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Q&A: Mansoor Mohammed on Navigating the 'Complex Ecosystem' of Personalized Diagnostics


mansoor.jpgBy Justin Petrone

Name: Mansoor Mohammed

Title: President and Founder, ManaGeneDx

Age: 38

Professional background: 2010-present, president and founder, ManaGeneDx, Toronto; 2007-2010, president and CEO, CombiMatrix Molecular Diagnostics, Irvine, Calif.; 2006-2007, chief scientific officer and chief operating officer, CombiMatrix Molecular Diagnostics; 2003-2006, director of advanced technologies, Quest Diagnostics, San Juan Capistrano, Calif.; 2001-2003, director of R&D, Spectral Genomics, Houston

Education: 2001, postdoc, clinical cytogenetics, Baylor College of Medicine and Spectral Genomics, Houston; 1999-2000, postdoc, clinical cytogenetics, University of Los Angeles; 1999, PhD, animal biotechnology and molecular genetics, University of Guelph, Ontario; 1994, BSc, molecular biology and genetics, University of Guelph

The last decade has been eventful for Mansoor Mohammed. In the span of 10 years he went from being a UCLA postdoc to head of R&D at a startup company, director of a global laboratory diagnostic-testing firm, and CEO of a molecular diagnostics-services company, CombiMatrix Molecular Diagnostics, that used array technology to play in the nascent personalized medicine market.

After three years at the helm of CMDX, which launched more than 10 array-based tests under his leadership, Mohammed decided to strike out on his own, founding a consultancy in Toronto called ManaGeneDx whose aim is to help clients develop genomic tests and tackle the technological, medical, and regulatory issues that affect them.

Today, Mohammed believes that he has the experience to help firms find their way through what he calls the "ecosystem" of personalized diagnostics. To gain more insights about the molecular diagnostics market and the role arrays play in it, BioArray News spoke with Mohammed last week. Below is an edited transcript of that interview.

Why did you leave CombiMatrix to start your own consultancy?

My decision was based on two primary considerations. First, when I accepted my position at CombiMatrix Molecular Diagnostics, I had recently moved my young family back to our home town of Toronto. Throughout my five-and-a-half-year tenure at CMDX, from my initial appointment as the chief scientific officer to chief operations officer, and ultimately to CEO, I maintained a residence in Toronto and would travel frequently between Toronto and [CMDX's headquarters in] Irvine.

This arrangement worked well, because when I was in Toronto I would liaise with the Centre for Applied Genomics and its director, Steve Scherer, an arrangement that benefitted CMDX tremendously. However, I did not want, nor did I intend, to continue crossing from East Coast to West Coast indefinitely.

Moreover, in the last few years, [former CombiMatrix CEO] Amit Kumar made the insightful decision to focus CombiMatrix on the growing genomic diagnostics sector, and in the past year or so, CombiMatrix has evolved and matured to focus almost entirely on this substantial opportunity. [Judd] Jessup's appointment as the new CEO of CombiMatrix [in August] is consistent with this focus, and I anticipate great things from this company under his skilled leadership.

The concerted focus of CombiMatrix on the diagnostics sector, and its centralization of its leadership in Irvine, posed a dilemma for me in that it justifiably called for my and my family's relocation to Irvine, a daunting prospect … given the then age of my children.

Considering the preceding, and that for some time now, I have received strong encouragement from other executives and mentors in the industry to capitalize on my breadth and depth of knowledge of the diagnostics service sector, I ultimately decided to step down from my role at CMDX and launch ManaGeneDx, a consulting and management firm focused on the personalized diagnostics and genomics medicine space.

What is your vision for ManaGeneDx?

I am absolutely convinced that the opportunity for genomic diagnostics is ripe now, and I am further convinced that personalized diagnostics and medicine will finally mature into their full potential, as opposed to being catch phrases with little substance. However, I have begun referring to the personalized-diagnostics space as more of an 'ecosystem' than a 'space.' It is the latter consideration, or realization, that defines the vision and ethos of ManaGeneDx.

Why the analogy to an ecosystem? I have found that the diagnostic industry of today is governed by multiple interrelated, interdependent, and sometimes competing considerations. A company aspiring to serve a particular segment in today's clinical diagnostic market must determine which technology platform is best-suited for the stated objective. They have to ask themselves questions like, 'Should a SNP array be used? An oligo CGH array? Should sequencing be considered? What about PCR? Should I attempt to offer my test as a home-brew? Does it even qualify for such? Who is my intended audience? Am I selling directly to the end user? Is the clinical relevance clear and apparent to the end user? If in oncology, will my test provide data that will guide the therapeutic decision process or will it be perceived as added data with little patient care relevance? Am I going to be able to justify a meaningful reimbursement for my test using existing [Current Procedural Terminology] codes? Are the existing CPT codes even relevant or appropriate to my test? Will the insurance providers consider my test 'medically relevant?'

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In summary, what I have learned over the years is that a successful diagnostic test is one that has been skillfully navigated through this complex ecosystem of questions and considerations.

The founding of ManaGeneDx has been exceptionally gratifying to me as it allows me to draw from my diverse background … to provide a uniquely rich and relevant insight into this industry that spans workbench to boardroom, and scientific and financial oversight to regulatory considerations.

In essence, therefore, ManaGeneDx is a management and consulting firm helping young and even established companies successfully navigate the personalized-diagnostics ecosystem.

You mentioned reimbursement and regulatory challenges. Are the issues for array-based personalized diagnostics different than other molecular tests, such as PCR-based assays?

Most certainly. In the personalized diagnostic space, tests generally fall into one of three buckets. The first bucket [comprises] existing, well-established methodologies with well-established CPT payment terms. For example, there is still a thriving market for FISH probes. It is conceivable that a company could be working with a group doing array-CGH discovery and through that process discover that something as simple as two FISH probes could be good enough for monitoring a certain cancer. The company decides to make a FISH probe panel for this cancer and they are going to market this panel as such. Here is a test that utilizes a technology that already exists and its payment [model] is already well established.

Bucket number two includes tests that utilize well-defined technologies, but the CPT reimbursement for that technology may not be appetizing for the company with that test. To be more specific, these are tests that utilize existing technologies with existing codes, but since the tests are unique, and offer more information, the company may be better off arguing for a reimbursement that is not defined by existing CPT codes. This allows the company to price the test based on its idea of what the test is worth. They do not base the test on some rubric of CPT codes because they believe the test in its fullness is worth more than what those codes might otherwise give.

An example of a test in bucket number three is one that utilizes a unique platform or some combination of unique platforms for which there is no well-defined CPT coding. What CPT codes are we are going to use to generate effective reimbursement when genome sequencing becomes a mainstay? With arrays, CPT codes were created around 2005, but were meant for tests with typically 50 to 500 probes. How does a company take these codes and use them as the base for pricing its array-CGH platform that contains 180,000 probes? Even if one applies the practice of using a multiplier, you will certainly not apply a 360-fold index. The point is, there is a marked degree of company-based justification in interpreting how to use existing CPT codes in this third group of tests.

As the industry matures, these types of decisions are going to have to be addressed and better pricing is going to have to be put into place. Of course 'better' in this context is totally dependent on whose perspective we're asking.

Who is going to lead that process?

That is a question I truly cannot answer yet. But if the [clinical diagnostic] labs take the lead on it, they of course would like the best reimbursement for the test that they are providing. At the other end of the spectrum, if you ask the insurance provider, they are going to challenge whether this high-complexity, data-rich information is actually needed and is medically relevant.

Array-CGH for postnatal clinical diagnostics is practically a clinical mandate when appropriate. It is now considered an incredibly well-vetted standard of diagnostic care. However, from thousands of cases I have personally experienced, we still find that array-CGH can be ordered by a physician for the diagnosis of a developmental abnormality and the initial response from the insurance provider is still a rejection of the claim, usually using the argument of 'lack of medical necessity.'

To take another stab at the question, I think it is up to a balanced interaction between the medical community and the provider community, the medical community being the voice of clinical reason, stating that these are tests that are making a meaningful and clinically relevant difference or improvement in their medical practice. The [clinical diagnostics] lab community, in turn, must work to bring the costs of these tests down to a balance that reflects appropriate reimbursement versus the costs inherent in developing and running these tests.

Moreover, the wildcard in this equation is going to be the level of regulatory oversight imposed by the FDA. The costs expended by companies forced to engage in an FDA submission route can be significantly more costly and can take significant more time to market than a test that is laboratory developed and validated in accordance with existing CLIA standards, for example.

CombiMatrix's model has been to provide laboratory-developed tests through its CLIA-certified lab. But with new oversight looming, the regulatory environment seems to be in limbo.

The regulatory environment in the industry is in limbo both for reasons that I think are warranted as well as for reasons that are less relevant to a meaningful clinical discourse. It is my personal contention that there are array-based applications, such as array-CGH, for which the interpretative analysis is straightforward, and for which all results can be independently verified. So long as these tests are reporting a simple catalogue of genomic changes — in essence, providing a high-resolution molecular karyotype for the patient — I believe an argument can be made that existing clinical validation standards and requirements are adequate.

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That said, if the interpretative process of a multiplex assay necessarily precludes any independent validation or confirmation, or if unduly complex algorithmic or statistical processes are required to derive an interpretation, then, depending on the ultimate claims and suggested clinical course from such a test, grounds may, and I stress may, be had for further regulatory oversight.

Ultimately there is no simple ''yes' or 'no' regulatory barometer that can be used, and ultimately, further data-supported discussions are going to be needed to keep a balance between appropriate regulation and other than that.

In terms of arrays, array-CGH tests for genetic abnormalities seem to be more widely accepted while tests related to oncology have not been as rapidly adopted. Why is that?

There is a primary reason for this: In the developmental genetic-diagnostics arena the questions being asked are fundamental 'diagnostic' questions such as, 'Is there an observable genomic gain or loss in the genome of the proband?' 'Is the gain or loss de novo in the proband?' 'Can the genomic gain or loss observed explain the phenotype that is seen in this child?' In this context, the utility of the array is generally clear: Simple diagnostic questions, simple diagnostic answers with tens of thousands of cases already analyzed by multiple labs across the industry.

In contrast to diagnostic questions asked in relation to developmental abnormalities, the discourse in oncology is heavily biased toward therapeutic considerations … as is largely appropriate. In oncology, the discourse is being driven by [questions like], 'How is this data going to help me treat my patient better?' 'Is this data going to change the therapy I would otherwise administer to my patient?'

From this perspective, array-CGH data in oncology is still lacking the large clinical trials that would be necessary to deduce the preceding. However, I firmly believe that with properly designed and executed clinical trials, genomic assays in general, [and] array-CGH [in particular], will yield a treasure trove of relevant genomic data that can be intimately tied to the therapeutic decision matrix relevant to individual patients, and, accordingly, herald true personalized diagnostics and concomitant personalized medicine.

Finally, I think it is absolutely worth pointing out that while the discourse surrounding patient care in oncology is overwhelmingly driven by therapeutic considerations, there is still an incredible amount of value in the stratifying capability array-CGH brings to oncology testing. The onus is on the providers of these new tests to certainly pursue the associations of genomic changes linked to direct therapeutic decisions. However, they must also help educate the physician population as to the substantive clinical value in understanding tumor stratification and grading at the genomic level, which can certainly be provided by array CGH.

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