Biomarkers in oncology drug development - Biomarkers by nyut545e2


									                                                                                                                     Focus – Oncology                       5

               in oncology drug development
                                                                            Biomarkers and oncology
  Authors                                                                   The use of biomarkers has significant implications in the field of
  Margaret Boulton, Director of Medical and Regulatory Affairs,             oncology, where there is:
  and Jonathan Dally, Clinical Projects Manager, Alliance                       A
                                                                            l	 	 n underlying need to treat the condition

  Pharmaceuticals Limited, UK                                                   A
                                                                            l	 	 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

  Abstract                                                                      effective medicines for the treatment of respective cancers for
  The development of validated methods for biomarker(s)                         specific patient populations and, therefore, enhance the risk–
  assessments offers hope for patients suffering from many                      benefit profile of approved medicines. 3
  disorders, including various forms of cancer. These diagnostic                In oncology drug development, the use of biomarkers is not limited
  techniques have the potential to revolutionise specific treatments        to assessments (eg, optimising dose/dosing regimen, assuring drug
  for sub-populations of patients by targeting only those who               safety, predicting which patients will respond and confirming how
  will benefit from the treatment, by reducing drug exposure and            tumours will respond to respective treatments) carried out prior to the
  side-effects for those who will not benefit from the respective           granting of a marketing authorisation.4 Biomarkers can also be used to
  treatment(s) and by reducing development costs/timelines for              assess drug safety for anticancer treatments post-authorisation and/
  new drug therapies and treatments. Close collaboration between            or resistance or potential lack of effect of adjuvant drug therapies.5,6
  sponsors, both pharmaceutical and academic, and regulatory                However, the value of biomarkers in oncology drug development – and
  agencies throughout all stages of development is essential for the        in subsequent drug combination treatments – depends on the validation
  continued success of this novel area of research.                         process that supports these techniques, to ensure acceptance by the
                                                                            regulatory authorities. There is a need to standardise the procedure(s)
  Keywords                                                                  used to validate these processes and techniques and, once achieved for
  Oncology; Biomarkers; Diagnostic techniques; Regulatory guidance;         each biomarker or group of biomarkers, to ensure the widespread use
  Personalised treatment; Clinical endpoint; Surrogate endpoint             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
Introduction                                                                the mechanism of action and efficacy of new anticancer treatments
In recent years, the advancement of laboratory techniques and               has allowed additional assessments which provide invaluable
bioanalytical assays has generated new hope for the development of          information that can assist in evaluating the oncology drug
‘personalised’ treatments and potential cures for diseases where there      development process (see Figure 1). They are particularly important in
has only been limited success in the past. The term ‘personalised’ in       addressing the question of whether to progress an oncology product
this context refers to the ability to categorise a population of patients   to Phase II or beyond.
into sub-groups who respond differently to current treatment(s) and/
or who may have differing susceptibility to a specific disease. It does     Biomarkers in oncology-based clinical trials
not relate to attempts to design a drug or treatment for a specific         A search of just one major clinical trial registry,, using
individual’s personal need.1                                                only the search term ‘biomarker’, generates more than 6,000 results
    An example of such a scientific advance is the identification and       for studies that have started to date using this process. Refining the
use of biomarkers in medicine. The measurement of biomarkers                search further to include the condition ‘cancer’ suggests that more
(the physiological, pathological, pharmacological feature under             than 40% of all studies involving biomarker(s) assessments are in
assessment) and biomarker-based diagnostic techniques (the                  the field of oncology.7 Among these trials, more than 80%8 of those
validated procedures used to measure the biomarker) could                   that specify a clinical trial phase are in either a Phase I and/or Phase II
potentially supplement and improve on existing drug strategies for          setting. One possible explanation for the majority of these studies
diseases/categories of diseases. Biomarkers can be used to assess           being Phase I/II is that biomarker assessments are now widely used
drug efficacy and safety, in addition to their value as diagnostic tools    as part of the critical decision-making process on whether to move
for the identification of patients with an underlying disease and the       on to the next development phase. However, concerns have been
stage to which the disease has progressed.                                  raised that many potential biomarkers cannot be used to predict
    In 2001, the US National Institutes of Health (NIH) Biomarkers          drug response or disease progression. These concerns have led
Definitions Working Group proposed terminology (see Table 1) which          regulators to stress the need to focus on a better understanding
has been widely referenced in subsequent years.2                            of the potential limitations of the biomarker under assessment.                                                                             Regulatory Rapporteur – Vol 7, No 4, April 2010
6     Focus – Oncology

     Table 1: Definitions, characteristics and terms proposed by the Biomarkers Definitions Working Group2 including potential uses
     in oncology.9,10

     term               definition/characteristic                                    Potential uses in oncology for diagnosis and drug development

     Biomarker/         A characteristic that is objectively measured and            Target discovery and validation, eg, in many cases of breast cancer
     a biological       evaluated as an indicator of normal biological               the HER2 proto-oncogene is amplified.
     marker             processes, pathogenic processes or pharmacological
                                                                                     New strategies for drug treatment, eg, development of anti-HER2
                        responses to a therapeutic intervention.
                                                                                     proto-oncogene treatments.

     Clinical           A characteristic or variable that reflects how a             Predictive modelling, eg, development of preclinical animal biomarker
     endpoint           patient feels, functions, or survives.                       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          A biomarker that is intended to substitute for a             Prediction of clinical outcomes by optimising drug dose and regimen
     endpoint           clinical endpoint. A surrogate endpoint is expected          and minimising maximum tolerated dose studies.
                        to predict clinical benefit (or ‘harm’ or ‘lack of benefit
                                                                                     Development of biomarker techniques to assess onset/progress of
                        or harm’) based on epidemiologic, therapeutic,
                                                                                     disease and how drugs interact with the advancement of cancer
                        pathophysiologic, or other scientific evidence.
                                                                                     under investigation.

    Therefore, meetings should be arranged with regulators at the earliest           process18,19 to provide support and guidance for novel methods, with
    opportunity, especially during the initial stages of development of              particular emphasis on biomarkers during the early phase of development.
    any new biomarker/biomarker assessment, in order to reduce time/                 For anticancer treatments it is crucial that the required biomarker/
    expenditure through improvement in the design of early Phase II/                 associated analytical technique is qualified and accepted by the respective
    dose-response studies.                                                           regulatory authority at the earliest opportunity during drug development.
                                                                                     The importance of this is underlined by the fact that between 2000 and
    Current regulatory framework                                                     2007, only six out of 26 submissions for novel anticancer treatments
    In recent years, the development and use of biomarkers have generated            reviewed under the Centralised Procedure contained adequate
    significant regulatory agency interest across the globe. In Europe and           pharmacogenetic data (obtained from preliminary and pivotal studies)
    the US, the use of biomarker methods and assessments remains a high              that influenced the assessment of the product information.20
    priority on the work programmes and listings of the European Medicines              During the early stages of any oncology drug programme which
    Agency (EMA)/the Committee for Medicinal Products for Human Use                  plans to use potential genomic biomarkers, briefing meetings are
    (CHMP) and the US FDA. Reliable and valid biomarker techniques might             recommended with the Pharmacogenetics Working Party15 and/or
    support a decision for earlier completion or termination of a drug               the Innovation Task Force (the ITF, an EMA multidisciplinary group
    programme, particularly where the investigational drug is less efficacious       that includes scientific, regulatory and legal competencies),21 as
    or has a poorer safety profile than originally predicted.11                      well as formal scientific advice interactions with the CHMP. These
        The primary responsibility for collecting sufficient valid data to           briefing/advice meetings are beneficial to all parties, as it is widely
    support the use of any biomarker during a specific drug development              acknowledged that once consensus is reached about the qualification
    process rests with the sponsor. However, the format, content and                 of the biomarkers/biomarker assessments for regulatory application,
    qualification/validation of these data must meet the expectations of             the use of the biomarker/technique can be accelerated.
    the regulatory authorities.                                                         With regard to oncology drug development, the EMA has also
                                                                                     specifically generated the following guidance:
    The European regulators                                                             A
                                                                                     l	 	 reflection paper in 2008 on the use of pharmacogenomics

    An array of guidance and guidelines has been generated by the                       in oncology20 which includes important points relating to the
    EMA,12 not to mention ad hoc training, eg, workshops,13,14 discussion               clinical trial design and clinical pharmacology requirements of
    fora, briefing meetings,15 process maps16 and clarifying definitions17 in           pharmacogenomic protocols, particularly with regard to efficacy
    order to define regulatory expectations of biomarker assessments for                and safety parameters
    potential drug treatments.                                                       l	 An update to the guideline on the evaluation of anticancer

        From a regulatory perspective, the use of biomarkers or surrogate               medicinal products in man22 in 2005, to include considerations
    markers in the early phase of drug development is non-controversial.3               on the use of biomarkers throughout the development of non-
    In fact, in 2009 the EMA generated a dedicated biomarker qualification              cytotoxic compounds.

    Regulatory Rapporteur – Vol 7, No 4, April 2010                                                                                 
                                                                                                                     Focus – Oncology                     7

 Table 2: Details relating to the nine oncology products approved between 2000 and 2008, which contained pharmacogenomic
 information in their respective marketing authorisation applications. 23, 24

 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                   of valid genomic biomarkers in the context of approved drug labels,
treatments is still in its early stages. Although the CHMP approved 33 new   which is updated on a quarterly basis30 and currently has initiated
oncology products between January 2000 and December 2008, only nine          more than 20 projects to evaluate biomarkers for toxicity and efficacy.
of these had pharmacogenetic implications,23 four of which were leukaemia
treatments and five of which were solid tumour treatments (see Table 2).     The collaborative environment
However, as all but one of these nine products are being ‘monitored          At the present time no formal parallel qualification advice exists between
intensively by the CHMP and MHRA’,24 any additional safety data generated    the EMA and any other regulatory agency regarding assessment of
will enhance the regulators’ understanding and knowledge with respect        biomarker techniques for oncology or any other disorder. However,
to similar biomarker/biomarker technique applications in the future.         applicants to the EMA are encouraged to apply in parallel to the FDA.31
                                                                                 Regulators in Europe and the US encourage the widespread
The US regulators                                                            publication of discussions from all arenas of drug development in
In conjunction with academia, the FDA has set up guidelines and              order to improve the development and qualification of biomarkers
processes equivalent to those of the EMA, including guidelines on            and the associated techniques used to measure them. In 2004, the FDA
definitions,25 submission requirements26 and an Interdisciplinary            issued an initial report on Critical Path Challenges and Opportunities,32
Pharmacogenomics Review Group (IPRG).27 The IPRG acts as a primary           which was followed by an updated report in 2006. In Europe, the
contact within the FDA for voluntary genomic submissions and                 Innovative Medicines Initiative (IMI) aims to accelerate the discovery
coordinates correspondence between the applicant and the FDA.                and development of new medicines in the field of cancer, inflammatory
In 2003, the FDA reported that between 1990 and 2002, the agency             and infectious diseases and this public/private partnership has
granted approval for 71 oncology drug applications;28 however,               gained support from the EMA; however, the EMA recognises there is
only 14 of these were ‘accelerated approvals’ based on a surrogate           a potential for conflict regarding the development of new methods
endpoint. The authors of this report concluded that although these           (eg, biomarkers) which could form part of a marketing authorisation
endpoints are less well established than classical responses used to         application or scientific advice procedure that will be assessed by the
define the efficacy of a treatment, they are as likely to predict a better   EMA’s Scientific Committees and Working Parties.33
quality of life and/or an extended life expectancy.                              The FDA’s Critical Path Initiative, the IMI and the EMA process for
   The FDA is undertaking a project to evaluate potential endpoints          qualification of novel methodologies are incentives to data share and
for cancer drug approval and for each cancer type (eg, lung, colon,          collaborate. It is thought that more collaborative pre-competitive
etc) the FDA will hold public workshops to identify important issues,        working by industry will aid in the speedier development of tools
which will then be discussed with the Oncologic Drugs Advisory               that can be applied throughout industry, and will benefit those who
Committee (ODAC) with a view to guidance being issued by the FDA.            discover the exploratory markers as well as those who participate in
More information (background materials, meeting transcripts, etc)            their qualification. Other examples of collaboration include the EMA/
can be obtained via the FDA website.29 The FDA also publishes a table        FDA joint transatlantic work on biomarker development and joint                                                                              Regulatory Rapporteur – Vol 7, No 4, April 2010
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/                      Clinical evaluation             Marketing authorisation            Marketing authorisation
            pre-clinical assessment                                                                                    and widespread use by
                                                        Early/late                   Submission/approval
                                                                                                                           general public

                           Discovery and initial                   Veri cation of e cacy or             Identi cation of potential safety
                         assessment of biomarkers                   diagnostic biomarker                 biomarkers to measure/assess
                                                               measurement and submission of          potential safety concerns associated
                                                               validated diagnostic assessment           with drug product registration

    validation for various product development purposes. In addition, the        safety of biomarkers,11 including their potential use in oncology
    EMA/FDA continue to compare their experience in the forum of an              drug development,35 has been reviewed by a Ministerial Industry
    oncology cluster teleconference once a month, which involves both            Strategy Group (MISG) New Technologies Forum, which consists
    sides detailing the applications they have received as well as reviewing     of representatives from the pharmaceutical industry, regulatory
    those they have prepared to take. Interestingly, there is increased          agencies and academia. The conclusions of this forum were that while
    regulatory (FDA/CHMP) acceptance of a prospective/retrospective              the biomarker identification and the associated diagnostic techniques
    approach (prospective for collection, retrospective for analysis) to         linked to this work are still developing, they have the opportunity
    define subpopulations. There is also acknowledgement that ‘restriction       to provide significant benefit for future public health. The MISG has
    of drug use to patient subsets to improve safe use of the drug might         also recognised that for many companies, less than 10% of drugs in
    not require the same level of scientific rigour as for claims for specific   their respective portfolios meet the current definition of personalised
    drug benefits’.34 Such examples of collaboration and harmonisation can       medicines. However, this could reach 80-100% by 2014 for those
    only benefit all parties involved in drug development.                       companies specialising in oncology drug development.35
                                                                                     Regulatory hurdles still exist in the development of biomarkers
    US and European case study                                                   as surrogate markers with regard to when and how to switch an
    There is evidence in recent years of improved understanding                  established surrogate for a new surrogate. However, once accepted as
    and sharing of pharmacogenomic knowledge not only between                    a surrogate, the use of biomarkers can accelerate the drug approval
    regulators but also between applicants and regulators. A case                process, and there is more optimism for the use of biomarkers in
    study which demonstrates this observation was discussed during               oncology drug development aimed at treating high-risk patients – or
    a recent presentation by the Chair of the CHMP,23 together with              targeting those most likely to respond – than in the development of
    other examples of how the approval process for novel anticancer              new surrogate markers for cancers. While biomarkers and surrogate
    treatments has been influenced in recent years by pharmacogenomic            endpoints have been used for compliance and safety monitoring in
    information included in the marketing authorisation application.             support of Phase III trials,36 their use as safety endpoints has proven
    The case study under review involved an anticancer treatment                 problematic, since benchmarking against an infrequent clinical
    (Vectibix) which received initial FDA accelerated approval in 2006           outcome is difficult and can lead to a high rate of false positives.
    but an initial EMA/CHMP recommendation against approval of the                   Further work across an array of disorders is still required before
    treatment in 2007.                                                           the use of biomarkers as surrogate endpoints is fully accepted by
        Following retrospective analysis of a pivotal Phase III study, the       all regulatory agencies. However, favourable consideration may be
    CHMP later recommended approval and the EMA subsequently                     granted to special cases, such as life-threatening disease where there
    approved the treatment but only for cases whereby the oncogene under         is high, unmet medical need, whereby unqualified/not fully validated
    investigation had not mutated. In follow-up to this case, in 2008 the FDA    surrogate endpoints are considered by regulators via accelerated/
    oncology drugs advisory committee met to review the requirements             staggered/conditional approval procedures.
    for retrospective evaluation of studies that may be appropriate for label        The hope for the future is that the closer harmonisation/interaction
    changes which subsequently include biomarker assessments.23                  between regulators should lead to:
                                                                                 l	 A standardised process for submission with regard to format and

    The future regulatory framework                                                  content
    It is anticipated that the use of biomarkers for suitable drug selection         A
                                                                                 l	 	 cceptance of common validation processes for analysis of

    will increase in the future and that these techniques will be used in            biomarker data generated from cancer clinical trials, which
    all areas of development, from preclinical to clinical and diagnostic            will help facilitate global oncology drug development with an
    therapy for specific sub-populations of patients. In the UK, the                 increased emphasis on targeted personal therapy

    Regulatory Rapporteur – Vol 7, No 4, April 2010                                                                          
                                                                                                                                       Focus – Oncology                         9

l	 	 iomarker(s)    use in safety monitoring increasing pre- and post-                     17 EMEA, 2007 (EMEA/CPMP/ICH/437986/2006). ‘Note for Guidance
     approval of oncology drugs                                                               on Definitions for Genomic Biomarkers, Pharmacogenomics,
l	   D
     	 ata based on a group(s) of biomarkers being assessed in tandem                         Pharmacogenetics, Genomic Data And Sample Coding Categories’. http://
     in a specific cancer condition rather than findings being assessed              (accessed 8 January 2010).
     on a single biomarker.                                                                18 EMEA, 2009 (EMEA/CHMP/SAWP/72894/2008 Corr1). ‘Qualification of Novel
                                                                                              Methodologies for Drug Development: Guidance to Applicants’, http://
Conclusion                                                                           (accessed 8 January 2010).
Biomarkers, and the associated techniques that are used to measure                         19 EMEA, 2009 (EMEA/CHMP/ICH/380636/2009). ‘ICH Topic E16. Genomic
them, are expected to play an increasingly important global role in                           Biomarkers Related to Drug Response: Context, Structure and Format
allowing informed development of future oncology drugs and in                                 of Qualification Submissions’. (accessed
improving the success rate with regard to progressing new oncology                            8 January 2010).
drugs and treatments through the various stages of testing prior to                        20 EMEA, 2008 (EMEA/ CHMP/PGxWP/128435/06). ‘Reflection Paper on
granting a marketing authorisation.                                                           Pharmacogenomics in Oncology’ (Released for consultation April 2008),
                                                                                     (accessed 21 December 2009).
                                                                                           21 EMEA, 2009. ‘Medicines and Emerging Science – Innovation Task Force’.
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