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!

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Mass Tort Nexus: Xarelto Settlement Update

Xarelto Settlement: Power in Numbers

(April 23, 2019) As stated in previous Mass Tort Nexus articles, we are of the opinion that the current proposed Xarelto Settlement is “dead on arrival.” Based on our conversations with non-leadership firms, we are of the belief that there is an implacable intention to reject or recommend that their clients reject the current settlement offer.

Numerous additional firms have contacted Mass Tort Nexus since our first article was published related to the proposed settlement last week. Since that release, Mass Tort Nexus has received ongoing inquiries from firms asking the same basic question:

Do the leadership firms control enough of the client cases in the Xarelto litigation, to reach a settlement participation level acceptable to the defendant under the current proposal, without regard to the number of non-leadership firms that might reject the offer?

In order to provide an informed answer to this question Mass Tort Nexus conducted an analysis:

Mass Tort Nexus accessed the JMPL and the USDC ED Louisiana ECF links to determine how many cases are pending in MDL 2592. For this analysis we are not considering cases filed in other venues; however, there is no cause to believe that cases in other venues would be of sufficient volume to skew these findings.

According to the JPML, there are 23,866 cases pending in Xarelto MDL 2592 as of 04/15/2019. We believe no major change in these numbers has occurred in the three days that have elapsed between the latest JPML report and this analysis.

We will assume for arguments sake, that all the PSC members are going to accept the proposed Xarelto settlement. From a pure business perspective, the PSC members will be paid according to the work their firms have performed for the “common benefit”, which for many PSC firms may be a more significant sum than the fees they would earn from the clients they represent. Based on this reasoning, we will assume that all of the PSC member firms will accept the current settlement offer.

Mass Tort Nexus accessed Pacer to determine how many cases were on file for the Plaintiff Steering Committee (PSC) members.

The following are the result of that review:

PSC Member Firm MDL Cases
Ferrer Poirot 1,679
Beasley Allen 1,466
Morgan & Morgan 800
Levin Papantonio 650
Aylstock Witkin Kreis Overholtz 515
Schlicter, Bogard & Denton 118
Seeger Weiss 100
Nast Law 90
Ross Feller Casey 70
Levine Fish Bein & Berman 50
Weitz & Luxenberg P.C. 81
Goza & Honnold, L.L.C. 310
Total Client MDL Cases PSC Members 5,929 24.82%
Total Client Cases MDL Non-PSC Members 17,937 75.18%
Xarelto MDL 2592 23866
http://www.laed.uscourts.gov/case-information/mdl-mass-class-action/xarelto/contacts/plaintiffs-steering-committee
https://www.jpml.uscourts.gov/sites/jpml/files/Pending_MDL_Dockets_By_Actions_Pending-April-15-2019.pdf

Based on the results of our findings, of cases filed by PSC members, “Leadership” represents 5,929 (24.82%) of the 23,866 Xarelto MDL 2592 cases on file, while non leadership firms represent 17,937 (75.18%) of the cases on file.

Therefore, the answer to the question “does leadership directly control enough of total number of Xarelto cases to meet the participation requirements by the defendant is NO, based on this informed analysis.

Based on information received from reliable sources, the “Participation Level” defendants require to “go through” with the current offer is 90%. Of course, the defendants would have the option of going through with the settlement at a participation level of less than 90% however, it would not make sense for a defendant in any mass litigation to move forward with a settlement, that left several thousand cases moving towards trial. The number of cases left unsettled is more important than the representation of that number as a percentage.

Note: Mass Tort Nexus’ analysis of the number of cases under the direct control of leadership did not include any cases filed by other firms, which may have subsequently been referred to leadership firms. Therefore, leadership may have direct control over a larger number of cases that cannot be confirmed through our analytical methodology. Without regard to the foregoing, Mass Tort Nexus was able to verify the number of cases on file by firms who have expressed an implacable intent to reject the current offer, and therefore, the conclusions reached through our analysis would not  impact the unknown variable arising from cases filed by non-leadership firms, that have been subsequently referred to leadership firms.

To complete our analysis, we calculated the number of cases that could reject the settlement offer and overall participation still reach a given percentage participation level.

 

Participation Level (PL) Maximum Rejections to Achieve PL
95% 1,193.3
90% 2,386.6
85% 3,579.9
80% 4,773.2
75% 5,966.5
70% 7,159.8
65% 8,353.1
60% 9,546.4
55% 10,739.7
50% 11933

 

Based on conversations with numerous firms with “small” to “large” dockets, in the Xarelto MDL (also verified in the same manner as MTN verified leaderships client numbers), Mass Tort Nexus is of the following opinion:

Firms that have expressed their position to be in absolute rejection of the current offer, (nothing can convince them to change their minds), that the hold outs from these firms along will prevent the participation level in the settlement from reaching 80%.

Firms that are leaning toward rejection but could possibly change their minds (if they split down the middle on their final decision, half going one way and half going the other) would likely prevent the settlement acceptance level form reaching 70%.

If additional firms that have not communicated with Mass Tort Nexus also add to the “implacable rejectors” count, reaching a participation percentage acceptable to defendants becomes even less probable.

Mass Tort Nexus would like to clarify past comments, as well as comments made in this article, and those that may be forthcoming in future coverage of the proposed Xarelto settlement. Our coverage of this issue is not intended to be a disparagement of the firms in leadership in the Xarelto MDL. Leadership did not make the current settlement offer, the defendants made the offer. When a defendant approaches leadership wishing to discuss settlement, leadership engages in the discussion. When defendants make an offer, leadership presents that offer to the non-leadership firms involved in the litigation (becoming the messenger.)  If the offer does not result in a consummated settlement, leadership will have to “go back to the table” with the defendants. Leadership can not be seen to have been the cause of the previous settlement offer “falling through” and retain the credibility with the defendants needed for additional rounds of negotiations.  It is never our intent to “shoot the messenger” even when our opinions differ from the message.

https://www.jpml.uscourts.gov/sites/jpml/files/Pending_MDL_Dockets_By_Actions_Pending-April-15-2019.pdf

 

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FDA Fails to Cite Big Pharma for False Marketing and Advertisements

“PROFITS BEFORE PATIENTS REIGNS SUPREME AT FDA”

By Mark A. York (April 22, 2019)

Purdue Pharma and OxyContin Never Warned By FDA

(MASS TORT NEXUS MEDIA)  In the midst of a national opioid crisis, the federal agency that monitors drug ads has issued a record low number of warning letters to pharmaceutical companies caught lying about their products.

The Food and Drug Administration has sent just three notice letters to drug makers busted for false marketing their medications to unknowing consumers, the lowest ever since the FDA historic decision to ease strict rules for drug ads in 1997. “It certainly raises questions,” said Dr. David Kessler, head of the FDA from late 1990 through 1996, who’s industry credentials would add weight to the issue of why the FDA is not doing more to monitor false marketing campaigns by Big Pharma and Opioid Drug makers in particular.

The FDA’s Office of Prescription Drug Promotion monitors all ads drug companies issue to make sure patients aren’t being scammed by false assertions or misleading marketing campaigns. Which now seems to be the norm, based on the hundreds of lawsuits filed against Opioid Drug Makers in the last 3 months, and recently consolidated into Opiate Prescription MDL 2804 see Opioid Crisis Briefcase-Mass Tort Nexus, where Big Pharma is being sued by states, cities and counties across the country. The primary claim in almost every suit is long term boardroom coordinated false marketing campaigns designed to push opioid drug prescriptions at any cost.

 BILLIONS IN PROFITS

The pharmaceutical industry spent a vast $6.4 billion in “direct-to-consumer” advertisements to hype new drugs in 2016, according tracking firm Kantar Media. That figure has gone up by 62% since 2012, Kantar Media says. This number may seem large at first but compared to the multi-billions in yearly profits just by opioid manufacturers over the last 15 years, the numbers is small.  Corporate earnings have risen every years since the push to increase opioid prescriptions in every way possible became an accepted business model Big Pharma boardrooms across the country.

In 2017 and continuing into 2018, Big Pharma has been fighting major legal battles related to off-label marketing of drugs for unintended uses. They also engaged in a parallel strategy, where they were influencing the FDA and other policy making agencies behind the scenes in Washington DC. Big Pharma was paying millions to lobbyists, making campaign donations and generally buying influence as they always have. It was a foregone conclusion that with the Trump administration view of , “no regulatory oversight required” that there would be some loosening of the FDA regulatory shackles.

Big Pharma was getting ready for freedom to sell, sell, sell their drugs in any way they could, including off-label marketing of the drugs for unintended use purposes. A corporate policy, that’s technically illegal, yet results in billions of dollars in profits every years for Big Pharma. Then the FDA rolled out an unexpected new proposed rule, in March 2017 cracking down on “off-label’ marketing of drugs. This new rule change wasn’t in Big Pharma’s bests interests, sending the drug industry into a furious lobbying scramble. Bring in the Trump camp and on January 12, 2018 Big Pharma and the army of lobbyists and elected officials that were recruited, seem to have succeeded in stopping the FDA rules change that would have tightened up “off label” marketing of drugs.

Trump stops FDA enforcement rule change: January 12, 2018 Food and Drug Administration Press Release: FDA Delays Change to “Off-Label” Drug Use Enforcement Rules

WHAT IS “OFF-LABEL” MARKETING?

Global health care giant Johnson & Johnson (J&J) and its subsidiaries will pay more than $2.2 billion to resolve criminal and civil liability arising from allegations relating to the prescription drugs Risperdal, Invega and Natrecor, including promotion for uses not approved as safe and effective by the Food and Drug Administration (FDA) and payment of kickbacks to physicians and to the nation’s largest long-term care pharmacy provider.  The global resolution is one of the largest health care fraud settlements in U.S. history, including criminal fines and forfeiture totaling $485 million and civil settlements with the federal government and states totaling $1.72 billion.

“The conduct at issue in this case jeopardized the health and safety of patients and damaged the public trust,” stated Eric Holder, then US Attorney General, “This multibillion-dollar resolution demonstrates the Justice Department’s firm commitment to preventing and combating all forms of health care fraud.  And it proves our determination to hold accountable any corporation that breaks the law and enriches its bottom line at the expense of the American people” he added.

The resolution includes criminal fines and forfeiture for violations of the law and civil settlements based on the False Claims Act arising out of multiple investigations of the company and its subsidiaries.

“When companies put profit over patients’ health and misuse taxpayer dollars, we demand accountability,” said Associate Attorney General Tony West.  “In addition to significant monetary sanctions, we will ensure that non-monetary measures are in place to facilitate change in corporate behavior and help ensure the playing field is level for all market participants.”

The Federal Food, Drug, and Cosmetic Act (FDCA) protects the health and safety of the public by ensuring, among other things, that drugs intended for use in humans are safe and effective for their intended uses and that the labeling of such drugs bear true, complete and accurate information.  Under the FDCA, a pharmaceutical company must specify the intended uses of a drug in its new drug application to the FDA.  Before approval, the FDA must determine that the drug is safe and effective for those specified uses.  Once the drug is approved, if the company intends a different use and then introduces the drug into interstate commerce for that new, unapproved use, the drug becomes misbranded.  The unapproved use is also known as an “off-label” use because it is not included in the drug’s FDA-approved labeling.

“When pharmaceutical companies interfere with the FDA’s mission of ensuring that drugs are safe and effective for the American public, they undermine the doctor-patient relationship and put the health and safety of patients at risk,” said Director of the FDA’s Office of Criminal Investigations John Roth.  “Today’s settlement demonstrates the government’s continued focus on pharmaceutical companies that put profits ahead of the public’s health.  The FDA will continue to devote resources to criminal investigations targeting pharmaceutical companies that disregard the drug approval process and recklessly promote drugs for uses that have not been proven to be safe and effective.”

FDA PLEADS NO STAFF

But the agency has long struggled to keep track of the thousands of ads published each year, largely due to lack of staff.

There are approximately 60 FDA staffers responsible for keeping track of at least 75,000 ads and other promotional material published each year. Although in the age of electronic monitoring and hi-tech tracking of data it would seem that monitoring drugs such as Schedule 2 – 4 narcotics or other drugs that are considered high risk for abuse, the FDA could create a quarterly e-review or a flagging system when new campaigns are started by Big Pharma.

“It’s a very, very small unit,” a former high-ranking FDA official said. “It’s historically been underfunded.” Which seems to support the contention that Washington D.C lawmakers are in the pockets of Big Pharma and the hundreds of lobbyists they utilize to ensure a true lack of oversight in the pharmaceutical industry as a whole.

Additionally, many of the ads are submitted to the FDA for review at the same time they begin to run. So by the time the assessment is complete the ad has “already had a significant impact,” the FDA insider said. This policy flies in the face of the creation regulatory oversight based on the fact that when a problem or an issue with a product is discovered, the FDA, EPA or other agency should enforce the law and correct the problem. In the case of the FDA, that is not happening and Big Pharma is and has been aware of the lack of oversight for years.

Critics say the FDA needs to do more to stay on top of an industry with a history of trying to maximize profits by at times misleading consumers, which has recently been described as a policy of “patients before patients” which has resulted in the current Opioid Crisis that’s firmly in place across the United States.

The number of public admonishment letters has been at or close to single digits from 2014 until 2016 during the Obama administration, records show. The FDA sent out 11 of those caution missives in 2016, nine in 2015 and 2014, and 24 in 2013.

A SINGLE FDA WARNING IN 2016

This year, one of the warning letters was sent to Canadian drugmaker Cipher Pharmaceuticals, ordering it stop using deceptive promotional material to hawk its extended-release opioid ConZip.

The ad failed to note “any risk information” highlighting the potentially addictive nature of the powerful painkiller, the FDA letter issued Aug. 24 said. The promotional material was also misleading because it asserted other treatment options “are inadequate,” the oversight agency concluded.

“By omitting…serious and potentially fatal risks, the detail aid…creates a misleading impression about the drug’s safety, a concern heightened by the serious public health impacts of opioid addiction, abuse and misuse,” the FDA said.

The agency demanded that Cipher “immediately cease misbranding” the medication. The drug company responded by yanking the promotional material, the firm’s execs said in a statement issued after the warning letter was made public.

But that was the single caution letter issued to an overhyped painkiller by the FDA this year so far, records show. The other caution letters were sent to Amherst Pharmaceuticals for the insomnia drug Zolpimist, and to Orexigen Therapeutics Inc. for its weight loss drug Contrave.

There are many long term FDA and other senior DC officials who have for whatever reasons, chosen to defer reigning in Big Pharma sales and marketing abuses and now it appears the corrective action has been undertaken in federal courts across the country by mass tort lawyers in litigation which will apparently make the “Tobacco Litigation” of the 1980’s pale in financial comparison.

With the primary lawsuits recently consolidated by in the Multidistrict Litigation titled “National Prescription Opiate Litigation” Case No. MDL 2804, recently assigned to the US District Court, Northern District of Ohio.  With the key case heading including “prescription and opiate” which reflects the federal court recognizing that opiate prescriptions have become such a major issue the federal courts will now determine the penalties assessed against Big Pharma. The focus will be on the long term “sales and marketing campaigns” designed in corporate boardrooms of Fortune 100 companies, to increase corporate profits, while ignoring the known catastrophic increases in addictions and other inter-connected healthcare, economic and social upheavels caused by the flood of opioid drugs in the US market.

The FDA maintains that letters to drug companies are merely one tool the agency uses to keep the pharmaceutical industry in line.

“We have many efforts to encourage compliance by industry, including our work on guidance, by providing advice to companies on draft promotional materials, and outreach to our stakeholders,” FDA spokeswoman Stephanie Caccomo said. “The FDA’s priorities regarding prescription drug promotion are policy and guidance development, labeling reviews, core launch and TV ad reviews, training and communications and enforcement.” The key terms referred to by Ms. Caccamo are “guidance and by providing advice” from the FDA, when direct enforcement actions are required, as Big Pharma see the terms “guidance and advice” as harmless and not applicable to their efforts to increase sales and profits. In-house lawyers at Big Pharma have reviewed FDA enforcement failures and offered opinions to the boardrooms for years about the FDA not willing to enforce anything close to restrictions on opioid drug marketing and sale practices, all the while reaping the profits of the opioid crisis.

U.S. DEPT OF JUSTICE INDICTMENTS

While the FDA has failed, the US Department of Justice has launched a massive crackdown on opiate drug makers including indictments of company executives, sales & marketing personnel as well as the doctors and pharmacies that have enabled the flood of easy access narcotics into the US market for over 15 years. The question is “how and why” did the FDA drop the ball or was this an intentional lack of enforcement and oversight by the FDA and other agencies due to Big Pharma influence over Congressional members who would blunt any true oversight of drug companies.

US CONGRESS IS NOT HELPING

Perhaps a look at former US Representative Tom Price, will provide insight into how our lawmakers work within the healthcare industry. Rep. Price was appointed by President Trump to head the Department of Health and Human Services, which the FDA reports to, was forced to resign as HHS head due to various transgression within 6 months of being appointed, as well as leaks that while a sitting congressman he enacted a bill favoring a medical device makers extension of a multi-year government contract. Not only did Price enact the bill, he purchased stock in the company prior to the bill introduction and secured a massive profit on the stock price increase after the contract extension was announced. In normal business circles this is considered “insider trading” and is illegal, but when you’re one of those people in charge of creating the rules and regulations, there’s an apparent “get out of jail card” that comes with your congressional seat.

As long as the US Congress fails to correct the lack of oversight by the FDA and other regulatory agencies into what and how dangerous drugs and products are placed into the US marketplace, there will always be bad drugs entering the healthcare pipeline in the United States, with the now enduring default misnomer of “Profits Before Patients” firmly in place in boardrooms and within our government.

WHITE HOUSE IGNORES BIG PHARMA ABUSE

With the Trump Administration still claiming that no regulatory oversight is needed to monitor the US drug industry, that they can self-regulate, it appears that there will be no letup in the rampant “off-label: and unintended use marketing of pharmaceutical drugs in the United States.  The one way that Big Pharma is held accountable is in the courtroom, although financial damages and penalties against the drug companies amounting to billions of dollars each year being awarded by juries, won’t change FDA policy, it does provide a small amount of official recognition that there are ongoing abuses by the pharmaceutical industry in the USA.

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Analysis of Proposed Xarelto Settlement Discount Rates – Debunking Defendants Rationale

 

 

Analysis of Proposed Xarelto Settlement Discount Rates

Debunking Defendants Rationale

 This is a follow up to the Mass Tort Nexus article “Xarelto Settlement: Dead on Arrival” – link: Xarelto-Settlement-Dead-on-Arrival? April 15, 2019

 

(MASS TORT NEXUS MEDIA) This article is intended to address the Xarelto defendants’ contentions that certain settlement offer “discounts” are justified for client cases arising in 2015 and 2016 due to changes in the FDA label,  which the defendant contends brought warnings contained in the label into adequacy. This paper will also address defendant’s contention that cases arising under the laws of the States of Texas and Michigan merit a massive discount in settlement value (offers).

We will focus on the Xarelto label change from 11/07/2018, AND an additional label change was made on 01/15/2019 related to Eosinophilia, which could be relevant to many of the Xarelto cases already filed as well as give rise to a Xarelto Litigation II, that could involve more injured individuals than the current Xarelto Litigation. The relevance and significance of the 01/15/2019 “Eosinophilia” label change will be addressed by Mass Tort Nexus in the near future.

Mass Tort Nexus has also received information that there is an ongoing investigation related to Xarelto potentially causing kidney injury, which may or not be related to Eosinophilia. We will continue to provide more information related to this subject in future articles. Given the new Eosinophilia warning and the investigation related to Kidney injury, and the 11/07/2018 label change related to anticoagulation tests (and the possible impact on future Xarelto case trials) Mass Tort Nexus understands why the defendants might be eager to reach a settlement sooner rather than later. Conversely, there is no reason why plaintiffs’ firms should believe the defendants to be in a superior negotiating position, nor be willing to accept subpar settlements for their existing cases.

It is worth nothing that the 11/07/2018 label change (admission) by the defendant that the most commonly used anticoagulation tests are “not recommended” (in reality likely have no diagnostic value) would make it far more difficult for the defendants to prevail in future trials under the Learned Intermediary Doctrine, as doctors would be less likely to testify that, “they would still do everything exactly as they did when originally prescribing Xarelto.” Had the defendant revealed the foregoing before the prior bellwether trials, the outcome of those trials may have been very different.  It is not surprising that the defendants are eager to settled Xarelto cases without having to face another trial post the 11/07/2018 and 01/15/2019 label changes.

Had the defendants revealed the information related to the most common anticoagulation tests used as “not being recommended” prior to the bellwether trials, doctors testifying in support of a defendants “Learned Intermediary Defense” would likely face questions like these:

 Plaintiffs’ Counsel:  So, Dr. Smith, I see that you performed an INR test to make sure that my client was correctly anticoagulated, that their blood was not to thick or too thin, is that right?

Dr. Smith: Yes

Plaintiffs’ Counsel:  Were you aware that as of 11/07/2018 the defendants recommend that this test not be used and in fact, the literature shows that this test provides no diagnostic value when a person is taking Xarelto?

Dr. Smith: It unlikely that Dr. Smith will say he knew the above when he prescribed Xarelto as he would essentially be admitting to medical malpractice.

Plaintiffs’ Counsel:  So, Dr. Smith, would you still today, follow the same protocol when prescribing Xarelto and use an INR test to make sure the dose of Xarelto did not have the patient’s blood to thick (likely to clot) or too thin (likely to bleed).

Dr. Smith: Unlikely that Dr. Smith would say he would still do what the defendant now recommends he not do.

Plaintiffs’ Counsel:  Dr. Smith, just out of curiosity, do you think the words “No Routine Blood Testing Needed” mean the same thing as “The blood test routinely used don’t work”?

The same line of questioning could be used for doctors that treated a Xarelto bleed or clot.

The contention that any label change could render a product adequately warned for all circumstances and facts relevant to every possible client injury scenario is somewhat preposterous; however, we will address and rebut the defendant’s contentions more directly. Although the Xarelto warning label has been changed numerous times since 2016, we only need to review the label change made on 11/07/2018 (see below) to conclude that the label was not adequate in any clients case in which the referenced anticoagulation tests were used in the “dosing” of Xarelto or the treatment of any Xarelto related injury 11/07/2018.

 11/07/2018 Xarelto Label Change

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022406s029lbl.pdf

 5.0 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.

Mass Tort Nexus Comment: The highlighted language above was added to the Xarelto FDA (U.S) 0n 11/07/2018, indicating that the use of PT, INR, aPTT anti-factor Xa (FXa) is not recommended. A more accurate statement (warning) would be that these tests have no diagnostic value and should not be used when evaluating dosing for individual patients nor treating bleeds and other conditions related to Xarelto, while the patient has Xarelto in their system.

 We will first address the 11/07/2018 label change as it related to the defendants contentions that the Xarelto label “adequately warned”  of the risks associated with label changes made in 2015 and 2016 as well as the justification (or lack thereof) for any discounts to base settlement offers arising therefrom.

Mass Tort Nexus opinion is as follows:

  1. At minimum, no discount is justified in any case arising before 11/07/2018, in which any of the anticoagulation tests now “not recommended” for use, where used by the prescribing physician immediately before and or any time after prescribing Xarelto, for use by the specific client. The doctor nor the patient were adequately warned with regard to these tests providing any diagnostic value that could serve to mitigate the risks associated with the use of Xarelto.  Additionally, for any client that presented at a medical facility (prior to 11/07/2018), with a Xarelto related injury which resulted in the use of the tests in the process of treating that injury, the warning label was not sufficient to mitigate the risks associated with the use of tests which the defendant now recommends not be used.
  2.  Today the warning label remains inadequate and no discount based on a contention that the warning label was brought into adequacy at any point in the past, is warranted. Until the defendants make further changes to the label including, but not limited to, giving the “anticoagulation” test “warning” greater prominence on the label as well as changing the “not recommended” portion of the statement to reflect a more truthful representation, that is less likely to be overlooked or misunderstood by prescribing physicians. An adequate warning would include information as to why the tests are not recommended (they likely have no diagnostic value).
  3.  It would be difficult for the defendants to argue that the fact that the most commonly used anticoagulation tests “are not recommended” for use in dosing Xarelto or treating a Xarelto injury, would not likely have impacted some doctors decision to prescribe the drug had they been previously warned prior to 11/07/2018. In reality, given the lack of prominence of the 11/07/2018 label change and the fact that no additional educational efforts are being made by defendants (that we are aware of), to insure that doctors are now aware that these tests are “not recommended” and in fact, likely have no diagnostic value, it is probable that the 11/07/2018 warning has not significantly decreased the risk posed Xarelto users, related to this new “warning.

 Before addressing Texas 82.007 and Michigan 600.2946, it is important to point out that one of the most Signiant claims made by the makers of Xarelto, in their effort to establish their product as being superior to Warfarin was that “no routine blood testing (anticoagulation tests) was needed” for patients using Xarelto. Patients taking Warfarin and other VKA’s (Vitamin K Antagonists) do require routine monitoring to insure their anticoagulation levels remain in a therapeutic range.

The “No Routine Blood Testing Needed” claim of the makers of Xarelto, made to the FDA and the public appears to have been very misleading. Mass Tort Nexus has yet to determine how the makers of Xarelto concluded that No Routine Blood Testing was needed for patients taking Xarelto. The 101,743 adverse event reports filed with the FDA related to Xarelto since 2011, is one indicator that “Routine Blood Testing” is needed to insure Xarelto user’s safety. If no Routine Blood Testing was needed, then why have Xarelto patients experienced such a high volume of bleeding and clotting events? The FDA warning letter sent to the makers of Xarelto (provided at the end of this document), is highly relevant to this topic.

If Xarelto was so well designed that a doctor could just assume that patients would be maintained with a therapeutic range (not too thin and likely to bleed or too thick and likely to clot), then why has the FDA received Xarelto 101,753 adverse event reports since 2011, many involving bleeding or clotting that might have been prevented with “routine testing’?

 

Texas and Michigan Cases

To the best of our knowledge, the defendant has yet to raise a defense under Texas 82.007 and Michigan 600.2946 in any case, much less prevail in arguments arising under these laws.

Neither Texas 82.007 nor Michigan 600.294 provide an absolute defense for drug manufacturers. Both state’s laws have language which provide a plaintiff with means, by which to overcome the presumption that these laws provide immunity for a given defendant. We will refer to the language in both States laws as the “savings clause” in the remainder of this article. We will also address each law separately with regard to the burden plaintiffs would face, in overcoming a defense raised under either Texas 82.007 or Michigan 600.294.

First, We Will review the “savings clause” for both Texas 82.007 and Michigan 600.2946 available to plaintiffs to overcome the presumption of drug manufacturer immunity arising under the two laws. See the relevant savings clauses and links to the entire statutes below:

Texas   82.007

(2)(b)  The claimant may rebut the presumption in Subsection (a) as to each defendant by establishing that:

(1)  the defendant, before or after pre-market approval or licensing of the product, withheld from or misrepresented to the United States Food and Drug Administration required information that was material and relevant to the performance of the product and was causally related to the claimant’s injury;

(3)(A) the defendant recommended, promoted, or advertised the pharmaceutical product for an indication not approved by the United States Food and Drug Administration;

(B)  the product was used as recommended, promoted, or advertised;  

Michigan 600.2946

(5) In a product liability action against a manufacturer or seller, a product that is a drug is not defective or unreasonably dangerous, and the manufacturer or seller is not liable, if the drug was approved for safety and efficacy by the United States food and drug administration, and the drug and its labeling were in compliance with the United States food and drug administration’s approval at the time the drug left the control of the manufacturer or seller. However, this subsection does not apply to a drug that is sold in the United States after the effective date of an order of the United States food and drug administration to remove the drug from the market or to withdraw its approval. This subsection does not apply if the defendant at any time before the event that allegedly caused the injury does any of the following:

(a) Intentionally withholds from or misrepresents to the United States food and drug administration information concerning the drug that is required to be submitted under the federal food, drug, and cosmetic act, chapter 675, 52 Stat. 1040, 21 U.S.C. 301 to 321, 331 to 343-2, 344 to 346a, 347, 348 to 353, 355 to 360, 360b to 376, and 378 to 395, and the drug would not have been approved, or the United States food and drug administration would have withdrawn approval for the drug if the information were accurately submitted

http://www.legislature.mi.gov/(S(5z3q41uoys1lzoajegixoc5p))/mileg.aspx?page=GetObject&objectname=mcl-600-2946

As a preliminary point, if any discount was justified arising under Texas 82.007or Michigan 600.2946, it should be minimal in light of the fact that the defendant has neither raised a defense in any individual case (to the best of our knowledge), nor prevailed in such a defense. A small discount might be warranted to allow plaintiffs to avoid the cost of litigating any matter raised by defense in the unlikely event that the defendants are willing to incur the cost of litigating the matter themselves.

Secondly, if any discount arising under Texas 82.007 and Michigan 600.2946 was justified, cases arising under Texas 82.007 would warrant a less significant discount than those arising under Michigan 600.2946, for reasons we will address below.

It is worth noting that the defendants must affirmatively raise a defense under Texas 82.007 or Michigan 600.2946 and doing so may expose their clinical trials, communications with the FDA, (including warning letters related to their advertising, one of which we have included at the end of this document), to discovery and scrutiny they may wish to avoid. Mass Tort Nexus would be interested in any internal communications, as well as third party communications the defendants engaged in related to the death of Arnold Palmer (including communications with his family) as we have long held the opinion that Xarelto may have caused or contributed to the death of Xarelto’s most famous spokesperson.

Comment: Texas 82.007, does not require a showing that any information that may have been withheld or misrepresentation made to the FDA was “intentional.” Texas 82.007 does not require a plaintiff to plead nor show that the FDA would, and the drug would not have been approved, or the United States Food and Drug Administration would have withdrawn approval for the drug if the information were accurately submitted. Michigan 600.2946, does require plaintiffs to show and plead that any misrepresentations or withholding of information and the drug would not have been approved, or the United States food and drug administration would have withdrawn approval for the drug if the information were accurately submitted.

Michigan 600.2946 obviously places a far more significant burden on a plaintiff seeking to rebut the presumption of immunity than does Texas 82.007. Pleading that a drug would not have been approved, or the United States food and drug administration would have withdrawn approval for the drug if the information were accurately submitted, can be problematic in light of the SCOTUS decision Buckman v. Plaintiff Legal Committee: https://www.loc.gov/item/usrep531341/

The foregoing should not be interpreted as presenting an impossible burden for plaintiffs to overcome under Michigan 600.2946 as was shown in the Second Circuit decision in DESIANO v. WARNER-LAMBERT & CO. https://caselaw.findlaw.com/us-2nd-circuit/1209786.html. Also see TAYLOR v. SMITHKLINE BEECHAM Michigan Supreme Court decision https://caselaw.findlaw.com/mi-supreme-court/1355001.html. These two well-reasoned rulings and opinions make it clear that 1. Plaintiffs can meet the requirements set forth in Michigan 600.2946 to overcome the presumption of immunity without running afoul of Buckman. 2. Plaintiffs can prevail in overcoming a defense raised under Michigan 600.2946 as they did in DESIANO.

Notwithstanding the foregoing, the burden placed un plaintiffs under Michigan 600.2946 is still far greater than that placed on plaintiffs by Texas 82.007.  It appears that any defendant has a better chance of prevailing in raising a defense under Michigan 600.2946 than one raised under Texas 82.007 however, given the fact that Michigan has a population of 9,996,000,(3.05% percent of the U.S. population) while Texas has a population of 27,700,000 (8.45% percent of the U.S. population), would the defendants be willing to undertake the time and expense (and continued concern from the market) involved in raising a defense under Michigan 600.2946, which would not dispose of a significant number of cases, if they prevail given that there is no reason to believe that a disproportionate number of the total Xarelto cases on file arise under Michigan law. Additionally, would the defendant be likely to undertake the time and expense (and continued concern from the market) involved in raising a defense under Texas 82.007, with a far less likelihood of prevailing than in Michigan.

The plaintiff’s burden with overcoming a defense raised under Texas  82.007 is obviously less arduous that than the burden over overcoming a defense raised under Michigan 600.2946. Due to the foregoing, the defendant’s application of the same discount (if any is justified) to cases arising under Texas law to those arising under Michigan Law, is not justified.

 

Michigan and Texas Law and the 11/07/2018 Label Change

Texas 82.007 and Michigan 600.2946:

Texas 82.007: The defendants’ statements in the 11/07/2018 label change “not recommending” these tests are still arguably misleading given that the test apparently have no diagnostic value when a patient is taking Xarelto and more importantly represent important information previously withheld from the FDA and/or mispresenting to the FDA. A strict interpretation of C would not require a plaintiff to show that that the actions or inactions of the defendant were intentional. Arguably, the 11/07/2018 label change related to these tests could be rebut the presumption that the protection provided from Texas 82.007 is available to the defendant.

Michigan 600.2946: The same reasoning applied to the analysis of Texas  82.007 applies to Michigan 600.2946 in this matter with one exception, Michigan 600.2946 requires a showing that the defendants actions or inactions were intentional and a showing that the FDA would not have approved or would have withdrawn the approval for the product if not for the information withheld or misrepresentations made. MTN provides an analysis below aimed at showing what the defendants knew and when they knew it relevant to the warnings they neglected to add to their label until 11/07/2018.

Analysis

The following analysis is more relevant to Michigan 600.2946 than to Texas 82.007. There is a high degree of confidence that Plaintiffs would prevail in any defense raised under Texas 82.007.

In that overcoming a defense raised under Michigan 600.2946 requires a showing that the defendant intentionally made misrepresentations the FDA or intentionally withheld information from the FDA. Additionally, under Michigan 600.2946   plaintiffs must make a colorable argument that the FDA would not have approved the drug or would have later withdrawn approval, absent the misrepresentations or withheld information. The 11/07/2018 FDA label change related to anticoagulant testing would be an example of evidence plaintiffs might present to meet the requirements of Michigan 600.2946. In that Michigan’s law require plaintiffs show the offending actions or inactions of the defendant were intentional, demonstrating what the defendants knew (relevant to the referenced anticoagulation tests) and when they knew it would be important in overcoming a defense raised under Michigan 600.2946.

It should be noted that a defense raised under Michigan 600.2946 or Texas 82.007 exposes the defendant to broad discovery, through which plaintiffs would likely discover far more evidence to support their rebuttal arguments than can be discovered in the public domain.  For our instant purpose however, we will focus on determining when the defendant knew or should have known that the anticoagulation tests listed in the 11/07/2018 label change provide no diagnostic value for patients on Xarelto.

Mass Tort Nexus has conducted a review of the publicly available literature in order to establish what the defendant knew or should have know and when, related to anticoagulation testing with commonly used modalities and methods. We will not present a chronological listing (not exhaustive) of information in the public domain relevant to this topic.

 It should be noted that any information or data published in clinical literature must be developed over time (before it is reported). We can safely assume that any information reported in the medical literature in 2012 was known to the defendant at the time they sought the initial FDA approval for Xarelto, granted in July of 2011. If the defendants were to raise a defense under Michigan 600.2946 or Texas 82.007, plaintiffs would likely be allowed broad discovery which would reveal that the defendants possessed or should have possessed the information related to anticoagulation tests that they withheld from the FDA and prescribing physicians until 11/07/2018.

 No Exhaustive Review of the Literature

2012

The data below was taken from a presentation from Ohio Society of Pharmacist Association in 2012. Given the fact that the information below was reliant on clinical observations prior to the presentation of the below, it is likely that the defendant was aware of the issue related to INR testing, prior to seeking U.S. FDA approval (granted July 1, 2011)

Summary
• Dabigatran
– aPTT
• Appears to be a useful measure in hemorrhagic emergency
• Therapeutic ranges have not yet been established
– Ecarin clotting time
• Also useful in hemorrhagic emergency, but not widely available.
• Rivaroxaban and Apixaban
– Prothrombin time, but not INR
• Appears to be useful in hemorrhagic emergency
• Therapeutic ranges have not yet been established
– HepTest, PiCT, and chromagenic assay all appear to be
useful, but not commonly available

https://cdn.ymaws.com/www.ohioshp.org/resource/resmgr/annualmeetinghandouts/effects_of_new_oral_anticoag.pdf

 May 2012

Rivaroxaban: Quantification by anti-FXa assay and influence on coagulation tests: a study in 9 Swiss laboratories.

RXA plasma levels can be quantified accurately and precisely by a chromogenic anti-FXa assay on different coagulometers in different laboratories. Ingestion of 10mg RXA results in significant alterations of both PT- and aPTT-based coagulation assays.

https://www.ncbi.nlm.nih.gov/pubmed/21840043?dopt=Abstract

July 2012 Rivaroxaban: A practical Guide

INR testing should be preformed just before the next intake of Rivaroxaban on the INR measurement

http://www.uclmontgodinne.be/files/RivaroxabanPracticalGuide06072012.pdf

Thrombosis Journal 2013

https://thrombosisjournal.biomedcentral.com/articles/10.1186/1477-9560-11-11

Because rivaroxaban and other target-specific oral anticoagulants have different mechanisms of action from traditional anticoagulant agents, laboratory tests used for these traditional agents (such as PT/international normalized ratio [INR] or activated partial thromboplastin time) are not suitable for target-specific oral anticoagulants

Pub Med   May 2017

https://www.ncbi.nlm.nih.gov/pubmed/28476405

Direct factor Xa inhibitors such as rivaroxaban or apixaban may prolong prothrombin time (PT) and elevate international normalized ratio (INR). However, these tests are not reliable for assessing the anticoagulation effects of these agents such as rivaroxaban or apixaban may prolong prothrombin time (PT) and elevate international normalized ratio (INR). However, these tests are not reliable for assessing the anticoagulation effects of these agents.

See the warning letter sent from the FDA to the makers of Xarelto. Mass Tort Nexus believes more warning letters like this one exist and will continue our efforts to discover all relevant FDA communications. This warning letter is highly relevant to the prior subject matter of this article.

(FDA Link to June 6, 2013 Warning Letter to Johnson & Johnson Re: Xarelto Label is Below)

NDA 202439 XARELTO (rivaroxaban) tablets   

June 6, 2013

Johnson & Johnson International, Inc.

 

 

______________________________________________________________________________________________________

 

 

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

 

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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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Why Didn’t Bayer’s October 2018 Forecast Include Monsanto Roundup Litigation MDL 2741? Several billion possible reasons!

By Mark A. York (March 25, 2019)

Jury Verdict Forms of March 19, 2019 Trial Findings Re: “Monsanto Roundup Caused Plaintiff’s Cancer”

Roundup MDL 2741 Federal Trial Jury Instructions of March 19, 2019

Roundup MDL 2741 Federal Trial Jury Verdict Form of March 19, 2019

 

Interim Report Third Quarter 2018

 

Explanatory Notes

Legal Risks

Product-related litigation

Mirena™: As of January 30, 2018, lawsuits from approximately 2,900 users of Mirena™, a levonorgestrel-releasing intrauterine system providing long-term contraception, had been served upon Bayer in the United States (excluding lawsuits no longer pending). Plaintiffs allege personal injuries resulting from the use of Mirena™, including perforation of the uterus, ectopic pregnancy or idiopathic intracranial hypertension, and seek compensatory and punitive damages. Plaintiffs claim, inter alia, that Mirena™ is defective and that Bayer knew or should have known of the risks associated with it and failed to adequately warn its users. Additional lawsuits are anticipated. In April 2017, most of the cases pending in U.S. federal courts in which plaintiffs allege idiopathic intracranial hypertension were consolidated in a multidistrict litigation (“MDL”) proceeding for common pre-trial management. As of January 30, 2018, lawsuits from approximately 400 users of Mirena™ alleging idiopathic intracranial hypertension had been served upon Bayer in the United States. Another MDL proceeding concerning perforation cases has, in the meantime, been dismissed. The Second Circuit Court of Appeals affirmed the perforation MDL district court’s summary judgment order of 2016 dismissing approximately 1,230 cases pending before that court. In August 2017, Bayer reached an agreement in principle with plaintiffs’ counsel leadership for global settlement of the perforation litigation, for a total amount of US$12.2 million. As of January 30, 2018, a total of approximately 4,000 cases would be included in the settlement. The idiopathic intracranial hypertension MDL proceeding is not included in the settlement.

As of January 30, 2018, five Canadian lawsuits relating to Mirena™ seeking class action certification had been served upon Bayer. Bayer believes it has meritorious defenses and intends to defend itself vigorously.

        XARELTO LITIGATION

Xarelto™: As of January 30, 2018, U.S. lawsuits from approximately 22,000 recipients of Xarelto™, an oral anticoagulant for the treatment and prevention of blood clots, had been served upon Bayer. Plaintiffs allege personal injuries from the use of Xarelto™, including cerebral, gastrointestinal or other bleeding and death, and seek compensatory and punitive damages. They claim, amongst other things, that Xarelto™ is defective and that Bayer knew or should have known of these risks associated with the use of Xarelto™ and failed to adequately warn its users. Additional lawsuits are anticipated. Cases pending in U.S. federal courts have been consolidated in an MDL for common pre-trial management. In May, June and August 2017, the first three MDL trials resulted in complete defense verdicts; plaintiffs have appealed all three verdicts. In January 2018, after the first trial to proceed in Pennsylvania state court had initially resulted in a judgment in favor of the plaintiff, the trial judge vacated the jury’s verdict and granted judgment in favor of Bayer. Further Pennsylvania state court trials are currently scheduled for the first and second quarters of 2018. Bayer anticipates that additional trials will be scheduled.

As of January 30, 2018, ten Canadian lawsuits relating to Xarelto™ seeking class action certification had been served upon Bayer. Bayer believes it has meritorious defenses and intends to defend itself vigorously.

Essure™: As of January 30, 2018, U.S. lawsuits from approximately16,100 users of Essure™, a medical device offering permanent birth control with a nonsurgical procedure, had been served upon Bayer. Plaintiffs allege personal injuries from the use of Essure™, including hysterectomy, perforation, pain, bleeding, weight gain, nickel sensitivity, depression and unwanted pregnancy, and seek compensatory and punitive damages. Additional lawsuits are anticipated.

As of January 30, 2018, two Canadian lawsuits relating to Essure™ seeking class action certification had been served upon Bayer. Bayer believes it has meritorious defenses and intends to defend itself vigorously.

Class actions over neonicotinoids in Canada: Proposed class actions against Bayer were filed in Quebec and Ontario (Canada) concerning crop protection products containing the active substances imidacloprid and clothianidin (neonicotinoids). Plaintiffs are honey producers, who have filed a proposed nationwide class action in Ontario and a Quebec-only class action in Quebec. Plaintiffs claim for damages and punitive damages and allege Bayer and another crop protection company were negligent in the design, development, marketing and sale of neonicotinoid pesticides. The proposed Ontario class action is in a very early procedural phase. In Quebec, the plaintiff sought authorization (certification) of a class for which a motion was heard in November 2017. Bayer believes it has meritorious defenses and intends to defend itself vigorously.

INSURANCE COMPANY PAYS THE BILLS

In connection with the above-mentioned proceedings, Bayer is insured against statutory product liability claims against Bayer to the extent customary in the respective industries and has, based on the information currently available, taken appropriate accounting measures for anticipated defense costs. However, the accounting measures relating to Essure™ claims exceed the available insurance coverage.

SHOULD BAYER HAVE INSERTED ROUNDUP MDL LITIGATION HERE?

https://www.masstortnexus.com/News/4362/Monsanto-Bayer-Facing-Over-11-000-Lawsuits-Over-Roundup-Cancer-Risk-As-New-Federal-Trial-Starts

Link to US District ND California Monsanto MDL 2741 litigation case outline and case related orders: https://www.cand.uscourts.gov/VC/roundupmdl

[End of Bayer-Mosanto Docket in MDL 2741]

March 6, 2019 https://www.masstortnexus.com/mass-torts-news/bayer-ag-completes-monsanto-purchase-whats-next-on-litigation-dockets/

Patent Disputes

Adempas™: In January 2018, Bayer filed patent infringement lawsuits in a U.S. federal court against Alembic Pharmaceuticals Limited, Alembic Global Holding SA, Alembic Pharmaceuticals, Inc. and INC Research, LLC (together “Alembic”), against MSN Laboratories Private Limited and MSN Pharmaceuticals Inc. (together “MSN”) and against Teva Pharmaceuticals USA, Inc. and Teva Pharmaceutical Industries Ltd. (together “Teva”). In December 2017, Bayer had received notices of an Abbreviated New Drug Application with a paragraph IV certification (“ANDA IV”) pursuant to which Alembic, MSN and Teva each seek approval of a generic version of Bayer’s pulmonary hypertension drug Adempas™ in the United States.

Betaferon™ / Betaseron™: In 2010, Bayer filed a complaint against Biogen Idec MA Inc. in a U.S. federal court seeking a declaration by the court that a patent issued to Biogen in 2009 is invalid and not infringed by Bayer’s production and distribution of Betaseron™, Bayer’s drug product for the treatment of multiple sclerosis. Biogen is alleging patent infringement by Bayer through Bayer’s production and distribution of Betaseron™ and Extavia™ and has sued Bayer accordingly. Bayer manufactures Betaseron™ and distributes the product in the United States. Extavia™ is also a drug product for the treatment of multiple sclerosis; it is manufactured by Bayer, but distributed in the United States by Novartis Pharmaceuticals Corporation, another defendant in the lawsuit. In 2016, the U.S. federal court decided a disputed issue regarding the scope of the patent in Biogen’s favor. Bayer disagrees with the decision, which may be appealed at the conclusion of the proceedings in the U.S. federal court.

Damoctocog alfa pegol (BAY 94‑9027, long-acting recombinant factor VIII): In August 2017, Bayer filed a lawsuit in a U.S. federal court against Nektar Therapeutics (“Nektar”), Baxalta Incorporated and Baxalta U.S., Inc. (together “Baxalta”) seeking a declaration by the court that a patent by Nektar is invalid and not infringed by Bayer’s drug candidate BAY 94‑9027 for the treatment of hemophilia A. In September 2017, Baxalta and Nektar filed a complaint in a different U.S. federal court against Bayer alleging that BAY 94‑9027 infringes seven other patents by Nektar. Regarding the complaint by Bayer, Nektar and Baxalta gave Bayer a covenant not to make any claims against Bayer for infringement of that patent. Bayer amended the complaint to now seek a declaration by the court that the seven other patents by Nektar are not infringed by BAY 94‑9027. The patents are part of a patent family registered in the name of Nektar and further comprising European patent applications with the title “Polymer-factor VIII moiety conjugates” which are at issue in a lawsuit Bayer filed against Nektar in 2013 in the district court of Munich, Germany. In this proceeding, Bayer claims rights to the European patent applications based on a past collaboration between Bayer and Nektar in the field of hemophilia. However, Bayer believes that the patent family does not include any valid patent claim relevant for Bayer’s drug candidate BAY 94‑9027 for the treatment of hemophilia A.

Nexavar™: In 2015, Bayer filed patent infringement lawsuits in a U.S. federal court against Mylan Pharmaceuticals Inc. and Mylan Inc. (together “Mylan”). In 2014 and 2015, Bayer had received notices of an ANDA IV application pursuant to which Mylan seeks approval of a generic version of Bayer’s cancer drug Nexavar™ in the United States. In October 2017, Bayer reached agreement with Mylan to settle this patent dispute. Under the settlement terms, Mylan will obtain a license to sell its generic version of Nexavar™ in the United States at a date after the expiration of the patent for the active ingredient expiring in January 2020. In 2016, Bayer had received another notice of such an ANDA IV application by Teva Pharmaceuticals USA, Inc. Bayer filed a patent infringement lawsuit against Teva in the same U.S. federal court. In January 2018, Bayer reached agreement with Teva to settle this patent dispute. Under the settlement terms, Teva will obtain a license to sell its generic version of Nexavar™ in the United States at a date after the expiration of the patent for the active ingredient expiring in January 2020.

Stivarga™: In 2016, Bayer filed patent infringement lawsuits in a U.S. federal court against Apotex, Inc. and Apotex Corp. (together “Apotex”) and against Teva. Bayer had received notices of an ANDA IV application pursuant to which Apotex and Teva each seek approval of a generic version of Bayer’s cancer drug Stivarga™ in the United States.

Xarelto™: In 2015, Bayer and Janssen Pharmaceuticals filed a patent infringement lawsuit in a U.S. federal court against Aurobindo Pharma Limited, Aurobindo Pharma USA, Inc. (together “Aurobindo”), Breckenridge Pharmaceutical Inc. (“Breckenridge”), Micro Labs Ltd., Micro Labs USA Inc. (together “Micro Labs”), Mylan, Prinston Pharmaceutical Inc. (“Prinston”), Sigmapharm Laboratories, LLC (“Sigmapharm”), Torrent Pharmaceuticals, Limited and Torrent Pharma Inc. (together “Torrent”). Bayer had received notices of an ANDA IV application by Aurobindo, Breckenridge, Micro Labs, Mylan, Prinston, Sigmapharm and Torrent, each seeking approval to market a generic version of Xarelto™, an oral anticoagulant for the treatment and prevention of blood clots, in the United States. In 2016, Bayer received another notice of such an ANDA IV application by InvaGen Pharmaceuticals, Inc. (“InvaGen”). Bayer and Janssen Pharmaceuticals filed a patent infringement lawsuit against InvaGen in the same U.S. federal court.

Bayer believes it has meritorious defenses in the above ongoing patent disputes and intends to defend itself vigorously.

Further Legal Proceedings

Trasylol™ / Avelox™: A qui tam complaint relating to marketing practices for Trasylol™ (aprotinin) and Avelox™ (moxifloxacin) filed by a former Bayer employee is pending in the United States District Court in New Jersey. The U.S. government has declined to intervene at the present time.

Newark Bay Environmental Matters: In the United States, Bayer is one of numerous parties involved in a series of claims brought by federal and state environmental protection agencies. The claims arise from operations by entities which historically were conducted near Newark Bay or surrounding bodies of water, or which allegedly discharged hazardous waste into these waterways or onto nearby land. Bayer and the other potentially responsible parties are being asked to remediate and contribute to the payment of past and future remediation or restoration costs and damages. In 2016, Bayer learned that two major potentially responsible parties had filed for protection under Chapter 11 of the U.S. Bankruptcy Code. While Bayer remains unable to determine the extent of its liability for these matters, this development is likely to adversely affect the share of costs potentially allocated to Bayer.

In the Lower Passaic River matter, a group of more than sixty companies including Bayer is investigating contaminated sediments in the riverbed under the supervision of the United States Environmental Protection Agency (EPA) and other governmental authorities. Future remediation will involve some form of dredging, the nature and scope of which are not yet defined, and potentially other tasks. The cost of the investigation and the remediation work may be substantial if the final remedy involves extensive dredging and disposal of impacted sediments. In the Newark Bay matter, an unaffiliated party is currently conducting an investigation of sediments in Newark Bay under EPA supervision. The investigation is in a preliminary stage. Bayer has contributed to certain investigation costs in the past and may incur costs for future investigation and remediation activities in Newark Bay.

Bayer has also been notified by governmental authorities acting as natural resource trustees that it may have liability for natural resource damages arising from the contamination of the Lower Passaic River, Newark Bay and surrounding water bodies. Bayer is currently unable to determine the extent of its liability.

Asbestos: A further risk may arise from asbestos litigation in the United States. In many cases, the plaintiffs allege that Bayer and co-defendants employed third parties on their sites in past decades without providing them with sufficient warnings or protection against the known dangers of asbestos. Additionally, a Bayer affiliate in the United States is the legal successor to companies that sold asbestos products until 1976. Union Carbide has agreed to indemnify Bayer for this liability. Bayer believes it has meritorious defenses and intends to defend itself vigorously.

There is no official reference to Monsanto Roundup MDL 2741, even though an August 2018 verdict award for the plaintiff in California State Court was for more than $280 million, and showed that non-hodgkins lymphoma was caused by use of Monsanto Roundup herbicide containing Glyphosate. f

https://www.reuters.com/article/us-bayer-glyphosate-lawsuit/bayer-shares-slide-after-latest-roundup-cancer-ruling-idUSKCN1R02O3

 

Bayer legal Disclaimer October 2018: Cautionary Statements Regarding Forward-Looking Information

Certain statements contained in this communication may constitute “forward-looking statements.” Actual results could differ materially from those projected or forecast in the forward-looking statements. The factors that could cause actual results to differ materially include the following: the risk that the parties may be unable to achieve expected synergies and operating efficiencies in the merger within the expected timeframes (or at all) and to successfully integrate the operations of Monsanto Company (“Monsanto”) into those of Bayer Aktiengesellschaft (“Bayer”); such integration may be more difficult, time-consuming or costly than expected; revenues following the transaction may be lower than expected; operating costs, customer loss and business disruption (including difficulties in maintaining relationships with employees, customers, clients or suppliers) may be greater or more significant than expected following the transaction; the retention of certain key employees at Monsanto; the parties’ ability to meet expectations regarding the accounting and tax treatments of the merger; the impact of refinancing the loans taken out for the transaction; the impact of indebtedness incurred by Bayer in connection with the transaction and the potential impact on Bayer’s rating of indebtedness; the effects of the business combination of Bayer and Monsanto, including the combined company’s future financial condition, operating results, strategy and plans; other factors detailed in Monsanto’s Annual Report on Form 10-K filed with the U.S. Securities and Exchange Commission (the “SEC”) for the fiscal year ended August 31, 2017, and Monsanto’s other filings with the SEC, which are available at http://www.sec.gov and on Monsanto’s website at www.monsanto.com; and other factors discussed in Bayer’s public reports which are available on the Bayer website at www.bayer.com. Bayer assumes no obligation to update the information in this communication, except as otherwise required by law. Readers are cautioned not to place undue reliance on these forward-looking statements that speak only as of the date hereof.

BAYER LITIGATION DOCKETS IN MDL’s ARE STILL GROWING

ROUNDUP-MONSANTO-(GLYPHOSATE)-MDL-2741-(USDC-ND-California) Mass Tort Nexus Briefcase

 

XARELTO-(rivaroxaban)-MDL-2592-(USDC-ED-Louisiana) Mass Tort Nexus Briefcase

 

XARELTO-Case-No-2349–Philadephia-Court-of-Common-Pleas-Complex-Litigation-(PA-State-Court) Mass Tort Nexus Briefcase)

To access the most relevant and 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 Jenny Levine at 954.520.4494 or Jenny@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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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

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 Jenny Levine at 954.520.4494 or Jenny@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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Purdue Pharma’s Historical Bad Conduct Started 50 Years Ago: “Crafted By The Sackler Brothers”

 DOCUMENTS SHOW LONG-TERM DRUG INDUSTRY MANIPULATION BY THE SACKLERS

By Mark A. York (January 16, 2019

 

 

 

 

 

 

 

(MASS TORT NEXUS MEDIA) In 2007, Purdue Frederick Co. (not Purdue Pharma) and three company executives pled guilty to misbranding OxyContin and agreed to pay $634.5 million to resolve a U.S. Department of Justice investigation, in the US District Court of Virginia, see Purdue Criminal Plea Agreement US Department of Justice May 10, 2007. This plea deal “a get-out-of-jail free card” was engineered by none other than former New York City Mayor and political/corporate fixer, Rudy Guiliani, by directly leveraging high level US DOJ contacts and other DC insiders to derail the prosecution of Purdue Pharma, and instead offer up Purdue Fredrick Co. as the guilty party and thereby permitting the multi-billion dollar per year Oxycontin assembly line to continue operations.

The Sackler family has always been protected by the company shield, even though their most profitable selling opioid drug Oxycontin, and its boardroom coordinated marketing campaign was the brainchild and a direct result of the Purdue Pharma company founders, the Sackler brothers and their tried and true business model.

That is now changing, as the State of Massachusetts has filed a lawsuit against Purdue Pharma and the Sackler family as well as various Purdue executives over the prescription painkiller OxyContin. Oxycontin is now recognized as the opioid fuse that ignited America’s opioid crisis, and in a positive move forward, the leading executives and members of the multibillionaire Sackler family, now known to be feuding over the opioid crisis have been named in civil litigation.

The Sacklers named in the lawsuits include Theresa and Beverly, widows of Purdue founders, brothers Mortimer and Raymond Sackler and Ilene, Kathe and Mortimer David Alfons Sackler, three of Mortimer’s children; Jonathan and Richard Sackler, Raymond’s two sons; and David Sackler, Raymond’s grandson. The Sackler family is worth conservatively, an estimated$13 billion according to Forbes, which has been generated from sales of OxyContin.  As is normal procedure by the Sackler family and the company itself, the Sackler family feuding members always decline requests for comment on the catastrophic opioid crisis and avoid discussing any Purdue Pharma links to how the crisis came about.

As Purdue Pharma comes to grips with the fact that they are being designated as the primary litigation targets of states, counties and cities across the country for being the Opiate Big Pharma leader in creating the current opioid crisis in the United States, they may need to determine how they will pay the billions of dollars in jury verdicts and affiliated legal settlements resulting from the lawsuits that now number over 1,200 cases in state and federal courts.

The entire Sackler brothers’ Oxycontin marketing plan followed their previously proven drug marketing test drive of “Valium” – when Hoffman-LaRoche hired the Sacklers to market their new drug “diazepam” commonly known as Valium and its sister drug Librium.

While running the drug advertising company, Arthur Sackler became a publisher, starting a biweekly newspaper, the Medical Tribune, which eventually reached 600,000 physicians. He scoffed at suggestions that there was a conflict of interest between his roles as the head of a pharmaceutical-advertising company and the publisher of a periodical for doctors. Later it emerged that a company he owned, MD Publications, had paid the chief of the antibiotics division of the FDA, Henry Welch, nearly $300,000 in exchange for Welch’s help in promoting certain drugs. Sometimes, when Welch was giving a speech, he inserted a drug’s advertising slogan into his remarks. After the payments were discovered, Welch was forced to resign from the FDA.

When Purdue Pharma started selling its prescription opioid painkiller OxyContin in 1996, Dr. Richard Sackler asked people gathered for the launch party to envision natural disasters like an earthquake, a hurricane, or a blizzard. The debut of OxyContin, said Sackler — a member of the family that started and controls the company and then a company executive — “will be followed by a blizzard of prescriptions that will bury the competition.”

Five years later, as questions were raised about the risk of addiction and overdoses that came with taking OxyContin and opioid medications, Sackler outlined a strategy that critics have long accused the company of unleashing: divert the blame onto others, particularly the people who became addicted to opioids themselves.

“We have to hammer on the abusers in every way possible,” Sackler wrote in an email in February 2001. “They are the culprits and the problem. They are reckless criminals.”

Sackler’s comments at the party and his email are contained in newly public portions of a lawsuit filed by the state of Massachusetts against Purdue that alleges that the company, the Sackler family, and company executives misled prescribers and patients as they aimed to blanket the country with prescriptions for their addictive medications.

“By their misconduct, the Sacklers have hammered Massachusetts families in every way possible,” the state’s complaint says, noting that since 2007, Purdue has sold more than 70 million doses of opioids in Massachusetts for more than $500 million. “And the stigma they used as a weapon made the crisis worse.”

The new filing also reveals how Purdue aggressively pursued tight relationships with Tufts University’s Health Sciences Campus and Massachusetts General Hospital — two of the state’s premier academic medical centers — to expand prescribing by physicians, generate goodwill toward opioid painkillers among medical students and doctors in training, and combat negative reports about opioid addiction.

Since the beginning of May, the attorneys general of Florida, Nevada, Massachusetts, North Carolina, North Dakota, Tennessee, Texas, Utah and Virginia have also filed lawsuits against the company.

New York City previously filed a $500 million suit, against pharmaceutical companies that make or distribute prescription opioids, the complaint was filed in New York state court, the Superior Court of Manhattan, which is a break from other Opioid lawsuits filed by cities, who filed into federal court, see Mass Tort Nexus Briefcase,  OPIOID-CRISIS: MDL-2804-OPIATE-PRESCRIPTION-LITIGATION. The primary claims state that the opiate drug companies fueled the deadly epidemic now afflicting the most populous U.S. city, joining Chicago, Seattle, Milwaukee and other major cities across the country in holding Big Pharma drug makers accountable for the opioid crisis. The case docket information is: City of New York v Purdue Pharma LP et al, New York State Supreme Court, New York County, No. 450133/2018.

Major US Cities Filing Suit Against Opioid Big Pharma-New York, Seattle, Chicago Join MDL 2804

Gov. Andrew Cuomo said in a statement “The opioid epidemic was manufactured by unscrupulous manufacturers and distributors who developed a $400 billion industry pumping human misery into our communities”.

The suit comes three months after Underwood first announced her intention to sue the pharma giant, joining several other states that have already targeted Purdue for its alleged role in the epidemic that saw more than 3,000 New Yorkers die of opioid overdoses in 2016. Daniel Raymond, deputy director of the Harm Reduction Coalition, said that the cities and states are forced to file suits now, after realizing initially that the opioid overdose rates “were primarily driven by prescription painkillers — they weren’t concentrated in urban areas.”

“But the recent rises in prescription overdoses, which in turn has accelerated a major increase in heroin overdoses, and particularly fentanyl, and the latter seems particularly prevalent in urban drug markets,” said Raymond, whose organization is based in New York City. “That’s certainly true in places like Ohio and Philadelphia, which are seeing a lot of fentanyl-involved overdose deaths. That doesn’t mean the problems have waned in smaller cities and rural areas, which are also seeing fentanyl, but we are seeing increasing vulnerability in major urban centers.”

The only bright spot — and it’s a dim one at that — was that the CDC found decreases in opioid overdoses in states like West Virginia, New Hampshire and Kentucky that have been leading the nation in the category.

“We hope this is a positive sign,” said Schuchat, who credited leadership, particularly in West Virginia, with taking bold steps to combat the crisis. “But we have to be cautious in the areas that have reported decreases.”

Dr. Rahul Gupta, then Director of Public Health for West Virginia has been at the forefront of addressing the opioid crisis in not only West Virginia but across the country, he stated “Sometimes places that have had such high rates have no place to go” but down, he added, with West Virginia being one of the states to address the issues pro-actively in all areas.

The same drug abuse related issues that are in New York and other major metropolitan areas are now at healthcare crisis levels, with the causation now being seen as based on the ongoing marketing abuses by Purdue Pharma and other opiate industry drug makers and distributors.

The new CDC “Vital Signs” report was released a week after Attorney General Jeff Sessions issued a “statement of interest” in support of local governments that are suing the big pharmaceutical makers and distributors, accusing them of swamping many states with prescription painkillers and turning millions of Americans into junkies.

The new CDC numbers come from analysis of emergency room data from 16 states, including some hardest hit by the plague — Delaware, Illinois, Indiana, Kentucky, Massachusetts, Maine, Missouri, Nevada, New Hampshire, New Mexico, North Carolina, Ohio, Pennsylvania, Rhode Island, West Virginia and Wisconsin.

Dozens of states, counties and local governments have independently sued opioid drugmakers in both state and federal courts across the country, (see OPIOID-CRISIS-BRIEFCASE-MDL-2804-OPIATE-PRESCRIPTION-LITIGATION by Mass Tort Nexus) with claims alleging all opiate drug makers, distributors and now the pharmacies engaged in fraudulent marketing to sell the powerful painkillers. They also failed to monitor and report the massive increases in opioid prescriptions flooding the US marketplace. Which has now resulted in fueling the nationwide epidemic, that’s reported to have killed over a quarter million people. The now organized approach steps up those efforts as officials sift evidence and are holding not only the companies, but the executives and owners culpable in the designing the opioid crisis.

Purdue Pharma is facing a legal assault on many fronts, as cities, counties and states have either filed suit or are probing the company for an alleged role in the United States’ opioid and addiction epidemic. The lawsuit filed by Massachusetts’ Attorney General Maura Healey, is the first to bring the company’s current and former execs into the mix, including the billionaire family with sole ownership of Purdue.

The Sackler family name graces some of the nation’s most prestigious bastions of culture and learning — the Sackler Center for Arts Education at the Guggenheim Museum, the Sackler Lefcourt Center for Child Development in Manhattan and the Sackler Institute for Developmental Psychobiology at Columbia University, to name a few.

Now for the first time since the opioid crisis came to the attention of America, the Sackler name is front and center in a lawsuit accusing the family and the company they own and run, Purdue Pharma, of helping to fuel the deadly opioid crisis that has killed thousands of Americans.

Lawsuit filed by the state of Massachusetts against Purdue Pharma

Under an agreement with Mass. General, Purdue has paid the hospital $3 million since 2009 and was allowed to propose “areas where education in the field of pain is needed” and “curriculum which might meet such needs,” the court document shows. Tufts made a Purdue employee an adjunct associate professor in 2011, Purdue-written materials were approved for teaching to Tufts students in 2014, and the company sent staff to Tufts as recently as 2017, the complaint says. Purdue’s New England staff was congratulated for “penetrating this account.”

A Tufts spokesman declined to comment, citing the ongoing legal process. Mass. General did not immediately comment.

In a statement Purdue criticized the Massachusetts Attorney General Maura Healey’s office, which is spearheading the lawsuit, and said the complaint was “a rush to vilify” Purdue. It noted that its medications were approved by the Food and Drug Administration and regulated by the government, and that the company promoted the medications “to licensed physicians who have the training and responsibility to ensure that medications are properly prescribed.”

“Massachusetts’ amended complaint irresponsibly and counterproductively casts every prescription of OxyContin as dangerous and illegitimate, substituting its lawyers’ sensational allegations for the expert scientific determinations of the [FDA] and completely ignoring the millions of patients who are prescribed Purdue Pharma’s medicines for the management of their severe chronic pain,” the company said.

It also said the state attorney general’s office omitted information about the steps Purdue has taken in the past decade to promote safe and appropriate use of opioid medicines.

“To distract from these omissions of fact and the other numerous deficiencies of its claims, the Attorney General has cherry-picked from among tens of millions of emails and other business documents produced by Purdue,” the company said. “The complaint is littered with biased and inaccurate characterizations of these documents and individual defendants, often highlighting potential courses of action that were ultimately rejected by the company.”

Healey’s office sued Purdue, current and former executives, and members of the Sackler family in June. In December, it filed an amended complaint that was nearly 200 pages longer than the June filing, with more allegations spelled out against the individual defendants. Many of the details were redacted; a portion of them were made public in an updated document filed Tuesday in state court, though much of the complaint is still blacked out.

The state’s suit focuses on Purdue’s actions since 2007, when the company and three current and former executives pled guilty in federal court to fraudulently marketing OxyContin and the company agreed to pay $600 million in fines. The case is separate from litigation being waged by STAT to obtain sealed Purdue documents in Kentucky, including the only known deposition of Richard Sackler, about the company’s marketing practices in earlier years, which have been blamed for igniting the current opioid addiction crisis.

The Massachusetts complaint sketches an image of the Sacklers, as board members, exercising tight control over the company, overseeing the deployment of a phalanx of sales representatives who were pushed to get Purdue medications into more hands, at higher doses, and for longer periods of time. The Sacklers, the complaint states, reaped “billion of dollars,” even as the company blurred the risks of addiction and overdose that came with the drugs.

Richard Sackler, who was named president of the company in 1999 before becoming co-chairman in 2003, is singled out in the complaint as particularly domineering as he demanded greater sales. In 2011, he decided to shadow sales reps for a week “to make sure his orders were followed,” the complaint states.

Russell Gasdia, then the company’s vice president of sales and marketing, who is also a defendant in the Massachusetts lawsuit, went to Purdue’s chief compliance officer to warn that if Sackler directly promoted opioids, it was “a potential compliance risk.”

“LOL,” the compliance officer replied, according to the complaint. Other staff raised concerns, but they ultimately said that “Richard needs to be mum and anonymous” when he went into the field.

After the visits to doctors, Richard Sackler claimed that Purdue’s drugs shouldn’t need a legally mandated warning. He wrote in an email cited in the complaint that the warning “implies a danger of untoward reactions and hazards that simply aren’t there.”

Secret trove reveals bold ‘crusade’ to make OxyContin a blockbuster

The following year, Sackler’s pressure on the staff grew so intense that Gasdia asked the CEO to intervene: “Anything you can do to reduce the direct contacts of Richard into the organization is appreciated,” Gasdia wrote in an email cited by the complaint.

It apparently didn’t work. The next week, Richard Sackler emailed sales managers to say that U.S. sales were “among the worst” in the world.

Sales managers were badgered on nights, weekends, and holidays, according to the filing. The marketing campaigns focused on high-volume doctors, who were visited repeatedly by salespeople, and pushed doctors to prescribe high doses. The demands on sales managers created such a stressful environment that in 2012, they threatened to fire all sales representatives in the Boston area because of lackluster numbers.

The complaint also accuses Purdue of rarely reporting alleged illegal activity, such as improper prescribing and massive Oxycontin order increases to government officials when it learned about it. In one 2009 case, a Purdue sales manager wrote to a company official that Purdue was promoting opioids to an illegal pill mill.

“I feel very certain this is an organized drug ring,” the employee wrote, adding “Shouldn’t the DEA be contacted about this?” Purdue did nothing for two years, according to the complaint.

In addition to relying on its sales force, Purdue cultivated ties with academic hospitals, which both treat patients and train the next generation of prescribers.

In 2002, the company started the Massachusetts General Hospital Purdue Pharma Pain Program after a Purdue employee reported that access to the hospital’s doctors “is great … they come to us with any questions, and allow us to see them when we need to.” The hospital, the staffer added, “has significant influence through most of New England, simply because they are MGH.”

As part of the program, Purdue gained influence over training programs and organized a symposium in the hospital’s famed “Ether Dome” — the site of the first public surgery with anesthetic.

The Sacklers renewed the deal with Mass. General in 2009 and agreed to contribute $3 million to fund the program, the lawsuit says.

Purdue’s funding, however, didn’t stop researchers at Mass. General from raising concerns about its products. The complaint cites a July 2011 email from Purdue’s then-chief medical officer Craig Landau — who is now the CEO and is a defendant in the lawsuit — flagging a study questioning the use of opioid painkillers for chronic pain that was conducted by Mass. General researchers with Purdue funding. Landau wanted to make sure that any Purdue-funded study supported the use of its medicines.

Purdue’s ties to Tufts date back even further, according to the lawsuit. In 1980, three Sacklers donated funding to launch the Sackler School of Graduate Biomedical Sciences. In 1999, the Sacklers gave money to help start the Tufts Masters of Science in Pain Research, Education, and Policy. Through the program, “Purdue got to control research on the treatment of pain coming out of a prominent and respected institution of learning,” the filing states. Purdue employees even taught a Tufts seminar about opioids, and Tufts and its teaching hospital collaborated with Purdue on a publication for patients called, “Taking Control of Your Pain.”

Purdue also allegedly used Tufts’s ties in Maine as reports about addiction emerged in the state. Tufts ran a residency program in the state, the complaint says, and in 2000 “agreed to help Purdue find doctors to attend an event where Purdue could defend its reputation.”

The bulk of the documents cited in the Massachusetts complaint were filed by Purdue in federal court in Ohio as part of a consolidated case involving hundreds of lawsuits filed by states, cities, counties, and tribes against Purdue, other opioid manufacturers, and others in the pharmaceutical industry.

Purdue says it produced 45 million pages of documents for the federal court case — known as a multidistrict litigation. In a motion filed last month and in an emergency hearing before the federal judge in Ohio overseeing the MDL, Purdue argued that the details in Massachusetts’ amended complaint were largely drawn from about 500 Purdue documents it had filed on a confidential basis in the federal court. The company’s lawyers argued the rules of confidentiality established in the federal court should apply to Massachusetts’ filing in state court, while state officials say the issue of what should be made public should be decided in state court.

Among the records Purdue said last month should remain confidential are those involving the company’s board of directors. Making them public, the company argued, would have a “chilling effect” on corporate governance.

The effort to protect the disclosure of board-related documents serves another purpose not cited by the company: It protects the Sackler family, whose members have long constituted the majority of board members.

In its filing last month, Purdue also said one company official, whom it did not name, was concerned for his safety because his home address was listed in the complaint along with “numerous irrelevant, incendiary, and misleading comments about his career at Purdue.”

Purdue’s attorneys contend the Massachusetts amended complaint is a “concerted effort by the Commonwealth to use confidential documents in an attempt to publicly embarrass Purdue and its officers, directors and employees.” They claim the information selected was “cherry-picked” to “bolster a series of inflammatory and misleading allegations against Purdue.”

In September 2017, Landau, by that time Purdue’s CEO, jotted down a note summarizing some of the roots of the opioid crisis. It reads:

“There are:
Too many Rxs being written
Too high a dose
For too long
For conditions that often don’t require them
By doctors who lack the requisite training in how
to use them appropriately.”

The state’s lawsuit concludes: “The opioid epidemic is not a mystery to the people who started it. The defendants knew what they were doing.”

The Sackler family is the 19th richest in the nation, with an estimated fortune of $13 billion, according to Forbes.

The Sacklers involved with Purdue Pharma are the descendants of brothers Mortimer and Raymond Sackler. Their eldest brother, Arthur, died in 1987, well before Purdue began making and selling OxyContin. Arthur also worked in pharmaceuticals and developed a reputation for cleverly marketing new drugs directly to doctors, convincing them to prescribe medications including tranquilizers to their patients.

Arthur was inducted into the Medical Advertising Hall of Fame after his death, but he has also been criticized for originating “most of the questionable practices that propelled the pharmaceutical industry into the scourge it is today,” as Allen Frances, the former chair of psychiatry at Duke University School of Medicine, told the New Yorker last year.

Arthur’s family has made a point of noting that he was not involved in the sale of OxyContin and would prefer him to be remembered for his philanthropy, including funding the Arthur M. Sackler Gallery of Chinese Stone Sculpture at The Metropolitan Museum in Manhattan and the Arthur M. Sackler Museum at Harvard University.

“None of the charitable donations made by Arthur prior to his death, nor that I made on his behalf after his death, were funded by the production, distribution or sale of OxyContin or other revenue from Purdue Pharma,” his widow, Jillian Sackler, said in a February statement. “Period.”

Seven of the Sacklers named in the suit have been on the Purdue board since the 1990s, according to the suit, while David Sackler, the grandson, has served since 2012.

The board met on a weekly — sometimes daily — basis while the company was being investigated by 26 states and the Justice Department from 2001 to 2007, according to the lawsuit. In 2007, the board settled and agreed to pay a $700 million fine after the company’s CEO at the time, Michael Friedman, and two other high-ranking company officials pleaded guilty to misleading doctors and patients about opioids.

KENTUCKY LEGAL FIGHT TO KEEP SACKLER TESTIMONY SEALED

In an example of the past coming back to haunt the present, in 2015 Purdue Pharma agreed to pay $24 million to settle a lawsuit filed by Kentucky, December 22, 2015 Purdue Pharma Settlement With State of Kentucky,  which Purdue thought would end that problem by paying a fine and moving on, which isn’t the case it seems. See Purdue Pharma settles with Kentucky over Oxycontin claim(statnews.com/pharmalot) for information on the claims in Kentucky.

That state court litigation is now subject to an ongoing legal battle in the Kentucky courts where Purdue is fighting to keep the original court records from that settlement sealed, due to the only deposition testimony of one of the Sackler brothers is known to be located. The Purdue court records were unsealed by Pike County Judge Stephen Combs in May 2016, and Purdue immediately appealed with oral arguments taking place June 26, 2017 in front of a three judge panel of the Kentucky Court of Appeals, which as of June 20, 2018 has not issued a ruling on releasing the records. The original Kentucky vs. Purdue docket information is case no. 07-CI-01303, Judge Stephen Combs, Pike County Circuit Court of Kentucky.

OxyContin was hailed as a medical marvel when it debuted in 1995. Pitched as balm for people suffering from moderate to severe pain, it reportedly generated more than $35 billion in revenue for Purdue Pharma.

Oxycontin’s chief ingredient is oxycodone, a cousin of heroin, and prosecutors say Purdue played down the dangers of addiction while getting hundreds of thousands of Americans hooked on opioids.

Purdue has argued that OxyContin is approved by the Food and Drug Administration and accounts for just 2 percent of the opioid prescriptions nationwide.

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Read More

Why Did The FDA Approve A Drug 10 Times Stronger Than Fentanyl-When Opiates Are Still Killing Thousands

HAS THE FDA LEARNED ANYTHING FROM THE OPIOID CRISIS THEY HELPED CREATE?

Mark A. York (November 6, 2018)

 

 

 

 

 

 

 

 

 

Just The Opioid Facts

Drugs kill more Americans than guns, cars and AIDS. How we got here.

(Mass Tort Nexus Media) More than 175 Americans will die today of drug overdoses, which equals a 737 crashing and killing all the passengers on board every single day. But it’s not a plane crash. It is America’s opioid epidemic, one that unchecked could claim 1 million lives by 2020.

See also: Briefcases/Drugs/254/OPIOID-National-Prescription-Litigation-MDL-2804-USDC-ND-Ohio-(Eastern-Division) by Mass Tort Nexus

Who’s Minding The FDA?

A new opioid tablet that is 1,000 times more potent than morphine and 10 times stronger than fentanyl was approved by the Food and Drug Administration Friday as a fast-acting alternative to IV painkillers used in hospitals.

The painkiller Dsuvia will be restricted to limited use only in health care settings, such as hospitals, surgery centers and emergency rooms, but critics worry the opioid will fuel an already grim opioid epidemic.

Also on Friday, the Drug Enforcement Administration released a report showing that prescription drugs were responsible for the most overdose deaths of any illicit drugs since 2001.

Democratic Senator Ed Markey of Massachusetts urged the FDA to not approve Dsuvia last month, saying “an opioid that is a thousand times more powerful than morphine is a thousand times more likely to be abused, and a thousand times more likely to kill.”

To that, FDA Commissioner Scott Gottlieb said in a statement that “very tight restrictions” will be placed on Dsuvia. This statement flies in the face of reality as proven by assigned federal agencies to monitor and enforce rules on the already existing opiates that have flooded the US marketplace and killed hundreds of thousands of Americans.

So why should we think that anything is different with a new drug that basically comes under the same oversight umbrella as fentanyl, oxycontin and all the other prescription opiates? The DEA, FDA and anyone else assigned to monitor narcotic drug use, prescribing practices as well as marketing have failed miserably again and again.

FDA Claims Restricted Access

Dsuvia will not be available at retail pharmacies or for any home use, Gottlieb said. The medication, which comes in a single-use package, also should not be used for more than 72 hours. The medicine comes in a tablet that can dissolve under the tongue. Side effects of the potent drug include extreme tiredness, breathing problems, coma and death.

Gottlieb said military use of the drug was “carefully considered in this case” as the FDA wants to “make sure our soldiers have access to treatments that meet the unique needs of the battlefield.”

Combined with the increase in overdoses, the fact that opioids are less effective than presumed creates a substantial public health problem. We are throwing large sums of public and private money at treating opioid addiction and related issues caused by a problem that could have been completely avoided by using more effective (and less habit-forming) medications.

In the midst of a national opioid crisis, the federal agency that monitors drug ads has issued a record low number of warning letters to pharmaceutical companies caught lying about their products.

The Food and Drug Administration has sent just three notice letters to drug makers busted for false marketing their medications to unknowing consumers, the lowest ever since the FDA historic decision to ease strict rules for drug ads in 1997. “It certainly raises questions,” said Dr. David Kessler, head of the FDA from late 1990 through 1996, who’s industry credentials would add weight to the issue of why the FDA is not doing more to monitor false marketing campaigns by Big Pharma and Opioid Drug makers in particular.

The FDA’s Office of Prescription Drug Promotion monitors all ads drug companies issue to make sure patients aren’t being scammed by false assertions or misleading marketing campaigns. This now seems to be the norm, based on the hundreds of lawsuits filed against Opioid Drug Makers in the last 3 months, and recently consolidated into Opiate Prescription MDL 2804 see Opioid Crisis Briefcase-Mass Tort Nexus, where Big Pharma is being sued by states, cities and counties across the country. The primary claim in almost every suit is long-term boardroom coordinated false marketing campaigns designed to push opioid drug prescriptions at any cost.

 FDA Told Not to Approve Dsuvia

https://www.cdc.gov/drug-overdose-data-death counts through Oct 2018

Drug overdose deaths hit the highest level ever recorded in the United States last year, with an estimated 200 people dying per day, according to a report by the U.S. Drug Enforcement Administration. Most of that was the result of a record number of opioid-related deaths.

 

How Big Pharma got into opiates: In 1898, Bayer released heroin to treat coughs and other health woes. Soon, people became addicted to heroin, a narcotic and precursor to the current Opioid Crisis.

 Preliminary figures show more than 72,000 people died in 2017 from drug overdoses across the country. About a week ago, U.S. Health and Human Services Secretary Alex Azar said overdose deaths, while still slowly rising, were beginning to level off, citing figures from late last year and early this year.

The DEA’s National Drug Threat Assessment, which was recently released, shows that heroin, fentanyl and other opioids continue to be the highest drug threat in the nation. But federal officials are concerned that methamphetamine and cocaine are being seen at much higher levels in areas that haven’t historically been hotspots for those drugs. The DEA is also worried that people are exploiting marijuana legalization to traffic cannabis into the illicit market or to states that don’t have medicinal or recreational-use marijuana laws, according to the report.

The preliminary data also showed 49,060 people died from opioid-related overdose deaths, a rise from the reported 42,249 opioid overdose deaths in 2016.

Fatal heroin overdoses rose nationwide between 2015 and 2016, with a nearly 25 percent increase in the Northeast and more than 22 percent in the South. Most of the heroin sold in the U.S. is being trafficked from Mexico, and U.S. Customs and Border Protection officers seize the most amount of heroin along the Mexico border, near San Diego, California, the report said.

Fentanyl and other related opioids, which tend to be cheaper and much more potent than heroin, remain one of the biggest concerns for federal drug agents.

The DEA has said China is a main source of fentanyl and other synthetic opioids that have been flooding the U.S. market. China has pushed back against the characterization, and U.S. officials have stressed they work closely with their Chinese counterparts as they try to stem the flow of drugs.

Legislation that Trump signed last week will add treatment options and force the U.S. Postal Service to screen overseas packages for fentanyl.

Azar said in a speech last week that toward the end of 2017 and through the beginning of this year, the number of drug overdose deaths “has begun to plateau.” However, he was not indicating that deaths were going down, but that they appear to be rising at a slower rate than previously seen.

Pot Vs. Pills for Pain Relief

Last month, the Centers for Disease Control and Prevention released preliminary figures that appear to show a slowdown in overdose deaths from December to March. In that period, the figures show that the pace of the increase over the previous 12 months has slowed from 10 percent to 3 percent, according to the preliminary CDC figures.

Even if a slowdown is underway, no one is questioning the fact that the nation is dealing with the deadliest drug overdose epidemic in its history. While prescription opioid and heroin deaths appear to be leveling off, deaths involving fentanyl, cocaine and methamphetamines are on the rise, according to CDC data.

The DEA’s report also noted that methamphetamine is making its way into communities where the drug normally wasn’t heavily used, the report said. Chronic use of meth, a highly addictive stimulant, can cause paranoia, visual and auditory hallucinations and delusions, studies have shown.

As the government enacted laws that limited access to cold medicines containing pseudoephedrine — the ingredient used to cook meth with other household chemicals — or required the medications to be placed behind pharmacy counters, officials discovered the number of meth labs began to drop.

But the DEA has found the gap is being filled by Mexican and Latin American drug cartels that had primarily dabbled in heroin and cocaine trafficking. A saturated market on the West Coast is now driving the cartels to peddle methamphetamine into the Northeast, using the same routes they use for heroin and other drugs.

Officials also warn that because of more cocaine production in South American countries including Colombia, they expect to see larger shipments at the Mexican border.

Who Said “Pain Was The Fifth Vital Sign?”

“Pain as the fifth vital sign” became policy at VA clinics as well as VA hospitals across the U.S.

It seemed odd to equate pain with something like breathing, but doctors were advised by Purdue Pharma and other opiate makers to understand the need to “dignify” and take care of pain.

Across the country doctors seemed too willing to prescribe these opioid pills for chronic pain, patients seemed too willing to take them, and insurers seemed too willing to pay.

The Joint Commission began requiring hospitals to assess all patients for pain on a scale of 1 to 10, which some claimed caused more doctors to prescribe opioids.

Purdue gave the commission a grant to produce a pain assessment and management manual.

Officials from the commission and Purdue denied the company had anything to do with the content of the manual, co-written by Dr. June Dahl, who served on the speakers bureau for Purdue.

The manual told health care facilities the side effects of opioids had been exaggerated and that physical dependence had been wrongly confused with addiction. “There is no evidence that addiction is a significant issue when persons are given opioids for pain control,” the manual said.

Paid Endorsements In Studies

Purdue officials explained that studies on opioid addiction depended on many factors, including mental health. They cited a 2008 article by Dr. David Fishbain of the University of Miami, who analyzed 79 published studies, saying he concluded the prevalence of abuse or addiction was 3.27 percent, or 0.19 percent for those with no past addiction.

Fishbain responded that his study was misinterpreted and that addiction could be anywhere between 3.27 and 20.4 percent.

Commission officials denied its new standards encouraged doctors to prescribe more opioids, blaming drug trafficking as well as diversion and abuse by individuals.

At that time, the “evidence was broadly supported by experts across the spectrum that pain was undertreated and a serious problem leading to poor clinical outcomes,” the commission said.

The commission concluded that “millions of people in the United States suffer from pain, and failure to treat their pain is inhumane.”

The Painkiller Market

Since 1987, Purdue Pharma had been selling a timed-release drug named MS Contin, the company’s version of morphine. Seven years later, annual sales topped $88 million — the best performing painkiller Purdue officials had — but they faced problems.

Doctors knew how addictive morphine could be, and most were reluctant to prescribe MS Contin to patients suffering from chronic pain.

The even bigger problem? MS Contin’s patent would expire soon.

That meant generic drug manufacturers could make their own versions of MS Contin and eat into Purdue’s share of the painkiller market.

A generation earlier, Arthur Sackler, the brother of Purdue’s owners, had marketed Valium and other tranquilizers to women experiencing anxiety, tension or countless other symptoms. The drug broke all sales records, turning many women into addicts and Sackler into a multimillionaire.

The Sackler family planned to repeat that success with a timed-release version of OxyContin, the company’s version of oxycodone.

In internal Purdue documents obtained by the USA TODAY NETWORK, company officials gushed that OxyContin could become a hit in “the $462 million Class II opioid marketplace.”

These documents detail their strategy: They would first market OxyContin strictly for cancer pain, where doctors were familiar with oxycodone.

Then the company would pivot to the lucrative market of chronic pain, which afflicted at least 25 million Americans.

Purdue’s plan included targeting primary care physicians, surgeons, obstetricians and dentists. The company even targeted home care and hospice care nurses who would “rate the patients’ pain and make a recommendation on the type of opioid and dosage for pain control.”

The plan also included targeting patients and caregivers through Purdue’s “Partners Against Pain” program. “You are the pain authority,” the website reassured patients. “You are the expert on your own pain.”

The website declared that “there are 75 million Americans living with pain, although pain management experts say they don’t have to,” reassuring patients that doctors could control their pain “through the relatively simple means of pain medications” and that the risk of addiction to opioids “very rarely occurs when under medical supervision to relieve pain.”

To ensure that OxyContin became a hit, Purdue sponsored more than 20,000 educational programs to encourage health care providers to prescribe the new drug and sent videos to 15,000 doctors.

The company also hosted dozens of all-expenses-paid national pain management conferences, where more than 5,000 physicians, pharmacists and nurses were trained for the company’s national speakers bureau.

By 2001, Purdue was spending $200 million on marketing and promotion and had doubled its sales force to 671. Before the year ended, sales bonuses reached $40 million.

No Addiction Knowledge 

Dr. Fannin, who practices in West Virginia remembers sales reps from Purdue flooding doctors’ offices in Appalachia, where poverty and pain are constant realities.

The reps gave away fishing hats, stuffed toys and music CDs titled “Get in the Swing with OxyContin.”

“Every time you turned around, you saw their faces,” Fannin said. “We had a population of doctors with very little grounding in pain, and I think Purdue took advantage of that.”

Many doctors knew about oxycodone from Percocet, which combined a small dosage of the potent opioid with 325 mg of acetaminophen.

What many of those doctors didn’t realize was that oxycodone was nearly twice as powerful as morphine, delivering a powerful high to those who use the drug.

“It’s more like heroin,” explained Dr. Andrew Kolodny, co-director of the Opioid Policy Research Collaborative at Brandeis University. “It crosses the blood-brain barrier more quickly.”

But the sales reps never mentioned that. Instead, they said OxyContin didn’t create highs like other opioids and was less likely to get people addicted.

Fannin recalled sales reps calling OxyContin “a revolution in pain care” and “much more effective” than the old drugs.

They also talked of studies, citing one that found only four of 11,882 patients — less than 1 percent — became addicted after using opioids. Portenoy and others repeatedly cited this research, with some calling it a “landmark study.”

The truth is it wasn’t even a study. It was a five-sentence letter to the editor that a doctor wrote the New England Journal of Medicine.

For the most part, Fannin believed what the sales reps were telling him, and so did other doctors in the region.

“Our knowledge about addiction,” he said, “was about zip.”

So they spread the opioid with their prescription pads, and it settled into the Appalachian mountains like the ever-present morning fog.

OxyContin, which some hailed as a “miracle drug,” became the blockbuster in 2001 that Purdue officials dreamed of, with more than 7 million prescriptions written and nearly $3 billion in revenue.

By 2015, the Sackler family, who owned Purdue, had made $14 billion, joining Forbes’ 2015 list of America’s richest families, edging out the Rockefellers.

MIDWEST AMERICA WAS TARGETED

According to sources at all levels from police and fire first responders to emergency room physicians across the country and analysts at the CDC, there’s been no slowdown in opiate based medical emergencies in the US over the last 2 years. Emergency response and ER visits for opioid overdoses went way up, with a 30 percent increase in the single year period of June of 2016 to June of 2017, according to the Centers for Disease Control and Prevention.

The increased emergency room visits also include more young children aged 3 to 14 years old, which truly reflects on the unknown number of who have access to still available opiates. These young children being able to readily find opiates at that age,  shows that anyone who has an interest in getting opiates can find them.  This often results in the inadvertent and tragic risks associated with younger victims who somehow are exposed and now being swept up in the opioid crisis.

Center for Disease Control’s Acting Director Dr. Anne Schuchat said overall the most dramatic increases were in the Midwest, where emergency visits went up 70 percent in all ages over 25. This is a figure that’s is comparative to prior medical emergency spikes during pandemic healthcare

Recently two important medical reports on opiate abuse have emerged indicating that the opioid crisis may be at its worst point ever.

The first study comes from the Centers for Disease Control and Prevention (CDC), a federal agency tasked with studying – and stopping – the spread of diseases, including everything from viral infections like the flu to mental health issues including drug addiction. Published in the agency’s monthly Vital Signs report, the study demonstrates that the number of opioid overdoses increased by 30% in a little more than one year from July 2016 to September 2017.

The second study comes from a group of VA medical personnel and public health researchers publishing in the Journal of the American Medical Association (JAMA), who wanted to learn how effective opioid prescription drugs were at managing long-term and chronic pain. As it turns out, opioid drugs showed less efficacy than non-opioid pain medications over a 12-month period – and in fact, over time opioids became worse for patients who had to deal with side effects that patients taking non-opioid medications did not have to deal with. Taken together, these two studies show that current opioid drug policies, procedures, prescription practices and standards of patient care clearly need to be rethought.

For Information on Opiate Litigation and other mass torts:

Kevin Thompson will speak on the Opiate NAS Addicted Infant MDL 2872 litigation as well as the status of opioid litigation and related issues at the upcoming Mass Tort Nexus “CLE Immersion Course”

November 9-12, 2018 at The Riverside Hotel in Fort Lauderdale , FL.

For class attendance information please contact Jenny Levine at 954.520.4494 or Jenny@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 contain real time mass tort updates, visit www.masstortnexus.com/news and sign up for                free access.

 

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XARELTO RECENT LABEL CHANGE: Is Rat Poison Safer?

A WHITE PAPER REPORT BY MASS TORT NEXUS

(The following information and conclusions are based on opinions formed after a review of relevant facts and data by John Ray and edited by Lisa Powell, Mass Tort Nexus www.masstortnexus.com)

XARELTO LABEL CHANGE AND CLINICAL TRIAL BACKGROUND

On October 11, 2018, Janssen Pharmaceuticals, Inc. (a division of Johnson & Johnson) changed its Xarelto® drug safety label as follows:

Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) for anti-factor XA (FXa) activity is not recommended.

Rivaroxaban is an anticoagulant medication. Anticoagulants thin blood. Rivaroxaban is sold under its trade name, Xarelto®. Xarelto® is used to prevent and/or treat blood clots that could result in strokes in patients with non-valvular atrial fibrillation, in patients undergoing knee and hip reconstruction or replacement surgery, and for secondary prevention in patients who have had an Acute coronary syndrome event.

Prior to FDA approval in 2011, clinical trials were conducted to test the safety and efficacy of Xarelto® and to compare it to other anticoagulants. Trial administrators measured both the medication’s effectiveness in thinning the blood and how long it took to be within the therapeutic range. A blood test is used to measure the international randomized ratio (INR). The INR was used to determine the appropriate dose and dosage (i.e., amount and rate of administration) specific to each patient; or, in this case, each trial participant.

The safety label update made last week by the drug maker, Janssen Pharmaceuticals, Inc. (a division of Johnson & Johnson) in effect states that the INR test used to gain FDA approval—and that doctors continue to use to dose and monitor the effects of Xarelto® in their patients—is arguably defective. Not only would this render the clinical trial results invalid but also bolster plaintiffs’ new and existing claims that the drug maker(s) failed to adequately inform doctors that there was no means by which to determine the correct dose and dosage for any given patient. Essentially a doctor would have to wait until the patient bleeds out or throws a clot before determining that the patient may not be on the right dose and/or dosage. In other words, the INR test likely has no diagnostic value and is no more effective than a shot in the dark.

Summary of Facts and Subsequent Findings

  • On October 11, 2018, the Xarelto® drug safety label was changed to “not” recommend INR testing to monitor the effects Xarelto® on patients
  • INR testing was used in clinical trials to establish the safety and efficacy of Xarelto® and to compare it to other anticoagulants prior to FDA approval and market release in 2011
  • Title 21 of the U.S. Code of Federal Regulation requires that drug labels include a summary of essential scientific information including a statement of the recommended or usual dosage
  • Results from Xarelto® clinical trials using INR testing are at best, questionable, and at worst, invalid
  • A change to the Xarelto® drug safety label likely indicates that the drug makers failed to adequately warn that there was no means by which to determine correct dosage for any given patient
  • A pharmaceutical product for which correct dose and dosage cannot be established for a given patient is arguably defective in a significant way
  • Physicians that rely on INR testing without knowing that it may render inaccurate results could lead them to incorrectly dose Xarelto® potentially causing significant harm to their patients

Methodology Flaws in the Xarelto Clinical Trials

INR testing was used in the original Xarelto® clinical trials known as the ROCKET-AF and EINSTEIN DVT/PE trials. These trials were paid for by the drug makers—Bayer Healthcare and Janssen Pharmaceuticals, Inc. (a division of Johnson & Johnson). These trials were conducted to establish the safety and efficacy of Xarelto® and to compare it to other anticoagulants.

The following is an excerpt from the EINSTEIN DVT/PE clinical trial results:

EINSTEIN DVT/PE trial design: Randomized, phase 3, multicenter, open-label, parallel group,

active-controlled, event-driven noninferiority studies (EINSTEIN DVT and EINSTEIN PE) with patients receiving XARELTO® at an initial dose of 15 mg twice daily with food for the first 3 weeks, followed by XARELTO® 20 mg once daily with food or enoxaparin 1 mg/kg twice daily for at least 5 days with VKA, then VKA only after target INR (2.0-3.0) was reached. Patients were treated for 3, 6, or 12 months at HCP discretion.

In other words, Xarelto® was administered to trial participants and after a target INR was reached, they received a different anticoagulant—a VKA (i.e., vitamin K antagonist).

Given the drug safety update added to the Xarelto® label by Janssen on October 11, 2018:

Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) for anti-factor Xa (FXa) activity is not recommended.

Results from Xarelto® clinical trials using INR testing are at best, questionable, and at worst, invalid.

Thank You for Sharing. Not!

In May 2017—17 months before Janssen changed the Xarelto® label—Clinical Therapeutics, an international peer-reviewed journal, published an article entitled, “International Normalized Ratio Is Significantly Elevated with Rivaroxaban and Apixaban Drug Therapies: A Retrospective Study Published.” An excerpt from the article follows (emphasis added):

Purpose

Direct factor Xa inhibitors such as rivaroxaban or apixaban may prolong prothrombin time (PT) and elevate international normalized ratio (INR). However, these tests are not reliable for assessing the anticoagulation effects of these agents. PT assay sensitivity is relatively weak at therapeutic drug concentrations and is subjected to significant variations depending on the reagent used. Conversion of PT to INR may even increase the variability. We conducted a retrospective cross-sectional study aiming to assess the prevalence and extent of INR elevation in hospitalized patients receiving rivaroxaban or apixaban as part of their home medications and to find out whether other existing factors could elevate INR apart from the drug entity itself. [Emphasis added.]

Methods

The data collected from 218 hospitalized patients׳ charts included PT and INR taken on admission, patients׳ characteristics, laboratory results, other medications regularly used, and coexisting clinical conditions.

Findings

No statistically significant association between INR elevation and the parameters examined was found in our study. INR was significantly elevated in both drug groups (P < 0.001), with 84.2% of rivaroxaban patients and 78.3% of apixaban patients presenting with INR levels above the higher limit of the normal range. Furthermore, INR was significantly higher in the rivaroxaban group than in the apixaban group (P < 0.001).

Implications

Both of the reviewed drugs significantly elevated INR. Moreover, rivaroxaban elevates INR significantly more than apixaban, and there are apparently no other factors affecting INR but the drugs themselves. Larger prospective studies are needed to confirm and clarify the clinical significance of these results.

In that the common tests used to determine the correct administration of Xarelto® are not recommended by the drug maker, how are doctors to determine what dose and dosage of Xarelto® is correct vs. what dose and dosage may render a patient over anticoagulated and more likely to experience severe bleeding, or under anticoagulated, leaving patients more likely to suffer the adverse events Xarelto® is intended to treat?

In other words, doctors have relied on—and may continue to rely on—the test that the makers of Xarelto® now say is not recommended to determine the blood-thinning effects of the drug without knowing that these tests were likely rendering inaccurate results which could lead to their treating patients in a manner likely to cause them significant harm.

If the means to determine the correct dosage to administer to a given patient does not exist, the product is arguably defective. In addition, it would be impossible for a drug maker to comply with the requirements of Title 21, as follows:

21 CFR § 201.56 (a)(1): The labeling must contain a summary of the essential scientific information needed for the safe and effective use of the drug.

21 CFR § 201.100(b)(2): Requires labels for prescription drugs bear a statement of the recommended or usual dosage.

Janssen’s Misleading Advertising Campaign

There are three types of anticoagulants used in the United States. Xarelto® is a direct factor Xa inhibitor type. Benefits claimed by its U.S. manufacturer, Janssen Pharmaceuticals, Inc., include once daily administration of an oral pill, no dietary restrictions, and less testing requirements resulting in fewer blood draws. Warfarin, another type of anticoagulant, is a vitamin K inhibitor.  If a patient’s blood becomes too thin after taking warfarin, vitamin K is administered to reverse its blood-thinning effects (i.e., an antidote or reversal agent). While the INR measurement is an effective test to dose and monitor warfarin in patients, Janssen’s advertising campaign touting less testing requirements for Xarelto® as a benefit is laughable given that the INR test used repeatedly to demonstrate the safety and efficacy of Xarelto® “is not recommended.” Until early 2018—approximately seven years after its market release–Xarelto® did not have a reversal agent, and to date, there is not a “recommended” test for doctors to accurately dose and monitor the effects of Xarelto® in their patients.

In 2014, the FDA required Janssen to add new language to its official warnings and precautions including an update to its “black box” because the test equipment used to measure the INR during clinical trials was deemed faulty. The black box is the strongest and most urgent FDA warning added to an official drug label. The update notifies patients and caregivers about certain risks and potentially dangerous side effects from Xarelto®. A year earlier, the FDA cited Johnson & Johnson for its misleading advertising campaign in contradiction to U.S. laws and regulations.

According to Recall Center, a consumer protection organization:

Since the drug’s release, there have been multiple updates to the label warning users of possible risks. In 2013, the FDA issued a determination letter to Johnson & Johnson advising them that their print advertising published in WebMD magazine earlier that year was misleading. They cited the following deficiencies:

  • Effects of the drug to potential patients were downplayed
  • Efficacy claims appeared to be disassociated from the potential risks
  • Assertions that Xarelto has “no dosage adjustments,” which the FDA noted is inaccurate according to the product information’s section on warnings and precautions, as well as its section on dosage and administration.

Because of these allegations, the FDA declared Johnson & Johnson to be in violation of U.S. laws and regulations that oversee drug marketing. [U.S. Food & Drug Administration. “Letter to Roxanne McGregor-Beck, RE: NDA #202439.” (June 6, 2013) FDA.gov. Accessed Oct. 27, 2014]

According to a 2017 PR Newswire press release published by Business Insider (emphasis added):

Johnson & Johnson (NYSE: JNJ), Janssen Pharmaceuticals and Bayer Healthcare (OTC: BAYRY) are accused of downplaying the risks of taking Xarelto and aggressively marketing the drug as an alternative for warfarin in patients needing blood thinners to reduce the risk of dangerous clots. The companies positioned the drug as more convenient, calling for a once-a-day dose and eliminating the need for regular monitoring of a patient’s blood. However, the lawsuits charge that doctors and patients were not fully informed of the risks.

While Janssen’s Xarelto® advertising campaign claims:

And with XARELTO® you can

  • Spend your time how you want to spend it, with no regular blood monitoring

MISLEADING. A more accurate statement would arguably be:

Regular blood monitoring would be useless because it will not identify whether a patient is under anti-coagulated [i.e. clotting too much] or over anti-coagulated [i.e., bleeding too much].

  • Enjoy a full variety of healthy foods with no known dietary restrictions

TRUE.

  • Know it’s working, with no frequent dosage adjustments

MISLEADING. A more accurate statement would arguably be:

There is no means by which to determine if a dosage adjustment is needed in that the common tests to make such a determination are inaccurate in patients who have been administered Xarelto®.

It bears repeating:

A pharmaceutical product for which correct dosage cannot be established or determined for any given patient is arguably defective in a significant way.

With Testing, Rat Poison Can Be Correctly Dosed for Benefit

There may be no better example of why correctly dosing an anticoagulant is important than warfarin. Warfarin first came into commercial use as a rat poison in 1948. Correctly dosed, warfarin is an effective anticoagulant for humans; incorrectly dosed, warfarin is poison.

Unlike Xarelto®, INR testing is reliable for dosing warfarin. To optimize the therapeutic effect without risking dangerous side effects such as bleeding, close monitoring of the degree of anticoagulation is required. During the initial stage of treatment, the INR is checked daily. Intervals between tests can be lengthened if the patient manages stable therapeutic INR levels on an unchanged warfarin dose. Newer point-of-care testing is available and has increased the ease of INR testing in the outpatient setting. Instead of a blood draw, the new INR point-of-care test involves a simple finger prick.

Therefore, an anticoagulant that cannot be accurately dosed is arguably not as safe as rat poison.

———-

The foregoing is an observation of statistics and data related to Xarelto®. The conclusions contained herein are based on opinions formed by the author after a review of the relevant data. We acknowledge that others could draw differing conclusions and opinions based on the same observations.

 References:

https://www.clinicaltherapeutics.com/article/S0149-2918(17)30242-4/pdf

https://www.recallcenter.com/xarelto/fda-news/

https://markets.businessinsider.com/news/stocks/report-more-than-15-000-adverse-events-linked-to-xarelto-in-2016-1002203317

https://www.xareltohcp.com/dvt-pe/clinical-trials

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