We have received numerous inquiries regarding the potential impact on the Xarelto Litigation(s) relating to the FDA Oct 11th publication of its findings after re-evaluating (re-analysis study) related to the Rocket AF study in relation to the INR Testing Device “InRatio.”
International Normalized Ratio (INR) is a metric which is tested to determine how long it takes for blood to clot in a given individual as compared to a standard range.
The InRatio was used in the Rocket AF Study to measure INR. After the Rocket AF Study was published and used as the primary study considered by the FDA in granting market approval for Xarelto. Then the InRatio device was subjected to a Class 1 Recall due to inaccuracy.
As a result of the recall of the device used to measure INR in the Rocket AF study, the FDA conducted a re-analysis of the Rocket AF study, using data and information provided by Janssen Pharmaceuticals. The re-analysis was for the limited purpose of determining whether or not the use of the defective “InRatio” device skewed the results of the Rocket AF study to a sufficient extent to invalidate the results and conclusion of that study.
On October 11, 2016 the FDA published a short notice with a link to the re-analysis study: See excerpt below:
[10/11/2016] In July 2016, the Alere INRatio device was recalled due to the potential to generate inaccurate results. This device was used to monitor warfarin therapy in the control group of the ROCKET-AF clinical trial, which provided the primary data to support the 2011 approval of the blood thinner drug Xarelto (rivaroxaban). Xarelto is indicated to reduce the rates of stroke and blood clots in patients with non-valvular atrial fibrillation.
Because of the concern about the Alere INRatio device, the FDA has completed a variety of analyses to assess the impact that this faulty monitoring device had on the ROCKET-AF study results. The Agency has determined that effects on strokes or bleeding, including bleeding in the head, were minimal. The FDA concludes that Xarelto is a safe and effective alternative to warfarin in patients with atrial fibrillation.
Concerns Related to the FDA Notice
This FDA notice has generated concern among some attorneys representing clients in the Xarelto Litigation and gives rise to the question: Will this FDA notice negatively impact the Plaintiffs Claims in the Xarelto Litigation(s)?
After carefully reviewing the re-analysis study as well as the Xarelto Exemplar Complaint in the Xarelto Federal Multidistrict Litigation and the Master Complaint in the Philadelphia Court of Common Pleas Xarelto Litigation, we have formed the opinion that the FDA Notice is not likely to have any major impact on the litigation(s).
Our Analysis Considered the Following Factors:
The re-analysis was limited to answering a single question: Could the FDA conclude that the use of the defective “InRatio” device skewed the results (which were already highly questionable) of the Rocket AF study to warrant rescinding of the market approval granted by the FDA based on Rocket AF study?
It should be noted that an inconclusive outcome of the re-analysis would not have prompted the FDA to rescind approval. In order for the FDA to rescind approval the re-analysis would have needed to show conclusively that the use of the InRatio Device skewed the results of the Rocket AF Study to such an extent as to make the study results completely invalid .
We concluded that the FDA notice and the re-analysis should not impact the Xarelto Litigations based on the following:
- The re-analysis was not conclusive and did not use commonly accepted scientific methodology.
- The re-analysis contains multiple instances of terms such as “were likely” and “it is unclear how relevant the results are” indicating a lack of conclusiveness.
“However, the effects of this increased intensity of anticoagulation on clinical outcomes were likely to have been quite modest.”
There is a moderately large margin for error on safety. Xarelto could increase the rate of major bleeding by as much as 50% compared to warfarin and it would still be considered an approvable therapy
To be complete in describing FDA’s pharmacovigilance efforts involving rivaroxaban, this study of rivaroxaban vs. warfarin in Medicare is presented. However, without inclusion of a control/warfarin arm, it is unclear how relevant these results are to the investigation of INR device issues in the ROCKET trial.
“With the limited data provided, a reliable estimate of variability seems unlikely.”
3. The re-analysis admits a large margin for error as well as a lack of reliability.
4. The re-analysis was an unscientific flawed analysis of a flawed study. See excerpt below from the FDA initial summary review of the Rocket AF study:
Excerpt from Initial FDA Review of Rocket AF Study:
At each site audited, how many violations involved each of the following specific issues? For each specific violation, list the clinical sites involved and provide a breakdown by treatment group for each site and overall for the four RECORD studies.
Enrollment of subjects that did not meet study eligibility criteria.
Failure of the Principal Investigator to ensure that all associates and colleagues assisting in the investigation were meeting the commitments of the study protocol.
Failure to report adverse events and serious adverse events.
Failure to randomize subject preoperatively.
5. The re-analysis addressed a very narrow issue not related the the majority of claims made in the Xarelto litigation while only being only marginally related to narrow issues to limited number of plaintiff claims.
Concerns Related to Implied Preemption Arguments
Some concern has been expressed due to the language in the FDA announcement and the re-analysis wording related to “No label change being required”. See excerpt below:
“No changes in rivaroxaban labeling to reflect the impact of use of the INRatio device in ROCKET are warranted. No other major regulatory action should be taken with respect to rivaroxaban.”
This language gives rise to the question: Could the defendants prevail in an implied preemption argument claiming that the FDA would not have allowed changes to the Xarelto label had the manufacture attempted to make changes though the Changes Being Effected (CBE) process?
We do not think an implied preemption of this nature would prevail. The FDAs decision not to require a label change was due to the fact that the re-analysis was limited in scope and made determination regarding a very narrow issue and was not conclusive. Given the lack of conclusiveness of the re-analysis, it was not sufficiently conclusive to warrant any action by the FDA, that same lack of conclusiveness makes the re-analysis worthless from an evidentiary stand point.
Although defense may raise an implied preemption argument, claiming that the FDA would not have allowed label changes made via the CBE process, related to broader issues than those observed within the limited scope of the re-analysis, would not be likely to prevail. An argument that the FDA statements related to the re-analysis indicates anything beyond the scope of the narrow focus of the re-analysis would not be supported by fact.
Guidance from Wythe v. Levine may be applicable to this scenario: “Wyeth argued that this Vermont law was federally preempted because it was in “actual conflict [with] a specific FDA order” regarding drug labeling. The trial court rejected this argument, as did the Supreme Court of Vermont, holding that the FDA requirements merely provide a floor, not a ceiling”
In that FDA approval of a pharmaceutical product does not create an affirmative defense under Wyeth v Levine, the FDA deciding not to rescind a previously granted approval should not create an affirmative defense either.
In Wyeth v Levine the court took note of FDAs approval processes in granting market approval for a pharmaceutical product largely relying on information and data supplied by the applicant. In this instant matter related to the FDA re-analysis of the Rocket AF study, the FDA again relied on information and data from the applicant, rendering any determinations made from the re-analysis no more of an affirmative defense than the initial FDA approval.
Other Xarelto Claims Not Affected
Among the claim being made against the manufacturers(s) of Xarelto are those related to over promotion and misrepresentations made in the promotion of the product. The FDAs enforcement division issued a warning letter on Judge 6, 2013 to Johnson and Johnson related to false and misleading advertisement. See excerpt below.
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:
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….”
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.
Despite the FDAs prior warning to the makers of Xarelto, misleading claims in Television Advertisements continue to be made. The frame from a Xarelto Television Commercial below shows the statement “No Blood Monitoring Required” is still included in Xarelto Advertising.
Although this Xarelto advertisement did not use the language “no dosing adjustments” required, the ad does include the wording “Xarelto has no regular blood monitoring”. In that the FDA has already determined statements regarding “no dosing adjustments” are misleading as dosing adjustments are needed for many Xarelto patients, the statement “Xarelto has no regular blood monitoring”, indicating that none is needed, is also arguably misleading in that dosing adjustments cannot be made without some form of monitoring.
We invite comments as well as dissenting opinions on this subject.
Nothing contained herein is intended to constitute legal advice.