Fosamax Ruling: “A Small Win for Defense, A Big Win for Plaintiffs”

SCOTUS Fosamax Ruling (May 20, 2019)

Issue: Whether a state-law failure-to-warn claim is pre-empted when the Food and Drug Administration rejected the drug manufacturer’s proposal to warn about the risk after being provided with the relevant scientific data, or whether such a case must go to a jury for conjecture as to why the FDA rejected the proposed warning

Small Win for Defendants

Defendants Won the argument that a Judge not a jury is the proper authority to decide impossibility preemption arguments arising under the FDCA (Food and Drug Cosmetics Act, Title 21). However, the win on this one issue is a hollow victory for defendants considering the entirety of SCOTUS order and opinion.

SCOTUS ruled that judges not juries are the proper authority to decide the issue however, SCOTUS also placed significant limits on what those lower court judges could and could not consider when ruling on impossibility pre-preemption arguments like those raise by Merck in the Fosamax Case.

JUSTICE THOMAS SUMMARY OF RULING

JUSTICE THOMAS, concurring:

I join the Court’s opinion and write separately to explain my understanding of the relevant pre-emption principles and how they apply to this case.

“Because Merck points to no statute, regulation, or other agency action with the force of law that would have prohibited it from complying with its alleged state-law duties, its pre-emption defense should fail as a matter of law”

Big Win for Plaintiffs

SCOTUS ruled that Judges decide however, SCOTUS went much further and defined limits on what facts and information could be considered by lower court judges when making decisions related to impossibly preemption arguments like those raised by Merck in Fosamax.

SCOTUS opinion limits the clear and convincing evidence standards to OFFICAL Acts taken by the FDA which would in general rise1. If the defendant did not go through the CBE process and make the change (the exact warning plaintiffs allege was needed) and the FDA later told them to remove the warning, then FDA OFFICALLY told them to remove the warning, then no pre-emption exists.

1. If the defendant did not go through the CBE process and make the change (the exact warning plaintiffs allege was needed) and the FDA later told them to remove the warning, then FDA OFFICALLY told them to remove the warning, then no pre-emption exists.

2. If the defendant did not ask to make the specific label change (which plaintiffs allege was needed) having provided the FDA all relevant information, and the FDA OFFICIALLY denied the label change, then no pre-emption exists.

Arguments that postulate “hypotheticals” (absent either of the above official actions (facts)) are not to be considered. Communications between the defendant and the FDA, Statements by the FDA that do not constitute an official act under the law, are not to be considered.

The pre-emption question dates back to the original Fosamax case, which was filed by patients who suffered femoral fractures while taking the osteoporosis drug. Merck added language to the product’s label about the risk in 2011, but more than 500 patients claimed that their injuries occurred before then, and Merck should have warned them sooner.

In January 2019, the full Supreme Court heard arguments in Merck Sharp & Dohme Corp. v. Albrecht, a case arising out of the In Re: Fosamax (Alendronate Sodium) Products Liability Litigation. Fosamax is a drug used to treat osteoporosis, with a cited adverse event being that it may inhibit bone repair, which could result in an atypical femoral fracture.

The central claim at issue concerns the Fosamax warning label, which initially did not warn of the risk of an atypical femoral fracture. Plaintiffs contend that the label should have included such a warning, while Merck counters that it tried to add language addressing the risk of a “Low-Energy Femoral Shaft Fracture,” but was prevented from doing so by the FDA, who affirmatively told Merck to “hold off” on adding any such language until the FDA could decide on “atypical fracture language, if it is warranted.”  Ultimately, the FDA rejected Merck’s proposed warning label, stating that the justification for such language was “inadequate.” The FDA reversed course the following year, and Merck then added a risk of atypical femoral fracture to Fosamax’s label.

Based on these facts, Merck moved for summary judgment on the plaintiff’s failure-to-warn claims, arguing that such claims were preempted under Wyeth v. Levine because “clear evidence” demonstrated that the FDA would not—and did not—approve of the proposed label change.  The District Court agreed, but the Third Circuit did not, holding instead that: (1) Levine’s reference to “‘clear evidence’ referred solely to the applicable standard of proof,” which Merck failed to satisfy; and (2) the issue of whether the FDA would have rejected the label change was a fact question for the jury, (see Fosamax [Merck] Appeal U.S. Court of Appeals 3rd Circuit).

SCOTUS RULED 9-0

Additional Concurring Opinion on the judgment only (Jury vs Judge only) from Justices Cavanaugh, Alito’s  and Chief Justice Roberts could be interpreted as allowing lower court Judges to consider other Official acts by the FDA other than those delineated above however, the additional opinion did not define what official acts other than the two discussed could be considered and inasmuch as these two official actions are constitute the limit of the powers relevant to such matters, delegated to the FDA by Congress, it is doubtful that a defendant could show a lower court Judge any other document (without posing hypotheticals) that would constitute an official action taken by the FDA that would have prevented the defendant from meeting its State Law duties (impossibility preemption).

In that the only powers delegated to the FDA by Congress (powers under the law) are those defined in the two types of actions listed above, relevant to the type of impossibility preemption arguments that were raised in Fosamax, based on unofficial actions, communications and statements from the FDA (and that defendants hoped to raise in numerous other cases) the Fosamax ruling taken in its entity, is a major blow to defendants hoping to open major cracks in Wyeth v Levine.

The central issue in this case concerns federal preemption, which as relevant here, takes place when it is “‘impossible for a private party to comply with both state and federal requirements.’” Mutual Pharmaceutical Co. v. Bartlett, 570 U. S. 472, 480 (2013). See also U. S. Const., Art. VI, cl. 2. The state law that we consider is state common law or state statutes that require drug manufacturers to warn drug consumers of the risks associated with drugs. The federal law that we consider is the statutory and regulatory scheme through which the FDA regulates the information that appears on brand-name prescription drug labels. The alleged conflict between state and federal law in this case has to do with a drug that was manufactured by petitioner Merck Sharp & Dohme and was administered to respondents without a warning of certain associated risks.

FOSAMAX HISTORY

Merck developed Fosamax to strengthen bones and reduce the risk of fractures from osteoporosis. However, numerous studies have linked the medication to an elevated risk of abnormal femur fractures. Furthermore, plaintiffs in the litigation argue that Merck had an intrinsic obligation to its consumers to provide stronger warnings that users could experience femur fractures from little or no trauma while taking the medication. This includes falling from standing height or less.

Merck introduced Fosamax in 1995, and the company didn’t add a thigh bone fracture risk warning label to the drug until 2011. Plaintiffs claim Merck knew about the risk for years but concealed it to maximize sales and profits.

Fosamax was a blockbuster drug with annual sales of over $3 billion, until the company  lost its exclusive patent rights in 2008, even then the brand name drug still brought in $284 million in sales in 2016.

MERCK SHARP & DOHME CORP. v. ALBRECHT Opinion of the Court(excerpt)

III

We turn now to what is the determinative question before us:

Is the question of agency disapproval primarily one of fact, normally for juries to decide, or is it a question of law, normally for a judge to decide without a jury?

The complexity of the preceding discussion of the law helps to illustrate why we answer this question by concluding that the question is a legal one for the judge, not a jury. The question often involves the use of legal skills to determine whether agency disapproval fits facts that are not in dispute. Moreover, judges, rather than lay juries, are better equipped to evaluate the nature and scope of an agency’s determination. Judges are experienced in “[t]he construction of written instruments,” such as those normally produced by a federal agency to memorialize its considered judgments. Markman v. Westview Instruments, Inc., 517 U. S. 370, 388 (1996). And judges are better suited than are juries to understand and to interpret agency decisions in light of the governing statutory and regulatory context. Cf. 5 U. S. C. §706 (specifying that a “reviewing court,” not a jury, “shall . . . determine the meaning or applicability of the terms of an agency action”); see also H. R. Rep. No. 1980, 79th Cong., 2d Sess., 44 (1946) (noting longstanding view that “questions respecting the . . . terms of any agency action” and its “application” are “questions of law”). To understand the question as a legal question for judges makes sense given the fact that judges are normally familiar with principles of administrative law. Doing so should produce greater uniformity among courts; and greater uniformity is normally a virtue when a question requires a determination concerning the scope and effect of federal agency action. Cf. Markman, 517 U. S., at 390–391.

We understand that sometimes contested brute facts will prove relevant to a court’s legal determination about the meaning and effect of an agency decision. For example, if the FDA rejected a drug manufacturer’s supplemental application to change a drug label on the ground that the information supporting the application was insufficient to warrant a labeling change, the meaning and scope of that decision might depend on what information the FDA had before it. Yet in litigation between a drug consumer and a drug manufacturer (which will ordinarily lack an official administrative record for an FDA decision), the litigants may dispute whether the drug manufacturer submitted all material information to the FDA.

But we consider these factual questions to be subsumed within an already tightly circumscribed legal analysis. And we do not believe that they warrant submission alone or together with the larger pre-emption question to a jury. Rather, in those contexts where we have determined that the question is “for the judge and not the jury,” we have also held that “courts may have to resolve subsidiary factual disputes” that are part and parcel of the broader legal question.  Teva Pharmaceuticals USA, Inc. v. Sandoz, Inc., 574 U. S. ___, ___–___ (2015) (slip op., at 6– 7). And, as in contexts as diverse as the proper construction of patent claims and the voluntariness of criminal confessions, they create a question that “‘falls somewhere between a pristine legal standard and a simple historical fact.’” Markman, 517 U. S., at 388 (quoting Miller v. Fenton, 474 U. S. 104, 114 (1985)). In those circumstances, “‘the fact/law distinction at times has turned on a determination that, as a matter of the sound administration of justice, one judicial actor is better positioned than another to decide the issue in question.’” Markman, 517 U. S., at 388 (quoting Miller, 474 U. S., at 114). In this context, that “better positioned” decisionmaker is the judge.

 IV

Because the Court of Appeals treated the pre-emption question as one of fact, not law, and because it did not have an opportunity to consider fully the standards we have described in Part II of our opinion, we vacate its judgment and remand the case to that court for further proceedings consistent with this opinion.

It is so ordered.

____________________________________________________________

How Big Pharma’s cadre of lobbyists and congressional insiders attempt to reap major dividends, as we address the Fosamax ruling remains to be seen, but considering the wide-open lack of federal oversight for pharmaceutical and medical device manufacturers by the current administration, it would appear that Big Pharma investments in the FDA and related oversight agencies is paying off very well.

To access the most relevant and real time information on Mass Torts  sign up for:

Mass Tort Nexus “CLE Immersion Course”

May 31 – June 3, 2019 at The Riverside Hotel in Fort Lauderdale , FL

For class attendance information please contact Anne Marie Kopek at 954.837.3423 or AnneMarie@masstortnexus.com.

  1. For the most up-to-date information on all MDL dockets and related mass torts visit  www.masstortnexus.com and review our mass tort briefcases and professional site MDL briefcases.
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FDA BANS THE USE OF PELVIC MESH PRODUCTS – How Will This Affect The TVM Litigation?

Will this move by the FDA re-ignite the mass tort engine in TVM litigation or possibly force settlement in Ethicon TVM MDL 2327?

By Mark A. York (April 17, 2019)

 

 

 

 

 

 

(MASS TORT NEXUS MEDIA) Manufacturers of pelvic synthetic surgical mesh products must stop selling and distributing their products in the United States immediately, the US Food and Drug Administration ordered Tuesday. The surgical mesh is typically used to repair pelvic organ prolapse (POP) and incontinence, but reported side effects have included permanent incontinence, severe discomfort and an inability to have sex.  The key issue with the product for many years is the fact that its made from polypropylene, basically the same material as fishing line.

The FDA said it “has determined that the manufacturers, Boston Scientific and Coloplast, have not demonstrated a reasonable assurance of safety and effectiveness for these devices.”

The FDA said its April 16, 2019 action to remove surgical mesh products from the market is part of its commitment to ensuring the safety of medical devices. In a November statement, the agency said that it “regulates more than 190,000 different devices, which are manufactured by more than 18,000 firms in more than 21,000 medical device facilities worldwide.”

FDA Release January 4, 2019

FDA strengthens requirements for surgical mesh for the transvaginal repair of pelvic organ prolapse to address safety risks

Summary: The U.S. Food and Drug Administration issued two final orders to manufacturers and the public to strengthen the data requirements for surgical mesh to repair pelvic organ prolapse (POP) transvaginally, or through the vagina. The FDA issued one order to reclassify these medical devices from class II, which generally includes moderate-risk devices, to class III, which generally includes high-risk devices, and a second order that requires manufacturers to submit a premarket approval (PMA) application to support the safety and effectiveness of surgical mesh for the transvaginal repair of POP.

FDA Finally Takes Action

Each year, thousands of women undergo transvaginal surgery to repair pelvic organ prolapse, a condition where weakened muscles and ligaments cause the pelvic organs to drop lower in the pelvis, creating a bulge or prolapse in the vagina. In the 1990s, gynecologists began implanting surgical mesh for the transvaginal repair of the condition and in 2002, the first mesh device specifically for this purpose was cleared for use by the FDA, according to the agency’s statement.

“We couldn’t assure women that these devices were safe and effective long term,” said Dr. Jeffrey Shuren, director of the FDA’s Center for Devices and Radiological Health.

For years, medical device companies have stated that the products they are developing and placing into the marketplace are safe and helping patients in the USA and worldwide. That is often not the case and people around the world are suffering.

Medical device makers and compensated doctors have touted FDA approved implants and other devices as the surgical cure for millions of patients suffering from a wide range of pain disorders, making them one of the fastest-growing products in the $400 billion medical device industry. Companies and doctors aggressively push them as a safe antidote to the deadly opioid crisis in the U.S. and as a treatment for an aging population in need of chronic pain relief and many other afflictions.

2017 Pelvic Mesh Study in England Showed High Number of Adverse Events:

Scientific Reports Volume 7, Article number: 12015 (2017) |

Complications following vaginal mesh procedures for stress urinary incontinence: an 8 year study of 92,246 women

Conclusions

Summary: This is the largest study to date of surgical mesh insertions for SUI. It includes all NHS patients in England over an 8-year period. We estimate that 9.8% of patients undergoing surgical mesh insertion for SUI experienced a complication peri-procedurally, within 30-days or within 5 years of the initial mesh insertion procedure. This is likely a lower estimate of the true incidence. Given concerns about the safety of these procedures, this study provides robust data to inform both individual decision-making and national guidance.

Why Device Makers Tout FDA Approvals

  1. “Medtronic receives FDA clearance for two heart devices”
  2. “FDA approves device to help curb cluster headaches”
  3. MRI approved for young infants in intensive care

Manufacturer headlines like these instill consumer confidence that medical devices are safe and effective. After all, they have the FDA’s stamp of approval, right? NO!

The reality is, the FDA seldom requires rigorous evidence that a device works well–and safely–before allowing it onto the market. Medical devices are the diverse array of non-drug products used to diagnosis and treat medical conditions, from bandages to MRI scanners to smartphone apps to artificial hips.

This low standard of evidence applies to even the highest risk devices such as those that are implanted in a person’s body. Surgical mesh, pacemakers and gastric weight loss balloons are just a few examples of devices that have had serious safety problems.

Devices are subject to weaker standards than drugs because they’re regulated under a different law. The Medical Device Amendments of 1976 was intended to encourage innovation while allowing for a range of review standards based on risk, according to legal expert Richard A. Merrill. An array of corporate lobbying has since prompted Congress to ease regulations and make it easier for devices to get the FDA’s approval.

In 2011, an Institute of Medicine panel recommended that the “flawed” system be replaced, because it does not actually establish safety and effectiveness. At the time the FDA said it disagreed with the group’s recommendations.

Defective devices cleared through this system have included hip replacements that failed prematurely, surgical mesh linked to pain and bleeding and a surgical instrument that inadvertently spread uterine cancer.

Bard took the Avaulta implants off the market in 2012 and did the same with the Align inserts in 2016. The company chose to remove the products the day after the U.S. Food and Drug Administration in 2010 ordered Bard and other mesh-manufacturers, including Johnson & Johnson (Ethicon), Boston Scientific and Endo (American Medical S), to review their mesh products, which also resulted in J&J removing four lines of synthetic surgical mesh products from the market. .J&J’s Ethicon subsidiary is facing more than 50 thousand lawsuits regarding its synthetic mesh device in Ethicon (J&J) Pelvic Mesh TVM Litigation MDL-2327.

The Ethicon MDL is in the same West Virginia federal court as the Bard and other mesh manufacturer multidistrict litigation, which are all being heard by Judge Goodwin.  Judge Goodwin has previously expressed his frustration with the parties not engaging in substantive settlements discussions to resolve the thousands of cases, the one option he has is to begin remanding cases back for trial in court venues around the country, possibly forcing both sides to begin earnest settlement talks. Goodwin has held hearings with leadership attorneys from both sides appearing before the court to possibly kickstart settlements. He has gone so far as to warn mesh manufacturers that if they do not settle, U.S. juries appear poised to inflict hundreds of millions, or even billions, of dollars in compensatory and punitive damages on them in thousands of cases that would overload the federal judicial system for years to come.

The FDA forcing mesh manufacturers to stop the use of synthetic mesh is long overdue, and how this action results in renewed interest by mass tort firms across the country, remains to be seen. Regardless, it would seem that Ethicon and the other defendants in the pending TVM litigation that have been unwilling to discuss settlement, may now be forced to deal with the catastrophic consequences of manufacturing and marketing medical devices that have injured untold thousands of patients around the world.

To access the most current TVM case status and other real time information on Mass Torts  sign up for:

Mass Tort Nexus “CLE Immersion Course”

May 31 to June 3, 2019 at The Riverside Hotel in Fort Lauderdale , FL

For class attendance information please contact  Barbara Capasso 954.383.3932 or Barbara@masstortnexus.com

  1. For the most up-to-date information on all MDL dockets and related mass torts visit www.masstortnexus.com and review our mass tort briefcases and professional site MDL briefcases.
  2. To obtain our free newsletters that contains real time mass tort updates, visit www.masstortnexus.com/news and sign up for free access.

 

 

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The FDA Revamped Their Website

 

 

https://www.fda.gov/ as of April 26, 2019

 

 FDA has announced the launch of a newly redesigned FDA public access website. They have made changes to provide a more modern and customer friendly access for the public. The new FDA website launch was completed April 26, 2019.

PRODUCTS THE FDA REGULATES

FoodDrugsMedical DevicesRadiation-Emitting ProductsVaccines, Blood, and BiologicsAnimal and VeterinaryCosmetics and Tobacco Products

____________________________________________________________

The FDA public website receives nearly 5 million visitors—consumers, health professionals, scientists/researchers, and industry stakeholders each month. It serves as the face of the agency and a critical vehicle for meeting FDA’s mission, as it’s home to agency policy and perspectives and information about recalls, safety alerts and important regulatory actions. Ensuring that this content is easy to find is a top priority.

The FDA has attempted to make the FDA.gov website more user friendly, by redesigning not only the functionality, but the way it looks as well. The new FDA site is cleaner and the overall layout is less distracting and the content is much more contemporary.

The goals for the new FDA.gov website include:

https://www.fda.gov/

  • Remodeled webpages that can be viewed on any internet-ready device
  • Easier access to popular content
  • Updated navigation based on data and audience behavior
  • Easier to find FDA content in search results
  • Better consistency of FDA content across web and social channels

The FDA.gov website refresh centers around the migration to a new web content management system (WCMS). The current WCMS is end-of-life and we are replacing it with a new modern publishing platform.

Here are some of the things we are doing to improve FDA.gov:

  • Using data to archive and expire webpages that aren’t being used, consolidating similar content/renaming page titles to reduce redundancy so it’s easier for online audiences to find what they are looking for.
  • Adding stronger and more relevant metadata to the webpages to optimize them for search and social media.
  • Updating FDA.gov’s design to provide more visuals and interactive content. Overall the site will have a more modern look-and-feel. FDA content will appear consistently regardless of web and social channels.
  • Upgrading to a modern publishing platform ensures that our content is accessible anywhere, anytime and on any device.

WHAT THE FDA DOES AND LINKS TO RESOURCES.GOV

FDA Mission

The Food and Drug Administration is responsible for protecting the public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices; and by ensuring the safety of our nation’s food supply, cosmetics, and products that emit radiation.

FDA also has responsibility for regulating the manufacturing, marketing, and distribution of tobacco products to protect the public health and to reduce tobacco use by minors.

FDA is responsible for advancing the public health by helping to speed innovations that make medical products more effective, safer, and more affordable and by helping the public get the accurate, science-based information they need to use medical products and foods to maintain and improve their health.

FDA also plays a significant role in the Nation’s counterterrorism capability. FDA fulfills this responsibility by ensuring the security of the food supply and by fostering development of medical products to respond to deliberate and naturally emerging public health threats.

FDA’s Regulatory Responsibilities: Laws and Regulations

Product Approval

Recalls, News, and Events

Guidance Documents, Rulemaking, and Freedom of Information

Navigating The New FDA Site

Being a large and diverse agency with aesthetics apart, just keeping track of pathways and names is overwhelming in such a complex website, and it is easy to lose track of what needs to be updated.  The FDA stated that one of the goals was to make the site more friendly to consumers and it has improved. The former site ran banner photos of some topical interest, the new site landing pages feature a topic with a photo array focused on a feature topic. To get to the information, you need to click on the box announcing the feature, not the photos. Key to success for this approach will be topics that change out frequently as well as the topics themselves. This month’s is about children and allergy relief, timely given the time of year and the number of children, but perhaps not as serious as the recall of blood pressure medications.

Each FDA division – DrugsFoodMedical Devices has “featured information” that generally mirrors the FDA landing page (though stylistically there is not consistency across all divisions in terms of layout). For FDA to achieve its consumer friendly goal here they will have to work at providing information that is of interest to consumers and not necessarily just focus on that information FDA wants most to talk about.

Longer, Less Crowded Landing Page – It used to be when you went to FDA’s landing page, you had a LOT of information crammed into the screen offering you pathways in a bunch of different directions at once – from links to speeches to advisory committee information to meetings information to the latest press releases, etc. All of that is still on the landing page, but it is more coherently laid out. That means that there is less splashed in your face on the screen, but the content has been elongated – and you now have to scroll down to find all the bits and pieces. That may not be entirely apparent to some. As you scroll down, you come to additional featured topics beyond the main one mentioned above. Right now one of them includes a link to information about the revamp of the site; a link to information about combatting opioids and one on FDA fostering drug competition. As noted above, these topics fall a little more into the category of things FDA may want to say versus the things we want to hear more about from a consumer perspective. As you scroll down, you come to press announcements (where curiously the title of the section is in smaller type than the titles of the most recent press releases). Scrolling down further takes you past many of the links that were formerly crammed into the landing square of the old site. It is almost all still there, just there more for your leisurely scrolling rather than in your face. But not everything is on the landing page. For that you need the next section.

Menu Function is Key – In the upper right hand corner is the Menu Function. You are going to need this as it is the key to providing you a one-size fits all access to various divisions of the agency. It takes you to a site-map-lite that is actually very helpful if there are some specific things you want to look up. Most notably on the left side are a list of “featured links”. These are vital. They take you not only to guidance documents, but also one is the link that gets you to Advisory Committee information — to the page that is set up for each committee containing such information as the committee roster and meeting notices as well as documents related to specific meetings. To the right of this menu you will also find access to the FDA’s divisions, though it is not called that – instead it is called “Products”. Under that heading you will not see links to “CDER”, “CBER” or the others and where is the Office of Prescription Drug Promotion? Actually CDER, CBER and the others are there, but they are not called that. They are under their generic names (haha) – Drugs, Food, Medical Devices, Radiation-Emitting Products, etc. FDA may want to consider adding the acronyms here. These pages are generally laid out in similar fashion to the initial agency landing page, with a heading that is meant to cover topical information, prompting the user to scroll down to find the bits desired. Here you will find a link as you travel down the page to the Warning and Untitled Letters issued (still only one issued this year so far). The link to the Office of Prescription Drug Promotion exists but not on this page – it is under the About FDA Tab, and then drilling down through organizational structure through CDER there before you find it – here.

Finding Specifics Related to Function in the About FDA Link – One thing you don’t see when you go to the Drug page or the Food page or any of the other division pages is a map for getting to where you want to go within that division (hence the lack of an OPDP link from the Drugs Page). To find that level of detail – to find a specific office that does a specific function, you may have to either conduct a Search (which can offer up a messy slew of links) or go to the About FDA link mentioned above. Here’s the thing – that is in very small letters at the very bottom of the landing page. It is a small, obscure link to an important function. Overall, navigation of the site is less confusing now that everything is removed from a single frame shot. The order of things as you scroll down is pretty logical, though the demarcation of sections is subtle. Of note, if you have links to FDA materials at any site, some of the material may have shifted.

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False Narratives Opioids and Xarelto

Mass Tort Nexus is compiling an evidentiary package for law firms who intend to reject the current Xarelto settlement offer and prepare for trial. This article represents an extremely small segment of what any firm who prepares for trial will have at their disposal; however, we believe most everyone involved in Mass Torts might find the following topic interesting.

It is well known how Big Pharma allegedly promoted a false narrative regarding Opioids and the risk posed by these highly addictive drugs. Despite the fact that thousands of people were dying every year from opioid overdose, doctors seemed unaware that the narrative they had bought into was false.

What might the death toll ultimately be for the new anticoagulants?

We are aware that both the Xarelto primary defendants are also accused of being party to the opioid false narrative conspiracy in opioid litigation complaints.  If Big Pharma can keep doctors prescribing opioids like skittles for decades, despite the rising death toll, how hard could it be to keep doctors prescribing an anticoagulant with a few tweaks to the truth?

Why Did Doctors Prescribe Xarelto and Why do they Continue to Prescribe Xarelto?

The clinical trials for Xarelto did not prove the drug to be superior in efficacy to Warfarin, only “non inferior.” It was not a better drug from an efficacy stand point. Doctors had no reason to switch patients to Xarelto because it “worked better” than Warfarin.

Xarelto is exponentially more expensive that Warfarin, so doctors had to reason to switch patients to Xarelto based on cost.

What were the makers of Xarelto able to claim about their new (unproven in the general patient population) to convince them to switch patients to Xarelto?

  1. No Routine Blood Testing (monitoring.)
  2. No Dietary Restrictions.

What if these claims were false, patients do need routine blood monitoring while on Xarelto?

What if patients taking Xarelto do need to restrict their diet (not consume certain food products?)

Would doctors keep prescribing Xarelto? Probably not, if the arguably false narrative first presented to them was corrected (warned) as having been false. That said, once a claim is made, people, including doctors, are not likely to realize that the claim is no longer being made once they have bought into the claim, unless they are specifically informed that the claim might have been false.

The following will explain why the makers of Xarelto may have stopped claiming (in their television and print ads,) that patients taking Xarelto did not need routine blood testing nor adhere to any dietary restrictions.

We will first review Xarelto television spots beginning in 2013 and more recent ads. Then we will explain why the makers of Xarelto quit claiming that users of their product stopped claiming that:

  1. No Routine Blood Testing (monitoring) was needed.
  2. No dietary restrictions.

You may view a larger selection of ads than those provided below at: https://www.ispot.tv/brands/ISA/xarelto

2013: Xarelto Bob Ad  (both “no routine monitoring” and “no dietary restrictions claims made”.)

 

 

 

 

 

 

 

https://www.ispot.tv/ad/7dJt/xarelto-bob

Start at 16 Seconds, “Bob took Wafarin and made a monthly trip to the clintic to get his blood tested but not anymore.”

Start at  36 Seconds,   “Xarelto is the first and only once per day prescription blood thinner… That does not require rountine Blood Monitoring.”

Start at 57 Seconds, “and there’s no dietary restrictions…Bob can eat the health foods he likes. ”

2014 Mary Ad (both “no routine monitoring” and “no dietary restrictions claims made.”)

 

 

 

 

 

 

https://www.ispot.tv/ad/7pGC/xarelto-mary-song-by-arturo-cardelus

Start at 12 Seconds  “Which required monthly testing, but that’s history.”

Start at 56 Seconds “Plus with no Known Dietary Restrictions.”

2015  Arnold Palmer (they did not specifically say no routine testing and dietary restrictions, but they  implied the claims. )

 

 

 

 

 

 

https://www.ispot.tv/ad/AYGi/xarelto-game-plan-feat-chris-bosh-arnold-palmer-brian-vickers

Start at 29 Seconds (claims worked into general conversation)

article link: https://www.masstortnexus.com/News/366/Did-Xarelto-the-Drug-Arnold-Palmer-Promoted-Lead-to-His-Death?

2016: Jerry West (neither of the claims were made in this ad.)

 

 

 

 

 

 

https://www.ispot.tv/ad/ARh_/xarelto-high-risk-of-stroke-featuring-jerry-west

2017  Xarelto “Protect Themselves” ad feature authority figures  (neither of the claims were made in this ad.)

 

 

 

 

 

 

 

 

https://www.ispot.tv/ad/wtdp/xarelto-protect-themselves

2018  “Learn all you can ad” (we do not think irony was intended), (neither of the claims were made in this ad)

 

 

 

 

 

 

https://www.ispot.tv/ad/wPmP/xarelto-learn-all-you-can

So Why Did the Makers of Xarelto Quit Making Their “Claims to Fame?”

We will first address why the makers of Xarelto most likely stopped making the “no rountine blood testing (monitoring claim.) This answer to this one is easy; Because the FDA warned them about making this claim.

It is difficult to understand why the makers of Xarelto did not unilaterally determine (and warn that their original messaging no routine blood monitoring needed) might have been misleading based solely on the number of adverse events reported to the FDA since the product’s introduction.

______________________________________________________________________________________________________

 

 

Food and Drug Administration

Silver Spring, MD 20993

Roxanne McGregor-Beck, Director

Johnson & Johnson International, Inc.

1000 Route 202 South

P.O. Box 300

Raritan, New Jersey 08869-0602

 

RE: NDA #202439

XARELTO (rivaroxaban) tablets

MA #215

Dear Ms. McGregor-Beck:

The Office of Prescription Drug Promotion (OPDP) of the U.S. Food and Drug Administration (FDA) has reviewed a direct-to-consumer (DTC) print advertisement (K02XS121040 AF) (Print Ad) for XARELTO (rivaroxaban) tablets (Xarelto) submitted by Johnson & Johnson International, Inc. (Johnson & Johnson) on behalf of Janssen Pharmaceuticals, Inc. under cover of Form FDA 2253 and observed during routine surveillance in the January/February 2013 issue of WebMD magazine. The Print Ad is false or misleading because it minimizes the risks associated with Xarelto and makes a misleading claim. Thus, the Print Ad misbrands Xarelto in violation of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 352(n) and FDA implementing regulations. 21 CFR 202.1(e)(5)(i); (e)(7)(viii), (ix).

Background:

Below is the indication and summary of the most serious and most common risks associated with the use of Xarelto.1 According to its FDA-approved product labeling (PI), in pertinent part:

Xarelto is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well controlled.

 The PI for Xarelto contains Boxed Warnings regarding increased risk of stroke after discontinuation in patients with nonvalvular atrial fibrillation and the risk of spinal/epidural

hematoma. The PI also contains Contraindications regarding active pathological bleeding and severe hypersensitivity reaction to Xarelto, as well as Warnings and Precautions regarding the risk of bleeding, use in patients with renal impairment and hepatic impairment, use with P-gp and strong CYP3A4 inhibitors or inducers, and risk of pregnancy related hemorrhage. The most common adverse reactions with Xarelto were bleeding complications.

Minimization of Risk Information

 Promotional materials are false or misleading if they fail to present risks associated with a drug with a prominence and readability reasonably comparable with the presentation of information relating to the benefits of the drug. Factors impacting prominence and readability include typography, layout, contrast, headlines, paragraphing, white space, and other techniques apt to achieve emphasis. The Print ad prominently presents various efficacy claims for Xarelto, such as, but not limited to, the following, that are presented in large, bolded and/or colorful text and graphics (emphasis original):

• “If you have atrial fibrillation (AFib)”

• “Ready to break your AFib routine?”

• “XARELTO® is the first and only once-a-day prescription blood thinner for patients with AFib not caused by a heart valve problem, that is proven to reduce

the risk of stroke—without routine blood monitoring.”

• “…With XARELTO®, there’s no routine blood monitoring—so you have more time for yourself. There are no dietary restrictions, so you’re free to enjoy the healthy foods you love. And there are no dosage adjustments, which means you can manage your risk with just one pill a day, taken with your evening meal. Learn how XARELTO® can help simplify your AFib-related stroke risk treatment….”

In contrast, the risk information is presented on the preceding adjacent page without any of the emphasis (i.e. color scheme, borders, layout, and graphics) used with the efficacy claims. The result is a presentation which appears unconnected to the efficacy claims and is therefore not likely to draw readers’ attention. This overall presentation misleadingly  minimizes the risks associated with Xarelto because it fails to convey this important risk information with a prominence and readability reasonably comparable to the efficacy claims. We note that the Print Ad contains the statement, “Please see accompanying Medication Guide on the following pages” (emphasis original) at the bottom of the page, and that risk information is presented on an adjacent page, but this is not sufficient to mitigate the overall misleading presentation.

Misleading Claim

 The Print Ad includes the following claim (emphasis original):

• “And there are no dosage adjustments…”

The above claim misleadingly suggests that dosage adjustments are not necessary with Xarelto. However, according to the DOSAGE AND ADMINISTRATION section of the PI, the dose should be lowered to 15 mg once daily for patients with renal impairment who may have a CrCL of 15 to 50 mL/min. In addition, the WARNINGS AND PRECAUTIONS section of the PI states, “…Periodically assess renal function as clinically indicated…and adjust therapy accordingly….” Thus, patients with renal impairment may need to have their dosage adjusted while on Xarelto therapy.

Conclusion and Requested Action

For the reasons discussed above, the Print Ad misbrands Xarelto in violation of the FD&C Act, 21 U.S.C. 352(n) and FDA implementing regulations. 21 CFR 202.1(e)(5)(i); (e)(7)(viii), (ix). OPDP requests that Johnson & Johnson immediately cease the dissemination of violative promotional materials for Xarelto such as those described above. Please submit a written response to this letter on or before June 20, 2013, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Xarelto that contain violations such as those described above, and explaining your plan for discontinuing use of such violative materials.

Please direct your response to the undersigned at the Food and Drug Administration,

Center for Drug Evaluation and Research, Office of Prescription Drug Promotion, 5901-B Ammendale Road, Beltsville, Maryland 20705-1266 or by facsimile at (301) 847-8444. To ensure timely delivery of your submissions, please use the full address above and include a prominent directional notation (e.g. a sticker) to indicate that the submission is intended for OPDP. Please refer to MA# 215 in addition to the NDA number in all future correspondence relating to this particular matter. OPDP reminds you that only written communications are considered official. The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Xarelto comply with each applicable requirement of the FD&C Act and FDA implementing regulations.

Sincerely,

{See appended electronic signature page}

Zarna Patel, Pharm.D.

Regulatory Review Officer

Office of Prescription Drug Promotion

{See appended electronic signature page}

Amy Toscano, Pharm.D., RAC, CPA

Team Leader

Office of Prescription Drug Promotion

____________________________________________________________________________________

It is difficult to understand why the makers of Xarelto did not unilaterally determine (and warn that their original messaging (no routine blood monitoring needed) might have been misleading bases solely on the number of adverse events reported to the FDA since the products introduction.

 

 

 

 

 

https://fis.fda.gov/sense/app/d10be6bb-494e-4cd2-82e4-0135608ddc13/sheet/59a37af8-d2bb-4dee-90bf-6620b1d5542f/state/analysis

 

 

 

 

 

 

https://fis.fda.gov/sense/app/d10be6bb-494e-4cd2-82e4-0135608ddc13/sheet/59a37af8-d2bb-4dee-90bf-6620b1d5542f/state/analysis

Having not corrected their prior claims (warned) related to the need for routine blood testing (monitoring) the makers of Xarelto did add the words underlined (below) to the label for Xarelto NDA -022406 in November of 2018. This statement in no way corrects the arguably false prior statements related to “No Routine Blood Testing” needed.  This statement simply warns that many of the common “blood monitoring tests used” are not recommended for individuals using Xarelto. A more accurate statement might have been: “These tests have no diagnostic value for individuals on Xarelto,” as the drug skews the test, and not in a predictable fashion, which would allow for adjustment of the test results.

Do these two statements seem the same to you?

  1. No Routine Blood Monitoring Needed with Xarelto.
  2. The test routinely used for anticoagulation monitoring has no diagnostic value for individuals taking Xarelto.

Which of the above two statements would likely increase revenues from the drug and which one would likely have the opposite effect?

11/07/2018 (SUPPL-29)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Risk of Bleeding

Reversal of Anticoagulant Effect

Additions and/or revisions underlined:

… anticoagulant activity of rivaroxaban. Use of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa, may be considered but has not been evaluated in clinical efficacy and safety studies. Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity is not recommended.

https://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges/index.cfm?event=searchdetail.page&DrugNameID=287

“Now We Turn to “No Dietary Restrictions Necessary”

 06/28/2017 (SUPPL-23)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Risk of Bleeding

(additions underlined)

(excerpts)

5.6 Use with P-gp and Strong CYP3A4 Inhibitors or Inducers

(additions underlined)

Avoid concomitant use of XARELTO with known combined P-gp and strong CYP3A4 inhibitors.

Avoid concomitant use of XARELTO with drugs that are known combined P-gp and strong CYP3A4 inducers.

7 Drug Interactions

7.1 General Inhibition and Induction Properties

(additions underlined)

Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Combined P-gp and strong CYP3A4 inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding. Combined P-gp and strong CYP3A4 inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events.

7.2 Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems

Interaction with Combined P-gp and Moderate CYP3A4 Inhibitors in Patients with Renal Impairment

XARELTO should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A4 inhibitors (e.g., erythromycin) unless the potential benefit justifies the potential risk.

End excerpt

What is the significance of the above?

The inducers make the user more susceptible to clots (ischemic stroke, DVT, PE, etc.)

The inhibitors make the user more likely to bleed.

On a side note, the GI tract is significant to the actions of CYPE4A as well as P-gp. And if you remember from above, what was the most reported AE with Xarelto:

 

So what does the use of Strong and Moderate CYP34A and P-gp Inhibitors and Inducers have to do with dietary restrictions?

Most everyone is familiar with the fact that some drugs carry a warning about restricting grapefruit juice from your diet while on the given drug (i.e. statins).

The relation to the above and the “no dietary restrictions” claim, that the makers of Xarelto use to promote their drug (and then stopped making but did not correct the narrative) is simple. There are numerous foods which are CYP34A, and P-gp inhibitors and/or inducers. We provide a small sampling of foods and dietary supplements below.

The dietary restrictions associated with Warfarin restricted foods high in Vitamin K, like Kale (yummy Kale).

Xarelto Potential Food Restrictions

It is worth nothing that due to genetic differences, the strength of a given CYP34A and P-gp Inhibitor or Inducer necessary to interfere with a drug is not the same for everyone. Women as a general rule are more susceptible to the effects of CYP34A and P-gp Inhibitors or Inducers than men.

Grape Fruit Juice: Inhibits CYP34A and P-gp Seville Orange Juice CYP34A and P-gp
Lime Juice Inhibits CYP34A Lemon Juice Inhibits CYP34A
Pomegranate Juice Inhibits CYP34A Star Fruit Juice Inhibits CYP34A
Kiwi Juice Inhibits CYP34A Passion Fruit Juice Inhibits CYP34A
 St. John’s wort Induction of P-gp Ginkgo Biloba Induces P-gp

 In addition to food interactions Approximately 50% of prescription drugs either induce or inhibit CYP34A or P-gp.

While many drugs are deactivated by CYP3A4, there are also some drugs which are activated by the enzyme. Some substances, such as grapefruit juice and some drugs, interfere with the action of CYP3A4. These substances will therefore either amplify or weaken the action of those drugs that are modified by CYP3A4.

https://en.wikipedia.org/wiki/CYP3A4

So, what the Xarelto label (warnings) universally adequate in 2015, 2016 or today?

We think not!

Read More

Xarelto Settlement: Dead on Arrival?

April 15, 2019

(Mass Tort Nexus Media) Bayer and Johnson & Johnson both issued press releases on March 25th indicating to the public, as well as stockholders and analysts, that the companies had reached a settlement to resolve approximately 25,000 claims related to Xarelto. This announcement was arguably highly misleading, in that the agreement reached has not actually resulted in the settlement of a single Xarelto lawsuit (to the best of our knowledge) and certainly not 25,000 cases.

This was the headline in Reuters:  Bayer, J&J settle U.S. Xarelto litigation for $775 million,see Reuters.com/article/us-bayer-xarelto/bayer-jj-settle-us-xarelto-litigation-for-$775-million

At the time of press release, in which Bayer and Johnson & Johnson led the public and the market to believe they had resolved (settled) 25,000 pending Xarelto lawsuits, the overwhelming majority of firms representing those 25,000 clients had yet to receive significant details related to the proposed settlement, and of course had yet to present any offer to their individual clients, who would have to accept any offer made before a case could actually be settled.

Law Firms attending the Mass Torts Made Perfect conference in Las Vegas last week received more details related to the defendants proposed settlement and the reaction was not positive.

Large Scale Rejection of Proposed Settlement?

Mass Tort Nexus has spoken with a great a number of firms who were in attendance at MTMP, as well as numerous others since that time, and the clear indication that we have received would lead us to the conclusion that it is highly unlikely that the defendants proposed settlement will be accepted by enough firms (or rather their clients), to make going forward with the current proposed settlement anything other than a waste of time.

Law Firms that have been in contact with Mass Tort Nexus have indicated that they will fulfill their duty to present any offer made by defendants for their cases to the individual clients; however, they will not likely recommend that clients accept the offers made under the proposed settlement scheme. Many of the firms made colorful comments that we will not publish; however, there was a common theme among the comments:

“I would feel like I was selling out my clients if I recommend they accept the current offer the defendants have made.”

Others went as far as to say:

“I think it would be malpractice to recommend that clients accept the final amounts likely to be offered in this settlement scheme”

Dilemma for Bayer and Johnson & Johnson

The premature and arguably misleading public announcement, which would likely be considered official stock holder guidance, may create additional problems for the corporations already plagued by legal woes, which pose risks to their respective stock prices and stock holder value. If the proposed Xarelto settlement does fall through, as it appears will likely be the case, the companies will be faced with having to walk back previous positive news  “We have resolved the risk associated with the Xarelto litigation” to “not only have we not resolved the risk associated with the Xarelto litigation, but that risk may now be more significant than it was before we proposed a settlement, and many plaintiffs firms see it as more of an insult than an offer.”

If the proposed settlement was even close to something plaintiffs might except in significant numbers, Bayer and J&J might have been in a position to “tweak the settlement” and avoid having to deliver bad news to their stockholders and the public. Unfortunately for Bayer and J&J, the proposed settlement seems to be so far from “acceptable” that their only option may be to scrap the current proposed settlement and come back with another proposal, that will not be received with such strong resistance. If the two corporate giants have any hope of salvaging their messaging to the market, they will need to act quickly.

Proposed Settlement Appears to be a “Non-Starter” 

      

For now, it appears that there is no amount of lipstick that would make the proposed Xarelto settlement scheme attractive.  Most of the firms Mass Tort Nexus has spoken to have indicated that the defendants offer is not even a starting point.

 

 

 

 

MTN will provide more information in future articles about the proposed settlement, as well as the reasons a large number of firms do not feel the settlement is fair and just to their clients. At this point in time; however, it seems likely that the proposed Xarelto settlement is:

The Industry Comment

       XARELTO SETTLEMENT

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TEXTURED BREAST IMPLANTS – “An Emerging Mass Tort”

 

France and Canada look to banning sale of textured implants-what’s the next move in the USA?

 

 

 

 

 

 

 

(MASS TORT NEXUS MEDIA) Recent studies have shown that patients with textured implants face a higher risk of a rare form of cancer called breast implant associated anaplastic large cell lymphoma (BIA ALCL). BIA ALCL is not a breast cancer but a cancer of the immune system. Plastic surgeons have identified at least 688 cases of BIA ALCL worldwide, as of February 2019. The FDA estimates the risk of BIA ALCL among patients with textured implants as between 1 in 3,817 and 1 in 30,000, but newer data from Australia has placed the risk as high as 1 in 1,000.

Nine deaths from a rare form of cancer have been linked to breast implants, the Food and Drug Administration announced as far back as 2017, the US oversight has not taken the warning seriously, however the international oversight apparently has. Countires around the globe are starting to ban the sale of “textured breast implants” based on the emerging clinical linbks to these implants and cancer. .

Red flags were raised as far back as  2011 regarding the safety of breast implants and their possible link to a type of lymphoma, but the FDA has only now updated information on the risk to women with both silicone and saline breast implants.

As of February 1, 2017, the FDA had received a total of 359 reports related to breast implant-associated anaplastic large cell lymphoma — a rare cancer of the immune system — including nine deaths, the agency said in a statement. ALCL is not a form of breast cancer, but it grows in the breast in implant patients.

The FDA says the exact number of cases of the disease remains difficult to determine due limitations in the reporting of breast implant sales data. Estimates of the frequency of the disease range from 1 in 3,000 women to 1 in 30,000, according to the Associated Press. The cancer is treatable with the removal of implants, though nearly a dozen deaths have occurred.

Additionally, thousands of women have blamed breast implants for a range of other health ailments, including rheumatoid arthritis, pain and chronic fatigue. In documents released before the meeting, the FDA contends “at the present time, there is not sufficient evidence to show an association between breast implants and rheumatologic or connective tissue disease diagnoses.”

A recent study published in JAMA Oncology concluded that  found that silicone breast implants with a textured surface are 400-times more likely to cause a rare type of cancer compared to silicone breast implants with a smooth surface.

Approximately 1 out of every 26 women in the United States have breast implants.

The primary makers of breast implants approved for use in the United States include:

Allergan, Inc.

Ideal Implant, Inc.

Mentor World Wide, LLC

Sientra, Inc.

Breast augmentation remains the most common cosmetic surgical procedure in the U.S. with more than 300,000 performed each year, according to the American Society of Plastic Surgeons.

The meeting comes a week after the FDA sent warning letters to two breast implant manufacturers for their failure to comply with requirements to conduct long-term studies assessing the safety of silicone gel-filled implants.

International Review

The International Consortium of Investigative Journalists revealed the ongoing health problems plaguing women with breast implants as part of its global Implant Files investigation in November 2018, and has covered breast implant safety extensively in the aftermath. In the wake of the investigation, health authorities from France to Brazil to the United States recently announced initiatives to better protect patient health.

Health Canada is advising a manufacturer of breast implants that it could soon ban the sale of its product in Canada because of a possible link to a

The Biocell implants, manufactured by Allergan, have a slightly textured surface, designed to adhere better to the surrounding tissue. Health Canada intends to remove them from the market as a precautionary measure, to “protect Canadians from the rare but serious risk of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL)” the department wrote in a news releaseThursday.

Of 28 confirmed cases of BIA-ALCL reported to Health Canada, 24 involved that particular implant, the department said.

 Quebec contacting women with textured breast implants to warn of cancer risk

BIA-ALCL is not a cancer of the breast tissue, but rather a rare type of non-Hodgkin lymphoma that can develop months or years after the implants were put in. It usually leads to an accumulation of fluid inside the breast. It’s generally treated by carefully removing the implant and fluid containing the cancerous cells. In some cases, it can spread throughout the body, warranting chemotherapy treatment, according to the World Health Organization.

WATCH: Winnipeg woman says breast implants ruined her life and her health

 

 

 

 

 

 

Health Canada will allow Allergan 15 days to present medical evidence about the implants’ safety. If the evidence isn’t “satisfactory,” Health Canada intends to suspend their medical license, meaning the product would no longer be permitted for sale in Canada.

France also announced that it intends to ban textured breast implants earlier this week.

 Breast implant safety under review by U.S. authorities

Health Canada is currently reviewing breast implant safety and BIA-ALCL and plans to present its entire report by the end of April. A second report looking at other symptoms reported among recipients of breast implants will be released this summer, according to the press release.

 Bowmanville woman wants Health Canada to push awareness of ‘breast implant illness’

If you have breast implants, Health Canada recommends that you speak with your surgeon to find out what type of implant you have received. If you experience any unusual changes to your breasts, you should contact a health-care professional and discuss any decisions about implant removal with them too.

Nearly all the lymphoma cases have occurred in women who had implants with a textured surface, rather than a smooth one. Textured implants made by Allergan, a major manufacturer, were taken off the market in Europe in December. Smooth implants are used more often than textured ones in the United States.

 FDA NOTICE ON TEXTURED IMPLANTS

 

 

 

 

 

 

March 20, 2019

FDA News Release March 20, 2019

FDA issues warning letters to two breast implant manufacturers for failure to comply with post-approval study requirements

For Immediate Release

Today, the U.S. Food and Drug Administration issued warning letters to two breast implant manufacturers for failure to comply with their requirements, under their premarket approval orders, to conduct post-approval studies to assess the long-term safety and risks of their silicone gel-filled breast implants.

The FDA issued warning letters to Mentor Worldwide LLC of Irvine, California, and Sientra, Inc. of Santa Barbara, California.  Every manufacturer of approved silicone gel-filled breast implants is required to conduct post-approval studies to further evaluate safety and effectiveness of the products and to answer additional scientific questions about the long-term safety and potential risks of breast implants that their premarket clinical trials were not designed to answer.

“Post-approval requirements are critical to ensuring the safety and effectiveness of the medical products we regulate and we’ll continue to hold manufacturers accountable when they fail to fulfill these obligations,” said FDA Commissioner Scott Gottlieb, M.D. “We’re issuing these warning letters based on the manufacturers’ low recruitment, poor data, and low follow-up rates in their required post-approval studies. We expect these manufacturers to meet the pre-specified study requirements in order to ensure the collection of long-term data that can be used to inform long-term patient safety.  Post-approval studies, along with other surveillance tools such as adverse event reports, registries, and scientific literature, allow the FDA to help ensure the safety of medical devices and protect patients.”

The FDA’s warning letter to Mentor Worldwide LLC (Mentor) noted several serious deficiencies in the manufacturer’s post-approval study for its MemoryShape breast implant, first approved in 2013, including that the manufacturer had failed to enroll the required number of patients in the study. The action also notes Mentor had poor follow-up rates with patients in the study. Finally, the FDA notified Mentor that there were significant data inconsistencies in the study, including poor patient accounting and missing race and ethnicity data. While the FDA had concluded after reviewing several interim study reports submitted by Mentor that progress on the post-approval study appeared adequate at that time, the agency advised Mentor of concerns about patient enrollment, follow-up rates and data inconsistencies.

Mentor’s failure to address these concerns and comply with its post-approval study requirements is a violation of the firm’s pre-market approval order.

The FDA’s warning letter to Sientra, Inc. (Sientra) noted a serious deficiency in the manufacturer’s post-approval study for its Silicone Gel Breast Implants, first approved in 2013. The manufacturer had poor follow-up rates with patients. Currently, the manufacturer reported a follow-up rate of 61 percent, which is below the target follow-up rate. In the response to the manufacturer’s most recent interim study report, the FDA notified the manufacturer that the study progress was inadequate because of low follow-up rates. Sientra’s failure to address these concerns and comply with its post-approval study requirements is a violation of the firm’s pre-market approval order.

The FDA requested responses from both manufacturers within 15 working days of the issuance of the warning letters, with details about how the noted violations will be corrected. The FDA may take action for a failure to comply with post-approval orders, including pursuing applicable criminal and civil penalties, where appropriate.

The FDA’s actions today are part of the agency’s ongoing commitment to its public health mission of ensuring patient access to safe and effective medical devices. As part of the Medical Device Safety Action Plan, the FDA committed to streamlining and modernizing how the agency implements postmarket actions to address device safety issues to make responses to risks more timely and effective, including taking actions against manufacturers when their postmarket studies are non-compliant with any study requirements. The FDA has issued several warning letters in recent years to manufacturers who did not adequately fulfill certain postmarket study requirements, reflecting the agency’s commitment to take more aggressive actions against manufacturers who fail to comply.

In addition to the required post-approval studies, the FDA has taken additional steps to ensure the agency is monitoring the safety and risks of breast implants. For instance, FDA staff have coordinated with the American Society of Plastic Surgeons and the Plastic Surgeons Foundation to develop the Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma (BIA-ALCL) Etiology and Epidemiology (PROFILE), which collects real world data regarding patients who have a confirmed diagnosis of BIA-ALCL. The data collected from this registry, have contributed to a better understanding of BIA-ALCL and FDA communication updatesto the public regarding BIA-ALCL.

Additionally, the FDA has worked with multiple stakeholders to facilitate the development of the National Breast Implant Registry (NBIR) to provide a platform for collecting additional real world data on the safety and performance of breast implants. This newly launched registry will greatly add to the information we collect in our own post-approval studies about the long-term safety of breast implants, and potentially enhance our understanding of the long term safety and risks associated with breast implants.

The FDA remains committed to thoughtful, scientific, transparent, public dialogue concerning breast implant safety and effectiveness. The FDA welcomes public dialogue about breast implant safety and risk at the upcoming public meeting of the General and Plastic Surgery Devices Panel at the FDA’s headquarters in Silver Spring, Maryland on March 25-26, 2019, which will also be available via webcast.

Health care professionals and consumers should report any adverse events related to breast implants to the FDA’s MedWatch Adverse Event Reporting program.  The FDA monitors these reports and takes appropriate action necessary to ensure the safety of medical products in the marketplace.

End of FDA Release

To access information on Breast Implants II and the most relevant and real time information on Mass Torts  sign up for:

Mass Tort Nexus “CLE Immersion Course”

May 31 – June 3, 2019 at The Riverside Hotel in Fort Lauderdale , FL

For class attendance information please contact Barbara Capasso at 954.530.9892 or Barbara@masstortnexus.com.

  1. For the most up-to-date information on all MDL dockets and related mass torts visit www.masstortnexus.com and review our mass tort briefcases and professional site MDL briefcases.
  2. To obtain our free newsletters that contains real time mass tort updates, visit com/news and sign up for free access.

 

 

 

 

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FDA identifies harm reported from sudden discontinuation of opioid pain medicines and requires label changes to guide prescribers on gradual, individualized tapering

fda-logo

 

 

 

 

 

 

 

FDA identifies harm reported from sudden discontinuation of opioid pain medicines and requires label changes to guide prescribers on gradual, individualized tapering

Safety Announcement

[4-9-2019] The U.S. Food and Drug Administration (FDA) has received reports of serious harm in patients who are physically dependent on opioid pain medicines suddenly having these medicines discontinued or the dose rapidly decreased. These include serious withdrawal symptoms, uncontrolled pain, psychological distress, and suicide.

While we continue to track this safety concern as part of our ongoing monitoring of risks associated with opioid pain medicines, we are requiring changes to the prescribing information for these medicines that are intended for use in the outpatient setting. These changes will provide expanded guidance to health care professionals on how to safely decrease the dose in patients who are physically dependent on opioid pain medicines when the dose is to be decreased or the medicine is to be discontinued.

Rapid discontinuation can result in uncontrolled pain or withdrawal symptoms. In turn, these symptoms can lead patients to seek other sources of opioid pain medicines, which may be confused with drug-seeking for abuse. Patients may attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

Opioids are a class of powerful prescription medicines that are used to manage pain when other treatments and medicines cannot be taken or are not able to provide enough pain relief. They have serious risks, including abuse, addiction, overdose, and death. Examples of common opioids include codeine, fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, and oxymorphone.

Health care professionals should not abruptly discontinue opioids in a patient who is physically dependent. When you and your patient have agreed to taper the dose of opioid analgesic, consider a variety of factors, including the dose of the drug, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. No standard opioid tapering schedule exists that is suitable for all patients. Create a patient-specific plan to gradually taper the dose of the opioid and ensure ongoing monitoring and support, as needed, to avoid serious withdrawal symptoms, worsening of the patient’s pain, or psychological distress (For tapering and additional recommendations, see Additional Information for Health Care Professionals).

Patients taking opioid pain medicines long-term should not suddenly stop taking your medicine without first discussing with your health care professional a plan for how to slowly decrease the dose of the opioid and continue to manage your pain. Even when the opioid dose is decreased gradually, you may experience symptoms of withdrawal (See Additional Information for Patients). Contact your health care professional if you experience increased pain, withdrawal symptoms, changes in your mood, or thoughts of suicide.

We are continuing to monitor this safety concern and will update the public if we have new information. Because we are constantly monitoring the safety of opioid pain medicines, we are also including new prescribing information on other side effects including central sleep apnea and drug interactions. We are also updating information on proper storage and disposal of these medicines that is currently available on our
Disposal of Unused Medicines webpage.

To help FDA track safety issues with medicines, we urge patients and health care professionals to report side effects involving opioids or other medicines to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page.

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Insys Therapeutics “Fentanyl Spray Criminal Trial” In Jury Deliberations

“Fentanyl Spray Federal Criminal Trial” Now In US District Court of Massachusetts Jury Deliberations

By Mark A. York (April 8, 2019)

Subsys: a highly addictive fentanyl spray.

December 2016 saw Insys Therpaeutics Founder John Kapoor, CEO Michael Babich and five other senior executives indicted on criminal charges for paying kickbacks and bribes to medical professionals and committing fraud against insurance companies across the country for offering a highly addictive Fentanyl prescription product “Subsys” to the masses. The Insys boardroom was indicted in the US District Court of Massachusetts, where the entire team has engaged a stable of top national law firms to defend the indictments. The “Subsys” sales teams were charged in federal indictments across the country, including Arkansas, Connecticut, Alaska and New York and the indictments will only increase as these cases proceed and “cooperating witnesses” decide that prison isn’t an option.

To compound further harsh scrutiny for Insys, it’s new CEO Saeed Motahari, moved over from Purdue Pharmaceuticals, the Oxycontin maker, who’s also a major target of criminal and civil investigations across the country by various agencies. Purdue is being investigated for false marketing, off-label use and ignoring Oxycontin’s highly addictive dangers for years, while bringing in literally billions of dollars in profits.

PRIOR DOCTOR INDICTMENTS

Doctors who’ve written massive numbers of Subsys prescription, under the “fee to speak” program have been indicted and they include pain clinics, medical centers and other healthcare facilities who now face federal criminal charges for fraudulent prescription writing, submitting false claims to insurance companies and numerous other federal charges and all face a minimum of 20 to 50 years in federal prison. Two of the busiest “Subsys” prescription writers in the country were Alabama doctors, John Couch and Xiulu Ruan, who earned over $40 million from Insys, and were charged with running a pill mill between 2013 and 2015, have been convicted and sentenced to 20 years each in federal prison.

The top “Subsys” prescriber of all, Dr. Gavin Awerbach, of Saginaw, MI pled guilty to defrauding Medicare and Blue Cross out of $3.1 million in improper Subsys prescriptions, his criminal sentence is pending. To show the far reach of Insys and its corporate plans to saturate the US market with opioids, in Anchorage, Alaska Dr. Mahmood Ahmad, was charged with a massive Subsys prescribing operation, which he denies, but immediately surrendered his Alaska medical license which caused the revocation of his license Arkansas.

THE OFF LABEL CAMPAIGN

The only people who are supposed to be taking Subsys are adult cancer patients, according to the FDA “Subsys” approval files, anything other than that is an “off label” indication. Now you can take a drug to treat something off label if you want to, but you have to get your doctor to get pass a prior authorization.

Anthem alleges that Insys has an entire unit to get around this requirement — it’s titled the “reimbursement unit.” Investigative journalists exposed this fraud initially as far back as 2015 on behalf of the Southern Investigative Reporting Foundation, see Insys Therapeutics “Subsys” Off Label Rx Fraud.

The Reimbursement Unit claim was basically the company’s fraudulent prescription approval factory, which helped participating doctors process claims (the doctors had so many they couldn’t handle them all). The unit falsified records to show patients had cancer and called insurers, pretending to be patients or other medical professionals, to facilitate approval of payment for off-label treatment.

This is the Unit’s script for obtaining off-label approval (taken from the Anthem suit):

The script read: “The physician is aware that the medication is intended for the management of breakthrough pain in cancer patients. The physician is treating the patient for their pain (or breakthrough pain, whichever is applicable).” The script deliberately omitted the word “cancer as applied to the patient treatment under discussion.”

Prosecutors also said that two former Insys employees who were first charged in 2016 in connection with the scheme, Jonathan Roper and Fernando Serrano, had secretly pleaded guilty and become cooperating witnesses. The five doctors were arrested last Friday morning and face charges including that they violated the federal anti-kickback law and conspired to commit fraud.

INSYS RX ABUSES WERE BLATANT

The case is the latest in a series of medical practitioners and former Insys executives and employees facing criminal charges related to Subsys, the company’s potentially addictive fentanyl-based spray.

Federal prosecutors in Boston are moving forward aggressively against the seven former Insys executives and managers as well billionaire founder John Kapoor, all accused of actively designing and participating in the scheme to bribe doctors to prescribe Subsys and to defraud insurers into paying for it. Insys has said it may need to pay at least $150 million towards part of a settlement with the U.S. Justice Department as well as numerous other state investigations around the country, not to mention the civil complaints filed against the company in the Opiate Prescription MDL 2804, see OPIOID-CRISIS-BRIEFCASE-INCLUDING-MDL-2804-OPIATE-PRESCRIPTION-LITIGATION, where the Insys sales and marketing tactics are listed as prime examples of boardroom designed “profits over patients” policies are cited.

Insys is joined in the massive Federal Opioid MDL 2804, by other Big Pharma defendants including Purdue Pharmaceuticals, Endo Health, J&J’s Janssen Pharmaceutical and other opioid manufacturers who were allowed to place profits over patients for more than 15 years, while earning billions in profits.

UNETHICAL SALES TACTICS

According to the most recent and prior doctor indictments, the physicians have participated in Insys’ speaker programs, which were in reality social gatherings at high-end restaurants. They earned kickbacks ranging from $68,000 and $308,000 and were among the top 20 prescribers of Subsys nationwide at some point during the marketing campaign. A few doctors indicted as far back as late 2016 have already been sentenced to federal prison terms up to 20 years and forfeit of millions of dollars in assets. The Insys marketing tactics included trips with doctors to strip clubs with Insys sales managers; and often with Insys executives, where they covered lap dances and drinks which on one trip ran up a tab of over $4,100 which was apparently enough to convince physicians to write massive numbers of off-label fentanyl prescriptions.

The Criminal Trial Status

A cooperating witness testified by calling the payments bribes, a former vice president of Insys Therapeutics stood by a giant spreadsheet in court Tuesday and described how the drug company funneled phony “speaking fees” to doctors in exchange for prescribing its highly addictive opioid painkiller.

Alec Burlakoff, who has pleaded guilty to racketeering charges and is testifying in US District Court in Boston against Insys founder John N. Kapoor and four former colleagues, said Kapoor encouraged the program in late 2012 to spur doctors to prescribe Subsys, an under-the-tongue fentanyl spray.

But Kapoor insisted that each practitioner generate at least twice as much revenue for Insys by writing Subsys prescriptions than he or she received from the company.

Burlakoff stood next to an enlarged spreadsheet that executives prepared in December 2012. One column showed what each “speaker” received every time he or she supposedly met with other doctors to promote Subsys. The amounts ranged from $1,000 to $1,600 to $2,400 depending on whether Insys designated them local, regional, or national experts.

In truth, he said, the designation “national expert” was ludicrous and some doctors had only sordid reputations for running “pill mills.”

Another column showed how many prescriptions the practitioners wrote for Subsys, while another displayed how many they wrote for competing fentanyl products.

Assistant US Attorney Fred Wyshak Jr. asked Burlakoff what another column listing sums of money represented.

“That’s the amount of money we paid in bribes to date,” said Burlakoff, the former vice president of sales, prompting one of the defense lawyers for the five defendants to object.

Kapoor and four other former executives of the Chandler, Ariz.-based company are on trial for allegedly conspiring to violate the federal criminal Racketeer Influenced and Corrupt Organizations Act, or RICO, by paying bribes and kickbacks to practitioners. Prosecutors typically use RICO to go after alleged mobsters.

It is the first criminal trial of pharmaceutical executives who marketed an opioid painkiller since the nation’s deadly opioid epidemic began.

Burlakoff, whom jurors first saw last month dressed as a bottle of Subsys spray in a jaw-dropping in-house rap video, said that at least one executive strenuously objected to the company tracking how many Subsys prescriptions participants in the speakers program wrote.

Matthew Napoletano, Insys’s former head of marketing, who has already testified under immunity for the government, rose from his chair at a meeting with Kapoor, Burlakoff, and other executives, Burlakoff said. Napoletano said such a spreadsheet could be viewed as evidence of a crime.

But the company went forward with the payment program.

The payments were hardly the only way Insys prodded doctors to write Subsys prescriptions, Burlakoff said. Leaders of the sales team, including Joseph Rowan, a former regional sales director who is among the defendants, would buy coolers full of steaks for doctors, according to Burlakoff.

In other cases, he said, Insys executives would put staffers in the offices of big Subsys prescribers on the payroll of the drug company; those staffers were often spending considerable time on the phone with insurers trying to get them to approve Subsys prescriptions, and “now doctors would no longer be complaining” about the expense of paying those employees to do that.

Burlakoff, who became vice president of sales in 2012 after spending years at Cephalon, Eli Lilly and Company, and other drug makers, said Insys didn’t only provide incentives to physicians; the company also gave incentives to members of the sales team.

Sales representatives at Insys, he said, had a starting salary of $40,000 a year, less than half of what such employees typically made at other drug companies. But they received an extraordinary commission of 10 percent on the sales they made each quarter, and it wasn’t capped.

Several sales representatives, he said, made $110,000 in a quarter based just on the commission.

As part of the boardroom strategy to get doctors to prescribe Subsys, Insys spent millions paying them off through a fraudulent “speakers program” meant to educate medical professionals about the drug. The speaking engagements were a veiled attempt to cover-up the direct payment to doctors for writing prescriptions, the more prescriptions you wrote, the higher your “speaking fees” increased. There are e-mails, texts and other Insys communications from all levels of company personnel stating “if they not writing prescription, they’re off the speaking program”, this policy resulted in one Alabama sales rep being paid over $700 thousand in Subsys based Rx commissions for one year, while her base salary was $40 thousand.

SALES REP NATALIE REED PERHAC

In the plea, Perhacs admitted that she was hired to be the personal sales representative for one of Insys’s most important prescribers, Dr. Xiulu Ruan. Ruan is one of two Alabama doctors who picked up over $115,000 in speaker fees from 2012 to 2015, and earned in excess of $40 million in related medical earnings during the same period. Earlier this year they were sentenced to 20 years in jail each for running a “pill mill” and helping Insys sales rep Natalie Reed Perhacs sell Subsys, for which she was paid in excess of $700 thousand in commissions, see Perhac Guilty Plea in Alabama Federal Court.

Perhac Plea Excerpts:

Admision No. 78: . Perhacs admitted that her primary responsibility at Insys was to increase the volume of Subsys® prescribed by Dr. Ruan, and his partner Dr. John Patrick Couch. This… was accomplished by (1) handling prior authorizations for their patients who had been prescribed Subsys®; (2) identifying patients who had been at the same strength of Subsys® for several months and recommending that Dr. Ruan or Dr. Couch increase the patients’ prescription strength; and (3) setting up and attending paid speaker programs.

Admission No. 79:. Ms. Perhac admitted that because of her involvement in the prior authorization process, she knew that the vast majority of Dr. Ruan and Dr. Couch’s patients did not have breakthrough cancer pain.

As you can see by the Perhac admissions, numbers 78 and 79, which reflect the vast number of charges lodged against her, the federal government is cracking down on everyone involved with the “Subsys” fraud. According to confidential sources, the recent June 2017 FDA “Opioid Crisis” Conference and related strategic review of the opioid crisis, will result in many more indictments and charges against drug makers and the medical providers who’ve helped facilitate the opioid epidemic that is currently in place across the United States.

How the results of the trail against the Insys Therapeutics boardroom plays out in the overall “Opioid Crisis” battle remains to be seen. There is always the question of why the Sackler family (Purdue Pharma) and the billions they’ve earned off improper marketing of Oxycontin and their scorched earth sales tactics, have not resulted in criminal indictments yet? Perhaps the Sackler family habit of donating billions to charities and having hospital wings named in their honor was a very strategic and forward looking business model that is now paying great dividends.

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AN EMERGING LITIGATION? “Breast Implants Round II”

 

 

 

 

 

 

FDA News Release March 20, 2019

FDA issues warning letters to two breast implant manufacturers for failure to comply with post-approval study requirements

For Immediate Release

Today, the U.S. Food and Drug Administration issued warning letters to two breast implant manufacturers for failure to comply with their requirements, under their premarket approval orders, to conduct post-approval studies to assess the long-term safety and risks of their silicone gel-filled breast implants.

The FDA issued warning letters to Mentor Worldwide LLC of Irvine, California, and Sientra, Inc. of Santa Barbara, California.  Every manufacturer of approved silicone gel-filled breast implants is required to conduct post-approval studies to further evaluate safety and effectiveness of the products and to answer additional scientific questions about the long-term safety and potential risks of breast implants that their premarket clinical trials were not designed to answer.

“Post-approval requirements are critical to ensuring the safety and effectiveness of the medical products we regulate and we’ll continue to hold manufacturers accountable when they fail to fulfill these obligations,” said FDA Commissioner Scott Gottlieb, M.D. “We’re issuing these warning letters based on the manufacturers’ low recruitment, poor data, and low follow-up rates in their required post-approval studies. We expect these manufacturers to meet the pre-specified study requirements in order to ensure the collection of long-term data that can be used to inform long-term patient safety.  Post-approval studies, along with other surveillance tools such as adverse event reports, registries, and scientific literature, allow the FDA to help ensure the safety of medical devices and protect patients.”

The FDA’s warning letter to Mentor Worldwide LLC (Mentor) noted several serious deficiencies in the manufacturer’s post-approval study for its MemoryShape breast implant, first approved in 2013, including that the manufacturer had failed to enroll the required number of patients in the study. The action also notes Mentor had poor follow-up rates with patients in the study. Finally, the FDA notified Mentor that there were significant data inconsistencies in the study, including poor patient accounting and missing race and ethnicity data. While the FDA had concluded after reviewing several interim study reports submitted by Mentor that progress on the post-approval study appeared adequate at that time, the agency advised Mentor of concerns about patient enrollment, follow-up rates and data inconsistencies.

Mentor’s failure to address these concerns and comply with its post-approval study requirements is a violation of the firm’s pre-market approval order.

The FDA’s warning letter to Sientra, Inc. (Sientra) noted a serious deficiency in the manufacturer’s post-approval study for its Silicone Gel Breast Implants, first approved in 2013. The manufacturer had poor follow-up rates with patients. Currently, the manufacturer reported a follow-up rate of 61 percent, which is below the target follow-up rate. In the response to the manufacturer’s most recent interim study report, the FDA notified the manufacturer that the study progress was inadequate because of low follow-up rates. Sientra’s failure to address these concerns and comply with its post-approval study requirements is a violation of the firm’s pre-market approval order.

The FDA requested responses from both manufacturers within 15 working days of the issuance of the warning letters, with details about how the noted violations will be corrected. The FDA may take action for a failure to comply with post-approval orders, including pursuing applicable criminal and civil penalties, where appropriate.

The FDA’s actions today are part of the agency’s ongoing commitment to its public health mission of ensuring patient access to safe and effective medical devices. As part of the Medical Device Safety Action Plan, the FDA committed to streamlining and modernizing how the agency implements postmarket actions to address device safety issues to make responses to risks more timely and effective, including taking actions against manufacturers when their postmarket studies are non-compliant with any study requirements. The FDA has issued several warning letters in recent years to manufacturers who did not adequately fulfill certain postmarket study requirements, reflecting the agency’s commitment to take more aggressive actions against manufacturers who fail to comply.

In addition to the required post-approval studies, the FDA has taken additional steps to ensure the agency is monitoring the safety and risks of breast implants. For instance, FDA staff have coordinated with the American Society of Plastic Surgeons and the Plastic Surgeons Foundation to develop the Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma (BIA-ALCL) Etiology and Epidemiology (PROFILE), which collects real world data regarding patients who have a confirmed diagnosis of BIA-ALCL. The data collected from this registry, have contributed to a better understanding of BIA-ALCL and FDA communication updatesto the public regarding BIA-ALCL.

Additionally, the FDA has worked with multiple stakeholders to facilitate the development of the National Breast Implant Registry (NBIR) to provide a platform for collecting additional real world data on the safety and performance of breast implants. This newly launched registry will greatly add to the information we collect in our own post-approval studies about the long-term safety of breast implants, and potentially enhance our understanding of the long term safety and risks associated with breast implants.

The FDA remains committed to thoughtful, scientific, transparent, public dialogue concerning breast implant safety and effectiveness. The FDA welcomes public dialogue about breast implant safety and risk at the upcoming public meeting of the General and Plastic Surgery Devices Panel at the FDA’s headquarters in Silver Spring, Maryland on March 25-26, 2019, which will also be available via webcast.

Health care professionals and consumers should report any adverse events related to breast implants to the FDA’s MedWatch Adverse Event Reporting program.  The FDA monitors these reports and takes appropriate action necessary to ensure the safety of medical products in the marketplace.

End

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FDA Statement March 15, 2019 Re: “Efforts to evaluate materials in medical devices to address potential safety questions”  

 

Statement from FDA Commissioner Scott Gottlieb, M.D. and Jeff Shuren, M.D., Director of the Center for Devices and Radiological Health, on efforts to evaluate materials in medical devices to address potential safety questions

For Immediate Release

March 15, 2019

FDA Statement

We’re in an unprecedented era of innovation in medical devices with advances in materials science that have led to technological breakthroughs such as the 3D printing of medical devices, continuous glucose monitoring patches for diabetes and miniaturized brain implants to treat epilepsy and Parkinson’s disease. Helping to ensure patients have access to safe medical devices that improve function and overall quality of life is a crucial part of the mission of the U.S. Food and Drug Administration. Our regulatory framework is designed to ensure that benefits patients receive from these devices are weighed against probable risks.

The vast majority of patients implanted with medical devices have no adverse reactions. The device works and performs as expected to treat medical conditions or help patients better manage their health. However, a growing body of evidence suggests that a small number of patients may have biological responses to certain types of materials in implantable or insertable devices. For example, they develop inflammatory reactions and tissue changes causing pain and other symptoms that may interfere with their quality of life.

Materials used in today’s medical devices vary as widely as the devices themselves—whether the material is metal, plastic, silicone, an animal-derived product or some combination of these. Because, in the case of implantable or insertable devices, these materials come into contact with tissue or other parts of the body for sometimes extended periods of time, we do a careful evaluation during our premarket review to determine if there is a potential adverse biological response resulting from contact of the device’s component materials with the body and whether the associated risks are unacceptable.

Specifically, we review information about the materials used in the composition of the device and require companies to include a biocompatibility evaluation or risk analysis, as well as clinical studies, when appropriate. In 2016, we finalized updated guidance for industry laying out what we look for in biocompatibility evaluations in order to ensure device manufacturers have adequately assessed the potential of their device to cause adverse biological responses in patients. By clarifying expectations for all devices requiring premarket submissions, we are helping to ensure that manufacturers are providing evidence that demonstrates that any risk to patient health or safety has been adequately evaluated prior to marketing.

These steps help to address any risks that may be posed by, for example, the potential presence of harmful chemicals or materials that might trigger allergic or other adverse reactions in some individuals. While such testing generally has been a reliable predictor of a material’s safety, we also recognize the importance of advancing the science we rely on to evaluate device materials and patient risk factors both before and after devices enter the market to assure we optimally reduce risks to patients and maximize benefits. Once a device is on the market we have a number of tools in place to monitor a device’s benefit-risk profile as it is used in a real-world setting. In cases where new information about safety or effectiveness becomes available, we can and have taken action to inform patients and health care providers about new risks or safety considerations and how to mitigate those risks. These actions include working with companies to recall and correct issues that arise postmarket, issuing safety communications or other updates for health care providers or patients about safe use of devices, requiring boxed warnings or contraindications be added to labeling, requiring postmarket studies, and up-classifying devices to allow us to regulate them more stringently, as we did with metal-on-metal total hip replacement devices. We are also working to fully implement the National Evaluation System for health Technology (NEST) that will link and synthesize data from different sources including clinical registries, electronic health records and medical billing claims; this will help improve the quality of real-world evidence that will empower the FDA to more quickly identify, communicate and act on new or increased medical device safety concerns.

Our understanding of medical technologies evolves over time. As we learn more about long-term effects of materials and as materials science advances and new innovations become a reality, it’s imperative our regulation of devices evolves along with these advances to ensure patients are protected.

Prior to, and as part of, our April 2018 Medical Device Safety Action Plan, the FDA has been carefully evaluating the body of evidence on this issue. This includes current published studies, and information submitted to us as reports in our public adverse events database or through data from postmarket studies that we required manufacturers to conduct. We also have our own team of FDA scientists and engineers conducting research to better understand device materials in our Center for Devices and Radiological Health’s (CDRH) Office of Science and Engineering Laboratories (OSEL).

Based on our evaluation and discussions with experts elsewhere in the government and academia, we believe the current evidence, although limited, suggests some individuals may be predisposed to develop an immune/inflammatory reaction when exposed to select materials.

The symptoms some patients experience may be limited to the region where the device is implanted or may be more generalized. Symptoms include but are not limited to fatigue, rash, joint and muscle pain or weakness. Although uncommon and varied, these symptoms may share common underlying immune/inflammatory pathways and mimic more well-established inflammatory conditions.

In the small subsets of patients who have reported these symptoms, the symptoms may not develop for several years following implantation. As a result, they may not be detected even in larger and longer clinical studies. To date, these symptoms have not been reported with most materials used in medical devices, including most metals. Moreover, when reported, they have tended to be limited to small subsets of patients.

As an example, some patients, mostly with a history of pre-existing allergies, may develop allergic skin lesions with certain device use. This risk is usually identified by patch testing for potential device material-related allergens. However, not all device-related reactions are allergic in nature. Therefore, the utility of skin patch testing is limited.

Enhancing our collective understanding of materials science could lead to identifying materials that may cause an exaggerated response in sensitive individuals and advance the development of safer materials. Development of new tests to identify at-risk patients would help ensure they do not receive implantable devices that contain the material to which they are sensitive, therefore further enhancing patient safety and advance a precision medicine approach to the selection of device interventions.

It’s clear more work needs to be done.

To this end, we’re undertaking a broad effort to engage the public, scientists and industry stakeholders to gather information and help us determine the current state of the science, critical gaps in the existing science that need to be addressed, what approaches should be considered to further our understanding of medical device materials and improve the safety of devices for patients.

Breast implants

Breast implants have a silicone outer shell, with either a textured or non-textured surface, and are filled with silicone gel or saline. The FDA has regularly communicated about risks associated with breast implants, such as capsular contracture, implant rupture and breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). More confirmed cases of BIA-ALCL have been reported in patients with textured surface implants than in patients with smooth-surface breast implants. We’ve also heard from patients who are concerned that their implants may be connected to other health conditions that could be associated with their immune system’s response to these devices, resulting in symptoms like chronic fatigue, cognitive issues and muscle pain. While the FDA doesn’t have definitive evidence suggesting breast implants are associated with these conditions, we’re looking to gain a fuller understanding of this issue to communicate risk, minimize harm and help in the treatment of affected patients. This topic will be discussed at our upcoming two-day public meeting of the General and Plastic Surgery Devices Panel on March 25 and 26 and will be informed by our ongoing assessment of the long-term health effects of various materials.

In addition, we’ve been coordinating on two different breast implant registries to learn more about how these devices perform and interact with the body’s tissues at the cellular and organ levels. For instance, we worked with the American Society of Plastic Surgeons/the Plastic Surgery Foundation to develop the Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma Etiology and Epidemiology (PROFILE). This registry collects real-world data regarding patients who have a confirmed diagnosis of BIA-ALCL. The data collected from this registry as well as from medical device reports submitted to the FDA, medical literature and meetings with patient advocates have contributed to our understanding of BIA-ALCL and our communication updates to the public regarding BIA-ALCL. Additionally, we’re working with multiple stakeholders to advance the development of the National Breast Implant Registry (NBIR) to provide a platform for evaluating real world data on the safety and performance of breast implants. This will help us better evaluate data from providers regarding their patients with breast implants.

We’ll continue to report on significant findings as new information and analyses become available and if any of these findings prompt the agency to issue new recommendations or policies to mitigate risks.

Metals in devices

Metal device implants have been used in patients for more than a century, beginning with bone- stabilizing plates to heal fractures and advancing to state-of-the-art stents, prostheses and implantable defibrillators. Many implants are meant to remain in a patient’s body for years or even a lifetime. During this time, we know that tiny amounts of metals may be gradually released into the bloodstream and surrounding tissues.

The FDA regularly conducts thorough reviews of the latest scientific evidence. We continue to find that most patients experience no adverse health effects from these metals interacting either locally where the devices are implanted or systemically throughout the body. However, after carefully reviewing the current scientific literature, reports in our public adverse event database as well as findings from post-approval and postmarket surveillance studies, we believe there’s a need to evaluate through a comprehensive process concerns that were brought to light with particular devices, such as metal-on-metal total hip replacement devices and the permanent birth control implant Essure, a coiled wire that’s composed of multiple metals, including nitinol (a nickel and titanium alloy) and stainless steel, and is inserted into a woman’s fallopian tubes.

Nitinol in devices

Last December, we announced a revised protocol for the postmarket surveillance study of the Essure device to, in part, better understand how the materials in the device interact with the body’s immune system. The FDA worked with Bayer, the manufacturer of the device, to make sure the company implemented several approved modifications to the study that we believe will strengthen the evidence collected.

First and foremost, women in the study will be followed for five years, rather than the three years that were initially required. This extension will provide us with longer-term information on adverse risks of the device, including issues that may lead women to have the device removed. We also required additional blood testing of patients enrolled in follow-up visits during the study to learn more about patients’ levels of certain inflammatory markers that can be indicators of increased inflammation. This could help us better evaluate potential immune reactions to the device and define whether these findings are associated with symptoms that patients have reported in relation to Essure. These reported symptoms include persistent pain and hypersensitivity reactions, headaches, fatigue and cognitive difficulties.

The use of nitinol in other devices has increased—particularly for cardiovascular stents, guidewires and other devices used in minimally-invasive medical procedures. This owes to the metal’s properties. Nitinol is flexible and bendable with the ability to spring back, like a Slinky, into its original shape.

Many of the symptoms reported by some patients who had Essure implanted have not been reported by patients who had other nitinol-containing devices implanted, which could be related to the location of the implants. The particular site in the body where a device is placed may contribute to the potential for the device to cause an immune/inflammatory reaction. In the next few months, we’re planning to publish draft guidance on the use of nitinol in medical devices. This new guidance will include recommendations from the FDA on what manufacturers should include in their premarket submission of a device containing nitinol, including technical testing recommendations, labeling and information on how the device is manufactured and other factors that could affect the breakdown of the material in the body.

Metal-on-metal total hip replacement devices

Three years ago, the FDA strengthened the regulation of metal-on-metal total hip replacement devices requiring that manufacturers submit premarket approval applications to keep their devices on the market. That decision was based on significant safety concerns associated with adverse biological reactions to the metal wear particles and ions generated by the metal ball rubbing the metal socket joint during everyday use. These metal particles were found to have the potential to cause damage to the surrounding bones and soft tissues (including muscle) in some patients leading to pain, device failure and the need for repeat surgery to replace the implant. Some patients also developed severe systemic conditions, including damage to their heart, kidneys and thyroid, from the metal ions entering their bloodstream and reaching distant organs.

There are currently no FDA-approved metal-on-metal total hip replacement devices marketed for use in the U.S. However, many patients still have these devices implanted in their body, and the FDA felt it was imperative that manufacturers continue to meet their obligations for completing their postmarket surveillance studies. Today, we’re sharing interim results from these studies. The results show significantly higher blood levels of metal ions (cobalt and chromium) in patients with metal-on-metal hip implants compared to those without metal implants. While that’s not unanticipated, the data also suggest that the standard blood level threshold measurement of 7.0 parts per billion (micrograms/liter) or higher for metal ions, is not optimal to determine if an implant is functioning safely. Some patients in the postmarket surveillance studies had levels higher than this with no adverse medical complications, while others had severe symptoms with lower ion levels in their blood. This suggests that there are additional factors, besides metal ion levels, that affect which patients experience adverse events from metal-on-metal total hip replacement devices.

In addition to the clinical evaluations, the postmarket surveillance studies included a detailed analysis of more than 2,000 devices from patients who elected to have their implants removed. On average, patients who had their devices removed had higher metal ion levels compared to other patients in the postmarket surveillance studies who didn’t. Also, the wear between the metal ball and metal socket was found to be higher than what was expected based on testing performed on the devices before they were allowed on the market. When considering all devices that were explanted, it appears that certain factors, including those related to the design or surgical placement of the device, may be associated with a higher wearing down of the device and elevated metal ion levels.

Based on these findings, the FDA is working with standards development organizations (such as the American Society for Testing and Materials) to develop new standards to improve how metal-on-metal total hip replacement devices are evaluated and identify additional testing protocols for new metal-on-metal devices that are submitted to the FDA for review.

Advisory panel meeting

To help us gain a broader understanding of nitinol and other metals in devices, we’re announcing today that we plan to hold an advisory committee meeting this fall to discuss metal implants and the potential risk for certain patients to have “hypersensitivity” or exaggerated immune and inflammatory reactions to these metals. We’ve been exploring the link between immune and inflammatory markers and symptoms such as pain, headaches and fatigue in patients who have these devices implanted. This advisory committee meeting is part of our ongoing effort to advance the evaluation of materials used in implantable devices.

The panel meeting will engage experts in the field to provide input on what relevant scientific information the FDA should solicit from manufacturers to be considered in both premarket review and postmarket surveillance. Importantly, we’d like to determine how to identify patients who might be at increased risk of having a hypersensitivity response before they receive a metal implant, so they can consider those risks along with the device’s benefits. An additional purpose of the meeting will be to identify gaps in current scientific knowledge to determine what studies are essential to further expand our understanding of this important public health issue, including to what extent immune/inflammatory responses to certain metals contribute to device-related adverse events and steps we can take to mitigate potential risks.

Prior to this meeting, the FDA will release a peer-reviewed white paper that summarizes the current scientific knowledge regarding different aspects of metal implants, including how the structure and function of these devices are impacted by the body’s tissues, muscles and blood supply and how the metal components dissolve and interact with immune cells.

These efforts are just a few aspects of our ongoing evaluation of the effects of materials in at-risk patients. Our goal in taking these steps is to ensure that the benefits of devices made of metal materials continue to outweigh their risks. For the vast majority of patients this is the case and will remain the case as we go through these steps. However, for certain small subsets of patients who exhibit sensitivities to select materials, we must determine what additional actions we should take to make sure they are protected and understand the unique risks they may encounter.

Animal materials in devices

We’re also making efforts to improve the safety of devices made from animal-derived materials such as additives used on device coatings or heart valves made from pig tissue. We know that animal-derived materials may provide benefits over metal or synthetic materials because they can more closely match the biophysical properties of tissues within the human body. But these materials may carry a risk of transmitting infectious disease when improperly collected, stored, or manufactured. Specifically, animal tissues can contain infectious agents known as prions, which cause neurodegenerative disorders such as Bovine Spongiform Encephalopathy (BSE) or Mad Cow Disease. Yesterday, we issued final guidance on Medical Devices Containing Materials Derived from Animal Sources to provide recommendations to device manufacturers for how to minimize the potential risk of transmitting these rare but serious infectious diseases while still providing patients access to beneficial devices made from animal-derived materials.

Research efforts to better understand innovative materials

We’re also beginning to see manufacturers incorporate new types of materials in devices. CDRH’s OSEL has been conducting a wide array of research studies to learn more about the new advances in device materials. For example, our scientists are looking to better understand and characterize an innovative form of carbon called graphene, which has enormous applications in biotechnology and device development because it is lightweight, flexible, a superb conductor of electricity and is many times stronger than steel.

In anticipation of new device applications for, say, graphene-containing drug delivery systems or ultrasensitive biosensors that can be used with diagnostic tests, our scientists are working quickly to characterize and learn more about graphene’s chemical properties—both in terms of how durable it will be in medical devices and how it will interact with the body’s tissues and immune system.

OSEL has also worked on understanding how nanoparticles—tiny particles composed of just a few atoms—in medical devices interact with the immune system and whether they’re causing any toxic effects in the body. While these advances are promising, OSEL researchers are working to ensure that the benefits of the new material outweigh any risks that may come from these particles interacting with human cells.

Next steps

Modernizing the regulatory framework pertaining to the FDA’s review of medical device materials requires a multi-step approach. We’ll gather input from patients, device manufacturers, researchers and physicians to learn more about their concerns and ideas for how the FDA should proceed. Any new initiatives we implement must be rooted in putting patient safety first and based on sound science.

More closely evaluating the potential for certain materials to cause immune/inflammatory reactions in a small number of patients may improve our understanding of materials, help uncover ways to identify patients predisposed to these reactions and improve the overall safety and performance of medical devices. This is part of our continuing effort to advance opportunities for enabling modern materials to improve the performance of medical devices while also advancing our assurance of safety for these products. We look forward to providing updates about our progress and ongoing research. We believe our continuing efforts will ultimately provide patients and doctors with better access to more effective and safer medical devices.

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