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GLOBAL ONCOLOGY CRO Your goal is to give people a better quality of life. We’re proud to be a part of your mission. Companion Diagnostics: Development, Regulation and Compliance Considerations This white paper outlines the necessary considerations for CDx development; these include the impacts of regulatory and quality compliance expectations in the US and European jurisdictions. A Novella Clinical White Paper Moving Potential. Forward. Oncology Clinical GlobalTrial Oncology Operations CRO Companion Diagnostics: Development, Regulation and Compliance Considerations Companion Diagnostics: Development, Regulation and Compliance Considerations Executive Summary The underlying basis of personalised medicine is the ability to select those individuals who Companion Diagnostics will benefit most from a given intervention. In As a full service clinical research its simplest form this requires two elements: a organization (CRO) specializing valid biomarker which determines treatment in oncology and medical device outcome for the individual and a reliable method and diagnostics, Novella Clinical for unambiguously determining the status of the noted companion diagnostics biomarker in the individual. Although there are many variants in detail of this simple scheme, it is this pairing between the intervention and the selection method which drives the development of a companion diagnostic test (CDx) for a personalised medicine. This white paper outlines becoming an increasing area of interest for sponsors. We asked one of Novella’s regulatory consultants, Dr. Mark Richardson, to explore the development of companion diagnostics with a particular focus on regulatory the necessary considerations for CDx development; and compliance expectations these include the impacts of regulatory and quality in both the US and Europe. compliance expectations in the US and European jurisdictions. 2 ©2012 Novella Clinical Oncology Clinical Trial Operations Companion Diagnostics: Development, Regulation and Compliance Considerations CDx Context and Precedents The requirement that medicines should be safe and effective inevitably moves us away from the model of treating an undifferentiated patient population in which only a proportion will derive the desired benefit and/or avoid the undesired risk. Our ability to identify the predisposing determinants of this proportion has accelerated the move and has truly enabled the concept of personalising the treatment of individuals for the best possible outcomes. Personalised medicine is often described as the right treatment for the right person at the right time. 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. The impact of this principle on both clinical practice and on the development of new drugs is considerable. In the clinical setting, the incorporation of an additional test in the normal exercise of differential diagnosis of patients with a given condition results in the stratification or enrichment of the population subset which can be considered either positively or negatively for a particular treatment. The additional diagnostic is therefore measuring a predictive biomarker of potential outcome which is specific to the The use of the CDx with the therapeutic product allows the product’s benefits to exceed its risks for the population selected by the CDx results. particular treatment. This is distinct from a prognostic biomarker which is an indicator of disease progress or future severity and is unrelated to the effect of clinical intervention. In the development of new drugs the opportunity therefore arises to screen for genotypes and phenotypes which correlate with optimal drug response in animal models and early clinical trials. This information simultaneously enables the stratification of likely responder populations and provides the data required to validate the corresponding biomarker as predictive for treatment effect. Generally, this means that the use of the CDx with the therapeutic product allows the product’s benefits to exceed its risks for the population selected by the CDx results. The precedent example of a biomarker status used to determine treatment is the oncogene product HER-2 which is over-expressed as a consequence of gene amplification in 25-30% of breast cancer patients. These patients have a poorer prognosis than those whose tumours do not over-express HER-2. Diagnosis of HER-2 overexpression is required for treatment with the monoclonal antibody product Herceptin® (trastuzumab) approved by the FDA initially in 1998 (and shortly after in the EU) for the treatment of metastatic breast cancer, together with an immunohistochemistry-based test kit called HercepTestTM (Dako, also approved in both jurisdictions); the first CDx. Subsequently approved tests use in situ DNA hybridisation of labelled probes to detect the HER-2 gene amplification with fluorescence or chromogenic readouts. 3 ©2012 Novella Clinical Oncology Clinical Trial Operations Companion Diagnostics: Development, Regulation and Compliance Considerations In another oncology setting the use of the monoclonal antibody product Vectibix® (panitumumab) for the treatment of colorectal cancer must only be used in patients with the wild type K-RAS gene. The use of the corresponding CDx to select the responsive patient population salvaged the approval of the product following the apparent failure to demonstrate sufficient clinical benefit in an unstratified population. Post hoc analysis of the pivotal trial data demonstrated the wild type K-RAS component of the population showed superior progression-free survival. It could be said that the CDx/biomarker combination retrospectively “saved” the drug in this case. Coincidentally, it provided a valuable therapeutic option to a significant number of patients in of a poorly served population which was otherwise “hidden” without stratification by the CDx. The FDA maintains an updated list of pharmacogenomic biomarkersi appearing in the labels of approved drugs and biologics which require testing with a CDx. This clearly illustrates both the rapid growth in, and the confirmation of the paradigm of personalised medicine. Compliance Expectations for a CDx: Regulatory Principles When results from a CDx are a determining factor in patient treatment, health care professionals must be able to rely on those results. Inadequate performance of a CDx could have severe clinical consequences. A CDx might fail analytically (e.g., by not accurately measuring the expression level of a protein of interest), or clinically (e.g., by not identifying those patients at increased risk for a serious adverse effect). Consequently, an incorrect result could lead to withholding effective therapy or to administering unsafe therapy. Therefore, the use of a CDx with a therapeutic product raises important and legitimate concerns about the safety and effectiveness of both the CDx as a diagnostic and the drug as therapeutic product individually. Because a CDx with inadequate “performance characteristics” or other issues related to safety and effectiveness could expose a patient to preventable treatment risks, regulatory compliance standards should be used to assess the safety and effectiveness of the CDx as used with the therapeutic when a therapeutic product Inadequate performance of a CDx could have severe clinical consequences. depends on the CDx for its safe and effective use. 4 ©2012 Novella Clinical Oncology Clinical Trial Operations Companion Diagnostics: Development, Regulation and Compliance Considerations Compliance Expectation: Qualification and Validation of the CDx The compliance standards of diagnostic performance should conform to the relevant national and international general standards for clinical diagnostic and analytical method qualification and validation. Specific aspects such as repeatability, reproducibility and precision estimates should be evaluated. The diagnostic performance relates essentially to the evaluation of sensitivity and specificity of the method. The principle elements in the validation of a novel CDx were described in FDA draft1 concept paper in 2005iii. 1. Studies to show that test performance can be applied to expected clinical use as a diagnostic with acceptable accuracy, precision, specificity and sensitivity: A demonstration of the device’s ability to accurately and reproducibly detect the analyte(s) of interest at levels that challenge the analyte concentration specifications of the device should be provided. (See number 3 below). 2. Sample requirements: All relevant criteria and information on sampling collection, processing, handling and storage should be clearly outlined. 3. Analyte concentration specifications: It is recommended that, when appropriate, a range of analyte concentrations that are measurable, detectable, or testable be established for the assay. 4. Cut-off: It is recommended that there be a clear rationale to support an analytical characterization of cut-off(s) value(s) which determine the positive and negative threshold results. Compliance Expectation: Clinical Utility of the CDx After a new CDx has been analytically characterized, additional studies should be performed to determine and validate clinical utility. This addresses and quantifies the risks and benefits to the patient associated with use of the test. It is the second element of CDx compliance which requires the unambiguous demonstration of the ability of the test to result in patient selection that will improve the benefit/risk of the drug in the selected and nonselected groups. Optimally, these studies will be performed based on informa- After a new CDx has been analytically characterized, additional studies should be performed to determine and validate clinical utility. tion known from analytical studies and based on pilot studies or careful analysis to determine relevant populations to be studied to establish clinical test performance and target cut-off points in biological specimens. Clinical utility testing can be conducted in one of two ways. First, the proposed final marketing format CDx can be used for patient selection in the pivotal clinical trial(s) under the conditions of its future routine clinical use. Second, and more commonly, retained patient samples This draft document has never been finalised or withdrawn (even though it is marked “not for implementation”). Its technical contents remain seminal and are complemented by more recent FDA draft guidanceiii which clarifies the regulatory pathway for approval of a CDx in concert with its corresponding drug. 1 5 ©2012 Novella Clinical Oncology Clinical Trial Operations Companion Diagnostics: Development, Regulation and Compliance Considerations which had been tested during the trial(s) in a central lab are used, in simple terms, to challenge the final format CDx to achieve the same results. The second strategy is more attractive to regulators because it removes the possibility of CDx usage variation influencing the data on which the primary assessment of drug efficacy is made. The assessment of clinical utility should also take into account operator dependent subjective influences which might be significant outside of the controlled environment of a central or reference clinical laboratory. Although medical staff are highly trained, they may not all be experts in the area of diagnostic testing, and so addressing human factors and the workflow required of the user from sample collection to ... addressing human factors and the workflow required of the user from sample collection to display of the test result is imperative for assuring the clinical utility of the CDx in routine use. display of the test result is imperative for assuring the clinical utility of the CDx in routine use. Data visualisation and interpretation are of particular relevance here to ensure that the test result is not open to subjective influence and consequent inconsistency between operators. The provision of specific training, instructional materials, and access to “live” advice and/or follow up are likely to be necessary to this end. Integration of CDx and Drug Development With the greater emphasis in modern drug development on design rather than screening, it is most usually the case that the pharmacological target is known at an early stage and well characterised at the molecular level. It is therefore typical that the determinant of treatment response, the predictive biomarker, is known long before clinical studies are initiated, and probably before formal preclinical development studies start. If the biomarker is novel a new test will be required. However the principles of CDx development also apply to a new version of an existing diagnostic marketed by a different manufacturer, or to an existing diagnostic that is already authorised for use in another indication or with a different drug. If there is an existing diagnostic method for the identified biomarker then the burden of method development and most of the analytical validation curriculum will be eliminated if the method is already fit for purpose. This will depend on the extent of possible variables such as sample collection, preparation and storage (and their compliance requirementsii), and analyte variations between the ways in which the method is used. When possible CDx for subsequent pivotal efficacy and/or safety studies should be developed and analytically validated early in the drug development process to allow clinical test validation and clinical test utility determination during the late stage clinical trials. Ideally, a new diagnostic intended to inform the use of a new drug will be studied in parallel with early drug development (preclinical, Phase I and possibly Phase II trials) and diagnostic development will then have led to pre-specification of all key analytical and clinical utility aspects for the 6 ©2012 Novella Clinical Oncology Clinical Trial Operations Companion Diagnostics: Development, Regulation and Compliance Considerations subsequent (late Phase 2 and Phase 3) pivotal clinical studies. These include the intended population and selection of diagnostic cut-off points for the biomarker intended to delineate test positives, test negatives, and, when appropriate, equivocal zones of decision making. This principle is illustrated in the schematic shown in Figure 1. Platform Change Marker Assay Validation Prototype Design or Discovery Basic Research Analytical Validation Diagnostic Kit Clinical Validation Diagnostic Kit; Final Platform Preclinical Development Clinical Phase 1 Phase 2 Phase 3 FDA Filing/ Approval & Launch Figure 1. Model outline of the integration of CDx and drug, taken from early FDA guidanceiii. The reference to “platform change” is to recognise that refinement modifications may be made to the CDx format during its development. Candidate biomarker definition, target selection & preclinical studies Analytical performance testing Marketing clearance/ approval (CE-marking/ 510(k)/PMA) Investigational Status During Clinical Development Clinical validation Clinical utility A CDx used to make treatment decisions in a clinical trial of a therapeutic product will be considered to be investigational unless its use for this purpose is already approved or cleared (e.g., CD EM ER A /C or BE R CD EM ER A /C or BE R CA N D B/ IV N rO o CA N D B/ IV N rO o CA N D B/ IV N rO o CD EM ER A /C or BE R the use of an existing CDx). If a CDx is being used to make critical treatment decisions, such as patient selection, treatment assignment, or treatment arm eligibility, it will generally be considered Joint Joint Joint a significant riskpre-clinical device under US and EUpivotal regulations because it presents a potential for serious pre-submission meeting meeting meeting risk to the health, safety, or welfare of the subject in the event of malfunction. Rx Dx Rx Dx Rx Dx • In the US the manufacturer of the CDx will be required to comply with the investigational device exemption (IDE) regulations. If a CDx and a therapeutic product are to be studied together to support their respective approvals, both can be studied in the same clinical trial if it is conducted in a manner that meets both the requirements of the IDE Filling/approvals Non-clinical Clinical Clinical Clinical Discovery & launch development Phase I Phase II Phase III regulations and the investigational new drug (IND) regulations. (MMA/NDA/BLA) • In the EU, there is no formal regulatory system governing the use or investigation of an in vitro diagnostic device in the context of a clinical trial of an investigational medicinal product. However the proposed use of a diagnostic test to determine treatment decisions in a clinical trial must be fully justified in submissions to the national competent authorities for clinical trial approvals. 7 ©2012 Novella Clinical Oncology Clinical Trial Operations Companion Diagnostics: Development, Regulation and Compliance Considerations Regulation of CDx as In Vitro Diagnostic Devices The critical function of the CDx in determining treatment decisions raises significant concerns about the safety and effectiveness of the test and any device used to perform that test. These safety concerns also have an influence on the development of any therapeutic product, as the companion diagnostic test will require regulatory clearance and will need to be marketed at the same time the therapeutic is available. The challenges to co-developing a CDx and its corresponding drug are the two classes of product have different timelines for their development and regulatory milestones, have separate submission pathways, and are regulated by different competent authorities. Drug development is a lengthy process of about 9-12 years which has a classical sequential structure of preclinical studies, clinical exploratory and confirmatory trials within a regulatory framework specific to investigational medicinal products. Interaction with the The challenges to co-developing a CDx and its corresponding drug are the two classes of product that have different timelines for their development and regulatory milestones, have separate submission pathways and are regulated by different competent authorities. regulators during this time is critical to maximise the chances for product approval after submission of the NDA or BLA in the US or the MAA in the EU. And of course the finer details of this summary view are very different between these two principle regulatory jurisdictions. Most importantly, the approval of diagnostic tests and the approval of drugs are administered and overseen separately both in the US and the EU by different entities under very different rules. US Framework In the US, the FDA oversees therapeutic products (drugs and biologics) and IVDs but this is within separate divisions of the Agency. Therapeutics are regulated by CDER or CBER and IVDs are regulated by the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD) within the Centre for Devices and Radiological Health (CDRH). FDA published a guidance document in July 2011iv which sets forth the principles of regulatory oversight and procedural control applied during the development and authorisation of a CDx and its partner drug. It is complementary to the technical and scientific guidance provided in the 2005 draft concept paper. One of the key messages behind the document is that the therapeutic product absolutely depends on the use of the respective diagnostic test and that a lack of test approval effectively equals lack of therapeutic product approval. This implies that the diagnostic test must be developed in parallel with the drug and ideally validated at the same Phase III clinical trial. Combined validation is critical in establishing the safe use of the drug based on the companion diagnostic test result. 8 ©2012 Novella Clinical Oncology Clinical Trial Operations Companion Diagnostics: Development, Regulation and Compliance Considerations EU Framework In the EU all medicinal products are regulated by the EMA or the individual national competent authorities. Oversight of medical devices, including diagnostics, is the responsibility of the Notified Bodies for evaluation of conformity with quality standards in manufacture for CE marking and of the individual national competent authorities for the evaluation of their clinical performance. In the EU the CDx can be an investigational in vitro diagnostic device (IVDD) during the development of the drug. However, it must be CE marked following review by a Notified Body (under the terms of Directive 98/79/EC) to allow its sale and use on the market, which would be the case once the drug product is launched following approval by the EMA or the national competent authorities. Historically, there has been no cross-talk or collaboration between the regulators of medicinal products and in vitro diagnostic devices, and no coordination of their separate evaluation and compliance oversight activities. The upcoming revision of the EU In Vitro Diagnostic Medical Devices Directive (98/79/EC) will incorporate the risk based categorisation of a CDx as an in vitro diagnostic device. A CDx used to make a treatment decision will be placed in Class C, the second highest of the four risk categories. This class assignment is indicative of “high individual risk and/or moderate public health risk,” and will determine the extent and rigour of the conformity assessment conducted by the Notified Body which will award the CE mark and the scrutiny of the clinical utility assessment by the National Competent Authority. Just as has been the case in the US, the EU regulatory framework is having to adapt to the coming together of the drug and (in vitro diagnostic) device development disciplines resulting from the progress of personalised medicine. A series of reflection papers have been issued which present further recommendations to drug and device manufacturers for considerationv,vi,vii,viii,ix. Importance of Dialogue with Regulators The complexity of the development of a CDx, particularly within a drug development programme, clearly requires a high degree of coordinated planning across several functions, very possibly in different organisations. The time and resource investment implications are considerable for all concerned. Dialogue and consequent “buy-in” from regulators is therefore essential; regulators expect and welcome this interaction. Coordination is also required to work with different regulators, both geographically (for a multinational development programme) and for therapeutics and diagnostics. A model scheme shown in Figure 2 illustrates plausible timings for such interactions relative to the development timeline. It is clear that regulators 9 ©2012 Novella Clinical Platform Change Clinical Trial Operations Marker Assay Analytical Validation Clinical Oncology Validation Diagnostic Diagnostic Validation Kit Kit; Final Platform and Compliance Considerations Companion Diagnostics: Development, Regulation Prototype Basic FDA Filing/ Clinical Preclinical Approval & Design or have acknowledged bridging required between the regulation of medicines Research their role in the Development Phase 1 Discovery Phase 2 Phase 3 Launch and diagnostic devices to enable personalised medicines. While it has been easier in the context of the infrastructure of the FDA to bring CBER or CDER and CDRH together, it has also become a matter of routine to bring together the EMA, the national competent authorities and the Notified Bodies for Scientific Advice procedures in the EU. Analytical performance testing Clinical validation Rx Discovery Dx Non-clinical development Rx Clinical Phase I Dx Clinical Phase II CD EM ER A /C or BE R CD EM ER A /C or BE R Joint pivotal meeting CA N D B/ IV N rO o Joint pre-clinical meeting Marketing clearance/ approval (CE-marking/ 510(k)/PMA) Clinical utility CA N D B/ IV N rO o CA N D B/ IV N rO o CD EM ER A /C or BE R Candidate biomarker definition, target selection & preclinical studies Joint pre-submission meeting Rx Clinical Phase III Dx Filling/approvals & launch (MMA/NDA/BLA) Figure 2. A schematic model of the relationship between the stages of a drug/CDx development programme which shows suggested interactions with drug and device regulators in the US (CBER/CDER and OIVD) and/or in the EU (EMA and Notified Bodies/National Competent Authorities). Conclusions The need for personalised medicine has successfully brought together and fully integrated the previously separate activities of drug and (in vitro diagnostic) device development. It is clear that regulators have responded by recognising that there must be cross-talk between the corresponding regulatory disciplines to provide guidance and interactive support to sponsors in this growing field. The early precedents, notably in oncology, and the subsequent accumulated experience of regulators has informed the establishment of achievable compliance expectations which maximise the utility of a CDx while simultaneously ensuring its safe and appropriate use in treatment decision making. 3 10 ©2012 Novella Clinical A Novella Clinical White Paper About Novella Clinical Novella Clinical, a Quintiles company, is a full service clinical research organization specializing in supporting emerging oncology companies. Headquartered in Research Triangle Park, N.C., and Stevenage, UK, Novella is experienced in early, mid- and late-phase oncology trials and provides the experience and insight to bring cancer medicines to market on time and on budget. For more information, visit novellaclinical.com/oncology or contact us at 866-303-4966. Mark Richardson PhD FTOPRA Mark is an independent regulatory affairs consultant specialising in the development of small molecule, biotech, biosimilar and advanced therapy products and is based near Oxford, UK. Originally a molecular biologist, he has 25 years industry experience in the biotech, pharma and CRO sectors in drug development and regulatory roles. http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm EMA Reflection Paper On Pharmacogenomic Samples, Testing And Data Handling, (EMEA/CHMP/PGxWP/201914/2006), 15 November 2007 iii FDA Drug-diagnostic co-development concept paper, Draft April 2005 iv FDA In vitro companion diagnostic devices, 14 July 2011 v EMA Reflection paper on methodological issues associated with Pharmacogenomic biomarkers in relation to clinical development and patient selection (EMA/446337/2011), Draft March 2011) vi EMA Reflection Paper On Pharmacogenomic Samples, Testing And Data Handling, (EMEA/CHMP/PGxWP/201914/2006), 15 November 2007 vii EMEA Reflection paper on Pharmacogenomics in oncology (EMEA/CHMP/PGxWP/128435/2006), Draft April 2008 viii EMA Reflection Paper on co-development of Pharmacogenomic biomarkers and assays in the context of drug development (EMA/CHMP/641298/2008), Draft June 2010 ix EMA Guideline on the use of pharmacogenetic methodologies in the pharmacokinetic evaluation of medicinal products (EMA/CHMP/37646/2009), December 2011 x Lawson et al. Activities to improve the regulatory framework for companion diagnostics step up. Regulatory Affairs Medtech, November/December 2010, pp 4-7 i ii You see beyond the clinical trial. Your goal is to ultimately give people a better quality of life and more time to enjoy those special little moments. Novella Clinical is proud to be a part of your mission. Moving Potential. Forward. Novella Clinical’s Global Headquarters: 1700 Perimeter Park Drive, Morrisville, NC 27560 | Phone: 919-484-1921 European Operations: Richmond House, Walkern Road, Stevenage, Hertfordshire SG1 3QP | Phone: +44 (0)1438 221122