was included in its label, and whether a specific diagnostic is named (see Supplementary Table 1; www.futuremedicine.com/ doi/suppl/10.2217/pgs.13.198). An authoritative list of all approved FDA diagnostics and assays for the biomarkers included in the FDA table was also identified [105]. The latest versions of drug labels were entered into a qualitative software program called Atlas.ti (version 6.2)

to analyze in more detail the contexts in which PGx biomarkers featured to identify cases of where testing was required or recommended before treatment [106]. This involved searching for the biomarker listed in the FDA table and reading the sections of the label in which it is cited to find language that specify or do not specify courses of action to be taken by the prescribing clinician in relation to the PGx biomarker (phrases such as ‘should test’, or ‘testing is required’). The Internet Archive [107] was also utilized to capture previous editions of the FDA table (captured on 14 June 2009 and 19 October 2010) in order to provide a historical comparison to the 2012 table. The PharmGKB table of drug labels with PGx information was also examined in January 2013 to determine how it differed from the FDA table. As outlined below, in a number of cases it was not possible to locate drug labels in the drugs@FDA database and in a few instances it was not possible to find the biomarker listed either by the FDA or PharmGKB cited in the label itself (see Supplementary Table 1).

Drug-biomarker associations (n)

the former Director of the Office of Clinical Pharmacology at the FDA, is on record as stating the aim of the FDA was to translate genetic knowledge into drug labels with the hope that this would also translate into changing patient care [15]. Specifically, the Office of Clinical Pharmacology at the FDA championed the relabelling of the anticoagulant drug warfarin, originally approved in 1954, to include information about CYP2C9 and VKORC1, two genes involved in its metabolism [16]. The Office of Clinical Pharmacology also produced guidance in 2009 on the clinical pharmacology section of drug labels to include clinically relevant knowledge on pharmacokinetics, pharmacodynamics and pharmacogenomics of drugs [17]. The FDA approach to PGx labelling has drawn criticism from those who argue that often the inclusion of PGx biomarker data is premature and is not supported by robust enough evidence about the clinical validity and utility of the biomarker [18]. Since 2009, the FDA has tabulated label information on its organizational website in the form of a Table of Pharmacogenomic Biomarkers in Drug Labels, which lists the names of drugs, their associated biomarkers, their therapeutic areas, and the relevant label sections in which biomarker information is included. This information about biomarkers relates to a number of factors: variability in clinical response to a drug, the risk of adverse reactions, to indicate genotype-specific dosing, to elucidate mechanisms of drug action or to describe polymorphic drug target and disposition genes. Having provided a brief overview of FDA actions and policies in this area, this paper now describes the method used to analyze the FDA data and discusses the key findings.

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Table 1. Analysis of current US FDA table by status and purpose of pharmacogenomic biomarker in drug labels.

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their initial approval. Fewer than half of this number includes drugs approved since Herceptin. In some cases, such as warfarin, the label change took place decades after initial approval. Inclusion of biomarker data is made on the grounds of drug safety in 71 instances and of efficacy in 41 cases (with five unable to be classified). „„ Therapeutic areas Ta ble  2 shows that the drugs included in the table cover 15 different therapeutic areas, with drugs to treat various cancers (36), psychiatric conditions (27) and cardiovascular disease (nine) as the three areas that appear most frequently. While psychiatry drugs are almost all associated with the CYP450 markers (CYP2D6 and CYP2C19) and are therefore related to how these drugs are metabolized, oncology drugs are linked to a more diverse number of biomarkers associated with the tumor types involved such as KRAS, HER2 or EGFR. „„ Clinical utility For which drugs PGx testing has clinical utility is a hotly debated question in the literature [18,19]. The question of clinical utility of PGx testing is a crucial issue. The table does not provide a clear picture of whether the biomarker is relevant to making clinical treatment decisions or not. In an early version of the table, the FDA previously distinguished between drugs for which it required or recommended testing prior to treatment and for which biomarker data in labels was included on an ‘advisory’ basis only [20]. The FDA no longer includes such distinctions in its table for unknown reasons. Therefore to investigate the clinical utility of PGx biomarkers, it is necessary to analyze the language used in individual drug labels. As summarized in Table 3, this study shows that these distinctions would not reflect well the different ways biomarker data is included in drug labels. In 26 cases, the biomarker is part of the drug’s licensing indication but in only seven instances does the label explicitly state that testing is required prior to treatment for that biomarker as in the case of crizotinib (Xalkori), which states that: “detection of ALK-positive NSCLC using an FDAapproved test, indicated for this use, is necessary for selection of patients for treatment with Xalkori because the drug has only shown efficacy in that patient group” [21]. This may 300

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in part be explained by the fact that several of these drugs are adjuvant or second-line therapies and the label drafters presume testing would have already taken place. In seven cases, the presence of the biomarker is contraindicated for the administration of the drug but no guidance on testing is given. In another six labels, testing is recommended, such as for the use of Imuran® (azathioprine), for which the FDA recommends that: “consideration be given to either genotype or phenotype patients for TPMT before starting treatment to detect patients more prone to a toxic reaction” [22]. In 72 cases, no specific course of action is recommended or required and information typically appears in the ‘clinical pharmacology’ section. This is typically where research reports an association between a drug and a specific biomarker but where evidence is currently lacking for its clinical validity or utility (but which may change over time). Although beyond the scope of this paper, how individual clinicians should interpret or act on this information and the potential legal consequences of not acting on it are interesting questions that others have begun to address [23]. In the 13 cases where testing is either required or recommended prior to treatment, few of the labels identify a specific diagnostic that must or should be used. Labels for both crizotinib and vemurafenib specify their companion diagnostics as required for their administration. A similar statement was included in trastuzumab’s label at the time of its original approval. Today, however, several HER2 tests have been approved by the FDA and this is reflected in the latest update of its label. These are all cases where the drug is indicated only for specific patient populations and has been demonstrated to provide clinical benefit only for that group. In other instances, the FDA only recommends the use of FDA-cleared tests, which should be conducted in laboratories that meet appropriate standards. However, for several of the drugs for which the FDA recommends testing, reference is made only to the availability of testing services and no further guidance is offered. „„ Industry trends All but one (Johnson and Johnson) of the 11 pharmaceutical companies listed in the 2011 Fortune Global 500 have drugs listed in the table which they developed and brought to market. Given that label changes to add PGx biomarker data can happen years after approval, future science group

Pharmacogenomic biomarkers in drug labels

it is not surprising to find that for the top five firms represented in the table (as shown in Table 3), the drugs listed are a mix of on-patent and off-patent products. The firms with the most on-patent drugs are: AstraZeneca (five), Novartis (six), Pfizer (four), GlaxoSmithKline (four) and Sanofi-Aventis (two). „„ Comparison with the PharmGKB table To complete the ana­lysis of the number of drugs on the market with PGx biomarker data in their labels, we can compare the FDA table with the PharmGKB table. Rather than only listing approved drugs, the PharmGKB table is a more general repository of PGx information. Viewed in January 2013, this source lists 131 unique drugs compared with 105 unique drugs in the FDA table. The difference is accounted for in two ways: there are seven instances of where the curators of the PharmGKB table have listed drug compounds separately when the FDA groups them together (for example isosorbide and hydralazine); and they have included 11 additional drugs associated with G6PD deficiency and another three drugs associated with CYP450 polymorphisms. Two of these drugs are discontinued (nalidixic acid and sulfisoxazole), and one, methylthioninium chloride (methylene blue) is not listed on the FDA-approved drug products database. Three drugs (timolol, tiotropium and primaquine) were in earlier versions of the FDA table. Only in one case is it possible to determine from the language of the drug label that testing is recommended prior to treatment, for a drug called pegloticase which does not feature in the FDA table. In the other cases, the label does not recommend or require a course of action. It is beyond the scope of this paper to investigate why these differences exist between FDA and PharmGKB.

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Table 2. Drug–biomarker associations in US FDA table by therapeutic area. Therapeutic area

Drug–biomarker associations (n)

Analgesics

3

Antiarrhythmics

1

Antifungals

2

Anti-infectives

2

Antivirals

5

Cardiovascular

9

Dermatology and dental

4

Gastroenterology

8

Hematology

5

Metabolic and endocrinology

1

Musculoskeletal

1

Neurology

6

Oncology

36

Psychiatry

27

Pulmonary

2

Reproductive and urologic

2

Rheumatology

2

Transplantation

1

However, given these different sources of information available on PGx drug labeling, does combining data from the FDA table with that produced by the PharmGKB alter the picture? Excluding the seven instances where the PharmGKB curators have listed drug compounds separately when the FDA groups them together, and methylene blue since it is not listed as FDA approved, Table 4 adds an additional 13 drugs to those included in the FDA table. This produces a new total of 118 unique drugs, 38 unique biomarkers and 130 drug–biomarker

Table 3. Top five pharmaceutical firms by number of drugs and patent status listed in the December 2012 US FDA table. Drug developer

On-patent drugs

Novartis

Afinitor , Arcapta™ neohaler, Fanapt , Gleevec®, Myfortic®, Tasigna®

Fanapt®, Clozaril®, Femara®, Tegretol®, Mellaril®

AstraZeneca

Prilosec®, Nexium®, Iressa®, Brilinta®, Faslodex®

Toprol-XL®, Nolvadex®

Sanofi-Aventis

Elitek®, Carac®

Aralen®, Plavix®, Norpramin®, Rifater®

Pfizer

Promacta®, Xalkori®, Selzentry®, Lipitor®, Vfend®

Camptosar®, Dilantin®

GlaxoSmithKline

Rythmol SR®, Tykerb®, InnoPran XL®

Ziagen®, Tabloid®

future science group

Off-patent drugs

®

®

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301

302

5 84 7 19 130

84 7 8

5

41

Unable to determine Safety Efficacy

Biomarker testing Advisory recommended only Biomarker contraindicates use of drug Biomarker Biomarker indicated indicated for in for in label label and testing required Drug-biomarker associations (n)

Table 4. Combined US FDA and PharmGKB data on pharmacogenomic drug labels.

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associations (Supplementary Table 2). This combined data shows that 49 drugs have had PGx biomarkers included in their labels at the time of their original approval and 79 drugs have had such biomarkers added after approval. This does not change the picture dramatically. However, Table 4 shows a greater number of drugs for which the inclusion of biomarkers is only of an ‘information only’ nature and a significant increase in the number of cases in which PGx biomarker information is included on grounds of improving drug safety.

Conclusion Analysis of the FDA and the PharmGKB tables provides an insight into what little has been achieved in PGx since the 1990s and its current limitations. Using trastuzumab (Herceptin) as the starting point (since this is generally considered to be the first personalized medicine), approximately 12% of the 385 drugs (both biologics and chemical entities) approved by the FDA in the period 1998–2012 have PGx biomarker data in their labels. Of that number, the FDA and PharmGKB tables indicate that clinicians are either required or recommended to utilize pharmacogenomic testing before prescribing for only 14 drugs on the market as of December 2012. This clearly falls short of expectations many had in the 1990s about the transformative potential of PGx to usher in a new paradigm of drug development. That being said, PGx research on already approved drugs has linked adverse reactions in patients to genetic differences and helped to improve the safety profiles of drugs such as the HIV drug abacavir (Ziagen®). However, PGx biomarker data seems concentrated in two therapeutic areas at present – oncology and psychiatry – so its wider application is for now unclear. Analysis of these sources also reinforces recent commentary on the difficulties of translating biomarkers into clinical practice. Poste has recently argued that while there are an estimated 500,000 biomarkers identified now in basic research, the number that have been validated for clinical use is much smaller at present [24]. The challenge in bringing validated and standardized biomarkers into the clinic remains and this situation is reflected in the FDA table. Only 16 new biomarkers have been added to the FDA table since its inception in June 2009 and many lack sufficient evidence behind them to be used in the clinic. The FDA has pursued the policy of including PGx biomarker data in labels of drugs Pharmacogenomics (2014) 15(3)

approved for the US market in part to raise the visibility of PGx, to encourage clinical uptake and to demonstrate its own relevance to fostering pharmaceutical innovation. Notwithstanding criticism of its approval decisionmaking, the FDA has been an important driver behind PGx as opposed to an obstacle. However, while label changes are meant to inform clinical practice, inclusion of PGx biomarker data does not guarantee uptake or reimbursement from healthcare payers as demonstrated vividly by the case of warfarin [18]. Studies indicate that a lack of evidence that PGx testing changes patient outcomes and practical issues such as cost and turnaround time of testing have a significant impact on determining uptake amongst doctors [25]. Previous research has also found that there is often disagreement between FDA labeling and clinical guidelines [23]. Therefore, to assess the impact of PGx on the practice of medicine, we can also examine which pharmacogenomic tests are covered by healthcare payers or recommended by organizations charged with writing clinical guidelines. As measures of the progress made in PGx, the FDA and the PharmGKB tables must be read with caution. Understanding the specific context in which the biomarker appears in a label and whether or not it is actionable in clinical decision-making is crucial. This paper has contributed towards a better understanding of what the FDA and PharmGKB tables tell us about the current state of PGx. As we evaluate progress made since the late 20th century it is important that good quality information is available to avoid fuelling unrealistic expectations.

Future perspective As this paper shows, making future projections for the field of PGx is fraught with difficulties. However, indications are that there is renewed interest and investment from industry in PGx and personalized medicine more generally and there are clear drivers from healthcare payers that targeted treatments are more likely to receive reimbursement than ‘one-size-fits-all’ drugs. However, the high cost of these drugs may come under greater scrutiny, especially outside of the US. We are likely to see continued growth in the number of drug labels including PGx biomarker data despite their limited and uncertain validity or utility, but payers not regulators are pivotal to the future impact of PGx on the practice of medicine. future science group

Pharmacogenomic biomarkers in drug labels

Acknowledgements L Everett and D Wright provided invaluable assistance in the preparation of the paper; M Hopkins, P Martin and S Hogarth gave comments on the work.

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organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Financial & competing interests disclosure The research reported on in this paper was funded by the Economic and Social Research Council (ESRC) and formed part of the work programme at the Centre for Economic and Social Aspects of Genomics (Cesagen). Grant No: RES-145-28-0003. The funders had no role in study design, data collection and ana­lysis, decision to publish or preparation of the manuscript. The authors have no other relevant affiliations or financial involvement with any

Ethical conduct of research The authors state that they have obtained appropriate insti­tutional review board approval or have followed the princi­ples outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investi­gations involving human subjects, informed consent has been obtained from the participants involved.

Executive summary Background ƒƒ Today, debate ensues amongst science journalists, scientists, regulators and other stakeholders about whether pharmacogenomics (PGx) has lived up to its potential. ƒƒ The number of ‘personalized medicines’ on the market is taken as a key barometer of the progress made in PGx. ƒƒ Inclusion of PGx biomarker data in drug labels has been the cornerstone of US FDA policies to promote the visibility and uptake of PGx. Findings ƒƒ As of December 2012, the FDA Table of Pharmacogenomic Biomarkers in Drug Labels indicated 117 known drug–biomarker associations. ƒƒ Analysis of drug label language shows that only in 13 cases does the FDA either require or recommend preprescription biomarker testing, while most drug labels include biomarker data with no specific course of action stated because of a lack of current evidence that the biomarker has clinical validity or utility. ƒƒ The two principal sources of public information on PGx biomarkers in drug labels, the FDA and PharmGKB, differ in the number of drugs and biomarkers they include in their databases. Conclusion ƒƒ Only 12% of the 385 drugs licensed in the period since the approval of Herceptin in 1998 have PGx biomarker data included in their labels, which falls short of expectations many had in the 1990s. ƒƒ As measures of the progress made in PGx, FDA and PharmGKB data must be read with caution. ƒƒ Understanding the specific context in which the biomarker appears in a label and whether or not it is actionable in clinical decision-making is crucial.

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Pharmacogenomic biomarkers in drug labels: what do they tell us?

This article investigates the number of drugs on the market with pharmacogenomics (PGx) biomarker data in their labels using two public sources - the ...
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