Next generation sequencing guidances intended to further precision medicine

The FDA is doing its part to support the precision medicine initiative by focusing on genomic study. Two draft guidances related to next generation sequencing (NGS) are intended to help industry continue pursuing innovation in the field while ensuring that tests are accurate and provide actionable results. The first draft guidance provides recommendations for NGS tests for hereditary diseases, and the second involves reliance on clinical evidence from existing genome databases to assist in obtaining marketing clearance or approval. The notices will officially publish in the Federal Register on July 8, 2016.

Sequencing for diagnosing hereditary diseases

Most in vitro diagnostic (IVD) tests are designed to search for certain genetic variants to test for known conditions, but NGS tests are designed to measure millions of substances and may detect new variations. These tests have broad uses, and the FDA has held various discussions to determine the best approach for regulatory oversight. At this time, NGS-based tests are automatically classified as Class III devices and subject to a premarket approval application (PMA). These tests may be reclassified into Class II following the de novo review process.

NGS-based testing will typically include several elements, from reagents to software, as well as a lengthy number of steps. Test developers should support the analytical validation by conforming with FDA standards or special controls to demonstrate that the developer has properly identified the intended clinical use and that the test is designed appropriately. This includes providing the indications for use, specific user needs for the test, specimen type, genome regions, performance needs, and components and methods for the test.

Database use

The FDA acknowledged that the adoption of NGS testing has generated an increasing amount of data, but noted that the newly discovered genetic variants are difficult to obtain and not publicly accessible. The aggregation of clinical genotype-phenotype association in generic variant databases could increase the amount of useful clinical evidence, which the agency encourages. If these databases follow the recommendations contained in the guidance, the agency would consider data and assertions obtained from these databases valid scientific evidence.

A database should: (1) provide sufficient information and assurances regarding the quality of source data; (2) provide transparency about the data source; (3) collect, store, and report data in compliance with regulations governing protected health information, data security, and subject protections; and (4) include information generated from validated methods. The database should strive for transparency and public accessibility, have a defined standard operating procedure (SOP), preserve data, and strive for a high level of security and privacy. The data must be of sufficient quality to ensure that the assertions made are accurate. Interpretation and assertions should conform to well-defined SOPs. The agency will also implement a recognition process for databases and their assertions.

Women urged to get regular cancer screenings, genetic testing options growing

Insurance companies are doing their part to make sure women take care of themselves, but some are calling the tactics into question. Despite some recommendations stating that women should get mammograms starting around ages 45 to 50, insurers and even the Medicaid program are providing incentives, such as cash and gift cards, to get the screenings earlier and more often.

The U.S. Preventive Services Task Force maintains its position that women should have screenings every two years from ages 50 to 74, while the American Cancer Society (ACS) has established guidelines of yearly mammograms between 45 and 54, with screenings every other year after that. The ACS also notes that women at higher than average risk for breast cancer should have both an MRI and a mammogram yearly. This applies to women with an elevated risk based on family history, gene mutations, a first degree relative with a gene mutation, a history of radiation therapy to the chest, or those with certain syndromes. Yet those with a low risk level should not get MRI screening, and the ACS is not yet willing to take a position on the appropriateness of MRI screening for those with a slightly elevated risk level. Still, organizations note that women should pursue screening as early as they are comfortable doing so, especially when they have concerns.

The confusing screening recommendations are compounded by the insurance companies’ incentives. According to the New York Times, there is no reporting requirement for these incentives, which range from $10 to $250. Although additional screening sounds like a great idea, the extra mammograms can result in overdiagnosis, especially for those with some cell abnormalities that are not inherently dangerous. This could lead to women undergoing painful treatments and procedures that are, in fact, unnecessary. Some think that women should be provided better guidance to allow them to make informed decisions, instead of financial inducements.

What’s in the genes?

In 2013, Angelina Jolie revealed that she underwent an elective double mastectomy after genetic testing revealed that she had a BRCA1 gene mutation. This drew more attention to the ability to tell whether a woman is genetically predisposed to having certain types of cancer. The BRCA1 and BRCA2 genes produce tumor suppressor proteins, and mutations that cause the genes to alter the protein formation can lead to further genetic changes, and then cancer. The gene mutations can be inherited from either parent, and together account for up to a quarter of hereditary breast cancers.

Genetic testing allows women, like Jolie, to take preemptive measures and elect to have surgery before cancer strikes. However, insurance companies are not required to cover these prophylactic mastectomies by federal law. Aetna, for example, considers such a procedure medically necessary in several categories of high-risk women, such as those with gene mutations, certain syndromes, or with a high degree of family history. Aetna also considers BRCA testing medically necessary, once per lifetime, for some high-risk adults.

If insurance would not cover testing, however, women were previously forced to pay up to thousands of dollars, depending on the type of testing. But Color Genomics, a startup which launched in April 2015, offers BRCA1 and BRCA2 testing for $250. Founded by former employees of tech and social media companies, Color Genomics focuses on ease of use of its website. Doctors can easily track the progress of the sample’s testing and learn whether the patient has been contacted by a genetic counselor. No patient or family history is required, and many patients can more easily afford the test without hassle from their insurance company. Because it is an e-commerce company, it is exempt from certain regulations for data storage, although Color Genomics says that it is Health Insurance Portability and Accountability Act (HIPAA) (P.L. 104-191) compliant.

Although the startup seems to be successful, the company is not the only game in town. The growth of affordable opportunities for consumers to take control of their health seems to be a welcome idea, and the company’s founder believes that human genome mapping will be the norm in coming years.

5,000 cases of adulterated crab products seized

U.S. Marshals seized 5,000 cases of ready-to-eat frozen Jonah crab products that were processed by Rome Packing Company, Inc. (Rome Packing) over concerns that the products were contaminated with harmful bacteria. The FDA and the Department of Justice announced the seizure after FDA inspections revealed that the products were prepared, packed, and held under unsanitary conditions and could present a risk to human health.

FDA Inspections

From late 2014 through early 2015, the FDA conducted inspections of Rome Packing’s facility in Massachusetts. The FDA investigators found that the company engaged in poor sanitary practices and that its crab cooking process did not maintain adequate temperatures so as to prevent the growth of pathogens such as Listeria monocytogenes (L. mono). Investigators also collected environmental swabs and found the presence of L. mono in the manufacturing area, which indicated that other areas of the facility were colonized with the pathogen.

L. mono

L. mono is a pathogenic bacterium, which can contaminate food and cause a life-threatening illness, listeriosis. L. mono can survive for long periods of time and can grow under refrigeration and in wet conditions. Individuals who have compromised immune systems are especially susceptible to listeriosis, including pregnant women, developing fetuses, and elderly individuals. While healthy individuals may suffer from only short-term symptoms such as abdominal pain, diarrhea, and a high fever, listeriosis can cause miscarriages and stillbirths. The Centers for Disease Control and Prevention (CDC) estimates that 1,600 illness and 600 deaths are attributable to listeriosis each year.

In 2012, the country experienced its largest outbreak of listeriosis, with 147 illnesses, 33 deaths, and one miscarriage among residents in 28 states, all associated with eating cantaloupe from a single farm.

Whole Genome Sequencing

In order to link the samples that were collected in Rome Packing facility, the FDA used a bacterial typing tool called whole genome sequencing (WGS), which reveals the complete genetic makeup of an organism and allows the FDA to define the scope of a foodborne illness outbreak by linking sick patients to food or a food production environment. The faster that a source of contamination can be identified, the faster the harmful ingredient can be removed from the food supply.

WGS was recently used to track the source of listeriosis in California that involved caramel apples. WGS is so precise that the FDA was able to use it identify a single apple supplier and two types of contaminated applies involved with the illness. As a result, the supplier was able to quickly take steps to recall the apples.

Genome Sequencing Efforts

The FDA is heading up an international effort to create a network of laboratories that can sequence genomes and upload the genomic sequence and the geographic location into a public database, the Genome Trakr, which can be used to speed up food borne illness investigations. The FDA has also partnered with the CDC in the attempt to sequence every isolate of L. mono collected in the entire U.S.

Previous Recalls

The seizure is not Rome Packing’s first run-in with L. mono. In October 2014, the company issued a voluntary recall of its crab leg meat after the company determined that some of its products may have been contaminated with L. mono. The company is currently not in operation or producing any food and is reportedly in receivership.

The FDA’s Associate Commissioner for Regulatory Affairs, Melinda K. Plaisier, said in a released statement, “The FDA made several efforts to help Rome Packing correct processes, but the company failed to take adequate corrective measures.” She added, “In this case, we had to intervene and seize this adulterated food to prevent it from reaching consumers.”


Lockheed Martin: Defense heavyweight now health care technology innovator?

What do a defense contractor, a Silicon Valley giant, and a Maryland community college have in common? It sounds like the beginning of a joke, but as implausible as it seems, they now have quite a lot in common, thanks to a new collaboration that brings the unlikely parties together to work on solving health information technology (IT) issues. Lockheed Martin Corporation, a global security and aerospace company, is jumping into the health information technology field, as it announced the launch of the Healthcare Technology Alliance, which it advertises as a combination of the expertise of leading health IT providers, medical technology companies, and academic institutions working for the advancement of public health.

Healthcare Technology Alliance

The founding members of the Alliance include Cisco Systems, Inc., Cloudera, Inc., Illumina, Inc., Intel Corporation, and Montgomery College. According to the announcement, the members of the Alliance will collaborate on finding technology solutions to improve care by working to secure patient medical information, advancing genomic research, and applying “big data solutions.” The Alliance’s website asks the public to imagine being able to access electronic medical records on any device, or imagine using patient genetic information to direct health care decisions for the prevention, diagnosis, or treatment of diseases.


The Alliance points out that more than 50 percent of identity theft occurs within the health care sector. Therefore, according to Lockheed, a focus must be placed on securing data with approaches that are efficient and affordable. Additionally, the partnership, which is formed between the industry, academia, and the government, claims that it will “revolutionize the way the health care industry securely computes, catalogs and stores data,” all with the aim of providing patients better access to care. Horace Blackman, Vice President of Health & Life Sciences at Lockheed said in a released statement, “Federal health IT is a dynamic and growing sector.” He further stated, “Through collaboration between health IT industry and academic partners, this team will develop and refine technologies that will help guide decisions for care, diagnosis and treatment of disease while protecting critical health information.”

Internet of Things solutions

Big Cloud Analytics (BCA) also announced that it will be assisting Intel with its role in the Alliance by creating “Internet of Things (IoT) solutions” for the Alliance. According to Forbes, the IoT is basically the idea that anything with an on and off device will be connected to the Internet and to each other. BCA reportedly will co-develop solutions that will incorporate sensors and wearable devices and other data streams to assist in the collection of patient data to better understand individual and public health.

Genomics program

Lockheed is not merely dipping a toe into the health care sector; it is diving in head first. The company previously announced its partnership with Illumina to develop solutions for national genomics programs. According to Lockheed, the collaboration will potentially create “the most advanced tools and best practices in large-scale genomic solutions.” In other words, Lockheed is hoping that genomics, or the study of a person’s DNA, can be used determine a personalized health care plan by determining a person’s health risks such as susceptibility to disease or drug reactions, which can result in better, more proactive approaches to health care. Additionally, according to Lockheed, the aggregation of genomic data for a large population can help public health officials in addressing health care issues while lowering costs and improving quality of lives. The Washington Post is reporting that, in addition to the Illumina partnership, Lockheed previously purchased smaller more specialized companies last year in the attempt to grow in the federal health IT market.