The primary reviewers of Johnson & Johnson/Bayer AGXarelto (rivaroxaban) for stroke risk reduction in atrial fibrillation patients argued that the still-recent approval of Boehringer Ingelheim Corp.’s Pradaxa (dabigatran) gave FDA grounds to demand comparative efficacy data to justify rivaroxaban’s approval. But the leadership of FDA’s Division of Cardiovascular and Renal Products cleared Xarelto on the basis of existing data, holding to a more limited view of what triggers the agency’s ability to require that comparative effectiveness be shown to alternative therapy.

Boehringer’s Pradaxa was cleared in October 2010 – months before the Xarelto submission for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation but well after the clinical study was conducted. Pradaxa’s approval was the first approval of a new oral anticoagulant in decades and arguably could have altered the expectations for trials of stroke prevention in atrial fibrillation patients.

Xarelto Indications

Initial approval in July 2011 for prevention of deep vein thrombosis and pulmonary embolism after hip or knee replacement.
Approved in November 2011 for stroke risk reduction in AF
Pending application for treating acute coronary syndromes received a negative advisory committee review Also see "FDA Panel Looks Beyond Xarelto’s Missing Data Problems To Broader Reforms" - Pink Sheet, 4 June, 2012.

In general, FDA approval does not require showing superiority to an active comparator – except in certain circumstances when marketing a less effective agent could pose a serious public health problem. The outline of the agency’s policy on demonstrating efficacy, including comparative efficacy, derives from a 1995 policy statement by then-Deputy Commissioner William Schultz. The meaning of key concepts like “effective” in real-world reviews has been bedeviling regulators ever since.

Unlike some new drug reviews where the reviewers disagree on approvability, the results of the pivotal Xarelto study, ROCKET AF, were not in dispute. “There appears to be no fundamental disagreement among the reviewers of this application about the data generated in ROCKET but rather about the implications of these data,” Deputy Division Director Stephen Grant said in a Nov. 4, 2011 memo explaining his decision in favor of approval of Xarelto to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

Grant acknowledged the “excellent review performed” even though “the decision was made difficult by the limitations in the design and conduct of ROCKET AF.” Trial design choices, including enrolling higher-risk patients than other stroke prevention in AF trials and doing without a central warfarin dosing algorithm, added to the difficulty of interpreting the trial Also see "ROCKET AF’s Design Causes Headaches For Xarelto Sponsors" - Pink Sheet, 19 September, 2011.. “Although ultimately coming to a different conclusion than some of the reviewers, both the Division Director [Norman Stockbridge] and the deputy shared the team’s concerns about this NDA,” Grant stated.

This story was contributed by Pharmaceutical Approvals Monthly, which features an ongoing series of Drug Review Profiles. The publication’s editors analyze key FDA documents and a product’s development history for insights on reviewer perspectives and agency regulatory standards.

The Trouble With Warfarin

Stroke prevention in AF is a challenging indication for drug developers because placebo-controlled trials are unethical but, until 2010, the only approved therapy to serve as an active comparator in a non-inferiority trial was warfarin, a tricky comparator due to its need for individualized dose monitoring. “In clinical trials testing a new drug vs. warfarin the relative efficacy/safety will be dependent not only on the properties of the new drug but also on how well the INR [International Normalized Ratio, a measure of blood clotting ability] in the warfarin group is controlled,” Grant explained.

Review team leader Aliza Thompson, who supported approval, emphasized that ROCKET AF “established rivaroxaban’s non-inferiority to warfarin as it was used in the study.” The key issue, she explained, “is how well the active comparator, warfarin, was managed in the trial and how to interpret the study’s findings in light of warfarin’s management.” Warfarin patients in ROCKET were less well-controlled than warfarin patients in other anticoagulant studies, including Pradaxa’s pivotal RE-LY trial. As a result, the approved indication for Xarelto adds that “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 primary reviewers looked at the ROCKET results and concluded that the Xarelto NDA “should not be approved unless the sponsor submits convincing information that it is as safe and effective for its target indication as warfarin when used skillfully,” or, alternatively, another approved drug such as Pradaxa (dabigatran).

The primary reviewers focused on the protection of public health aspect of the Schultz policy statement. “The policy is broadly written and lacks a discussion of operational details,” Martin Rose, clinical reviewer for efficacy, stated. “It does not state whether comparable effectiveness to an approved therapy used in an unskilled manner would be adequate for approval. However, if it is essential for a therapy to be as effective as an approved therapy to protect public health, then it is logical that the new therapy should be as effective as the approved therapy when the approved therapy drug is used skillfully. Otherwise the public health protection afforded by this policy might be weakened or negated completely” (emphasis in original).

The policy statement “also does not explain the implications of ambiguous data or data that are insufficient to determine whether the new therapy is as effective as the approved therapy,” the clinical review continues. “Again, if the underlying goal of protecting public health is to be advanced, the logical course is to reject the new therapy because it has not been convincingly demonstrated to be as effective as approved therapy.”

But Deputy Director Grant argued for a broader view of the Schultz statement published in the Federal Register. “Essentially these documents state the obvious, that it is undesirable to approve for marketing a therapy intended to reduce mortality or serious irreversible morbidity that is worse than available therapy because less effective therapy may displace more effective therapy, resulting in worse health outcomes,” he said. “The policy had to be enunciated because the Food, Drug and Cosmetic Act only requires drugs be safe and effective to be approved and does not mention comparison to available therapy.”

“The application of the Schultz FR notice to [non-inferiority] studies, the only studies possible when there is existing therapy for conditions resulting in mortality or serious irreversible morbidity, is generally not straightforward,” Grant stated.

“The division’s interpretation of the Schultz FR notice is that approval should be withheld only if the drug is clearly inferior on an important endpoint to approved therapy in an appropriately conducted trial,” Grant explained. “For example, the Division has cited the Schultz FR notice to recommend non-approval of a drug for a condition with a high mortality rate in which available therapy substantially reduced mortality while the proposed drug was demonstrated to reduce hospitalization but not mortality in a placebo-controlled trial.”

What Does “As Effective” Mean?

Thompson addressed another aspect of the Schultz policy – what is meant by the term “as effective as alternatives.”

One school of thought holds that only a study showing a new drug’s superiority really passes muster, Thompson noted. But, although the FDA team did focus on the effectiveness policy, which cites stroke as an example of a disease that merits the “as effective” standard, the clinical reviewers did not dispute the choice of a non-inferiority study in this therapeutic area. “Instead, their focus has been on the meaning of the term ‘as effective’ as it relates to the management of the active comparator warfarin and the achieved TTR [time in therapeutic range, a measure of INR control over time] in non-inferiority studies.”

“Clearly, robustly showing non-inferiority to warfarin (or any active comparator) when used particularly well or skillfully provides convincing evidence of a new drug’s efficacy,” Thompson said. However, she cautioned, it is not as obvious that this should be an absolute criterion for approval. After all, she pointed out, a significant number of U.S. patients and centers do not achieve desired levels INR control of warfarin.

“It is unclear how well rivaroxaban compares to well-administered warfarin,” Thompson acknowledged. “At the same time there are strong indicators that rivaroxaban is reasonably effective,” she stated. “Considering the data in their totality and keeping in mind that the skillful use of warfarin is not always realized in clinical practice, I think the applicant has satisfied the regulatory requirement for effectiveness. Any uncertainty about rivaroxaban’s effectiveness relative to warfarin or skillfully managed warfarin can be and should be reflected in labeling.”

Labeling does include a statement, in the Indication and Clinical Studies section, that 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.

Should Pradaxa Approval Change The Game For Xarelto?

Interpretation of Xarelto’s efficacy was further complicated by the approval of Pradaxa. “There has been some discussion about what, if any, precedent dabigatran has set for the approval of drugs in this therapeutic area,” Thompson said, noting that it had been discussed by both the primary Xarelto clinical review team and the FDA advisory committee held Sept. 8, 2011. FDA sought input from the panel on whether warfarin or dabigatran was the appropriate comparator for rivaroxaban in light of the 1995 policy requiring new drugs to be “as effective” as approved treatments for serious diseases.

“Importantly,” Thompson emphasized in her review, the Pradaxa RE-LY trial findings “were seen in the context of what would be widely accepted as reasonable warfarin management (and perhaps what many would consider ‘well-administered’ warfarin).” Thompson was the primary clinical reviewer for Pradaxa.

“RE-LY shows it is possible for the results of a study of thrombotic event prevention in AFib patients to provide reasonably robust and interpretable data regarding the effect of an experimental drug at centers where warfarin is used skillfully,” the clinical reviewers said. “ROCKET does not provide such robust data.”

Dabigatran’s approval “makes me at least more interested in being sure that the comparison with warfarin is really solid,” Temple said.

A majority of advisory committee members said Xarelto should not be required to directly show comparable efficacy to dabigatran Also see "Xarelto Review Puts FDA’s Comparative Effectiveness Stance To The Test" - Pink Sheet, 19 September, 2011.. Office of Drug Evaluation I Director Robert Temple joined in the advisory committee discussion. “There is an interesting and provocative issue here,” Temple said. “Suppose in the course of the study, something new and really hot comes along. Do we ever say, ‘I’m sorry, you compared it to a dog, we have something better now? We don’t usually do that, but I wouldn’t rule out the possibility.” Dabigatran’s approval “makes me at least more interested in being sure that the comparison with warfarin is really solid,” Temple said.

The market can demand what FDA cannot require, and demand has been growing for comparative effectiveness research. An August 2011 editorial in the New England Journal of Medicine accompanying publication of the pivotal ARISTOTLE results for Bristol-Myers Squibb Co./Pfizer Inc.’s pending anticoagulant Eliquis (apixaban) points out the need for head-to-head comparisons to “allow for direct assessments among these novel compounds.” Pradaxa sponsor Boehringer Ingelheim is gearing up to provide some of these answers in stroke prevention in AF with the GLORIA-AF registry program examining long-term safety and efficacy for anticoagulants including Pradaxa, Xarelto and warfarin. Results of the 56,000-patient registry trial are due in 2020 Also see "Boehringer Will Test How Pradaxa Stacks Up To The Competition In Real-World Study" - Pink Sheet, 1 May, 2012..

The clinical review argues that ROCKET’s failure to “convincingly demonstrate” that rivaroxaban is as effective as skillfully used warfarin “suggests that rivaroxaban should only be used in patients whose INR cannot be well controlled on warfarin or are unwilling to take it.” However, Rose et al. continue, “such patients have an alternative, dabigatran, which is approved for rivaroxaban’s proposed indication.”

Pradaxa’s approval does not erase all unmet medical need for chronic prevention of stroke and systemic embolism in atrial fibrillation patients, the cross discipline team leader argued. “One could also argue that with only two drugs approved in this indication (both with advantages and disadvantages), there is still unmet need for highly effective therapies in this disease area,” Thompson said – “even for therapies that haven’t definitively established robust non-inferiority to skillfully used warfarin.”

Pradaxa’s Approval Precludes Priority Review For Xarelto

The Pradaxa approval did figure into FDA’s rejection of Johnson & Johnson’s request for priority review of the SPAF claim. Comparative efficacy is, of course, one of the aspects of deciding on priority vs. standard review. In a possible preview of market dynamics, not only did Pradaxa receive priority review, but Bristol-Myers Squibb/Pfizer’s Eliquis (apixaban), a Factor Xa inhibitor with a June 28 user fee goal, also has priority status.

“There was no comparison of rivaroxaban to dabigatran, which did show superiority to warfarin overall in the RE-LY study,” Rose declared in a Feb. 4, 2011 memo denying the priority review request. Dabigatran, like rivaroxaban, has an advantage in ease of use over warfarin.

“While a drug with arguable superiority over dabigatran might merit priority review, one with questionable data for superiority over warfarin does not,” Rose concluded. “There is no need to rush to get an action on rivaroxaban now that dabigatran is available.”

Dabigatran has a “back door” superiority claim over warfarin in labeling, with no formal superiority statement in the indication but a more subtle and qualified statement in the Clinical Trials section. The division did not find a true superiority claim to be warranted because the effect was driven entirely by patients in the warfarin arm whose INR was not well controlled. As Office of Drug Evaluation I Acting Director Ellis Unger observed, “the superiority is really conditional, and depends on how well warfarin was used” Also see "Pradaxa Review Shows FDA Doubts About The Power Of REMS To Change Prescribing Practices" - Pink Sheet, 1 April, 2011..

Second-Line Use Is Not An Option

One alternative widely discussed at the advisory committee meeting, and promoted by the primary clinical reviewers, was the idea of limiting Xarelto to second- or even third-line use.

“I don’t favor pursuing this approach,” Thompson said of the second-line concept. “One problem is that rivaroxaban was never directly tested against any agent other than warfarin; it is hard to draw conclusions about comparative effectiveness in this setting.”

“Another problem” relating to the second-line use of rivaroxaban behind warfarin “is that patients who do poorly on warfarin … may or may not be good candidates for rivaroxaban,” Thompson said. “If the issue is poor compliance, such patients may not do well on a drug with a short half-life which may be less forgiving with regard to missed doses.”

Xarelto Approval For AF Stroke Risk Reduction Tested FDA’s Comparative Efficacy Powers, But Conservative View Prevailed

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