News, Analysis, Trends, Management Innovations for
Clinical Laboratories and Pathology Groups

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Clinical Laboratories and Pathology Groups

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Targeted Cancer Therapies Bring New Precision Medicine Tools to Anatomic Pathologists and Clinical Laboratories

FDA is streamlining how new diagnostic tests are approved; encourages IVD companies to focus on ‘qualifying biomarkers’ in development of new cancer drugs

It is good news for the anatomic pathology profession that new insights into the human immune system are triggering not only a wave of new therapeutic drugs, but also the need for companion diagnostic tests that help physicians decide when it is appropriate to prescribe immunotherapy drugs.

Rapid advances in precision medicine, and the discovery that a patient’s own immune system can be used to suppress chronic disease, have motivated pharmaceutical companies to pursue new research into creating targeted therapies for cancer patients. These therapies are based on a patient’s physiological condition at the time of diagnosis. This is the very definition of precision medicine and it is changing how oncologists, anatomic pathologists, and medical laboratories diagnose and treat cancer and other chronic diseases.

Since immunotherapy drugs require companion diagnostic tests, in vitro diagnostic (IVD) developers and clinical laboratory and pathology group leaders understand the stake they have in pharma companies devoting more research to developing these types of drugs.

New cancer drugs combined with targeted therapies would directly impact the future of anatomic pathology and medical laboratory testing.

Targeted Therapies Cost Less, Work Better

Targeted therapies focus on the mechanisms driving the cancer, rather than on destroying the cancer itself. They are designed to treat cancers that have specific genetic signatures.

One such example of a targeted therapy is pembrolizumab (brand name: Keytruda), a humanized antibody that targets the programmed cell death 1 (PD-1) receptor. The injection drug was primarily designed to treat melanoma. However, the FDA recently expanded its approval of Keytruda to include treatment of tumors with certain genetic qualities, regardless of the tumor’s location in the body. It was the first time the FDA has expanded an existing approval.

In a Forbes article, David Shaywitz, MD, PhD, noted that pembrolizumab had “an unprecedented type of FDA approval … authorizing its use in a wide range of cancers.” Shaywitz is Chief Medical Officer of DNAnexus in Mountain View, Calif.; Visiting Scientist, Department of Biomedical Informatics at Harvard Medical School; and Adjunct Scholar, American Enterprise Institute.

Cancers with high mutational burdens respond to the therapy because they are more likely to have what Shaywitz calls “recognizable novel antigens called mutation-associated neoantigens, or MANAs.” Such cancers include melanomas, non-small cell lung cancer, some rare forms of colorectal cancers, and others.

Such therapies require genetic sequencing, and because sequencing is becoming faster and less expensive—as is the analysis of the sequencing—the information necessary to develop targeted therapies is becoming more accessible, which is part of what’s motivating pharma research.

Biomarkers and Traditional versus Modern Drug Testing and Development

At the same time pharma is developing new immunotherapies, the FDA is recognizing the benefit of faster approvals. In an FDA Voice blog post, Janet Woodcock, MD, Director of the Center for Drug Evaluation and Research (CDER) at the FDA, wrote, “In the past three years alone, [we have] approved more than 25 new drugs that benefit patients with specific genetic characteristics … and we have approved many more new uses—also based on specific genetic characteristics—for drugs already on the market.”

In his Forbes article, Shaywitz notes that pembrolizumab’s development foreshadows a “More general trend in the industry,” where the traditional phases of drug testing and development in oncology are becoming less clear and distinct.

Along with the changes to drug development and approval that precision medicine is bringing about, there are also likely to be changes in how cancer patients are tested. For one thing, biomarkers are critical for precision medicine.

However, pharmaceutical companies have not always favored using biomarkers. According to Shaywitz, “In general, commercial teams tend not to favor biomarkers and seek to avoid them wherever possible.” And that, “All things being equal, a doctor would prefer to prescribe a drug immediately, without waiting for a test to be ordered and the results received and interpreted.”

In July, just weeks after expanding its approval for Keytruda, the FDA approved a Thermo Fisher Scientific test called the Oncomine Dx Target Test. A Wired article describes it as “the first next-generation-sequencing-based test” and notes that it “takes a tiny amount of tumor tissue and reports on alterations to 23 different genes.”

Thermo Fisher’s Oncomine DX Target Test (above) is the first multi-drug next-generation sequencing test approved by the FDA. The test is a companion diagnostic for lung-cancer drugs made by Novartis and Pfizer. (Caption and photo copyright: Thermo Fisher Scientific.)

Unlike pembrolizumab, however, the Oncomine Dx Target Test did not enjoy fast-track approval. As Wired reported, “Getting the FDA’s approval took nearly two years and 220,000 pages of data,” in large part because it was the first test to include multiple genes and multiple drugs. Thus, according to Joydeep Goswami, PhD, President of Clinical Next Generation Sequencing at Thermo Fisher, “That put the technology under extraordinary scrutiny.”

FDA Encouraging Use of Biomarkers in Precision Medicine Therapies

The FDA, however, is taking steps to make that process easier. Woodcock noted in her FDA Voice blog post that the agency is actively encouraging drug developers to “use strategies based on biomarkers.” She added that the FDA currently “works with stakeholders and scientific consortia in qualifying biomarkers that can be used in the development of many drugs.”

Additionally, in a column he penned for Wired, Robert M. Califf, MD, former Commissioner of the FDA, states that the organization has “begun to lay out a flexible roadmap for regulatory approval.” He notes, “Given the complexity of NGS [next-generation-sequencing] technology, test developers need assurance as well, and we’ve tried to reduce uncertainty in the process.”

Regulations that assist IVD developers create viable diagnostics, while ensuring the tests are accurate and valid, will be nearly as important in the age of precision medicine as the therapies themselves.

All of these developmental and regulatory changes will impact the work done by pathologists and medical laboratories. And since precision medicine means finding the right drug for the individual patient, then monitoring its progress, all of the necessary tests will be conducted by clinical laboratories.

Faster approvals for these new drugs and tests will likely mean steep learning curves for pathologists. But if the streamlined regulation process being considered by the FDA works, new immunoassay tests and targeted therapies could mean improved outcomes for cancer patients.

—Dava Stewart

Related Information:

How Precision Medicine, Immunotherapy Are Influencing Clinical Trial Design for Cancer Drugs

Pharma Cooperates to Achieve Precision Medicine

The Startling History Behind Merck’s New Cancer Blockbuster

Two Recent Scientific Advances Underscore an Encouraging Future for Precision Medicine at FDA

Fast, Precise Cancer Care Is Coming to a Hospital Near You

Biomarker Trends Are Auspicious for Pathologists and Clinical Laboratories

Precision Healthcare Milestone Reached as Food and Drug Administration Clears New Multi-Marker Medical Laboratory Test to Detect Antibiotic-Resistant Bacteria

Genetic Tests and Precision Medicine Start to Win Acceptance by Some Payers; Pathologists and Clinical Laboratories Have Opportunity as Advisors

Pathologists and Researchers Predict Development Trajectory for Biomarker-based Molecular Diagnostics in Support of Translational Medicine

Emerging field of translational medicine expected to contribute to more informative studies that provide superior data for making medical decisions

These are boom times for translational medicine. That’s the term used to describe how the health of individuals and the community can be improved through applying new knowledge into diagnostic tools (including medical laboratory tests), medicines, procedures, policies, and education.

Rapid developments in the field of translational medicine include a role for pathologists who are discovering and validating molecular biomarkers associated with diseases.

Pathologists Have a Role in the Science of Translational Medicine

Translational medicine was the centerpiece in an interview conducted with an expert in biomedical research. Translational medicine is “where unproven observations advance to increasingly large and more informative studies to provide definitive and comparative information for a medical decision in routine clinical practice” contended Biomedical Consultant John Sninsky, Ph.D., former Vice President of Discovery Research at Alameda, California-based Celera Diagnostics. He was quoted in an interview published by GenomeWeb.

In validating translational medicine findings, Sninsky noted that everyone (e.g. pathologists, clinical laboratory scientists, and medical technologists) who contribute to the process must “weigh and balance” information so that it’s not used prematurely, but also not delayed when it has been proven useful to medical decisions. “So, in the end, no one piece of information, whether it be the conventional diagnostic test or the new test, will suffice for medical decisions, but will require gathering and reflecting on as much of the information as possible,” added Sninsky.

Large-scale Studies Better Sources for Personalized Medical Data

The goal of “personalized medicine” is for doctors to be able to prescribe treatments that more effectively “target” their patients’ unique physiologies and conditions. How to best conduct research and interpret the findings in ways that advance clinical care is under debate, as experts address the issues of individualized care versus population management.

What makes translational medicine relevant to pathologists, clinical chemists, and other clinical laboratory scientists is that this field of science is already changing how research studies and clinical trials are designed and conducted. Experts knowledgeable in this field predict that the principles of translational medicine will support important improvements.

First, these methods will be used to design clinical studies that are less expensive and faster to complete. Second, when such studies are conducted in this fashion, there will be a faster timeline between publication of findings and acceptance by providers, payers, and patients. Both improvements have the potential to directly benefit clinical labs as they develop new medical laboratory tests, conduct the clinical studies needed to demonstrate patient benefits, and then clear regulatory requirements needed to bring these new diagnostic assays to market.

The best method for gathering that data, however, is in question, noted Sninsky. He thinks large-scale studies are a better source for accumulating the needed data than research on individuals. “If you identify personalized medicine as information that’s truly unique to an individual, we actually think that information applicable to segments of the population will prove more timely and more important,” stated Sninsky, who then added, “we think that maybe calling it ‘targeted medicine’ rather than personalized medicine makes the case in point.”

Biomedical Consultant John Sninsky, Ph.D

Biomedical Consultant John Sninsky, Ph.D. (pictured above), former Vice President of Discovery Research at Alameda, California-based Celera Diagnostics, said in an interview with GenomeWeb that Targeted Medicine is more descriptive of where disease management is heading, rather than Personalized Medicine, because gathering information on a segment of the population is more straight forward than gathering information on an individual. (Photo copyright Celera Diagnostics)

Sninsky pointed out that validation and demonstration of utility only comes with replication in large studies. Therefore, in order to be effective, he suggested that applicable information would usually address about 10% of the population, “so disease management or health management, in the context of targeted medicine, is the way we think about it.”

Role of Clinical Laboratories in the Accelerated Development of In Vitro Diagnostic Assays

According to Sninsky, the natural progression and availability of diagnostics won’t change much. Large clinical reference laboratories will continue to create laboratory-developed assays. These “home-brews” will then evolve into FDA-approved in vitro diagnostic products that get distributed to “lower-throughput” clinical laboratories.

Sninsky further observed that sometimes these “smaller service laboratories” end up offering the assays as a [clinical] service after they’re launched. This accelerates the assay’s development as an in vitro product, he said, noting that the advantage of in vitro diagnostic products over services is their widespread availability.

NIH Support for Translational Medicine Steps Up FDA Regulatory Process

Sninsky acknowledged that getting biomarker-based molecular diagnostics validated and cleared through the Food and Drug Administration (FDA) and into the hands of physicians continues to be an onerous process. The FDA, however, has taken steps to accelerate the process, which Sninsky welcomes.

“One of the things I think is really good news is the stand that the U.S. regulatory agency has taken in terms of saying we’re going to help this process along,” he noted. “If someone would have said to me 15 years ago that the FDA was going to be leading the charge of the application of biomarkers, I would have been pessimistic about that.”

Since launching its Experiential Learning Program (ELP), the FDA’s Center for Devices and Radiological Health (CDRH) has accelerated the pre-market approval rate of medical and diagnostic devices, which includes in vitro diagnostic products.

Support for advancing the translational medicine approval process was demonstrated by the National Institutes of Health (NIH) in 2011 with the establishment of the National Center for Advancing Translational Sciences (NCATS). NIH also recently launched a Precision Medicine Initiative that aims to use genetic data from individuals to personalize diagnostic and therapeutic strategies. This $215 million project is pending Congressional approval of the President’s 2016 budget. (See Dark Daily, “Obama’s $215 Million Precision Medicine Initiative: Will Congress Fund It and Can It Advance Genetic Testing and the Value of Clinical Laboratory Services?”, March 23, 2015.)

Clinical Laboratories Provide the Diagnostic Tests for Physicians

While the clinical laboratories that run these tests do help in the development and wider distribution of in vitro diagnostic assays, Sninsky believes that caregivers, health plans, and patients have a greater role in demonstrating clinical effectiveness. “What our experience has been is it’s not the clinical labs who will decide whether new biomarkers are used, but instead will be the practicing clinicians, the reimbursement agencies, and the patients who see value in them that will make those decisions,” concluded Sninsky.

–Patricia Kirk

Related Information:

‘Targeted Medicine’: New Name of the Game 

Obama’s $215 Million Precision Medicine Initiative: Will Congress Fund It and Can It Advance Genetic Testing and the Value of Clinical Laboratory Services? 

Weill Cornell and New York Presbyterian to Create New Precision Medicine Institute to Use Genome Sequencing to Individualize Cancer Treatment 

FDA Pushes Forward with Plans to Regulate Laboratory-Developed Tests, in a Move that Will Impact Many Clinical Laboratory Companies and Pathology Groups 

FDA Approving Devices Faster 

FDA Presents Plans to Ensure the Reliability of Laboratory-Developed Diagnostic Tests 

NIH and FDA Join Forces to Advance Translational Medicine and Regulatory Science 

FDA Expands Its Internal Program to Learn More from Companies about Medical Device Manufacturing