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European Biopharmaceutical Review

Hand-in-Hand

Precision medicine, a key strategy in the development of more effi cacious drug therapies, aims to provide a better means of classification and differentiation of disease subgroups that previously had been categorised together under broader terms (1). This data-driven understanding of disease conditions enables evidence-based drug therapy decisions using biomarkers to label patients with a specific disease or disorder into subgroups based on their likely response to a particular therapeutic product, or to enhance safety by reducing adverse events.

Biomarkers are defined as “objectively measured and evaluated indicators of normal biological processes, pathogenic processes or pharmacologic responses to a therapeutic intervention" (2). Clinically validated biomarker assays, developed in conjunction with a specific therapeutic agent and approved by health authorities for that purpose, are called in vitro companion diagnostic (IVD CDx) devices.

Efficient pathways for the development of the most successful targeted therapies involve simultaneous and coordinated co-development of the therapeutic drug product and the IVD CDx product. From the regulatory viewpoint, co-development requires integration of three distinct development pathways: clinical development of the therapy; identifi cation of the biomarker; and development of the IVD CDx product. From the clinical perspective, a concerted partnership is required among developers of the therapy, the CDx and regulators to ensure concurrent and integrated development, as well as demonstration of safety and efficacy, leading to timely regulatory marketing authorisations.

This article discusses co-development pathways and strategies that support a comprehensive and well-coordinated diagnostic testing approach with targeted therapies, to help drive the practical application of precision medicine in the clinic.

Current Practice

2014 FDA guidance defi nes an IVD CDx device as a test that “provides information that is essential for the safe and effective use of a corresponding therapeutic product” (3). They are most often used to identify individuals who are likely to have an effective response to a drug, or likely to be at risk for drug-induced adverse events. The devices may also be utilised to monitor a person’s response to treatment and to adjust treatment to achieve improved safety or effectiveness.

The introduction of the targeted breast cancer therapy Herceptin® (trastuzumab) in 1998 marked the first coordinated approvals in the US of a therapy and an IVD CDx. Herceptin – which is indicated in as many as 30% of patients with oncogene HER2 overexpression – is used together with the immunohistochemistrybased test kit HercepTestTM (Dako) to identify candidates who are most likely to benefit from Herceptin therapy.

Since 1998, the FDA has approved only 21 CDx for 13 therapies (4). However, the pipeline is improving as the use of biomarker data in clinical development increases. Approximately 60% of drugs now in preclinical development use biomarker data, compared to 33% of agents in late clinical development (5) – showing a growing trend for co-development of products moving through the cycle.

Co-Development Pathways

Innovative co-development strategies should focus on systematically aligning the different development pathways of the therapeutic, biomarker and IVD CDx to achieve simultaneous marketing authorisation for the therapy and its enabling diagnostic test.

In real practice, standard pathways often lack the synchronised alignment necessary for efficient and effective co-development. Challenges exist as developers must integrate the technical, quality, clinical and regulatory aspects of biomarker and CDx development into the drug discovery process.

Alignment of timelines must allow for determination of the clinical performance and significance of the IVD CDx, using data from the clinical development of the therapeutic. Ideally, the IVD CDx is advanced in parallel with Phase 1 or 2 studies. This facilitates detection of key analytic and clinical validation aspects for subsequent Phase 2 and 3 trials, and culminates in synchronised regulatory approval of the therapeutic and CDx.

The US regulatory pathway is guided by the ‘intended use’ of the IVD CDx, and ensures appropriate analytical and clinical validation of the test with evidence to support specific claims. A well-established pathway allows for effective IVD CDx development following a ‘phase- or stage-gated development process’ governed by the design control requirements of the quality system regulation (QSR) or ISO 13485 standard (12,13), which integrate technical, quality, clinical and regulatory development tasks. Design controls cover the lifecycle of the device to ensure that specified design requirements are met, and the device will be safe and effective for its intended use.

Working Together

Partnerships are vital to progress the development of a biomarker into an approved IVD CDx, as test format and technology are driving factors. Few pharmaceutical and biotechnology companies have the necessary technical expertise needed to support IVD CDx technological development. Partnering with an experienced diagnostics business or a CRO that has a wellestablished technology and global presence can meet this need. Crossfunctional (and often cross-company) collaboration is essential to optimally align processes.

A partnership model with a CRO that has clinical expertise and clinical labs can accelerate initial test development, mitigate risk, and maintain alignment with crucial therapeutic and regulatory milestones. This approach allows comprehensive and integrated test system development and requires capabilities including:
  • Good Laboratory Practice (GLP) biomarker assay development
  • Central labs worldwide to deploy validated test methods to support the clinical development programme
  • Current Good Manufacturing Practice and QSR-compliant labs to support development, manufacturing, and reagent and release testing for submission
  • IVD CDx global regulatory expertise to gain international market registration
Essential Steps

Research and Feasibility
Early identification of a clinically relevant biomarker is critical to the development of the therapeutic drug and IVD CDx. Biomarker targets may be based on relevant pharmacogenomic, proteomic or transcriptomic signatures, and used for patient stratification or therapeutic response monitoring. Biomarker assay development effectively occurs in a GLP lab setting to generate a validated test with verified cut-offs for use in a clinical trial.

Diagnostic Assay Development

Preclinical development pathways and prototype modelling may be guided by device-related precedents and guidelines that outline important characteristics regarding the IVD CDx design, analytical studies, and software or instrument characteristics (14). The assay will usually migrate from an early biomarker test to a different format and technology for use as an IVD CDx.

Current practice offers a stable technology platform with a core group of technologies that test for a single gene or molecule to define disease characteristics of the patient, tumour or virus, including assays based on immunohistochemistry, in situ hybridisation and polymerase chain reaction. However, rapidly advancing technologies – such as microarrays and next-generation sequencing (NGS) – support the detection and assessment of multi-gene or multi-analyte signatures of complex diseases to demonstrate clinical applicability. Recent clearance of the first NGS platform, albeit not as an IVD CDx, has considerable ramifications for use of this cutting-edge technology in precision medicine (15). The development of universal NGS oncology multi-gene panels is ongoing to support clinical trials of targeted cancer therapies (16).

Analytical Validation

Analytical performance studies assess the IVD CDx test’s ability to accurately and reproducibly detect the analyte(s) of interest by correlating to a reference method. Validation of the proposed test in Phase 1 or 2 studies will demonstrate key analytical and clinical performance aspects for subsequent Phase 2 and 3 studies. They may leverage consensus standards – like the Clinical and Laboratory Standards Institute – or device-related precedents to identify assay performance characteristics such as accuracy, precision, sensitivity and specificity.

Assay development and validation should be completed, and the assay cut-offs that define test positive and test negative results established, prior to use in clinical studies to avoid bias. Preclinical feasibility or early-phase clinical studies may be used to determine relevant clinical populations and to evaluate clinical test performance and target cut-offs in biological specimens. Cut-off selection may be chosen to balance the test’s sensitivity (true positive rate) and specificity (true negative rate), emphasise sensitivity (when the test predicts the occurrence of drug-related adverse events) or highlight specificity (when the test predicts which patients are likely to respond to treatment).

Investigational Assay

Test Validation and Utility
To align therapeutic and test regulatory approvals, the clinical performance and significance of the IVD CDx are established using data from pivotal Phase 3 trials. Clinical studies should be prospective, supporting both the use of the IVD CDx analytically in patients and assessing the test’s relationship to clinical outcome. IVD CDx clinical performance is based on two main criteria: clinical test validation and clinical test utility. The former assesses the safety and effectiveness (risk/benefit) of the test for the intended indication and patient population. Ideally, this can be established using Phase 2 study data to determine the test’s positive and negative predictive values for identifying patients who respond to treatment.

Meanwhile, clinical test utility verifies that use of the test resulted in improved patient outcomes. Typically, this is established in a pivotal Phase 3 study. Key issues for crucial IVD CDx studies include IVD CDx study designs (17,18) and statistical analysis (19); biomarker cut-off selection and refinement; and the study of biomarker-positive and -negative patient subgroups. Stratification, enrichment and other adaptive trial designs are considerations to be used for assessing clinical utility of a proposed IVD CDx based on the strength of the biomarker (20).

Novel clinical study designs are increasingly used in clinical validation to account for disease heterogeneity and complexity of multiple biomarkers models. Examples include:
  • I-Spy2 (The Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And Molecular Analysis 2) is a Phase 2 screening study model using an adaptive randomisation strategy to test multiple biomarkers and drugs for neoadjuvant chemotherapy in locally advanced breast cancer (21)
  • Lung-MAP (The Lung Cancer Master Protocol) is a Phase 2/3 study for non-small cell lung cancer using NGS to assign patients with the same biomarker profile to one of five sub-studies testing investigational therapies against a randomised control arm (22)
  • PREDICT (The Profile-Related Evidence Determining Individualised Cancer Therapy) was a basket navigation trial that assigned patients with metastatic cancers to targeted therapy treatment groups, irrespective of tissue origin (23)
Marketing Authorisation
To ensure concurrent approval, the therapeutic drug product and IVD CDx should be reviewed and approved by the appropriate regulatory authorities in parallel and under their relevant drug/ device regulations. Before approval is granted, regulators will assess that the IVD CDx is properly validated and meets standards for safety and effectiveness for the use indicated in the IVD CDx and therapeutic drug product labelling. Information on the labelling depends on how the IVD CDx test is used; for example, tests that aid appropriate patient selection are listed in the ‘Indications and Usage’ section, while tests essential for monitoring therapeutic or toxic effects are addressed under ‘Warnings and Precautions’.

Commercialised Assay
Regulatory oversight continues following marketing authorisation; IVD CDx lifecycle management is required to demonstrate ongoing safety, effectiveness and performance. Activities may include post-market surveillance studies, post-approval submissions (such as updates to the label or changes to the test), as well as reports (for instance, complaints and adverse events, medical device reports, recalls, corrections and removals).

Post-approval challenges include cost coverage and reimbursement issues. Data to support clinical utility and costeffectiveness are critical for IVD CDx reimbursement and full integration in the clinic. Insurers reluctant to provide coverage typically request more rigorous assessment of therapeutic- CDx cost effectiveness, compared to current standard of care and impact on health outcomes (24). Innovative strategies – like the use of real-world observational data – may be used to provide evidence to support the fact that a precision medicine approach can improve outcomes while controlling costs.

Towards Targeted Therapies

As precision medicine advances, the number of targeted therapies reliant on IVD CDx will dramatically increase. Improvements in technology are providing better predictive assessments of disease and treatments, as well as cutting-edge assays to interrogate molecular pathways. The use of multiple technology platforms and multi-factorial testing (multi-gene or multi-analyte signatures) for common and complex diseases is furthering our scientific capabilities to support a comprehensive and well-coordinated diagnostic testing approach with targeted therapies. This will help drive the practical application of precision medicine in the clinic.

Co-development and validation of targeted therapies and IVD CDx is the most efficient – though more challenging – pathway to deliver precision medicine to patients. Keys to successful co-development include: early identification of a biomarker; thorough planning to implement parallel development of the therapeutic drug product, biomarker and IVD CDx; and close coordination, integration and collaboration among the therapeutic drug and diagnostic developers and regulatory authorities. Novel and adaptive clinical trial designs that better facilitate co-development and simultaneous introduction of targeted therapies and unique IVD CDx technologies will speed precision medicine advances.

Acknowledgements

The authors appreciate the critical review of this article by Pat Bennett, Robert Cumming, Karla Jacobus and Nancy Teague.

References

1. Katsnelson A, Momentum grows to make ‘personalized’ medicine more ‘precise’, Nat Med 19: p249, 2013
2. Atkinson AJ et al, Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework, Clin Pharmaco Ther 69(3): pp89-95, 2001
3. FDA, Guidance for Industry and Food and Drug Administration staff: In vitro companion diagnostic devices, August 2014
4. FDA, List of cleared or approved companion diagnostic devices (In vitro and imaging tools), June 2015. Visit: www.fda.gov/medicaldevices/productsandmedicalprocedures/ invitrodiagnostics/ucm301431.htm
5. Personalized Medicine Coalition, The Case for Personalized Medicine, 3rd edition, 2013. Visit: www. personalizedmedicinecoalition.org/ userfiles/pmc-corporate/file/the_case_ for_pm1.pdf
6. US Food, Drug and Cosmetic Act, Medical Device Amendments of 1976
7. Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical devices. Visit: http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:31998L0079&from=en
8. Japanese Revised Pharmaceutical Affairs Law, 2005
9. EMA draft Reflection Paper on methodological issues associated with pharmacogenomic biomarkers in relation to clinical development and patient selection (EMA/446337/2011), March 2011
10. EMA draft Reflection Paper on co-development of pharmacogenomic biomarkers and assays in the context of drug development (EMA/CHMP/641298/2008), June 2010
11. Pharmaceuticals and Medical Devices Agency, Technical guidance on companion diagnostic and related pharmaceutical products, PMDA Notification No. 1224029, December 2013. Visit: www.pmda.go.jp/english/service/in_vitro_e.html
12. Code of Federal Regulations. Title 21, Chapter I, Subchapter H, Part 820:Quality systems regulation, revised 1 April 2013. Visit: www.accessdata.fda. gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?cfrpart=820
13. International Standards Organization, ISO 13485:2003, Medical devices – quality management systems – requirements for regulatory purposes
14. FDA, Guidance for Industry and Food and Drug Administration staff: Pharmacogenetic tests and genetic tests for heritable markers, June 2007.Visit: www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm071075.pdf
15. Collins FS and Hamburg M, First FDA authorization for next-generation sequencer, NEJM 369: pp2,369- 2,371, 2013
16. Morrison C, Illumina, Thermo Fisher build consortia to develop ‘universal’ cancer tests, Nature Biotechnol 32: pp1,073-1,074, 2014
17. FDA, Guidance for Industry and Food and Drug Administration staff: In vitro diagnostic device studies – frequently asked questions, June 2010. Visit: www. fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm071230.pdf
18. FDA, Guidance for Industry and Food and Drug Administration staff: Design considerations for pivotal clinical investigations for medical devices, November 2013. Visit: www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm373766.pdf
19. FDA, Guidance for Industry and Food and Drug Administration staff: Statistical guidance on reporting results from studies evaluating diagnostic tests, March 2007. Visit: www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm071287.pdf
20. Hilton H and Butz K, Precision medicine: Hitting targets, Eur Pharma Cont 74: pp10- 15, March 2015
21. Barker AD et al, I-Spy2: An adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy, Clin Pharmacol Ther 86: pp91-100, 2009
22. Trial offers new model for drug development, Cancer Discov 4: pp266-267, 2014
23. Tsimberidou AM et al, Personalized medicine in a Phase I clinical trials program: The MD Anderson Cancer Center initiative, Clin Cancer Res 18: pp6,373-6,383, 2012
24. Ramsey SD et al, Toward evidencebased assessment for coverage and reimbursement of laboratory-based diagnostic and genetic tests, Am J Manag Care 4: pp197-202, 2006


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Kenneth Butz is Associate Director, Medical Devices and Diagnostic Consulting at PPD, where he provides diagnostics and CDx lifecycle management services from early development through to marketing authorisation and post-approval product support. Prior to joining PPD in 2012, Kenneth worked for Conatus Consulting as a Regulatory Affairs and Quality Systems Associate, and founded Vista Bioconcepts. He also worked for ParagonDx, supporting the development and commercialisation of tests and controls based on pharmacogenomics biomarkers. Kenneth earned a Master’s degree in Biological Sciences from Marshall University, and a BSc in Natural Sciences from Muhlenberg College, US.

Holly Hilton
is Director, Biomarkers and Translational Sciences at PPD, and coordinates biomarker services for the company’s central, bioanalytical and vaccines laboratories. Prior to joining PPD in 2013, she worked at Hoffmann-La Roche in the Translational Research Sciences department for 15 years, where she oversaw translational genomics research from preclinical to early development. Holly received her BSc in Biology from Creighton University, and her PhD in Genetics from Rutgers University, US. She is also an Adjunct Professor at Rutgers University Graduate School of Biomedical Sciences.
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