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Current Status and Future Direction of Companion Diagnostics
C H A P T E R
25 Current Status and Future Direction of Companion Diagnostics Edward Meinert1,2, Abrar Alturkistani2, Dee Luo3, Kimberley Foley2, Ching Lam1, Alison Carter1, Donna Seyfried1, Josip Car2 and David Brindley4,5,6,7 1
Healthcare Translation Research Group, Department of Paediatrics, Level 2, Children’s Hospital, John Radcliffe, University of Oxford, Oxford, United Kingdom 2Global Digital Health Unit, Department of Primary Care and Public Health, Imperial College London, London, United Kingdom 3Department of Biological Basis of Behaviour, University of Pennsylvania, Philadelphia, PA, United States 4Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA, United States 5Harvard Medical School, Division of Engineering in Medicine, Boston, MA, United States 6Brigham and Women’s Hospital, Boston, MA, United States 7Partners Healthcare, Boston, MA, United States O U T L I N E 25.1 Overview of Companion Diagnostics 25.2 Current Status of Companion Diagnostics 25.2.1 Current Status of Companion Diagnostic in Selected Disease Areas 25.2.2 Companion Diagnostic in Oncology 25.2.3 Companion Diagnostic for Infectious Diseases
Companion and Complementary Diagnostics DOI: https://doi.org/10.1016/B978-0-12-813539-6.00025-0
25.2.4 Companion Diagnostic for Cystic Fibrosis 25.2.5 Companion Diagnostic for Asthma 25.2.6 Companion Diagnostic for Aging-Related Diseases 25.2.7 Reproductive Health
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25.3 Considerations About Current Companion Diagnostic Tests 25.3.1 Reliability and Validity of Companion Diagnostic
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© 2019 Elsevier Inc. All rights reserved.
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25.3.2 Regulatory Considerations for Companion Diagnostic 25.3.3 Companion Diagnostic Adoption 25.3.4 Codevelopment of Companion Diagnostic 25.4 Companion Diagnostic Economic Value 25.4.1 Economic Evaluations of Companion Diagnostic 25.4.2 Economic Incentives
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25.5 Forward Direction of Application of Companion Diagnostic in Various Disease Areas 25.5.1 Immunotherapy 25.5.2 Future of Alzheimer’s Disease 25.5.3 Infectious Diseases 25.5.4 Psychiatry
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25.6 Summary
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25.1 OVERVIEW OF COMPANION DIAGNOSTICS A companion diagnostic (CDx) is a test that helps determine the suitability of a therapeutic drug for an individual patient. It is identified as a tool in the field of precision medicine, a growing approach to medical treatment that uses specific patient characteristics such as genes, proteins, metabolites to customize treatment and care [1,2]. The US Food and Drug Administration (FDA) has defined CDx as a medical device, often an in vitro device, which provides information that is essential for the safe and effective use of a corresponding drug or biological product [3]. CDx enables personalization of treatment by ensuring that a patient only receives a therapeutic product if he or she is likely to respond positively to the therapy, and the benefits from the therapy have the potential to outweigh risks. CDx does this by classifying patients into subpopulations based on specific characteristics that can influence the effects of the drug [4]. CDx differentiates through the following four ways [5]: 1. Determining which patients will benefit from the therapeutic drug. 2. Determining which patients will be harmed by the therapeutic drug through adverse side effects or increased risk. 3. Identifying patients’ response to treatment. 4. Identifying the subpopulation of patients who can safely use the therapeutic drug. In general, CDx can classify patients into those who can benefit from therapy, those who will have no response to therapy, and those who might be harmed by therapy (Fig. 25.1). Development of CDxes requires that the corresponding therapeutics’ mechanism of processing in the body is understood. When a therapeutic enters the body, it targets specific molecular agents that use specific enzymes, mutations, or antibodies known as biomarkers to help facilitate therapeutic action. The presence of certain biomarkers can indicate increased or decreased the efficacy of a therapeutic regimen, so determining the presence of these molecules is important in determining the best course of medication. CDx works by looking for the targets that affect the efficacy of the therapeutic drug, with a focus on
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25.1 CDxes can help classify patients; patients who can benefit, patients who will have no response, and patients who might be harmed by a particular therapy. CDxes, Companion diagnostics.
FIGURE 25.2 Pharmacogenetic biomarker types listed in approved FDA therapeutic products in the years 1945 2005 [7]. FDA, Food and Drug Administration.
gene expressions, mutations, and antibodies that are found to enhance or block drug effects. Development of a CDx, therefore, helps create more targeted treatments with greater benefit to risk prior to administration of any therapeutic. The categorization of patients based on their response to treatment relies heavily on biomarkers that indicate changes in biological measurements, such as mutations or amplifications in the gene [6]. A 2012 review of the pharmacogenetic biomarkers listed in approved FDA therapeutic drugs found that most biomarkers listed were human genomic biomarkers (69/121) while 52 of 121 listed were microbial genomic biomarkers [7] (Fig. 25.2). Biomarkers give rise to genomic CDx assays that look for pharmacogenetic biomarkers or biomarkers that indicate genetic variation. Besides pharmacogenomic biomarkers, there are also nongenomic assays, which are predicted to be utilized more widely in the future [8]. The presence of both human genomic and microbial genomic biomarkers not only indicates a change in the response to therapy but also acts to either enhance or block the effect of a drug. This relationship means that CDx becomes a necessary tool to predict the success of a given drug treatment, especially for highly heterogeneous, complex diseases, such as cancer.
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Biomarker discovery remains the most critical step in enabling improvements in clinical outcomes for patients. Both the FDA and the Institute of Medicine recommend that the development of a CDx be completed as soon as biomarker discovery of a disease occurs while accounting for its applicability in clinical practice [9]. To emphasize the importance of this recommendation, FDA Type C meetings are being permitted for early engagement with biomarkers. The push for increased knowledge of biomarkers and disease mechanisms as well as the policy-level emphasis on CDx codevelopment is aimed at encouraging discoveries in diagnostics tests. However, looking at the current status of CDx, research shows that there remain many considerations that need to be considered before CDx tests can reach their full potential. There are positive signs of increasing developments in oncology and other disease areas, including aging-related diseases, but questions remain regarding CDx validity, regulation, and adoption. Codevelopment of CDx with their corresponding therapeutic product and their economic value is also a significant consideration in the current status of CDxes. The future direction of CDx is moving toward including more disease types and adopting new technology and methods for the development of improved CDx tests.
25.2 CURRENT STATUS OF COMPANION DIAGNOSTICS The greatest development and utilization of CDx have been for highly complex, typically chronic, diseases. The advantages of using CDx for diseases, such as cancer, cystic fibrosis (CF), asthma, and human immunodeficiency virus (HIV), are especially clear. Complex chronic diseases typically have diverse pathophysiological pathways, meaning that within patients diagnosed with the same condition, the mechanisms that lead to therapeutic effects could differ in each patient subgroup. This makes CDx beneficial in determining these subgroups and tailoring treatments based on the genetic and immunologic pathways [10]. Identification of the right pathways and biomarkers involved in the mechanism of action for a therapeutic drug is of chief importance for the safe delivery of the drug. Significant progress is being made in unraveling the different mechanisms involved in disease progression and treatment, especially in the field of oncology, and in other disease areas characterized by complex underlying mechanisms, such as aging-related diseases, infectious diseases, CF, and asthma.
25.2.1 Current Status of Companion Diagnostic in Selected Disease Areas Development of CDx has been constrained to disease indications because of our limited knowledge of certain disease pathways. Understanding of pathophysiological pathways and biomarkers is necessary to elucidate the differences that may exist between subpopulations of patient. With these discoveries in disease progression pathways, CDx can then create efficacious clinical trials in earlier stages of disease and test for improvements in disease progression. It is suggested that improved knowledge of genetics, pathophysiological pathways of disease, and a better understanding of key players of disease progression will help improve CDx tests and consequently will contribute to the development of more targeted
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and tailored treatments [11]. Therefore most progress in CDx development has been made in disease areas where there is some knowledge about the pathophysiological pathways of disease progression, specifically about the therapeutic product’s targets in the body. Such knowledge has mostly been discovered in oncology through the identification of somatic driver mutations. In other disease areas, some CDx tests are emerging due to the discovery of disease-specific biomarkers or assays that can be used in CDx.
25.2.2 Companion Diagnostic in Oncology CDx was first adopted in the field of oncology. As of 2015, oncology drug-related tests made up 40% of all marketed products [12]. CDx was specially designed to address the heterogeneity of complex diseases, such as cancer, which can differ in their causes, rates of progression, and their response to drugs. Such factors are highly diverse in different cancers, but more importantly, in individual cancer patients with the same type of cancer [13]. For many cancer patients, it is possible to obtain a biopsy sample of a tumor, which allows identification of the expression of the therapeutic target in the tumor tissue or mutations in the gene more efficiently than other diseases where biopsy samples are not practical [10]. This helps provide a precise identification of the biomarkers involved, enabling easier target identification for the CDx test [10]. CDx will remain a significant tool in delivering therapeutics in oncology because drugs developed for treating cancer are often highly individualized therapies designed to interact with specific markers in the body, making CDx commonly used for this purpose [14]. The first therapeutic drug used in oncology that was accompanied by a CDx was Trastuzumab, also known as Herceptin, and it revolutionized the treatment of breast cancer. Breast cancer is caused by unregulated proliferation of breast tissue cells due to specific mutations. One such mutation that causes unregulated cell proliferation is the overexpression of estrogen receptors (ER). Tumors that have ER 1 overexpression can be treated with tamoxifen, an established estrogen receptor inhibitor. However, tumors that do not have ER 1 overexpression (ER- tumors) have poor prognosis and are treated with a cocktail of radiation, surgery, and general chemotherapy. The discovery of Herceptin was preceded and made possible by the discovery of a biomarker, HER2/neu. It was discovered that, like ER 1 tumors, some ER 2 tumors overexpressed human epidermal growth factor receptor 2 (HER2/neu) [7]. HER2 is a receptor in the receptor tyrosine kinase family (RTK) that activates cell growth pathways. Therefore, over activation or overexpression of HER2 receptors cause continual activation of cell growth pathways leading to cancer. Suddenly, ER 2 tumors could be further stratified into HER2 1 tumors, creating three main categories of breast tumors: 1. ER 1 , HER2 2 (tumors that overexpress estrogen receptors and do not overexpress HER2 receptors) 2. ER 2 , HER2 2 / 1 (tumors that do not overexpress estrogen receptors and may or may not overexpress HER2 receptors) 3. ER 2 , HER2 2 (tumors that do not show overexpression of either estrogen receptors or HER2 receptors).
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Tumors in the first category had the best prognosis because they could be treated with estrogen receptor inhibitors. Now researchers had a target, HER2, in which to test interventions for the second category. Herceptin became the first drug that specifically inhibited the HER2 receptor, and in patients with HER2/neu overexpression, treatment with Herceptin has significantly improved prognosis with decreased risk for cancer recurrence and death [15]. Not all patients benefit from Herceptin: patients with tumors in the first and third category receive little therapeutic benefit. The CDx is necessary to test for HER2/neu overexpression and identifies patients who would benefit more from Herceptin therapy. Clinically, Herceptin cannot be administered without a positive CDx test showing HER2/neu overexpression. HER2/neu as a biomarker has become one of the most used CDx assays in the US [8]: a 2013 review found that HER2/neu was used in 10 out of 15 FDA-approved CDx assays which test for protein overexpression or as gene amplification [8]. The CDx for Herceptin is inextricably linked to development and efficacy of Herceptin, and current drug development in oncology is focused on biomarker discovery and further stratification of tumor subtypes. Within the field of oncology, most of the approved CDx tests are designed for therapeutic drugs that inhibit the signal transduction pathways where the CDx detects the presence or absence of somatic driver mutations in the therapeutic drug target [16]. This limits the number of CDx tests that can be used to determine the suitability of the therapeutics used in oncology, since many other therapeutic drugs that use different mechanisms exist. However, the challenge lies in the difference in complexity between tumors that proliferate due to targeting somatic driver mutations. In tumors with a driver mutation, a therapeutic drug inhibits the signaling pathway that occurs as a result of the driver mutation, therefore inhibiting proliferation of a tumor [16]. CDx tests for such a mutation use a singleanalyte assay and are relatively simple because they look for a single mutation [16]. However, tumors that involve more complicated pathways, such as single nucleotide polymorphisms, somatic mutations, gene, or protein expression, are not yet considered in CDx tests since they require multiple assays [16].
25.2.3 Companion Diagnostic for Infectious Diseases Not all treatments work the same way in different patients, and this underlying idea has been especially important in the development of CDx for infectious diseases [11]. CDx for infectious disease treatments has been shown to help determine the most beneficial, most effective treatments, as well as the optimum suitable dose of each treatment for patients [11]. However, few infectious diseases have received attention in CDx development. HIV disease and hepatitis B were two of the first infectious diseases with improved knowledge about the underlying biomarkers of disease. The earliest example of CDx developed in infectious diseases is the coreceptor tropism testing which tests for the presence of R5 virus in HIV-1 patients [17]. If the R5 virus is present, then the patient can receive an antiretroviral treatment regimen that includes CCR5 antagonist [17]. For hepatitis B, the immune-based therapies of the disease require identification of patient groups based on their response to treatment. Biomarkers were identified for this disease which include serum hepatitis B surface antigen and hepatitis B virus DNA, the presence of these two biomarkers can interchangeably be used to predict response to therapy [18]. COMPANION AND COMPLEMENTARY DIAGNOSTICS
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25.2.4 Companion Diagnostic for Cystic Fibrosis CF is an irreversible, genetic disorder, which previously has only been treated by managing patients’ symptoms due to lack of knowledge of underlying genetic mechanisms [19]. Cystic fibrosis causes a pathological thickening of mucus due to impaired transport of chloride ions out of cells. Thickened mucus means the lungs have impaired ability to clear out infections and the pancreas cannot secrete digestive enzymes that need mucus to travel into the small bowel. Patients experience failure to thrive and are at high risk of pneumonia that can prove fatal. Treatment typically involved antibiotics, bronchodilators, and other medications to resolve immediate symptoms. Later, it was found that CF is characterized by five to six classes of mutations resulting in a dysfunctional CFTR channel protein [19]. Mutations range from defective folding of the CFTR protein to defective transportation of the CFTR protein to the surface of the cell where it can exert its physiological function. More importantly, each mutation class is characterized by single, unique mutations in the CF gene. Therefore, it was possible to create mutation targeted therapy in which therapies directly counteract the specific mutation [19]. The improved understanding of the CF mutations along with the development of mutation-targeted therapies assisted in the development of therapies and corresponding CDx that directly targeted the underlying disease. For example, in patients with a deletion of the amino acid phenylalanine at the 508th position of the CFTR gene (deltaF508 mutation), the personalized therapeutic Orkambi (lumacaftor/ivacaftor) can greatly improve CFTR function. Orkambi is most effective in patients with the deltaF508 mutation and this specificity led to development of two CDx assays, which were approved by the FDA in 2013 as an in vitro diagnostic device [18,20]. The developed assay improved diagnosis of patients with CF as well as categorized patients for different CFTR-targeted therapies [18].
25.2.5 Companion Diagnostic for Asthma Asthma is also characterized by heterogeneity between patients and diversity in patient’s phenotypic characteristics [18]. These complexities of asthma require personalized treatment, and a variety of disease phenotypes can be used for decision-making concerning therapies [18]. The earliest biomarker discovery in asthma came from understanding that the periostin gene, along with the CLCA1 and serpinB2 genes, is associated with IL-13 in the epithelial cells of asthma patients [21].
25.2.6 Companion Diagnostic for Aging-Related Diseases Adults aged 60 years or older are the fastest growing age group, with predictions that this population will more than double by 2050 and more than triple by 2100 [22]. Dementia is a major cause of disability in this age group, and Alzheimer’s disease (AD) accounts for 60% 70% of dementia cases [23]. The discovery of aging-related biomarkers can help prevent and treat aging-related diseases, such as AD. Some knowledge about biomarkers linked to the early onset of the disease have been identified [24,25], but there is a need to identify patient subgroups for treatment and a need to increase the use of these biomarkers in clinical practice [18]. The need for early-on inclusion of healthy,
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predementia individuals in trial design and end-point selection for the development of better targeted therapies [25] is reflected in the FDA’s guidelines to regulate development of therapeutics in the early onset of Alzheimer’s (before the occurrence of dementia). The FDA’s regulation of early AD prognosis and therapeutic drug treatment is titled “Early Alzheimer’s Disease: Developing Drugs for Treatment Guidance for Industry” [26]. The goal of this document was to guide drug developers in creating treatments targeted of the stages of sporadic AD that occur before the onset of overt dementia. Prior to these guidelines, the FDA had been focused on recruitment of AD patients into clinical trials only after the disease has progressed, which leaves little to chance for improvement for patient outcomes [26]. In this respect, the FDA is now encouraging guidelines for patient recruitment for efficacy trials for Alzheimer’s patients for each of the stage of the disease.
25.2.7 Reproductive Health In reproductive medicine, CDx is used as an anti-Mu¨llerian hormone (AMH) assay for determining the optimal gonadotropin dosing for controlled ovarian hyperstimulation. This works by categorizing patients by very narrow categories of AMH [27]. However, the availability of two different commercial AMH assays has led to comparisons indicating a superiority of one assay over the other in clinical laboratories and has highlighted the need for standardization [27].
25.3 CONSIDERATIONS ABOUT CURRENT COMPANION DIAGNOSTIC TESTS The increased prevalence of complex diseases, such as cancer and other chronic diseases, is motivating the advancement of CDx. However, questions remain regarding the reliability of CDx tests and their regulatory aspects on an international level. There is also an increased emphasis on codevelopment of CDx with their corresponding therapeutics, which will need to be considered in the development of new CDx tests.
25.3.1 Reliability and Validity of Companion Diagnostic Identification of the right pathways and biomarkers involved in the therapeutic drug is critically important for the safe delivery of the drug. Since the success of the therapeutic product depends on the success of the CDx assay, any errors in determining the right biomarkers can put the patient receiving the therapy at risk of no response from treatment or even at an increased risk of harm from treatment [28]. As with any medical test, a CDx test is also subject to measurement error possibly resulting in misclassification of patients which might lead to deliver the suboptimal treatment to patients [14]. Misclassification occurs due to the presence of false marker negatives or false marker positives which can significantly affect the variance and statistical power of the CDx. This, in turn, may attenuate the true treatment effect of a drug in clinical trials and lead to misclassification of patients [14]. To create a reliable CDx, there is a need to validate the test before it is used
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in clinical trials or in clinical practice. This is to avoid misclassifying patients into the inappropriate treatment group and to prevent patients from receiving a treatment that has no effect or worse, might have adverse effects on the patient [14].
25.3.2 Regulatory Considerations for Companion Diagnostic CDx regulation by FDA in the United States [29] and European Medicines Agency (EMA) in the European Union (EU) countries has seen both agencies imposing similar regulatory instructions with slight differences in testing and labeling requirements [12]. For instance, 78% of the drugs in 2015 that came with a CDx stated similar requirements in the label of the therapeutic drug by both the FDA and EMA, except for few CDxes that were required by the EMA but only recommended by the FDA [12]. Other countries including Japan, Canada, and Australia have also initiated regulatory guidelines for CDx [30]. However, guidelines in each of these countries differ in certain regulatory aspects. A 2014 review of approved CDx and their corresponding therapeutics found that for the same therapeutics, only 52% in the United States, 63% in the EU, and 38% in Japan required biomarker measurement in the label of the product [31]. Also, while both the United States and Japan require the codevelopment of a CDx with its corresponding therapeutic if a CDx is required for a certain therapy, the EU recommends codevelopment but does not have any mandatory requirements [31]. While regulation of CDx is of high importance to ensure validity and safety, there are still areas to be further refined in patient safety. There is high heterogeneity between regulatory frameworks used in different countries especially regarding risk classification and approval of CDx test [30,32]. It is recommended for all regulatory organizations to commence a harmonization process through the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use.
25.3.3 Companion Diagnostic Adoption There are currently few approved CDx tests available in the market. Adoption rates are low due to several challenges [33]. First, developing a CDx test is costly. While it can reduce health-care costs for long term, there are up-front costs associated with training health staff to use the tests and implementing tests into integrated care pathways [12]. Along with costs, CDx manufacturers also face a lack of adequate return on investment due to the relative unsustainability of the commercial CDx market. It was found that there is a significant disparity between the cost of a CDx test and the cost of the corresponding therapeutic, meaning that CDx as products were affected by different economic factors than those that influence traditional pharmaceuticals. CDx assays in general cost substantially less than their corresponding therapeutics, suggesting that the incentive to invest upfront in CDx development is often not sufficiently compelling [33]. In addition, diagnostic tests are typically administered once to each patient, and this inherent characteristic creates a low incentive for diagnostic developers [33], especially for rare diseases with small patient populations [12]. Since CDx tests are viewed as a separate product to the therapeutic drug, payment and reimbursement methods are complicated, requiring
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FIGURE 25.3 Codevelopment of CDx with the therapeutic drug during clinical trial stages. CDx, Companion diagnostic. Source: Adapted from Figure 3 in Cheng S, Koch WH, Wu L. Co-development of a companion diagnostic for targeted cancer therapy. N Biotechnol 2012;29(6):682 88 [34].
separate payments; one for the CDx and one for the drug, further complicating the acceptance of CDx in routine clinical practice [33]. All these factors contribute to the low number of CDx tests developed and available in the market today.
25.3.4 Codevelopment of Companion Diagnostic Codevelopment impacts CDx by allowing the diagnostic test to be developed in parallel with its corresponding therapeutic product. This is done by incorporating the CDx from the early clinical trial stages of the drug development [12] as illustrated in (Fig. 25.3). The FDA recommends that drug companies include CDx development in the early stages of the therapeutic product development (during the clinical trial stage) to help determine and validate the biomarkers that can indicate optimal response to certain treatments and determine the patient subpopulation most likely to respond best to a therapeutic medicine [12]. The CDx codevelopment occurs in parallel to the drug development and starts as early as phase I and phase II of the clinical trial. Before that, a hypothesis about biomarkers involved in the pharmaceutical product’s targeted therapeutic pathway is identified in the preclinical phase [35] (Fig. 25.3). Validation of CDx occurs in phase III in which diagnostics metrics such as sensitivity and specificity are calculated [35]. This method helps increase the efficacy of the drug and helps identify patients with increased likelihood of response to a certain drug from the early stages [15]. Codevelopment can also improve regulatory processes. Approval of pharmaceutical products is made more accessible if a CDx is included in the developmental phases. This is especially true for cancer drugs [16]. In addition, codevelopment can help regulate the labeling of CDx assay on its corresponding therapeutic drug label (Fig. 25.3). As such, if a particular therapeutic drug requires a CDx test before administration, the FDA requires the drug labels to explicitly stat such information in the instructions to ensure patients
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receive the correct treatment [36,37]. Other regulatory requirements associated with codevelopment include prescribing a medication with an assigned CDx only after the patient was found positive in the CDx test. This is true for many cancer drugs which are only delivered after a CDx test is performed [30]. Developing a CDx test after the drug is produced can cause inconsistencies in the validity and effectiveness of the test [38]. The challenge with codevelopment lies with the requirement of identifying the subpopulation of patients that will benefit from the therapeutic drug in the very early stages of the clinical trial (by phase II). This is only possible if the researchers have a strong hypothesis about the pathways or biomarkers involved in the processing of the drug early on [12]. Thus the more that is known about the fundamental mechanisms of the disease and its therapeutic pathways, the greater the chance of successfully developing an optimal CDx assay. Although incorporating CDx in the early stages of the drug development is recommended and beneficial, it may face resistance from therapeutic drug developers due to the intellectual property protection regulation differences between CDx and other pharmaceuticals [12]. For instance a single therapeutic drug can have more than one diagnostic test developed by different CDx developers, disincentivizing pharmaceutical companies from making significant investments in a CDx development commitment when there is a risk that new and better tests and/or suppliers may present and obsolete the CDx test in the future [12].
25.4 COMPANION DIAGNOSTIC ECONOMIC VALUE In addition to increasing the chance of the drug’s efficacy, CDx tests can have significant economic benefits. Economic benefits from CDx tests come from the ability to reduce wastage of health resources by identifying those not likely to respond to treatment beforehand [39]. Although CDx may decrease the number of patients who can receive a specific treatment, it does not necessarily diminish the amount of drug sales [12], though systemwide cost savings may come from reduced long-term side effects in a population that do not require treatment. Also, the diagnostic tests also help shorten time and complexity involved in clinical trials. Since CDx can allow better prediction of patients who will respond to the treatment, it may require the recruitment of fewer subjects to the trials (Fig. 25.4), although different clinical trial study designs do exist where even participants who are not likely to respond to treatment are recruited for the study [35].
25.4.1 Economic Evaluations of Companion Diagnostic Current economic evaluations of CDx may be limited in their representation of all economic outcomes associated with a CDx. The reason for their limitation is due to the high heterogeneity between studies especially in terms of diagnostic test characteristics used in economic models [40]. In addition, current evaluations may only report the added value of the CDx to the therapeutic intervention rather than evaluating CDx as a stand-alone intervention [41]. However, the effectiveness of CDx is highly correlated with a therapeutic
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FIGURE 25.4 One-way CDxes can help optimize participant recruitment to clinical trials by lowering the number of participants required since CDx can help predict which participants are more likely to respond to treatment early on. CDX, Companion diagnostic.
drug’s effectiveness. CDx increases the value of drugs delivered by increasing the likelihood of effectiveness and by creating more efficient clinical trials if codeveloped with the therapeutic product [14]. In contrast, CDx may also hinder clinical trials concerning sample size. This is true if the CDx used is subject to high measurement error, necessitating a larger sample size to avoid dilution of the treatment effect or impacting the variance of the outcome [14].
25.4.2 Economic Incentives Economic factors will play a major role in determining the future of CDx. There is a need for higher incentives and risk sharing in order for pharmaceutical companies to be open to codevelopment of CDx with diagnostic manufacturers, and there is a need for uncomplicated and encouraging reimbursement models for consumers [12]. CDx has many economic benefits that can benefit most of the key players involved in the codevelopment, use, or reimbursement of CDx. For therapeutic drug developers, CDx can help reduce overall development time and costs associated with clinical trials and increase likelihood of successful outcomes. In addition, CDx can help ensure better patient results from therapy by increasing the chances of the drug’s effectiveness [12]. For CDx patients, it can simply help them get the most benefit from the treatment and can save them from unintended, adverse events that would not be known in the absence of a CDx test. For CDx payers, it can help them get better value for what they pay by reducing unnecessary, costly, or ineffective treatments [12]. From the perspective of CDx developers, it is believed that a more sustainable business model and return on investment (ROI) are needed. The potential may be achieved if they diversify a wider menu of diagnostic tests they offer. For example, by including different CDx tests specializing in each of the CDx tests types; screening and detection, prognosis, recurrence, as well as theranostics and monitoring [12].
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25.5 FORWARD DIRECTION OF APPLICATION OF COMPANION DIAGNOSTIC IN VARIOUS DISEASE AREAS The future direction of CDx is in increasing adoption beyond medical fields to assist in the delivery in more disease types in therapies. Also, CDx will help not only in identifying treatment suitability but may also help with disease prevention and wellness.
25.5.1 Immunotherapy Immunotherapy is one of the therapies currently used in oncology, and research on biomarkers for immunotherapy is rapidly advancing. However, creating CDx that can predict patients’ response to immunotherapy will not be as simple as creating CDx for other oncology therapies, such as the CDx created to detect driver mutations in some cancers. This is because treatment by immunotherapy is not affected by driver mutations but by complex interactions of tumor cells with the immune system, and the biomarkers for these interactions have not yet been identified [16]. CDx for immunotherapy will require the use of many diverse assays including cellular, protein, and molecular assays [16]. In immunotherapy the presence or absence of an immune response to tumor cells determines the type of treatment [16]. New immunotherapies being developed will use certain techniques such as novel checkpoint inhibitors, cancer vaccines, or T cell redirection and will require more complicated methods for the developments of CDx tests [16]. Nevertheless, developing these therapies with CDx tests will help increase the therapeutic’ efficacy and clinical approvals as well as help deliver more personalized cancer treatments.
25.5.2 Future of Alzheimer’s Disease Similar to cancer, AD has shown that patients can be significantly different from each other, especially in their response to treatment. Consideration of this diversity will increase with new clinical trial designs which will help create more targeted therapies addressing the needs of different subpopulations with AD. The FDA’s regulation of early AD prognosis and therapeutic drug treatment was published in their document titled “Early Alzheimer’s Disease: Developing Drugs for Treatment Guidance for Industry” [26]. The goal of the document was to guide drug developers in creating treatments targeted at the stages of sporadic AD that occur before the onset of overt dementia. The FDA is looking to change from the prior directive in recruiting Alzheimer’s patients into clinical trials only after the disease has progressed, which has been unsuccessful in improving to patient outcomes [26]. In this respect the FDA has provided updated guidelines for patient recruitment for efficacy trials for Alzheimer’s patients in each stage of the disease [26]. FDA’s efforts to regulate inclusion of earlier stages of Alzheimer’s patients into clinical trials are seen as a significant step toward the improvement in treatments for agingrelated diseases [24]. Such developments in research can offer promise in bringing transformational therapeutics which may ultimately prevent healthy individuals who may be at future risk of AD from the devastating disease progression to advanced cognitive impairment [24]. However, there are many other aging-related, debilitating
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neurodegenerative diseases, and more effort is needed to better understand the fundamental mechanisms of these diseases in order to develop novel therapies to improve or prevent these conditions. Advocates of rejuvenation biotechnologies believe that this may be possible by identifying and accepting biomarkers responsible for cellular and molecular damage and creating targeted treatments to resist and repair the damage in the very early stages, or preferably in the preventing such mutations [24].
25.5.3 Infectious Diseases The emergence of antimicrobial resistant infectious diseases is driving the appearance of host-directed therapies that target the patient’s ability to fight the infection versus traditionally accepted standard of care treatments, such as antibiotics, which target the pathogen itself [42]. Standardization of such therapies will require interdisciplinary research [42] and may offer the potential for codevelopment of appropriate CDx tests to determine suitability of treatments [11].
25.5.4 Psychiatry Regarding CDx tests used in psychiatry, today, they are most frequently used to identify the phenotypic characteristics of patients before administering treatments [43]. These tests are recommended to be performed before prescribing psychotropic drugs metabolized by CYP2D6 and CYP2C19 enzymes in the body [43]. There are multiple methods to test for these enzymes [43]. Nonetheless, it has been proposed that the most accurate diagnostic test would be noninvasive, delivered through a phenotype diagnostic breath test which could measure the target enzymes through exhaled CO2 from patient’s breath [43]. Approval for such a test is still underway, and it is believed that it could help meet a clinical need for individualized psychiatric drug therapy [43].
25.6 SUMMARY CDx tests continue to enable and improve the field of personalized medicine and have the potential to significantly contribute to delivering more effective and efficient treatments to the right patients at the right time. CDx can help determine the best treatment for each patient and help predict treatment effects, allowing better response to treatment. Understanding the fundamental molecular level processes that are involved in disease development, such as mutations, antibodies, and gene expression, has helped create more targeted treatments and therapies. This has impacted clinical care by requiring the use of CDx to test for these molecular level indicators before prescribing treatment. There are several types of biomarkers involved in CDx tests such as pharmacogenetic biomarkers, or microbial genomic biomarkers, but more types of biomarkers are expected to be validated in the future. CDx was initially developed to address the differences in response to treatment between individual patients with the same disease. Diseases that are primarily characterized by
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heterogeneity and variation in response to treatment are currently the only indications that have developed CDx tests or have enough based knowledge of biomarkers to enable the use and development of CDx tests. The first and most prominent disease area that adopted CDx tests was oncology. The HER2neu assay for breast cancer was the first CDx developed for effective delivery of Herceptin and was later included in more CDx assays. Although oncology remains to be the disease area with the highest number of approved CDx tests, most of the available CDx oncology tests are based on therapeutics that target somatic driver mutations and is limited to only certain types of cancer. Other disease areas that have developed or are in the process of developing CDx tests include infectious diseases, CF, asthma, agingrelated neuro-degenerative diseases, and reproductive health. CDx tests will continue to develop, and their adoption is likely to increase in the future. Validation of CDx tests is a key regulatory consideration. Other factors include the current inconsistencies between different countries regarding regulatory guidelines concerning CDx tests. These discrepancies must be addressed to create and ensure universal global standards for the tests. Also, certain limitations exist in the clinical adoption of CDx tests due to differences in the price of the CDx and its corresponding therapeutics, along with complexities in reimbursement of the CDx. Codevelopment is a process recommended for the development of CDx in parallel with their relevant therapeutics. Such development can help improve the therapies developed, reduce the time required for clinical trials, and increase the drug’s efficacy. CDx tests offer significant health care economic benefits by reducing the number of treatments that will have no response, therefore reducing waste of therapeutic products. It can also help decrease the time and number of participants required for clinical trials. However, the current economic evaluations of CDx tests are lacking regarding CDx outcomes included and concerning evaluating CDx as part of the therapeutic product rather than a standalone product. There are incentives for pharmaceutical companies to use CDx since it can reduce the time and costs of clinical trials. There are also benefits for patients because it can help them receive more effective treatments. However, incentives to invest in the development if CDx tests can be low due to their lower costs per test, modest economic returns relative to their corresponding therapeutic products, and price pressure associated with CDx reimbursements. The future direction of CDx will include targeting more diseases and will involve newer technologies and techniques. For instance, immunotherapy is emerging as a cancer treatment, which will target a range of biomarkers in the body. The complexity of immunotherapy will require a CDx that can test for this wide range of biomarkers and identification of more complex pathways and will help create better and more effective treatments. Developments are also expected in AD and potentially other neurodegenerative diseases. New regulations by the FDA are encouraging the incorporation of patients with earlier forms of the AD to be recruited for clinical trials, which will not only help our understanding of the development of the disease but will also help create more targeted treatments that can prevent disease progression. In infectious diseases, CDx may contribute to reducing antimicrobial resistance by helping with host-directed therapies which avoid using antibiotics. In the field of psychiatry, discoveries of biomarkers are helping develop new CDx tests, although regulatory approvals are still underway. These tests will help identify enzymes that can help improve the delivery of psychotropic drugs.
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25 Current Status and Future Direction of Companion Diagnostics Edward Meinert1,2, Abrar Alturkistani2, Dee Luo3, Kimberley Foley2, Ching Lam1, Alison Carter1, Donna Seyfried1, Josip Car2 and David Brindley4,5,6,7 1
Healthcare Translation Research Group, Department of Paediatrics, Level 2, Children’s Hospital, John Radcliffe, University of Oxford, Oxford, United Kingdom 2Global Digital Health Unit, Department of Primary Care and Public Health, Imperial College London, London, United Kingdom 3Department of Biological Basis of Behaviour, University of Pennsylvania, Philadelphia, PA, United States 4Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA, United States 5Harvard Medical School, Division of Engineering in Medicine, Boston, MA, United States 6Brigham and Women’s Hospital, Boston, MA, United States 7Partners Healthcare, Boston, MA, United States O U T L I N E 25.1 Overview of Companion Diagnostics 25.2 Current Status of Companion Diagnostics 25.2.1 Current Status of Companion Diagnostic in Selected Disease Areas 25.2.2 Companion Diagnostic in Oncology 25.2.3 Companion Diagnostic for Infectious Diseases
Companion and Complementary Diagnostics DOI: https://doi.org/10.1016/B978-0-12-813539-6.00025-0
25.2.4 Companion Diagnostic for Cystic Fibrosis 25.2.5 Companion Diagnostic for Asthma 25.2.6 Companion Diagnostic for Aging-Related Diseases 25.2.7 Reproductive Health
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25.3.2 Regulatory Considerations for Companion Diagnostic 25.3.3 Companion Diagnostic Adoption 25.3.4 Codevelopment of Companion Diagnostic 25.4 Companion Diagnostic Economic Value 25.4.1 Economic Evaluations of Companion Diagnostic 25.4.2 Economic Incentives
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25.5 Forward Direction of Application of Companion Diagnostic in Various Disease Areas 25.5.1 Immunotherapy 25.5.2 Future of Alzheimer’s Disease 25.5.3 Infectious Diseases 25.5.4 Psychiatry
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25.1 OVERVIEW OF COMPANION DIAGNOSTICS A companion diagnostic (CDx) is a test that helps determine the suitability of a therapeutic drug for an individual patient. It is identified as a tool in the field of precision medicine, a growing approach to medical treatment that uses specific patient characteristics such as genes, proteins, metabolites to customize treatment and care [1,2]. The US Food and Drug Administration (FDA) has defined CDx as a medical device, often an in vitro device, which provides information that is essential for the safe and effective use of a corresponding drug or biological product [3]. CDx enables personalization of treatment by ensuring that a patient only receives a therapeutic product if he or she is likely to respond positively to the therapy, and the benefits from the therapy have the potential to outweigh risks. CDx does this by classifying patients into subpopulations based on specific characteristics that can influence the effects of the drug [4]. CDx differentiates through the following four ways [5]: 1. Determining which patients will benefit from the therapeutic drug. 2. Determining which patients will be harmed by the therapeutic drug through adverse side effects or increased risk. 3. Identifying patients’ response to treatment. 4. Identifying the subpopulation of patients who can safely use the therapeutic drug. In general, CDx can classify patients into those who can benefit from therapy, those who will have no response to therapy, and those who might be harmed by therapy (Fig. 25.1). Development of CDxes requires that the corresponding therapeutics’ mechanism of processing in the body is understood. When a therapeutic enters the body, it targets specific molecular agents that use specific enzymes, mutations, or antibodies known as biomarkers to help facilitate therapeutic action. The presence of certain biomarkers can indicate increased or decreased the efficacy of a therapeutic regimen, so determining the presence of these molecules is important in determining the best course of medication. CDx works by looking for the targets that affect the efficacy of the therapeutic drug, with a focus on
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25.1 CDxes can help classify patients; patients who can benefit, patients who will have no response, and patients who might be harmed by a particular therapy. CDxes, Companion diagnostics.
FIGURE 25.2 Pharmacogenetic biomarker types listed in approved FDA therapeutic products in the years 1945 2005 [7]. FDA, Food and Drug Administration.
gene expressions, mutations, and antibodies that are found to enhance or block drug effects. Development of a CDx, therefore, helps create more targeted treatments with greater benefit to risk prior to administration of any therapeutic. The categorization of patients based on their response to treatment relies heavily on biomarkers that indicate changes in biological measurements, such as mutations or amplifications in the gene [6]. A 2012 review of the pharmacogenetic biomarkers listed in approved FDA therapeutic drugs found that most biomarkers listed were human genomic biomarkers (69/121) while 52 of 121 listed were microbial genomic biomarkers [7] (Fig. 25.2). Biomarkers give rise to genomic CDx assays that look for pharmacogenetic biomarkers or biomarkers that indicate genetic variation. Besides pharmacogenomic biomarkers, there are also nongenomic assays, which are predicted to be utilized more widely in the future [8]. The presence of both human genomic and microbial genomic biomarkers not only indicates a change in the response to therapy but also acts to either enhance or block the effect of a drug. This relationship means that CDx becomes a necessary tool to predict the success of a given drug treatment, especially for highly heterogeneous, complex diseases, such as cancer.
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Biomarker discovery remains the most critical step in enabling improvements in clinical outcomes for patients. Both the FDA and the Institute of Medicine recommend that the development of a CDx be completed as soon as biomarker discovery of a disease occurs while accounting for its applicability in clinical practice [9]. To emphasize the importance of this recommendation, FDA Type C meetings are being permitted for early engagement with biomarkers. The push for increased knowledge of biomarkers and disease mechanisms as well as the policy-level emphasis on CDx codevelopment is aimed at encouraging discoveries in diagnostics tests. However, looking at the current status of CDx, research shows that there remain many considerations that need to be considered before CDx tests can reach their full potential. There are positive signs of increasing developments in oncology and other disease areas, including aging-related diseases, but questions remain regarding CDx validity, regulation, and adoption. Codevelopment of CDx with their corresponding therapeutic product and their economic value is also a significant consideration in the current status of CDxes. The future direction of CDx is moving toward including more disease types and adopting new technology and methods for the development of improved CDx tests.
25.2 CURRENT STATUS OF COMPANION DIAGNOSTICS The greatest development and utilization of CDx have been for highly complex, typically chronic, diseases. The advantages of using CDx for diseases, such as cancer, cystic fibrosis (CF), asthma, and human immunodeficiency virus (HIV), are especially clear. Complex chronic diseases typically have diverse pathophysiological pathways, meaning that within patients diagnosed with the same condition, the mechanisms that lead to therapeutic effects could differ in each patient subgroup. This makes CDx beneficial in determining these subgroups and tailoring treatments based on the genetic and immunologic pathways [10]. Identification of the right pathways and biomarkers involved in the mechanism of action for a therapeutic drug is of chief importance for the safe delivery of the drug. Significant progress is being made in unraveling the different mechanisms involved in disease progression and treatment, especially in the field of oncology, and in other disease areas characterized by complex underlying mechanisms, such as aging-related diseases, infectious diseases, CF, and asthma.
25.2.1 Current Status of Companion Diagnostic in Selected Disease Areas Development of CDx has been constrained to disease indications because of our limited knowledge of certain disease pathways. Understanding of pathophysiological pathways and biomarkers is necessary to elucidate the differences that may exist between subpopulations of patient. With these discoveries in disease progression pathways, CDx can then create efficacious clinical trials in earlier stages of disease and test for improvements in disease progression. It is suggested that improved knowledge of genetics, pathophysiological pathways of disease, and a better understanding of key players of disease progression will help improve CDx tests and consequently will contribute to the development of more targeted
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and tailored treatments [11]. Therefore most progress in CDx development has been made in disease areas where there is some knowledge about the pathophysiological pathways of disease progression, specifically about the therapeutic product’s targets in the body. Such knowledge has mostly been discovered in oncology through the identification of somatic driver mutations. In other disease areas, some CDx tests are emerging due to the discovery of disease-specific biomarkers or assays that can be used in CDx.
25.2.2 Companion Diagnostic in Oncology CDx was first adopted in the field of oncology. As of 2015, oncology drug-related tests made up 40% of all marketed products [12]. CDx was specially designed to address the heterogeneity of complex diseases, such as cancer, which can differ in their causes, rates of progression, and their response to drugs. Such factors are highly diverse in different cancers, but more importantly, in individual cancer patients with the same type of cancer [13]. For many cancer patients, it is possible to obtain a biopsy sample of a tumor, which allows identification of the expression of the therapeutic target in the tumor tissue or mutations in the gene more efficiently than other diseases where biopsy samples are not practical [10]. This helps provide a precise identification of the biomarkers involved, enabling easier target identification for the CDx test [10]. CDx will remain a significant tool in delivering therapeutics in oncology because drugs developed for treating cancer are often highly individualized therapies designed to interact with specific markers in the body, making CDx commonly used for this purpose [14]. The first therapeutic drug used in oncology that was accompanied by a CDx was Trastuzumab, also known as Herceptin, and it revolutionized the treatment of breast cancer. Breast cancer is caused by unregulated proliferation of breast tissue cells due to specific mutations. One such mutation that causes unregulated cell proliferation is the overexpression of estrogen receptors (ER). Tumors that have ER 1 overexpression can be treated with tamoxifen, an established estrogen receptor inhibitor. However, tumors that do not have ER 1 overexpression (ER- tumors) have poor prognosis and are treated with a cocktail of radiation, surgery, and general chemotherapy. The discovery of Herceptin was preceded and made possible by the discovery of a biomarker, HER2/neu. It was discovered that, like ER 1 tumors, some ER 2 tumors overexpressed human epidermal growth factor receptor 2 (HER2/neu) [7]. HER2 is a receptor in the receptor tyrosine kinase family (RTK) that activates cell growth pathways. Therefore, over activation or overexpression of HER2 receptors cause continual activation of cell growth pathways leading to cancer. Suddenly, ER 2 tumors could be further stratified into HER2 1 tumors, creating three main categories of breast tumors: 1. ER 1 , HER2 2 (tumors that overexpress estrogen receptors and do not overexpress HER2 receptors) 2. ER 2 , HER2 2 / 1 (tumors that do not overexpress estrogen receptors and may or may not overexpress HER2 receptors) 3. ER 2 , HER2 2 (tumors that do not show overexpression of either estrogen receptors or HER2 receptors).
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Tumors in the first category had the best prognosis because they could be treated with estrogen receptor inhibitors. Now researchers had a target, HER2, in which to test interventions for the second category. Herceptin became the first drug that specifically inhibited the HER2 receptor, and in patients with HER2/neu overexpression, treatment with Herceptin has significantly improved prognosis with decreased risk for cancer recurrence and death [15]. Not all patients benefit from Herceptin: patients with tumors in the first and third category receive little therapeutic benefit. The CDx is necessary to test for HER2/neu overexpression and identifies patients who would benefit more from Herceptin therapy. Clinically, Herceptin cannot be administered without a positive CDx test showing HER2/neu overexpression. HER2/neu as a biomarker has become one of the most used CDx assays in the US [8]: a 2013 review found that HER2/neu was used in 10 out of 15 FDA-approved CDx assays which test for protein overexpression or as gene amplification [8]. The CDx for Herceptin is inextricably linked to development and efficacy of Herceptin, and current drug development in oncology is focused on biomarker discovery and further stratification of tumor subtypes. Within the field of oncology, most of the approved CDx tests are designed for therapeutic drugs that inhibit the signal transduction pathways where the CDx detects the presence or absence of somatic driver mutations in the therapeutic drug target [16]. This limits the number of CDx tests that can be used to determine the suitability of the therapeutics used in oncology, since many other therapeutic drugs that use different mechanisms exist. However, the challenge lies in the difference in complexity between tumors that proliferate due to targeting somatic driver mutations. In tumors with a driver mutation, a therapeutic drug inhibits the signaling pathway that occurs as a result of the driver mutation, therefore inhibiting proliferation of a tumor [16]. CDx tests for such a mutation use a singleanalyte assay and are relatively simple because they look for a single mutation [16]. However, tumors that involve more complicated pathways, such as single nucleotide polymorphisms, somatic mutations, gene, or protein expression, are not yet considered in CDx tests since they require multiple assays [16].
25.2.3 Companion Diagnostic for Infectious Diseases Not all treatments work the same way in different patients, and this underlying idea has been especially important in the development of CDx for infectious diseases [11]. CDx for infectious disease treatments has been shown to help determine the most beneficial, most effective treatments, as well as the optimum suitable dose of each treatment for patients [11]. However, few infectious diseases have received attention in CDx development. HIV disease and hepatitis B were two of the first infectious diseases with improved knowledge about the underlying biomarkers of disease. The earliest example of CDx developed in infectious diseases is the coreceptor tropism testing which tests for the presence of R5 virus in HIV-1 patients [17]. If the R5 virus is present, then the patient can receive an antiretroviral treatment regimen that includes CCR5 antagonist [17]. For hepatitis B, the immune-based therapies of the disease require identification of patient groups based on their response to treatment. Biomarkers were identified for this disease which include serum hepatitis B surface antigen and hepatitis B virus DNA, the presence of these two biomarkers can interchangeably be used to predict response to therapy [18]. COMPANION AND COMPLEMENTARY DIAGNOSTICS
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25.2.4 Companion Diagnostic for Cystic Fibrosis CF is an irreversible, genetic disorder, which previously has only been treated by managing patients’ symptoms due to lack of knowledge of underlying genetic mechanisms [19]. Cystic fibrosis causes a pathological thickening of mucus due to impaired transport of chloride ions out of cells. Thickened mucus means the lungs have impaired ability to clear out infections and the pancreas cannot secrete digestive enzymes that need mucus to travel into the small bowel. Patients experience failure to thrive and are at high risk of pneumonia that can prove fatal. Treatment typically involved antibiotics, bronchodilators, and other medications to resolve immediate symptoms. Later, it was found that CF is characterized by five to six classes of mutations resulting in a dysfunctional CFTR channel protein [19]. Mutations range from defective folding of the CFTR protein to defective transportation of the CFTR protein to the surface of the cell where it can exert its physiological function. More importantly, each mutation class is characterized by single, unique mutations in the CF gene. Therefore, it was possible to create mutation targeted therapy in which therapies directly counteract the specific mutation [19]. The improved understanding of the CF mutations along with the development of mutation-targeted therapies assisted in the development of therapies and corresponding CDx that directly targeted the underlying disease. For example, in patients with a deletion of the amino acid phenylalanine at the 508th position of the CFTR gene (deltaF508 mutation), the personalized therapeutic Orkambi (lumacaftor/ivacaftor) can greatly improve CFTR function. Orkambi is most effective in patients with the deltaF508 mutation and this specificity led to development of two CDx assays, which were approved by the FDA in 2013 as an in vitro diagnostic device [18,20]. The developed assay improved diagnosis of patients with CF as well as categorized patients for different CFTR-targeted therapies [18].
25.2.5 Companion Diagnostic for Asthma Asthma is also characterized by heterogeneity between patients and diversity in patient’s phenotypic characteristics [18]. These complexities of asthma require personalized treatment, and a variety of disease phenotypes can be used for decision-making concerning therapies [18]. The earliest biomarker discovery in asthma came from understanding that the periostin gene, along with the CLCA1 and serpinB2 genes, is associated with IL-13 in the epithelial cells of asthma patients [21].
25.2.6 Companion Diagnostic for Aging-Related Diseases Adults aged 60 years or older are the fastest growing age group, with predictions that this population will more than double by 2050 and more than triple by 2100 [22]. Dementia is a major cause of disability in this age group, and Alzheimer’s disease (AD) accounts for 60% 70% of dementia cases [23]. The discovery of aging-related biomarkers can help prevent and treat aging-related diseases, such as AD. Some knowledge about biomarkers linked to the early onset of the disease have been identified [24,25], but there is a need to identify patient subgroups for treatment and a need to increase the use of these biomarkers in clinical practice [18]. The need for early-on inclusion of healthy,
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predementia individuals in trial design and end-point selection for the development of better targeted therapies [25] is reflected in the FDA’s guidelines to regulate development of therapeutics in the early onset of Alzheimer’s (before the occurrence of dementia). The FDA’s regulation of early AD prognosis and therapeutic drug treatment is titled “Early Alzheimer’s Disease: Developing Drugs for Treatment Guidance for Industry” [26]. The goal of this document was to guide drug developers in creating treatments targeted of the stages of sporadic AD that occur before the onset of overt dementia. Prior to these guidelines, the FDA had been focused on recruitment of AD patients into clinical trials only after the disease has progressed, which leaves little to chance for improvement for patient outcomes [26]. In this respect, the FDA is now encouraging guidelines for patient recruitment for efficacy trials for Alzheimer’s patients for each of the stage of the disease.
25.2.7 Reproductive Health In reproductive medicine, CDx is used as an anti-Mu¨llerian hormone (AMH) assay for determining the optimal gonadotropin dosing for controlled ovarian hyperstimulation. This works by categorizing patients by very narrow categories of AMH [27]. However, the availability of two different commercial AMH assays has led to comparisons indicating a superiority of one assay over the other in clinical laboratories and has highlighted the need for standardization [27].
25.3 CONSIDERATIONS ABOUT CURRENT COMPANION DIAGNOSTIC TESTS The increased prevalence of complex diseases, such as cancer and other chronic diseases, is motivating the advancement of CDx. However, questions remain regarding the reliability of CDx tests and their regulatory aspects on an international level. There is also an increased emphasis on codevelopment of CDx with their corresponding therapeutics, which will need to be considered in the development of new CDx tests.
25.3.1 Reliability and Validity of Companion Diagnostic Identification of the right pathways and biomarkers involved in the therapeutic drug is critically important for the safe delivery of the drug. Since the success of the therapeutic product depends on the success of the CDx assay, any errors in determining the right biomarkers can put the patient receiving the therapy at risk of no response from treatment or even at an increased risk of harm from treatment [28]. As with any medical test, a CDx test is also subject to measurement error possibly resulting in misclassification of patients which might lead to deliver the suboptimal treatment to patients [14]. Misclassification occurs due to the presence of false marker negatives or false marker positives which can significantly affect the variance and statistical power of the CDx. This, in turn, may attenuate the true treatment effect of a drug in clinical trials and lead to misclassification of patients [14]. To create a reliable CDx, there is a need to validate the test before it is used
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in clinical trials or in clinical practice. This is to avoid misclassifying patients into the inappropriate treatment group and to prevent patients from receiving a treatment that has no effect or worse, might have adverse effects on the patient [14].
25.3.2 Regulatory Considerations for Companion Diagnostic CDx regulation by FDA in the United States [29] and European Medicines Agency (EMA) in the European Union (EU) countries has seen both agencies imposing similar regulatory instructions with slight differences in testing and labeling requirements [12]. For instance, 78% of the drugs in 2015 that came with a CDx stated similar requirements in the label of the therapeutic drug by both the FDA and EMA, except for few CDxes that were required by the EMA but only recommended by the FDA [12]. Other countries including Japan, Canada, and Australia have also initiated regulatory guidelines for CDx [30]. However, guidelines in each of these countries differ in certain regulatory aspects. A 2014 review of approved CDx and their corresponding therapeutics found that for the same therapeutics, only 52% in the United States, 63% in the EU, and 38% in Japan required biomarker measurement in the label of the product [31]. Also, while both the United States and Japan require the codevelopment of a CDx with its corresponding therapeutic if a CDx is required for a certain therapy, the EU recommends codevelopment but does not have any mandatory requirements [31]. While regulation of CDx is of high importance to ensure validity and safety, there are still areas to be further refined in patient safety. There is high heterogeneity between regulatory frameworks used in different countries especially regarding risk classification and approval of CDx test [30,32]. It is recommended for all regulatory organizations to commence a harmonization process through the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use.
25.3.3 Companion Diagnostic Adoption There are currently few approved CDx tests available in the market. Adoption rates are low due to several challenges [33]. First, developing a CDx test is costly. While it can reduce health-care costs for long term, there are up-front costs associated with training health staff to use the tests and implementing tests into integrated care pathways [12]. Along with costs, CDx manufacturers also face a lack of adequate return on investment due to the relative unsustainability of the commercial CDx market. It was found that there is a significant disparity between the cost of a CDx test and the cost of the corresponding therapeutic, meaning that CDx as products were affected by different economic factors than those that influence traditional pharmaceuticals. CDx assays in general cost substantially less than their corresponding therapeutics, suggesting that the incentive to invest upfront in CDx development is often not sufficiently compelling [33]. In addition, diagnostic tests are typically administered once to each patient, and this inherent characteristic creates a low incentive for diagnostic developers [33], especially for rare diseases with small patient populations [12]. Since CDx tests are viewed as a separate product to the therapeutic drug, payment and reimbursement methods are complicated, requiring
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FIGURE 25.3 Codevelopment of CDx with the therapeutic drug during clinical trial stages. CDx, Companion diagnostic. Source: Adapted from Figure 3 in Cheng S, Koch WH, Wu L. Co-development of a companion diagnostic for targeted cancer therapy. N Biotechnol 2012;29(6):682 88 [34].
separate payments; one for the CDx and one for the drug, further complicating the acceptance of CDx in routine clinical practice [33]. All these factors contribute to the low number of CDx tests developed and available in the market today.
25.3.4 Codevelopment of Companion Diagnostic Codevelopment impacts CDx by allowing the diagnostic test to be developed in parallel with its corresponding therapeutic product. This is done by incorporating the CDx from the early clinical trial stages of the drug development [12] as illustrated in (Fig. 25.3). The FDA recommends that drug companies include CDx development in the early stages of the therapeutic product development (during the clinical trial stage) to help determine and validate the biomarkers that can indicate optimal response to certain treatments and determine the patient subpopulation most likely to respond best to a therapeutic medicine [12]. The CDx codevelopment occurs in parallel to the drug development and starts as early as phase I and phase II of the clinical trial. Before that, a hypothesis about biomarkers involved in the pharmaceutical product’s targeted therapeutic pathway is identified in the preclinical phase [35] (Fig. 25.3). Validation of CDx occurs in phase III in which diagnostics metrics such as sensitivity and specificity are calculated [35]. This method helps increase the efficacy of the drug and helps identify patients with increased likelihood of response to a certain drug from the early stages [15]. Codevelopment can also improve regulatory processes. Approval of pharmaceutical products is made more accessible if a CDx is included in the developmental phases. This is especially true for cancer drugs [16]. In addition, codevelopment can help regulate the labeling of CDx assay on its corresponding therapeutic drug label (Fig. 25.3). As such, if a particular therapeutic drug requires a CDx test before administration, the FDA requires the drug labels to explicitly stat such information in the instructions to ensure patients
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receive the correct treatment [36,37]. Other regulatory requirements associated with codevelopment include prescribing a medication with an assigned CDx only after the patient was found positive in the CDx test. This is true for many cancer drugs which are only delivered after a CDx test is performed [30]. Developing a CDx test after the drug is produced can cause inconsistencies in the validity and effectiveness of the test [38]. The challenge with codevelopment lies with the requirement of identifying the subpopulation of patients that will benefit from the therapeutic drug in the very early stages of the clinical trial (by phase II). This is only possible if the researchers have a strong hypothesis about the pathways or biomarkers involved in the processing of the drug early on [12]. Thus the more that is known about the fundamental mechanisms of the disease and its therapeutic pathways, the greater the chance of successfully developing an optimal CDx assay. Although incorporating CDx in the early stages of the drug development is recommended and beneficial, it may face resistance from therapeutic drug developers due to the intellectual property protection regulation differences between CDx and other pharmaceuticals [12]. For instance a single therapeutic drug can have more than one diagnostic test developed by different CDx developers, disincentivizing pharmaceutical companies from making significant investments in a CDx development commitment when there is a risk that new and better tests and/or suppliers may present and obsolete the CDx test in the future [12].
25.4 COMPANION DIAGNOSTIC ECONOMIC VALUE In addition to increasing the chance of the drug’s efficacy, CDx tests can have significant economic benefits. Economic benefits from CDx tests come from the ability to reduce wastage of health resources by identifying those not likely to respond to treatment beforehand [39]. Although CDx may decrease the number of patients who can receive a specific treatment, it does not necessarily diminish the amount of drug sales [12], though systemwide cost savings may come from reduced long-term side effects in a population that do not require treatment. Also, the diagnostic tests also help shorten time and complexity involved in clinical trials. Since CDx can allow better prediction of patients who will respond to the treatment, it may require the recruitment of fewer subjects to the trials (Fig. 25.4), although different clinical trial study designs do exist where even participants who are not likely to respond to treatment are recruited for the study [35].
25.4.1 Economic Evaluations of Companion Diagnostic Current economic evaluations of CDx may be limited in their representation of all economic outcomes associated with a CDx. The reason for their limitation is due to the high heterogeneity between studies especially in terms of diagnostic test characteristics used in economic models [40]. In addition, current evaluations may only report the added value of the CDx to the therapeutic intervention rather than evaluating CDx as a stand-alone intervention [41]. However, the effectiveness of CDx is highly correlated with a therapeutic
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FIGURE 25.4 One-way CDxes can help optimize participant recruitment to clinical trials by lowering the number of participants required since CDx can help predict which participants are more likely to respond to treatment early on. CDX, Companion diagnostic.
drug’s effectiveness. CDx increases the value of drugs delivered by increasing the likelihood of effectiveness and by creating more efficient clinical trials if codeveloped with the therapeutic product [14]. In contrast, CDx may also hinder clinical trials concerning sample size. This is true if the CDx used is subject to high measurement error, necessitating a larger sample size to avoid dilution of the treatment effect or impacting the variance of the outcome [14].
25.4.2 Economic Incentives Economic factors will play a major role in determining the future of CDx. There is a need for higher incentives and risk sharing in order for pharmaceutical companies to be open to codevelopment of CDx with diagnostic manufacturers, and there is a need for uncomplicated and encouraging reimbursement models for consumers [12]. CDx has many economic benefits that can benefit most of the key players involved in the codevelopment, use, or reimbursement of CDx. For therapeutic drug developers, CDx can help reduce overall development time and costs associated with clinical trials and increase likelihood of successful outcomes. In addition, CDx can help ensure better patient results from therapy by increasing the chances of the drug’s effectiveness [12]. For CDx patients, it can simply help them get the most benefit from the treatment and can save them from unintended, adverse events that would not be known in the absence of a CDx test. For CDx payers, it can help them get better value for what they pay by reducing unnecessary, costly, or ineffective treatments [12]. From the perspective of CDx developers, it is believed that a more sustainable business model and return on investment (ROI) are needed. The potential may be achieved if they diversify a wider menu of diagnostic tests they offer. For example, by including different CDx tests specializing in each of the CDx tests types; screening and detection, prognosis, recurrence, as well as theranostics and monitoring [12].
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25.5 FORWARD DIRECTION OF APPLICATION OF COMPANION DIAGNOSTIC IN VARIOUS DISEASE AREAS The future direction of CDx is in increasing adoption beyond medical fields to assist in the delivery in more disease types in therapies. Also, CDx will help not only in identifying treatment suitability but may also help with disease prevention and wellness.
25.5.1 Immunotherapy Immunotherapy is one of the therapies currently used in oncology, and research on biomarkers for immunotherapy is rapidly advancing. However, creating CDx that can predict patients’ response to immunotherapy will not be as simple as creating CDx for other oncology therapies, such as the CDx created to detect driver mutations in some cancers. This is because treatment by immunotherapy is not affected by driver mutations but by complex interactions of tumor cells with the immune system, and the biomarkers for these interactions have not yet been identified [16]. CDx for immunotherapy will require the use of many diverse assays including cellular, protein, and molecular assays [16]. In immunotherapy the presence or absence of an immune response to tumor cells determines the type of treatment [16]. New immunotherapies being developed will use certain techniques such as novel checkpoint inhibitors, cancer vaccines, or T cell redirection and will require more complicated methods for the developments of CDx tests [16]. Nevertheless, developing these therapies with CDx tests will help increase the therapeutic’ efficacy and clinical approvals as well as help deliver more personalized cancer treatments.
25.5.2 Future of Alzheimer’s Disease Similar to cancer, AD has shown that patients can be significantly different from each other, especially in their response to treatment. Consideration of this diversity will increase with new clinical trial designs which will help create more targeted therapies addressing the needs of different subpopulations with AD. The FDA’s regulation of early AD prognosis and therapeutic drug treatment was published in their document titled “Early Alzheimer’s Disease: Developing Drugs for Treatment Guidance for Industry” [26]. The goal of the document was to guide drug developers in creating treatments targeted at the stages of sporadic AD that occur before the onset of overt dementia. The FDA is looking to change from the prior directive in recruiting Alzheimer’s patients into clinical trials only after the disease has progressed, which has been unsuccessful in improving to patient outcomes [26]. In this respect the FDA has provided updated guidelines for patient recruitment for efficacy trials for Alzheimer’s patients in each stage of the disease [26]. FDA’s efforts to regulate inclusion of earlier stages of Alzheimer’s patients into clinical trials are seen as a significant step toward the improvement in treatments for agingrelated diseases [24]. Such developments in research can offer promise in bringing transformational therapeutics which may ultimately prevent healthy individuals who may be at future risk of AD from the devastating disease progression to advanced cognitive impairment [24]. However, there are many other aging-related, debilitating
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neurodegenerative diseases, and more effort is needed to better understand the fundamental mechanisms of these diseases in order to develop novel therapies to improve or prevent these conditions. Advocates of rejuvenation biotechnologies believe that this may be possible by identifying and accepting biomarkers responsible for cellular and molecular damage and creating targeted treatments to resist and repair the damage in the very early stages, or preferably in the preventing such mutations [24].
25.5.3 Infectious Diseases The emergence of antimicrobial resistant infectious diseases is driving the appearance of host-directed therapies that target the patient’s ability to fight the infection versus traditionally accepted standard of care treatments, such as antibiotics, which target the pathogen itself [42]. Standardization of such therapies will require interdisciplinary research [42] and may offer the potential for codevelopment of appropriate CDx tests to determine suitability of treatments [11].
25.5.4 Psychiatry Regarding CDx tests used in psychiatry, today, they are most frequently used to identify the phenotypic characteristics of patients before administering treatments [43]. These tests are recommended to be performed before prescribing psychotropic drugs metabolized by CYP2D6 and CYP2C19 enzymes in the body [43]. There are multiple methods to test for these enzymes [43]. Nonetheless, it has been proposed that the most accurate diagnostic test would be noninvasive, delivered through a phenotype diagnostic breath test which could measure the target enzymes through exhaled CO2 from patient’s breath [43]. Approval for such a test is still underway, and it is believed that it could help meet a clinical need for individualized psychiatric drug therapy [43].
25.6 SUMMARY CDx tests continue to enable and improve the field of personalized medicine and have the potential to significantly contribute to delivering more effective and efficient treatments to the right patients at the right time. CDx can help determine the best treatment for each patient and help predict treatment effects, allowing better response to treatment. Understanding the fundamental molecular level processes that are involved in disease development, such as mutations, antibodies, and gene expression, has helped create more targeted treatments and therapies. This has impacted clinical care by requiring the use of CDx to test for these molecular level indicators before prescribing treatment. There are several types of biomarkers involved in CDx tests such as pharmacogenetic biomarkers, or microbial genomic biomarkers, but more types of biomarkers are expected to be validated in the future. CDx was initially developed to address the differences in response to treatment between individual patients with the same disease. Diseases that are primarily characterized by
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heterogeneity and variation in response to treatment are currently the only indications that have developed CDx tests or have enough based knowledge of biomarkers to enable the use and development of CDx tests. The first and most prominent disease area that adopted CDx tests was oncology. The HER2neu assay for breast cancer was the first CDx developed for effective delivery of Herceptin and was later included in more CDx assays. Although oncology remains to be the disease area with the highest number of approved CDx tests, most of the available CDx oncology tests are based on therapeutics that target somatic driver mutations and is limited to only certain types of cancer. Other disease areas that have developed or are in the process of developing CDx tests include infectious diseases, CF, asthma, agingrelated neuro-degenerative diseases, and reproductive health. CDx tests will continue to develop, and their adoption is likely to increase in the future. Validation of CDx tests is a key regulatory consideration. Other factors include the current inconsistencies between different countries regarding regulatory guidelines concerning CDx tests. These discrepancies must be addressed to create and ensure universal global standards for the tests. Also, certain limitations exist in the clinical adoption of CDx tests due to differences in the price of the CDx and its corresponding therapeutics, along with complexities in reimbursement of the CDx. Codevelopment is a process recommended for the development of CDx in parallel with their relevant therapeutics. Such development can help improve the therapies developed, reduce the time required for clinical trials, and increase the drug’s efficacy. CDx tests offer significant health care economic benefits by reducing the number of treatments that will have no response, therefore reducing waste of therapeutic products. It can also help decrease the time and number of participants required for clinical trials. However, the current economic evaluations of CDx tests are lacking regarding CDx outcomes included and concerning evaluating CDx as part of the therapeutic product rather than a standalone product. There are incentives for pharmaceutical companies to use CDx since it can reduce the time and costs of clinical trials. There are also benefits for patients because it can help them receive more effective treatments. However, incentives to invest in the development if CDx tests can be low due to their lower costs per test, modest economic returns relative to their corresponding therapeutic products, and price pressure associated with CDx reimbursements. The future direction of CDx will include targeting more diseases and will involve newer technologies and techniques. For instance, immunotherapy is emerging as a cancer treatment, which will target a range of biomarkers in the body. The complexity of immunotherapy will require a CDx that can test for this wide range of biomarkers and identification of more complex pathways and will help create better and more effective treatments. Developments are also expected in AD and potentially other neurodegenerative diseases. New regulations by the FDA are encouraging the incorporation of patients with earlier forms of the AD to be recruited for clinical trials, which will not only help our understanding of the development of the disease but will also help create more targeted treatments that can prevent disease progression. In infectious diseases, CDx may contribute to reducing antimicrobial resistance by helping with host-directed therapies which avoid using antibiotics. In the field of psychiatry, discoveries of biomarkers are helping develop new CDx tests, although regulatory approvals are still underway. These tests will help identify enzymes that can help improve the delivery of psychotropic drugs.
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