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.
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Few anatomical tools hold more potential to revolutionize the science of diagnostics than biomarkers, and pathologists and medical laboratories will be first in line to put these powerful tools to use helping patients with chronic diseases
There’s good news for both anatomic pathology laboratories and medical laboratories worldwide. Large numbers of clinically-useful new biomarkers continue to be validated and are in development for use in diagnostic tests and therapeutic drugs.
Clinical laboratories rely on biomarkers for pathology tests and procedures that track and identify infections and disease during the diagnostic process. Thus, trends that highlight the critical role biomarkers play in medical research are particularly relevant to pathology groups and medical laboratories.
Here’s an overview of critical trends in biomarker research and development that promise to improve diagnosis and treatment of chronic disease.
Emerging Use of Predictive Biomarkers in Precision Medicine
Recent advances in whole genome sequencing are aiding the development of highly accurate diagnostics and treatment plans that involve the development and use of Predictive Biomarkers that improve Precision Medicine (PM).
PM involves an approach to healthcare that is fine-tuned to each patient’s unique condition and physiology. As opposed to the conventional one-size-fits-all approach, which looks at the best options for the average person without examining variations in individual patients.
Predictive biomarkers identify individuals who will most likely respond either favorably or unfavorably to a drug or course of treatment. This improves a patient’s chance to receive benefit or avoid harm and goes to the root of Precision Medicine. (Image copyright: Pennside Partners.)
The National Institutes of Health (NIH) defines PM as “an emerging approach for disease treatment and prevention that considers individual variability in genes, environment, and lifestyle for each person.” It gives physicians and researchers the ability to more accurately forecast which prevention tactics and treatments will be optimal for certain patients.
Combining Drugs for Specific Outcomes
Cancer treatment will be complimented by the utilization of combination drugs that include two or more active pharmaceutical ingredients. Many drug trials are currently being performed to determine which combination of drugs will be the most favorable for specific cancers.
Combination drugs should become crucial in the treatment of different cancers treatments, such as immunotherapy, which involves treating disease by inducing, enhancing, or suppressing an immune response.
Biomarkers associated with certain cancers may enable physicians and researchers to determine which combination drugs will work best for each individual patient.
Developing More Effective Diagnostics
In Vitro diagnostics (IVDs) are poised for massive growth in market share. A report by Allied Market Research, states the worldwide IVD market will reach $81.3 billion by 2022. It noted that IVD techniques in which bodily fluids, such as blood, urine, stool, and sputum are tested to detect disease, conditions, and infections include important technologies such as:
Allied Market Research expects growth of the IVD market to result from these factors:
- Increases in chronic and infectious diseases;
- An aging population;
- Growing knowledge of rare diseases; and
- Increasing use of personalized medicines.
The capability to sequence the human genome is further adding to improvements in diagnostic development. Pharmaceutical companies can generate diagnostic counterparts alongside related drugs.
Biopsies from Fluid Sources
Millions of dollars have been spent on developing liquid biopsies that detect cancer from simple blood draws. The National Cancer Institute Dictionary of Cancer Terms defines a liquid biopsy as “a test done on a sample of blood to look for cancer cells from a tumor that are circulating in the blood or for pieces of DNA from tumor cells that are in the blood.”
At present, liquid biopsies are typically used only in the treatment and monitoring of cancers already diagnosed. Companies such as Grail, a spinoff of Illumina, and Guardant Health are striving to develop ways to make liquid biopsies a crucial part of cancer detection in the early stages, increasing long-term survival rates.
“The holy grail in oncology has been the search for biomarkers that could reliably signal the presence of cancer at an early stage,” said Dr. Richard Klausner, Senior Vice President and Chief Medical Officer at Grail.
Grail hopes to market a pan-cancer screening test that will measure circulating nucleic acids in the blood to detect the presence of cancer in patients who are experiencing no symptoms of the disease.
Clinical Trials and Precision Medicine
The Precision Medicine Initiative (PMI), launched by the federal government in 2015, investigates ways to create tailor-made treatments and prevention strategies for patients based on their distinctive attributes.
Two ongoing studies involved in PMI research are MATCH and TAPUR:
- MATCH (Molecular Analysis for Therapy Choice) is a clinical trial run by The National Cancer Institute. The researchers are studying tumors to learn if they possess gene abnormalities that are treatable by known drugs.
- TAPUR (Targeted Agent and Profiling Utilization Registry), is a non-randomized clinical trial being conducted by the American Society of Clinical Oncology (ASCO). The researchers are chronicling the safety and efficacy of available cancer drugs currently on the market.
New Tools for Pathologists and Clinical Laboratories
The attention and funds given to these types of projects expand the possibilities of being able to develop targeted therapies and treatments for patients. Such technological advancements could someday enable physicians to view and treat cancer as a product of specific gene mutations and not just a disease.
These trends will be crucial and favorable for clinical laboratories in the future. As tests and treatments become unique to individual patients, pathologists and clinical laboratories will be on the frontlines of providing advanced services to healthcare professionals.
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