A CRO Partner in Rx/CDx Co-Development

The following article is an excerpt from an interview conducted by Clinical Leader with Mark Roberts, Ph.D., Director of Diagnostics Development at Covance. (http://www.clinicalleader.com/Doc/covance-cro-partner-rxcdx-co-development-0001#)

Mark Roberts - CRO Partner in Rx/CDx Co-DevelopmentPersonalized medicine presents a complex technological challenge. Combining an in vitro test for patient diagnosis and selection with a specific drug therapy — each traditionally the product of a separate industrial sector — requires the integration of two somewhat disparate development tracks, as well as all the skills needed to navigate both paths. It is hardly a theoretical conundrum. Short of producing a mass-market blockbuster with unprecedented safety and efficacy, the fate of the typical pharma company may hang on whether it can achieve superior outcomes by using biomarker tests to match new, targeted drugs to the right patients for the best-possible therapeutic management and response. Despite the innate challenge of integrating drug and device development inside traditional pharma companies, personalized medicine has them rushing to develop and commercialize companion diagnostics (CDx) products.

“Most drug therapies don’t work for all potential patients,” says Mark Roberts, Ph.D., Director, Diagnostics Development at Covance. “Historically, a given drug only worked in a fraction of the target population, and in many cases, that may have been good enough to get it to market. However, the bar is continually being raised and future drug approvals, especially in oncology, will require much improved clinical outcomes. Thankfully we now possess an array of tools to identify, based on the pathways to which they are targeted, why some drugs are effective for some patients and conversely why other patients see reduced or no benefit or experience adverse drug reactions. As such, there is great opportunity to make clinical trials more effective and improve the outcome of drug therapies.”

Regulators and payers have begun to reward and, in some cases, demand a CDx approach with new therapeutics. Payers especially see the potential of CDx to reduce the cost of unnecessary therapy and drive comparative effectiveness.  Pharma companies historically resisted the use of Dx tests to tailor therapy as it may raise questions around the safety or efficacy of the drug, potentially impeding its adoption. Diagnostics makers were also slow to accept the CDx concept because the markets for targeted drugs may be small and the CDx development would require significant investment with little guarantee that the drug would receive approval. More recently, many pharma companies have made significant investments in their diagnostic capabilities either through acquisition, internal investment or the establishment of strategic partnerships with Dx companies. However, according to Roberts, many companies still lack the full set of capabilities for optimum, parallel development of drug/diagnostic combinations (CDx).

“What I’m seeing in many cases is a lack of understanding of the key differences between the diagnostic market and the pharmaceutical market. We advise clients very early on to keep a clear eye on the commercialization strategy, to understand and plan for all the steps required to develop a CDx product. Many companies are looking for expertise that can help them fill that knowledge gap — to guide them through the process of choosing the right commercialization partner, selecting the right device format, and the most optimal way to take the drug and diagnostic through the regulatory approval process and on to the market together. In the big picture, a CDx strategy is more than a drug or device — it is a unified therapy that involves more precise patient stratification and outcome management.”

What Roberts says about companies’ needs is based on more than his own analysis. Covance has studied the requirements of pharma companies regarding CDx development. (See sidebar on previous page, “Why Use the CRO for CDx?”) In general, the needs span the entire development chain, from drug and biomarker discovery and device design, through clinical trials and commercialization — and they are not just operational, but also tactical and strategic.

Rx/Dx CO-DEVELOPMENT IS CDx-EFFECTIVE

In all cases, says Roberts, the expressed needs of companies create an opportunity for CRO leadership in CDx development. Covance has responded to the opportunity with a “Client Value Proposition.” Client companies can rely on the CRO for collaborative co-development of drug and device, thus removing problems with sample availability or the need for additional device trials. “Being able to piggyback the device trial on top of the drug trial yields real-time validation of CDx clinical utility and performance, expedites the timeframe for device approval and reduces the cost, while reducing the risks of performing the device trial separate from the drug trial.”

The FDA is on the record favoring CDx drug and device co-development: “In most circumstances, if use of an in vitro companion diagnostic device is essential for the safe and effective use of a therapeutic product, the IVD companion diagnostic device and therapeutic product should be approved or cleared contemporaneously by FDA for the use indicated in the therapeutic product labeling.”

Regulatory authorities and markets around the globe reflect similar preferences but in localized contexts — another challenge to which Covance can apply considerable advantages. Roberts points to oncology, where CDx is expanding most rapidly, as the clearest example of how the CRO helps companies cover the ground.

“Oncology trials are increasingly global, and there is competition for patients as the trials become much more widespread. They are also spreading to places like China where there are a lot of restrictions on exporting of human materials. We have resources available in all of those territories, with many identical analytical systems installed in our wholly-owned laboratories in Europe, Singapore, China, Japan, and the United States and a fully compatible data network worldwide to allow for the most rapid processing of clinical samples and reporting of data.”

FULL-SPECTRUM CDx SUPPORT

From the earliest stages, Roberts says Covance helps sponsors assess and evaluate design alternatives for the device and for the device/drug combination, including basic but critical aspects such as choice of analytical platform and optimal global distribution. “To be most effective as a companion diagnostic, the test needs to both provide accurate data and be widely available. If you cannot provide the physician with ready access to the test nor report the results in the timeframe the physician needs, it may reduce market adoption of the drug.”

Covance coaches clients to understand the endmarket needs, asking key questions early regarding the patient demographics, treatment regimen, sample type and result turnaround time as all of these factors are important in the development process. Based on the answers to these questions Covance advises the client on the optimal analytical platform and commercialization strategy.

“Your choice of a diagnostics technology, format, and partner can dictate how successful your drug-3-will be. If you make a mistake in your choice it may take a long time and be costly to unravel. We help companies find the best platforms and players, with the best global reach, technology support, and performance.” says Roberts.

“Historically, these discussions have taken place when the drug was in advanced development. We encourage our clients to accelerate the discussions with the commercialization partners, so the parties can work hand in hand through the whole development process and more readily respond to issues that may arise,” he says. Roberts says the CRO’s perspective can be especially useful at the early stage. “With our long experience working with device and pharma companies, we can help guide them toward a CDx technology set-up that delivers the correct sensitivity and specificity in predicting patient response, on an appropriate and flexible assay platform. We also help them adapt the set-up for regulatory clearance in global markets”

While building up a large menu of CDx-related services, Covance has chosen to forego one specific role — it has no plans to directly commercialize in vitro diagnostic test kits rather it has chosen to partner with industry-leading companies that provide technology specific solutions and a global commercial reach.

“We focus on our core competences, which are to be the solutions provider for pharma clients that are developing their drug pipelines. We’re now offering the companion diagnostic capability on top of that, helping them develop the CDx and facilitating partnerships with the medical device companies (whether they be large platform or point-of-care device manufacturers) best suited to bring the CDx to market.”

ADAPTING TO THE CDx ENVIRONMENT

The CRO’s knowledge and experience translate into its guidance of CDx development down to the finest details of protocols and procedures, effectively limiting costly complexity with strong doses of practicality. However, with multiple parties now at the table one should always remember that the requirements of the drug and device development are not always complementary; in fact, they can be quite disparate.

“You’re essentially running two trials together, and you have to understand the impact a request from one party may have on the other party. We focus very heavily on engaging the device manufacturers as strongly as the pharma client. The device manufacturer is not just a vendor of a test used in a clinical trial, but a sponsor of a device trial — and has to be treated accordingly.”  The ability to evaluate a great variety of technologies results from the CRO’s core business: the running of clinical trials for drug development, Roberts says.

“For every trial, we run single, dozens, hundreds of tests on any given day, on any given sample that comes into any of our labs globally.” The same core capability allows the CRO to handle multiple CDx projects at any given time, he says. “In the lion’s share of cases, the models, structure, techniques and processes we have in place are transferrable to companion diagnostics. Instead of running a lipid panel on a blood sample, we bring in an assay that has never been run before in a clinical setting, but we run it on the same sample. If it is a platform we don’t routinely utilize we have processes and procedures to rapidly install and validate the platform. Such projects may sometimes form the basis of a new service offering to other trial sponsors.”

PARTNERS IN COMMERCIALIZATION

The CRO frequently receives calls from existing or potential commercialization partners who are looking to take existing CDx partnerships with pharma into the clinic to provide both clinical validation of and data to support the regulatory filing of the assay. The confluence of pharma and diagnostic discussions reflects the CRO’s networking role in CDx development — matchmaking based across a broad service offering to a diverse customer base in both worlds.

For all pharma clients, the approach is similar: start by selecting and securing a commercial partner. As part of the process, the CRO moderates a discussion between the prospective partners meant to air out possible problems:

“If the client is requiring a certain level of sensitivity that the chosen technology will struggle to deliver its better to have those discussions up front and consider alternative approaches, rather than try to address the issue down the line once there’s already been significant investment in the development program.”

Seasoned advice and guidance amidst the often mighty clash of the converging forces driving CDx development — that may be the ultimate service the CRO can offer a client. It is clear, at least in Covance’s case, that such expert guidance qualifies it as a key partner in the business of combining drugs and diagnostics for personalized medicine.

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