in oncology drug development l An underlying need to treat the condition l A need to predict, at the earliest opportunity, when the disorder

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1 5 Biomarkers in oncology drug development Authors Margaret Boulton, Director of Medical and Regulatory Affairs, and Jonathan Dally, Clinical Projects Manager, Alliance Pharmaceuticals Limited, UK Abstract The development of validated methods for biomarker(s) assessments offers hope for patients suffering from many disorders, including various forms of cancer. These diagnostic techniques have the potential to revolutionise specific treatments for sub-populations of patients by targeting only those who will benefit from the treatment, by reducing drug exposure and side-effects for those who will not benefit from the respective treatment(s) and by reducing development costs/timelines for new drug therapies and treatments. Close collaboration between sponsors, both pharmaceutical and academic, and regulatory agencies throughout all stages of development is essential for the continued success of this novel area of research. Keywords Oncology; Biomarkers; Diagnostic techniques; Regulatory guidance; Personalised treatment; Clinical endpoint; Surrogate endpoint Introduction In recent years, the advancement of laboratory techniques and bioanalytical assays has generated new hope for the development of personalised treatments and potential cures for diseases where there has only been limited success in the past. The term personalised in this context refers to the ability to categorise a population of patients into sub-groups who respond differently to current treatment(s) and/ or who may have differing susceptibility to a specific disease. It does not relate to attempts to design a drug or treatment for a specific individual s personal need. 1 An example of such a scientific advance is the identification and use of biomarkers in medicine. The measurement of biomarkers (the physiological, pathological, pharmacological feature under assessment) and biomarker-based diagnostic techniques (the validated procedures used to measure the biomarker) could potentially supplement and improve on existing drug strategies for diseases/categories of diseases. Biomarkers can be used to assess drug efficacy and safety, in addition to their value as diagnostic tools for the identification of patients with an underlying disease and the stage to which the disease has progressed. In 2001, the US National Institutes of Health (NIH) Biomarkers Definitions Working Group proposed terminology (see Table 1) which has been widely referenced in subsequent years. 2 Biomarkers and oncology The use of biomarkers has significant implications in the field of oncology, where there is: l An underlying need to treat the condition l A need to predict, at the earliest opportunity, when the disorder began or is likely to begin l The opportunity to facilitate development of safer and more effective medicines for the treatment of respective cancers for specific patient populations and, therefore, enhance the risk benefit profile of approved medicines. 3 In oncology drug development, the use of biomarkers is not limited to assessments (eg, optimising dose/dosing regimen, assuring drug safety, predicting which patients will respond and confirming how tumours will respond to respective treatments) carried out prior to the granting of a marketing authorisation. 4 Biomarkers can also be used to assess drug safety for anticancer treatments post-authorisation and/ or resistance or potential lack of effect of adjuvant drug therapies. 5,6 However, the value of biomarkers in oncology drug development and in subsequent drug combination treatments depends on the validation process that supports these techniques, to ensure acceptance by the regulatory authorities. There is a need to standardise the procedure(s) used to validate these processes and techniques and, once achieved for each biomarker or group of biomarkers, to ensure the widespread use and success of these assays in the drug development process, from initial laboratory assessments through to marketing authorisation. The development of biomarkers/biomarker techniques to assess the mechanism of action and efficacy of new anticancer treatments has allowed additional assessments which provide invaluable information that can assist in evaluating the oncology drug development process (see Figure 1). They are particularly important in addressing the question of whether to progress an oncology product to Phase II or beyond. Biomarkers in oncology-based clinical trials A search of just one major clinical trial registry, ClinicalTrials.gov, using only the search term biomarker, generates more than 6,000 results for studies that have started to date using this process. Refining the search further to include the condition cancer suggests that more than 40% of all studies involving biomarker(s) assessments are in the field of oncology. 7 Among these trials, more than 80% 8 of those that specify a clinical trial phase are in either a Phase I and/or Phase II setting. One possible explanation for the majority of these studies being Phase I/II is that biomarker assessments are now widely used as part of the critical decision-making process on whether to move on to the next development phase. However, concerns have been raised that many potential biomarkers cannot be used to predict drug response or disease progression. These concerns have led regulators to stress the need to focus on a better understanding of the potential limitations of the biomarker under assessment.

2 6 Focus Oncology Table 1: Definitions, characteristics and terms proposed by the Biomarkers Definitions Working Group 2 including potential uses in oncology. 9,10 Term Definition/characteristic Potential uses in oncology for diagnosis and drug development Biomarker/ a biological marker Clinical endpoint A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention. A characteristic or variable that reflects how a patient feels, functions, or survives. Target discovery and validation, eg, in many cases of breast cancer the HER2 proto-oncogene is amplified. New strategies for drug treatment, eg, development of anti-her2 proto-oncogene treatments. Predictive modelling, eg, development of preclinical animal biomarker modelling for comparison with affected patient populations. Preclinical biomarker assessment of toxicity and drug safety in the validation of new disease models, eg, effect of novel treatments on transgenic mice. Clinical trial assessment of drug combinations to improve success rate of treatments. Surrogate endpoint A biomarker that is intended to substitute for a clinical endpoint. A surrogate endpoint is expected to predict clinical benefit (or harm or lack of benefit or harm ) based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence. Prediction of clinical outcomes by optimising drug dose and regimen and minimising maximum tolerated dose studies. Development of biomarker techniques to assess onset/progress of disease and how drugs interact with the advancement of cancer under investigation. Therefore, meetings should be arranged with regulators at the earliest opportunity, especially during the initial stages of development of any new biomarker/biomarker assessment, in order to reduce time/ expenditure through improvement in the design of early Phase II/ dose-response studies. Current regulatory framework In recent years, the development and use of biomarkers have generated significant regulatory agency interest across the globe. In Europe and the US, the use of biomarker methods and assessments remains a high priority on the work programmes and listings of the European Medicines Agency (EMA)/the Committee for Medicinal Products for Human Use (CHMP) and the US FDA. Reliable and valid biomarker techniques might support a decision for earlier completion or termination of a drug programme, particularly where the investigational drug is less efficacious or has a poorer safety profile than originally predicted. 11 The primary responsibility for collecting sufficient valid data to support the use of any biomarker during a specific drug development process rests with the sponsor. However, the format, content and qualification/validation of these data must meet the expectations of the regulatory authorities. The European regulators An array of guidance and guidelines has been generated by the EMA, 12 not to mention ad hoc training, eg, workshops, 13,14 discussion fora, briefing meetings, 15 process maps 16 and clarifying definitions 17 in order to define regulatory expectations of biomarker assessments for potential drug treatments. From a regulatory perspective, the use of biomarkers or surrogate markers in the early phase of drug development is non-controversial. 3 In fact, in 2009 the EMA generated a dedicated biomarker qualification process 18,19 to provide support and guidance for novel methods, with particular emphasis on biomarkers during the early phase of development. For anticancer treatments it is crucial that the required biomarker/ associated analytical technique is qualified and accepted by the respective regulatory authority at the earliest opportunity during drug development. The importance of this is underlined by the fact that between 2000 and 2007, only six out of 26 submissions for novel anticancer treatments reviewed under the Centralised Procedure contained adequate pharmacogenetic data (obtained from preliminary and pivotal studies) that influenced the assessment of the product information. 20 During the early stages of any oncology drug programme which plans to use potential genomic biomarkers, briefing meetings are recommended with the Pharmacogenetics Working Party 15 and/or the Innovation Task Force (the ITF, an EMA multidisciplinary group that includes scientific, regulatory and legal competencies), 21 as well as formal scientific advice interactions with the CHMP. These briefing/advice meetings are beneficial to all parties, as it is widely acknowledged that once consensus is reached about the qualification of the biomarkers/biomarker assessments for regulatory application, the use of the biomarker/technique can be accelerated. With regard to oncology drug development, the EMA has also specifically generated the following guidance: l A reflection paper in 2008 on the use of pharmacogenomics in oncology 20 which includes important points relating to the clinical trial design and clinical pharmacology requirements of pharmacogenomic protocols, particularly with regard to efficacy and safety parameters l An update to the guideline on the evaluation of anticancer medicinal products in man 22 in 2005, to include considerations on the use of biomarkers throughout the development of noncytotoxic compounds. Regulatory Rapporteur Vol 7, No 4, April

3 7 Table 2: Details relating to the nine oncology products approved between 2000 and 2008, which contained pharmacogenomic 23, 24 information in their respective marketing authorisation applications. Product Cancer type Biomarker/disorder targeted by product Glivec Leukaemia Philadelphia chromosome (bcr-abl) positive (Ph+) chronic myeloid leukaemia (CML) Gastro-intestinal stromal tumours (GIST) expressing c-kit (c-kit +) Tasigna Leukaemia Ph+ CML t Sprycel Leukaemia Ph+ acute lymphoblastic leukaemia (Ph+ALL) and lymphoid blast CML Trisenox Leukaemia Pro-Myelocytic Leukaemia/Retinoic-Acid-Receptor-alpha (PML/RAR-α) gene positive acute promyelocytic leukaemia (APL) Herceptin Solid Tumours HER2 proto-oncogene positive metastatic breast cancer Erbitux Solid Tumours KRAS wild-type metastatic colo-rectal cancer which are Epidermal growth factor receptor (EGFR) positive Tarceva Solid Tumours Locally advanced or metastatic nonsmall cell lung cancer but not in patients who have EGFR negative tumours. Vectibix Solid Tumours Non-mutated (wild-type) KRAS metastatic colorectal carcinoma which are EGFR positve Tyverb Solid Tumours Breast cancer (metastatic or advanced) where the tumours overexpress HER2 The EMA/CHMP experience of approval of pharmacogenetic treatments is still in its early stages. Although the CHMP approved 33 new oncology products between January 2000 and December 2008, only nine of these had pharmacogenetic implications, 23 four of which were leukaemia treatments and five of which were solid tumour treatments (see Table 2). However, as all but one of these nine products are being monitored intensively by the CHMP and MHRA, 24 any additional safety data generated will enhance the regulators understanding and knowledge with respect to similar biomarker/biomarker technique applications in the future. The US regulators In conjunction with academia, the FDA has set up guidelines and processes equivalent to those of the EMA, including guidelines on definitions, 25 submission requirements 26 and an Interdisciplinary Pharmacogenomics Review Group (IPRG). 27 The IPRG acts as a primary contact within the FDA for voluntary genomic submissions and coordinates correspondence between the applicant and the FDA. In 2003, the FDA reported that between 1990 and 2002, the agency granted approval for 71 oncology drug applications; 28 however, only 14 of these were accelerated approvals based on a surrogate endpoint. The authors of this report concluded that although these endpoints are less well established than classical responses used to define the efficacy of a treatment, they are as likely to predict a better quality of life and/or an extended life expectancy. The FDA is undertaking a project to evaluate potential endpoints for cancer drug approval and for each cancer type (eg, lung, colon, etc) the FDA will hold public workshops to identify important issues, which will then be discussed with the Oncologic Drugs Advisory Committee (ODAC) with a view to guidance being issued by the FDA. More information (background materials, meeting transcripts, etc) can be obtained via the FDA website. 29 The FDA also publishes a table of valid genomic biomarkers in the context of approved drug labels, which is updated on a quarterly basis 30 and currently has initiated more than 20 projects to evaluate biomarkers for toxicity and efficacy. The collaborative environment At the present time no formal parallel qualification advice exists between the EMA and any other regulatory agency regarding assessment of biomarker techniques for oncology or any other disorder. However, applicants to the EMA are encouraged to apply in parallel to the FDA. 31 Regulators in Europe and the US encourage the widespread publication of discussions from all arenas of drug development in order to improve the development and qualification of biomarkers and the associated techniques used to measure them. In 2004, the FDA issued an initial report on Critical Path Challenges and Opportunities, 32 which was followed by an updated report in In Europe, the Innovative Medicines Initiative (IMI) aims to accelerate the discovery and development of new medicines in the field of cancer, inflammatory and infectious diseases and this public/private partnership has gained support from the EMA; however, the EMA recognises there is a potential for conflict regarding the development of new methods (eg, biomarkers) which could form part of a marketing authorisation application or scientific advice procedure that will be assessed by the EMA s Scientific Committees and Working Parties. 33 The FDA s Critical Path Initiative, the IMI and the EMA process for qualification of novel methodologies are incentives to data share and collaborate. It is thought that more collaborative pre-competitive working by industry will aid in the speedier development of tools that can be applied throughout industry, and will benefit those who discover the exploratory markers as well as those who participate in their qualification. Other examples of collaboration include the EMA/ FDA joint transatlantic work on biomarker development and joint

4 8 Focus Oncology Figure 1: Various stages of identification and validation of biomarkers/associated diagnostic techniques within a typical drug development process. Drug development process Drug discovery/ pre-clinical assessment Clinical evaluation Early/late Marketing authorisation Submission/approval Marketing authorisation and widespread use by general public Discovery and initial assessment of biomarkers Verification of efficacy or diagnostic biomarker measurement and submission of validated diagnostic assessment Identification of potential safety biomarkers to measure/assess potential safety concerns associated with drug product registration validation for various product development purposes. In addition, the EMA/FDA continue to compare their experience in the forum of an oncology cluster teleconference once a month, which involves both sides detailing the applications they have received as well as reviewing those they have prepared to take. Interestingly, there is increased regulatory (FDA/CHMP) acceptance of a prospective/retrospective approach (prospective for collection, retrospective for analysis) to define subpopulations. There is also acknowledgement that restriction of drug use to patient subsets to improve safe use of the drug might not require the same level of scientific rigour as for claims for specific drug benefits. 34 Such examples of collaboration and harmonisation can only benefit all parties involved in drug development. US and European case study There is evidence in recent years of improved understanding and sharing of pharmacogenomic knowledge not only between regulators but also between applicants and regulators. A case study which demonstrates this observation was discussed during a recent presentation by the Chair of the CHMP, 23 together with other examples of how the approval process for novel anticancer treatments has been influenced in recent years by pharmacogenomic information included in the marketing authorisation application. The case study under review involved an anticancer treatment (Vectibix) which received initial FDA accelerated approval in 2006 but an initial EMA/CHMP recommendation against approval of the treatment in Following retrospective analysis of a pivotal Phase III study, the CHMP later recommended approval and the EMA subsequently approved the treatment but only for cases whereby the oncogene under investigation had not mutated. In follow-up to this case, in 2008 the FDA oncology drugs advisory committee met to review the requirements for retrospective evaluation of studies that may be appropriate for label changes which subsequently include biomarker assessments. 23 The future regulatory framework It is anticipated that the use of biomarkers for suitable drug selection will increase in the future and that these techniques will be used in all areas of development, from preclinical to clinical and diagnostic therapy for specific sub-populations of patients. In the UK, the safety of biomarkers, 11 including their potential use in oncology drug development, 35 has been reviewed by a Ministerial Industry Strategy Group (MISG) New Technologies Forum, which consists of representatives from the pharmaceutical industry, regulatory agencies and academia. The conclusions of this forum were that while the biomarker identification and the associated diagnostic techniques linked to this work are still developing, they have the opportunity to provide significant benefit for future public health. The MISG has also recognised that for many companies, less than 10% of drugs in their respective portfolios meet the current definition of personalised medicines. However, this could reach % by 2014 for those companies specialising in oncology drug development. 35 Regulatory hurdles still exist in the development of biomarkers as surrogate markers with regard to when and how to switch an established surrogate for a new surrogate. However, once accepted as a surrogate, the use of biomarkers can accelerate the drug approval process, and there is more optimism for the use of biomarkers in oncology drug development aimed at treating high-risk patients or targeting those most likely to respond than in the development of new surrogate markers for cancers. While biomarkers and surrogate endpoints have been used for compliance and safety monitoring in support of Phase III trials, 36 their use as safety endpoints has proven problematic, since benchmarking against an infrequent clinical outcome is difficult and can lead to a high rate of false positives. Further work across an array of disorders is still required before the use of biomarkers as surrogate endpoints is fully accepted by all regulatory agencies. However, favourable consideration may be granted to special cases, such as life-threatening disease where there is high, unmet medical need, whereby unqualified/not fully validated surrogate endpoints are considered by regulators via accelerated/ staggered/conditional approval procedures. The hope for the future is that the closer harmonisation/interaction between regulators should lead to: l A standardised process for submission with regard to format and content l Acceptance of common validation processes for analysis of biomarker data generated from cancer clinical trials, which will help facilitate global oncology drug development with an increased emphasis on targeted personal therapy Regulatory Rapporteur Vol 7, No 4, April

5 9 l l Biomarker(s) use in safety monitoring increasing pre- and postapproval of oncology drugs Data based on a group(s) of biomarkers being assessed in tandem in a specific cancer condition rather than findings being assessed on a single biomarker. Conclusion Biomarkers, and the associated techniques that are used to measure them, are expected to play an increasingly important global role in allowing informed development of future oncology drugs and in improving the success rate with regard to progressing new oncology drugs and treatments through the various stages of testing prior to granting a marketing authorisation. References 1 ABPI, The stratification of disease for personalised medicines: Research-driven recommendations from the ABPI. yjernk6 (accessed 18 December 2009). 2 Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework, Clin Pharmacol Ther, 2001;69: R Katz. 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