by Reshma Jagasia, Ph.D., Scientist
“Doctors have always recognized that every patient is unique, and doctors have always tried to tailor their treatments as best they can to individuals. You can match a blood transfusion to a blood type — that was an important discovery. What if matching a cancer cure to our genetic code was just as easy, just as standard? What if figuring out the right dose of medicine was as simple as taking our temperature?” — President Barack Obama, January 30, 2015
While this concept seems to touch on science fiction, the FDA is nevertheless gearing up to embrace this new approach to healthcare in their regulatory oversight. Let us start with some definitions.
What is Precision Medicine?
The current format of healthcare is to provide standardized treatments to individual patients. It is a one-size-fits-all approach to medicine that often works. However, in many cases, treatment is non-optimal or fails altogether because little or no adjustment could be made for a patient’s unique situation.
Precision medicine is an innovative approach to healthcare in which medical decisions, practices, and products are tailored to the individual patient, their genetics, environment, and lifestyle. Customization can be applied in diagnosis and intervention, drug development and usage, and cancer genomics, and almost certainly begins with diagnostic testing or other molecular or cellular analyses. Already several FDA-approved treatments have been tailored to a patient’s genetic makeup or the genetic profile of a patient’s tumor. In fact, cancer patients routinely undergo genetic testing as part of patient care, potentially enabling physicians to improve chances of survival and to reduce exposure to adverse events.
President Obama signed the Precision Medicine Initiative (PMI) in January, 2015, infusing $215 million into the advancement of this medical movement.
What is Next-Generation Sequencing?
Many advances in precision medicine will depend on the use of next generation DNA sequencing (NGS), a catch-all term used to describe a number of modern, high-throughput sequencing technologies that are much faster and less expensive compared with traditional techniques. NGS enables broad and deep sequencing of a portion of a gene, an entire exome, or a whole genome, with clinical application for diagnosis, risk prediction, and treatment for a disease or condition. The rapid adoption of NGS-based tests in both research and clinical practice is leading to the increased identification of genetic variants, including rare variants that may be unique to a single individual or family lineage. Understanding the clinical significance of these genetic variants is key to the future of precision medicine.
How Has the FDA Responded?
To help accelerate research and the clinical adoption of the PMI, the FDA is focused on optimizing their regulatory oversight for NGS in vitro diagnostics (IVDs) to help assure the safety and effectiveness of these tests. While most IVDs typically detect a limited number of analytes to diagnose pre-specified conditions, NGS-based tests can measure millions of analytes (i.e., bases) associated with numerous conditions. Moreover, the intended uses of NGS-based tests are often broad, and the nature of the resulting clinical information and types of genetic variants is often unknown until after the test has been conducted. As a result, shaping the appropriate regulatory oversight for NGS-based tests presents a challenge for the FDA.
Recently, the FDA has released two draft guidance documents outlining the proposed regulatory oversight for NGS-based tests intended to aid in the diagnosis of individuals with suspected germline diseases. The FDA has crafted its regulatory approach to be appropriately flexible and adaptive to accommodate innovation and evolution in development and validation while still assuring that NGS-based tests provide accurate and useful results.
The New Draft Guidances
Use of Standards in FDA’s Regulatory Oversight of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Used for Diagnosing Germline Diseases
This guidance document, when finalized, will provide recommendations for designing, developing, and validating NGS-based tests intended to aid in the diagnosis of individuals with suspected germline diseases or other conditions. The recommendations apply to these tests whether results are provided directly to patients or through healthcare professionals; however, for the former, additional recommendations and controls would be required. This draft guidance document does not apply to NGS-based tests intended for stand-alone diagnostic purposes, screening, microbial genome testing, risk prediction, cell-free DNA testing, fetal testing, pre-implantation embryo testing, tumor genome sequencing, RNA sequencing, or use as companion diagnostics, as these uses may require further analytical characterization.
To date, the FDA has cleared a small number of single-gene, disease-specific, targeted, NGS-based tests, but has not previously classified NGS-based tests with a broad intended use for suspected germline diseases. As a result, such tests are automatically classified into class III by operation of law. There are currently no legally marketed devices of this type that could serve as a predicate device in a premarket notification under section 510(k) of the Federal Food, Drug and Cosmetic Act (FD&C Act). Thus, these NGS-based tests are subject to FDA approval of a premarket approval application (PMA).
The draft guidance document outlines considerations for possibly classifying certain NGS-based tests for germline diseases in class II, potentially exempting them from premarket notification requirements. Specifically, The FDA encourages that applicants submit a de novo request for classification by operation of section 513(f)(1) of the FD&C Act. This request is applicable when there is not a legally marketed predicate device on which to base substantial equivalence in a 510(k), and the applicant believes that the test is appropriate for classification in class I or class II. If the de novo request for class II classification is granted, the test may then be marketed, serve as a predicate for future 510(k) submissions, and would be subject to both general and special controls.
Use of Public Human Genetic Variant Databases to Support Clinical Validity for Next Generation Sequencing (NGS)-Based In Vitro Diagnostics
There are numerous publicly accessible databases of human genetic variants that can serve as sources of valid scientific evidence to support the clinical validity of genotype-phenotype relationships. This draft guidance document describes recommendations that would confer recognition to these databases as sources of valid scientific evidence supporting the clinical validity of NGS tests. Criteria under consideration includes:
- types of variants in the database (e.g., germline, somatic);
- the use of standard operating procedures (SOPs) for general operation, confidentiality and privacy of patient health information, data security, curation, variant interpretation, and reinterpretation;
- personnel qualifications;
- the plan for data preservation; and
- policies for conflict of interest and their disclosure.
This draft guidance document also outlines the process by which database administrators could apply to the FDA for recognition, and how the FDA would review such applications and periodically reevaluate the recognized databases.
The FDA’s engagement in the PMI is foundational, establishing regulatory controls that encourage advancement in genomic testing while assuring that NGS-based tests are safe and effective. These two new guidances, once finalized, will strike that important balance between safeguarding public health and promoting innovation.
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