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Barry S. Sall is Principal Consultant, Parexel Consulting. Angela X. Qu, MD, PhD, is Senior Director â Biomarkers & Genomic Medicine, Parexel.
To succeed in developing targeted medicines, companies need a biomarker strategy and the expertise to make smart decisions about clinical trial design, assays, technology platforms and collaborative partners, write Barry S. Sall and Angela X. Qu.
Pharmaceutical companies are investing heavily in targeted medicines, and with good reason. Tightly defined patient populations, selected via biological marker (biomarker) tests performed on cells, tissues and blood, can streamline recruitment for clinical trials and boost success rates, helping developers improve R&D efficiency. Indeed, recent data suggest clinical trials using biomarkers – including genomic biomarkers – are twice as likely to succeed as those that don’t and, overall, the probability of a drug making it from Phase I to market triples when biomarkers are used in development.
An accelerating understanding of cancer genetics has led to treating patients based on the precise molecular signature of their tumor(s) rather than the originating organ(s), making a biomarker strategy ever more essential for successful development efforts. For example, in May 2017 the FDA, for the first time, approved a treatment based on a common biomarker rather than on the location in the body where the tumor originated (some have called it a “tissue-agnostic” cancer indication). Pembrolizumab (a PD-1 checkpoint inhibitor) was granted accelerated approval for patients whose solid tumors have microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) biomarkers and who either have failed prior therapies or have no therapeutic options.
However, developing a precision medicine that relies on a companion diagnostic test (CDx)-a test based on biomarkers that prospectively predict likely responses-to stratify patients is becoming increasingly complex due to rapidly growing knowledge about tumor biology and the swift evolution of diagnostic technologies. For these reasons, to succeed in developing targeted medicines, companies need a biomarker strategy and the expertise to make smart decisions about clinical trial design, assays, technology platforms and collaborative partners.
In an ideal scenario, co-development of a drug and a predictive biomarker starts early, preferably during pre-clinical development, and proceeds in tandem. However, the reality of co-development is often less linear. Why?
Sometimes, the need for a biomarker to stratify a sub-population of patients becomes apparent only midway through development, requiring companies to innovate on the fly. Sometimes, the biomarker development strategy relies on a research-based or laboratory-developed test (LDT) assay for initial stages of clinical research but then must transition to a commercial assay for later stages of research and commercialization. Other times, a company that used a research-based or prototype assay to generate its clinical data finds that a commercial assay has become available during development.
Regardless of whether there’s been a textbook co-development process from the start, or it has followed a less direct path, the drug and the biomarker test should obtain FDA approval at the same time. That’s because the agency classifies most CDxs as Class III medical devices requiring the most stringent approval route: a Premarket Approval Application (PMA), with the assay and drug cross-labeled. Sponsors of PMAs must demonstrate the clinical utility of the PMA device and, in this case, clinical utility is linked to the performance of the drug in the patient population defined by the CDx assay.
Further complicating co-development, basic research continues to reveal the genetic complexity of oncogenesis, and new technologies, such as next generation sequencing (NGS), are changing the CDx model from testing for single gene mutations to mass profiling of hundreds of genes and employing other techniques, such as immunoassays.
Companies working in this space can better manage complexity and risk if they follow five steps:
1. Begin with a biomarker strategy
Many companies recognize that they eventually will need a biomarker strategy but may put off developing one in the early stages of R&D and preclinical work. Unsure when to initiate such a strategy or what its scope should be, smaller companies with limited budgets understandably may want more proof of concept (PoC) data before investing in a long-term strategy. However, once there is preclinical data that suggest a mechanism of action (MoA), it is time to start evaluating clinical applications, including whether and how biomarkers might play a role.
The initial version of such a strategy can be brief and expand as the drug development effort progresses. In cases where a specific biomarker or CDx has not yet been identified, the initial biomarker strategy would mostly focus on assessing biomarker candidates relevant to the drug target and pathway(s), defining the scope for exploratory biomarker interrogation, and the number and type of biosamples for collection and their management.
It’s critical to select the right indication and target the right patient subpopulations, especially in the crowded oncology space (the therapeutic area in which many drug-CDx combinations have been approved). The presence of a CDx or investigational assay" to select patients will also influence clinical trial design. In some cases, regulators will want to evaluate data from both biomarker positive and biomarker negative patients, so that negative predictive value for the test can be determined.
An in-depth analysis of the biomarker/genomic landscape – leveraging domain experts, public data and internal records – will be required to pinpoint target patient populations and to clarify:
• The genetic mutation profiles with functional impact on or associations with your drug-target activities and intended indications.
• Other drugs that have the same MoA and biomarker associated with their absorption, distribution, metabolism and excretion (ADME) profile, including their efficacy and safety.
• Whether you need additional evidence, such as an exploratory biomarker investigation. If so, how that would be done.
A sound biomarker strategy is also rooted in knowledge about the target disease condition(s): What types of samples are obtained from subjects? How many? When are they obtained? Where are they stored? Should pre-analytical processing steps (extractions) be performed prior to storage? Are the samples stable in storage or do they degrade? Are procedures in place for labeling samples and for accountability in handling them?
2. Collect and manage human biosamples properly
Competency in biosample (i.e., urine, blood, tissue, cells, DNA, RNA and protein) collection and management is required to co-develop a drug and a biomarker test. Samples collected in early trials may turn out to be critical years later.
For example, one company recently began its clinical program using a research-based biomarker test that was never intended for commercial use. While the trials were in progress, a commercial assay was developed. The company now had a mixed bag of data: early studies that used the research assay and later studies that used the commercial assay. The company had to conduct a bridging study to prove the two assays performed equivalently. To compare the two assays and bridge the data gap, the sponsor needed enough patient samples – properly stored – from both the early and late phase studies.
For many experimental cancer agents, biomarker testing may serve purposes beyond just selecting patients. For instance, biomarker evaluation could allow deeper exploration of a new MoA. To accommodate these exploratory aims, companies must collect and store the right patient samples and ensure that well-crafted consent language allows for the use of those samples to measure biomarkers such as blood-based genomic profiling.
Proper management of human samples entails, among other things:
• Obtaining informed consent from patients for current and potential (but currently unknown) future use such as genomic testing or bridging studies.
• Banking samples for future retrieval in environments that will prevent tissue degradation.
• Building the appropriate infrastructure and IT to validate a sample’s chain of custody by tracking it through the complex ecosystem of laboratories, depositories and internal research and development facilities through which it will pass in its lifespan.
3. Choose the optimal assay and technology platform
The technology platforms for biomarker testing are constantly evolving, not just for CDxs but also for complementary diagnostics (tests not used for patient selection but to improve disease management, early diagnosis, risk stratification and monitoring).
Currently driving a technology transformation, NGS can deliver a report on different mutations across a series of different genes (versus a simple yes/no status for a specific mutation in a specific gene). This provides coverage and efficiency advantages, as well as lowering costs.
Other technology platforms comprise the majority of companion and complementary diagnostics that have gained FDA approval and include:
• Real-time quantitative polymerase chain reaction (qPCR);
• Proteomics (protein, peptide, immune-cytokine);
• In situ hybridization (FISH) tests
• Molecular pathology (IHC) – immunohistochemistry (IHC); and
• Others (imaging, metabolite)
No particular assay technology is preferred by regulators: each is evaluated on a case-by-case basis.
There are several considerations in biomarker assay/technology selection depending on the intended biomarker utility (Is it used for patient selection? Is it exploratory? etc.). Among commercially available assays and technologies, companies must choose an optimal platform and approach (e.g. from single-plex to multi-plex, from single gene to whole-genome).
For example, the FoundationOne CDx (F1CDx) is an NGS-based IVD device approved in late 2017 for detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB). It is currently on the label of 17 different targeted medicines to treat five types of cancer. (The F1CDx assay is a single-site assay performed at Foundation Medicine, Inc.).
4. Find the right partner(s)
Selecting an assay development partner is the next critical decision. A good partner should have the technical capability to develop a robust and cost-effective assay in a timely manner. It needs internal systems compliant with the U.S.’s Quality System Regulation (QSR), the European Union’s IVD Regulation and any other jurisdictional regulations.
The partner also should possess an assay platform consistent with the needs of the drug developer and its commercial stage customers. For example, if it is anticipated that laboratories will need to evaluate large numbers of patient samples per day, the assay platform should be compatible with high throughput. The size and geographic distribution of the partner’s installed base of instrumentation should also be considered during the selection process. Generally, manual and semi-automated assays can be developed more quickly and less expensively than assays that utilize high throughput instrumentation.
Sometimes, companies discover they need a biomarker – and an IVD development partner – relatively late in the development process. In such cases, one option is to leverage an existing relationship with a Contract Research Organization (CRO), having it serve as the point of contact to manage complex CDx partner development issues.
For example, a company scouring its unexpectedly weak Phase I and II efficacy data began to see strong signals of activity when it segmented the patient population according to a biomarker. The presence of this biomarker could clearly identify the patients most likely to respond to the drug. Already in Phase II development, the medium-sized company, not equipped to develop its own IVD, faced a host of pressing questions including how to incorporate the biomarker/CDx test into the existing development plan, would the validated assay be available, and how to find a qualified partner for developing the IVD.
In the United States, a commercial CDx assay must be developed in accordance with the Design Control provisions (21CFR 820.30) of the QSR. The new EU IVD Regulation will require compliance with the ISO 13485 Quality System standard and other requirements. Compliance with these regulations requires multiple standard operating procedures (SOPs) and considerable documentation once the assay development process is underway. This is one reason that drug developers rarely develop CDx assays internally, usually engaging diagnostic development partners that already have systems and staff in place to generate the necessary documentation.
Companies must determine whether there is a commercially available assay that can be used. If not, can they find an assay not yet commercially available but already in development? (Caveat: It is often difficult for outsiders to find out if an investigational assay exists because assay developers generally do not discuss them publicly.) In either case, a company will need to work out an arrangement with a manufacturer if it is going to use it to select patients for clinical trials. If an assay is already approved for the relevant analyte – for another drug or for another disease – an investigational device exemption (IDE) may still be necessary if assay data will be used to select subjects for treatment with the investigational drug.
5. Validate biomarkers and regulatory options
Once there is enough data to analyze, computational and other analytical techniques can be used to identify informative biomarkers. Biomarker candidates must be interrogated rigorously to inform CDx development.
If there is no existing assay that measures the relevant biomarker (that is, you are developing a novel drug with a novel MOA that will require a novel diagnostic test), there are many regulatory considerations. A novel CDx faces the same regulatory hurdles as any diagnostic tool: you will have to demonstrate that it performs properly in terms of specificity, accuracy, precision (with reproducibility and repeatability), and clinical utility.
In an attempt to streamline the CDx process, the FDA recently released two guidances with recommendations for designing, developing and validating genetic and genomic-based tests, including in vitro diagnostics (IVDs), NGS technology, and other precision medicine devices.
The April 2018 draft guidance Investigational In Vitro Diagnostics in Oncology Trials: Streamlined Submission Process for Study Risk Determination Guidance for Industry provides what could be a simpler path for companies to evaluate their assay risk status (that is, is an IDE needed?). Assays can now be considered during the investigational new drug (IND) application review, rather than in a pre-submission meeting with the Center for Devices and Radiological Health (CDRH). This could potentially reduce the time needed to prepare for and engage in an extra meeting, but still requires that a comprehensive data package be included in the IND filing.
In the United States, a detailed analysis of the regulatory process and commercial landscape associated with any one CDx may suggest that the LDT route may be more appropriate, at least for early commercialization. Currently, LDTs do not require FDA approval and an LDT assay can utilize any assay technology (including when there are multiple biomarkers that need to be tested and validated at the protein/cytokine level).
The advantage of an laboratory development test (LDT) is that it can be made available quickly, without the need for FDA approval. The disadvantages include: 1) In order to be considered an LDT, the assay must be developed, validated and performed in the same CLIA high-complexity certified clinical laboratory; it cannot be performed in multiple laboratories; 2) The enforcement discretion that FDA is currently exercising with respect to LDTs could end with an administrative policy change, and 3) Reimbursement for LDT assays may be more difficult to obtain than for PMA-approved assays.
Even when there are commercial assays available (such as the PMA-approved PD-L1 assays) in some limited cases, it may be possible for FDA to review a CDx assay via the de novo classification process.
Even if a relevant CDx already is approved (with a different drug), before a company can cross label their new drug and the existing CDx assay, a new PMA that mentions the name of the drug in the assay labeling must be submitted and approved by FDA.
Biomarkers not only help identify patients who will receive meaningful benefits from a drug, they also identify those who won’t, reducing the risks unnecessary treatments pose to patients and the costs ineffective ones impose on payers.
Because of their obvious efficiencies and superior efficacy, the biopharmaceutical industry will continue to focus on targeted medicines in cancer and other therapeutic areas. As a result, competing successfully in this space will require developers to perform at the highest levels of strategic, operational and technological excellence.
Trade Name (generic name)
Companion Diagnostic (CDx)
CDx Molecular Target
Approval Date/ Reference
Gilotrif (afatinib) (1)
Boehringer Ingelheim International GmbH
metastatic non-small cell lung cancer (NSCLC) with non-resistant epidermal growth factor receptor (EGFR) mutations
therascreen® EGFR RGQ PCR Kit (1)
EGFR mutations L861Q, G719X and S768I
January 12, 2018
FDA Approval Letter
Lynparza (olaparib tablets) (2)
AstraZeneca Pharmaceuticals LP
deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer
BRACAnalysis CDx® test (2)
Myriad Genetic Laboratories Inc.
BReast CAncer susceptibility gene (BRAC)
January 12, 2018
FDA Press Release
Tasigna (nilotinib) (3)
Novartis Pharmaceuticals Corporation
addition of treatment-free remission data to label for Philadelphia chromosome-positive
chronic myeloid leukemia (CML)
MolecularMD MRDxTM BCR-ABL test (3)
breakpoint cluster region–Abelson (BCR-ABL1) mRNA transcript levels
December 22, 2017
FDA Press Release
Ogivri (trastuzumab-dkst) (4)
Mylan N.V. and Biocon Ltd.
breast or metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma) with overexpression of HER2 gene
FDA-approved tests for HER2 protein overexpression and HER2 gene amplification
December 1, 2017
FDA Press Release
relapsed or refractory acute myeloid leukemia (AML) with an IDH2 mutation
RealTime IDH2 Assay
isocitrate dehydrogenase-2 (IDH2)
August 1, 2017
FDA Press Release
Novartis Pharmaceuticals Corporation
newly diagnosed AML with an FLT3 mutation
LeukoStrat CDx FLT3 Mutation Assay
Invivoscribe Technologies Inc.
fms-like tyrosine kinase 3 (FLT3)
April 28, 2017
FDA Press Release
(1) Supplemental application for a new indication on the label.
(2) Granted regular approval from original accelerated approval.
(3) Label update.
(4) Biosimilar of Herceptin
Barry S. Sall is Principal Consultant, Parexel Consulting. Angela X. Qu, MD, PhD, is Senior Director – Biomarkers & Genomic Medicine, Parexel.
 Wong, C., Siah, K. and Lo, A. (2018). Estimation of clinical trial success rates and related parameters. Biostatistics. [online] Available at: https://academic.oup.com/biostatistics/advance-article/doi/10.1093/biostatistics/kxx069/4817524 [Accessed 10 Apr. 2018].
 Thomas, D. W., Burns, J., Audette, J., Carrol, A., Dow-Hygelund, C., & Hay, M. (2016). Clinical development success rates 2006-2015. San Diego: Biomedtracker/Washington, DC: BIO/Bend: Amplion.