Life Science Compliance Update

November 17, 2017

FDA Approves Sixth United States Biosimilar


Recently, the FDA announced that it approved Boehringer Ingelheim’s Cyltezo (adalimumab-adbm), the second biosimilar to AbbVie’s blockbuster Humira and sixth biosimilar in the United States. “Cyltezo is the first biosimilar from Boehringer Ingelheim to be approved by the FDA and marks an important step towards our goal of providing new and more affordable treatment options to healthcare providers and patients,” said Ivan Blanarik, Senior Vice President and Head of Therapeutic Area Biosimilars at Boehringer Ingelheim. “Chronic inflammatory diseases collectively affect 23.5 million people in the U.S., and Cyltezo has the potential to deliver significant benefits to many of these individuals.”

More Details

Cyltezo is a tumor necrosis factor (TNF) blocker approved for the treatment of adults with moderately to severely active rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, moderately to severely active Crohn's disease, moderately to severely active ulcerative colitis, and moderate-to-severe plaque psoriasis. In addition, adalimumab-adbm is approved for children aged 4 years or older with moderately to severely active polyarticular juvenile idiopathic arthritis.

A biosimilar is a drug that has been demonstrated to be "highly similar" to the already-approved reference product. "The biosimilar also must be shown to have no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products," FDA explains.

Future Biosimilar Predictions

As reported by Regulatory Focus, Bernstein biotech analyst Ronny Gal told investors in a note that adoption of biosimilars in the EU “continues to surprise to the upside” as member states have increased their adoption.

“Prices are lower (say ~50% discount of pre-biosimilar entry) and the commercial model is supported by very light marketing requirements. Further, the number of late-stage competitors in key markets (Enbrel, Epogen, and Remicade) is only 3-4, suggesting continuation of profitability. The big upcoming test is the adoption of the oncology products (Rituxan launched and Herceptin expected). Neulasta will presumably launch in 2018 and will do very well in the EU markets,” Gal wrote, according to Regulatory Focus.

For the US marketplace, Gal points to “two key speed bumps”: Approvals of Epogen and Neulasta have been delayed for a year and the Remicade biosimilars approved in April 2016 and last April have “failed to gain traction, exposing some weaknesses in the US market when it comes to encouraging biosimilars and casting doubt on the market,” though he expects this to change in the next 12 months. In terms of other predictions, Gal said Epogen and Neulasta biosimilars will launch in the US though he expects “relatively weak adoption” before the end of 2018.

November 08, 2017

FDA Provides Guidance on Medical Devices


Recently, the FDA released two final guidances and a new draft guidance to increase the regulatory clarity around medical devices, including software as a medical device. The agency also announced the first qualified tool under the voluntary Medical Device Development Tools (MDDT) program.

Final Guidances

The two final guidances released are designed to help developers understand when a modification to a device — which would include a software update — requires a new 510(k) clearance. The guidances, "Deciding When to Submit a 510(k) for a Change to an Existing Device” and “Deciding When to Submit a 510(k) for a Software Change to an Existing Device,” update a similarly-named guidance document from 1997.

For the guidance related to change to an existing device, it uses flowcharts and text to guide manufacturers through the logic scheme FDA recommends to arrive at a decision on whether to submit a new 510(k) for a change to an existing device. A single logic scheme containing all the necessary steps would be large and cumbersome and could be quite daunting.

This guidance will aid manufacturers of medical devices subject to premarket notification requirements who intend to modify a 510(k)-cleared device (or group of devices) or other device subject to 510(k) requirements, such as a preamendments device or a device that was granted marketing authorization via the De Novo classification process under section 513(f)(2) of the FD&C Act during the process of deciding whether the change exceeds the regulatory threshold for submission and clearance of a new 510(k).

Related to the other guidance, FDA issued the original guidance Deciding When to Submit a 510(k) for a Change to an Existing Device on January 10, 1997 to provide guidance on regulatory language. As stated in that guidance, the key issue in the interpretation of 21 CFR 807.81(a)(3) is that the phrase “could significantly affect the safety or effectiveness of the device” and the use of the adjectives "major" and "significant" sometimes lead FDA and device manufacturers to different interpretations.

The original guidance provided the FDA’s interpretation of these terms, with principles and points for manufacturers to consider in analyzing how changes in devices may affect safety or effectiveness and determining whether a new 510(k) must be submitted for a particular type of change. The current guidance preserves the basic format and content of the original, with updates to add clarity. The added clarity is intended to increase consistent interpretations of the guidance by FDA staff and manufacturers and provide a more transparent framework for determining when submission of a new 510(k) is required.

Draft Guidance

The draft guidance describes the FDA's new Breakthrough Devices Program, which will supersede the agency's Expedited Access Pathway. The program, which allows novel technologies that present a significant improvement over the status quo to move more quickly through the clearance process, was created in the 21st Century Cures Act that passed last year.

MDDT Program

According to Commissioner Gottlieb, the agency completed its “first qualification of a medical device development tool (MDDT) to provide a more objective platform for developing devices in a key area of medicine – cardiovascular health. Fostering the creation and validation of development tools that can be used to provide more efficient and accurate ways to measure risk and benefit, as part of the medical product development process, is a key goal of the FDA. At the FDA, we’re undertaking a comprehensive policy effort to facilitate the development and validation of these kinds of medical device development tools.”

He continues: “Today’s newly qualified MDDT is a 23-item questionnaire that measures health information that is reported directly by patients with heart failure. The tool can be used to measure a heart failure patient’s health status, including clinical symptoms and the physical and social limitations caused by this condition. Such a tool has the potential to help engineers designing heart failure devices to more efficiently and accurately quantify how much their device could actually improve a patient’s quality of life. By qualifying the tool under the FDA’s new, voluntary program, it will make it easier for product developers to rely on the outputs of this newly qualified tool as part of their development plans. Innovators can trust in advance that the agency has already found the outputs of these measures to be reliable.”

October 27, 2017

Aegerion Resolves Criminal and Civil Actions


Aegerion recently finalized a $40.1 million settlement that resolves civil and criminal charges over its marketing of JUXTAPID®. We previously published an article outlining agreements in principle with the Department of Justice (DOJ) and Securities and Exchange Commission (SEC), following inquiries into the company to determine whether the company’s commercial activities violated laws and regulations.

The $40.1 million settlement is split between cases brought by the DOJ and the SEC – with $36 million resolving cases by the DOJ and $4.1 million resolving an SEC lawsuit. Sales representatives were trained to tell doctors and patients that JUXTAPID® would “take patients out of harm’s way” and prevent “impending” heart attacks and strokes, despite the lack of data supporting those claims, prosecutors alleged.

On September 22, 2017, Aegerion agreed to plead guilty to two misdemeanor counts of violating the Federal Food, Drug, and Cosmetic Act (FD&C Act) regarding the introduction of misbranded JUXTAPID® into interstate commerce. The criminal information alleged that JUXTAPID® was misbranded because Aegerion failed to comply with the requirements of the JUXTAPID® Risk Evaluation and Mitigation Strategy (REMS) program and because the labeling lacked adequate directions for all of the prescription’s intended uses.

The FDA approved JUXTAPID® in 2012 to treat high cholesterol in patients with a rare genetic disease called homozygous familial hypercholesterolemia. Prosecutors have said that Aegerion managers and sales staff touted JUXTAPID® as a treatment for high cholesterol generally, and failed to give healthcare providers sufficient information to safely prescribe the drug.

Aegerion and one of its senior vice presidents, Charles M. Gerrits, agreed to enter into a consent decree of permanent injunction with the United States. The consent decree includes a comprehensive compliance program and legal tools for the FDA to ensure that the defendants comply with the law, subject to judicial oversight.

As alleged in court documents filed by the DOJ, instead of following the REMS requirement to distribute JUXTAPID® for the narrow indication for which it was approved, Aegerion sought to include the diagnosis of homozygous familial hypercholesterolemia (HoFH), a rare disorder that that causes high cholesterol levels and early cardiovascular disease, as vague and indefinite as possible in order to extend the product use to additional patient populations.

As part of the required REMS, Aegerion failed to give health care providers complete and accurate information about HoFH and how to properly diagnose it. Aegerion also filed a misleading REMS assessment report to the FDA in which the company failed to disclose that it was distributing JUXTAPID® using a definition of HoFH that was inconsistent with Aegerion’s pre-approval filings with the FDA and that did not correspond to any peer-reviewed clinical standard for diagnosing HoFH. With these actions, Aegerion failed to comply with the required elements under the REMS to assure safe use of JUXTAPID®, in violation of the FD&C Act. In addition, Aegerion management and sales personnel also distributed JUXTAPID® not only for the treatment of HoFH, but also as a treatment for high cholesterol generally, without adequate directions for such use.

The SEC’s complaint alleges that Aegerion told investors that the number of unfilled prescriptions for JUXTAPID® was not material and the “vast majority” of patients receiving prescriptions ultimately purchased the drug. The SEC alleges that Aegerion’s records reflect that it was actually around 50 percent of prescriptions that resulted in actual drug purchases.

Once entered by the court, the plea and consent decree will be part of a global resolution of multiple government investigations into Aegerion’s conduct with respect to the marketing and distribution of JUXTAPID®. This resolution was the result of a coordinated effort by the DOJ and other government agencies.


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