Clinical Trial Methodology He Personalized medicine: challenges in bio- marker-related clinical trial design 5 Clinical Trial Methodology Personalized medicine: challenges in biomarker-related clinical trial design Clin. Invest. (Lond.) Personalized medicine becomes an area of great interest following the recent Pei He development in human genetics, proteomics and metabolomics. There is an increasing Amgen, Inc. 1120 Veterans Boulevard, need to embed the scientific discoveries from basic medical research into real life clinical South San Francisco, CA 94080, USA [email protected] practices, such that a patient’s biological traits can be used to facilitate treatment. Those individualized biological traits, termed as biomarkers, are actively involved in developing personalized medicine and therefore bring out challenges to clinical trial designs. The necessity of biomarker validation and patient subgroup selection make the trial design more complex. This paper will first introduce different types of biomarkers and then review the challenges of clinical trial design with biomarkers from the clinical, statistical and regulatory perspectives. Keywords: biomarkers • clinical trial design • personalized medicine • predictive • prognostic • targeted cancer therapy Personalized medicine is an increasingly recently added more complexity to clinical promising field of interest that connects trial design and data analysis. biological research with clinical practices. All biomarkers of different types require Recent developments in human genetics and clinical trials to confirm their properties and 10.4155/CLI.14.123 sequencing techniques make it possible to to inform and influence daily clinical prac- identify disease-related genes that affect the tices. Regulatory agencies, such as FDA in onset risk of a certain disease and influence the U.S. and the EMA in Europe, have set the type and course of treatment. Informa- requirements for approving the use of bio- tion about each individual’s unique genetic markers in medicine [1,2]. Statistical analy- or biological traits can therefore be utilized ses are used to confirm the exact function of 2 for personalized disease prevention, diagno- biomarkers and their interactions with newly sis, monitoring and treatment. The ultimate developed treatments. In some cases, retro- goal in personalized medicine is to develop spective analyses using previously conducted patient-specific medical procedures based on clinical trials are sufficient to verify the bio- 2015 ‘biomarkers’ (clinically meaningful biological marker function. In other cases, prospective traits) and optimize medical efficiency for all. studies are needed in order to scrutinize the Clinical trials are used as essential tools clinical effectiveness, safety and benefit/risk in medical research to validate new medical of the biomarkers. All emerging treatments practices, and they therefore play an impor- and associated biomarkers require clinical tri- tant role in the advancement of personalized als and regulatory reporting before achieving medicine. Clinical trials must be conducted approval for professional and/or commercial on newly developed preventative procedures, release. diagnostic tools, treatments and monitoring We will begin this review with an overview processes before such as these can be adapted of definitions, classifications, and functions into standard clinical practice. The emphasis of biomarkers and their roles in clinical appli- on biomarkers in personalized medicine has cations. We will then review the issues and part of 10.4155/CLI.14.123 © 2015 Future Science Ltd Clin. Invest. (Lond.) (2015) 5(2), 175–188 ISSN 2041-6792 175 Clinical Trial Methodology He challenges of biomarker-related clinical trial design. are only found in cancer cells. The third type, the ‘gen- Later sections of this review are structured as follows: eral’ biomarkers, comprises ‘all other forms of biomark- the first section primarily describes the different clas- ers, such as RNA, protein, or metabolite measurements sifications of biomarkers in the existing literature and which can be measured in biofluid, tissue, or even cell proposes a function-based classification for further lines’ [5]. The major difference among DNA biomark- discussion; the following section discusses the chal- ers, DNA tumor biomarkers and general biomarkers is lenges of biomarker-related clinical trial design when it that the former are stable over time and location while comes to clinical concerns, statistical issues and regula- the latter two are often only observed after specific tory difficulties. We then present an elaborate review mutations and in certain types of cells. of complications, when designing biomarker-related clinical trials, for each type of biomarker based on the The preventative, diagnostic, prognostic, proposed classification. The last section of this review predictive biomarkers: definition & examples presents concluding remarks. Although Ziegler et al. provided a clear and intrinsic clas- sification of the current biomarkers based on their vari- Existing definitions & categories of ous characteristics [5], we prefer to use a function-based biomarkers in literature categorization of biomarkers to identify their various Although recent developments in genetics and molecu- roles in personalized medicine. We classify biomarkers lar biology have highlighted the concept of ‘biomarker’, into four categories: preventative, diagnostic, prognostic there have been various definitions of ‘biomarker’ in and predictive. Table 1 lists the general definition and the research literature serving multiple purposes. For related properties of each type of biomarkers. example, Gallo et al. have noted the most commonly adopted definition: ‘any substance or biological struc- Preventative ture that can be measured in the human body and may The definition of preventative biomarker is easily influence, explain or predict the incidence or outcome revealed by its name: a biological trait that can help of disease’ [3]. Some scholars argued that being ‘mea- in patient-specific disease prevention. This type of sured in the human body’ has been too limited that marker is most prevalent in cancer researches. For the more general alternative is preferred, which is also example, patients with BRCA1 or BRCA2 mutations noted by Gallo et al.: ‘any substance, structure or pro- have the lifetime risk of 56 and 87% to develop breast cess that can be measured in bio-specimen and which cancer [6]. As a general preventative practice, NIH rec- may be associated with health-related outcomes’ [3]. ommends women carrying these biomarkers to con- However, we found this definition too broad for our sider a bilateral prophylactic mastectomy to reduce purpose. We prefer the NIH version, which defines their risk of breast cancer [7], because studies show that the biomarker as ‘a characteristic that is objectively mastectomy reduces the risk by at least 95% among the measured and evaluated as an indicator of normal biomarker carriers [8–10]. Another example of preventa- biologic processes, pathogenic processes, or pharmaco- tive biomarker is the mutation in the tumor suppressor logic responses to a therapeutic intervention’ [4]. This adenomatous polyposis coli gene, which poses a high definition provides a foundation that accommodates a risk for developing colorectal cancer [11] . For such bio- broad range of current biomarker applications while marker carriers, one preventative recommendation is to also maintaining specificity by limiting the focus on have a prophylactic colectomy [12] . biologic, pathogenic and pharmacologic processes. Both preventative biomarkers noted above have Ziegler et al. have defined various biomarkers based either a somatic mutation or germline mutation form. on their roles, such as cancer biomarker, copy number The somatic mutations are often acquired but not variant biomarker, DNA biomarker, epigenetic bio- hereditary, and they only present in certain cells. The marker, safety biomarker, etc [5]. They also divide the germline mutations, however, are often hereditary biomarkers into three intrinsically different types: the and can be passed on to the next generation. Accord- DNA biomarker, the DNA tumor biomarker and the ing to the definition of Ziegleret al., a preventative general biomarker [5]. The DNA biomarkers are patient- marker might be a DNA biomarker or a DNA tumor specific genetic information that remains stable through biomarker, depending on whether they present only a patient’s lifetime across different cell structures. Some in cancer cells (somatic mutations) or in all cell types examples are single nucleotide polymorphisms; simple (germline mutations) [5]. sequence repeats; or insertion, deletions and other vari- ations on the DNA level. DNA tumor biomarkers refer Diagnostic to the DNA changes specific to cancer cells that lead Diagnostic biomarkers refer to those clinical indications to the cellular or functional changes. These biomarkers that help doctors screen, diagnose or predetermine the 176 Clin. Invest. (Lond.) (2015) 5(2) future science group Personalized medicine: challenges in biomarker-related clinical trial design Clinical Trial Methodology Table 1. Categorization of different biomarkers. Term Definitions Properties Examples Preventative Biological traits that can help in Often DNA biomarkers, stable over BRCA1 and BRCA2 in breast biomarkers patient-specific disease prevention time and across tissue types cancer prevention Diagnostic