A Successful Failure? Lartruvo’s Speedy Withdrawal Sets New Bar For Accelerated Approval Drugs
Executive Summary
Lilly withdraws soft tissue sarcoma drug for failure to confirm clinical benefit two and a half years after US FDA awarded accelerated approval, becoming the fastest withdrawal yet under the regulatory pathway.
Eli Lilly & Co.’s Lartruvo (olaratumab) may well be viewed as a successful failure under the US Food and Drug Administration’s accelerated approval pathway.
The soft tissue sarcoma treatment came to market on the strength of impressive survival data in a Phase II trial, and with a confirmatory study well underway at the time of approval.
However, when the results of that trial failed to demonstrate a survival benefit, the company quickly announced plans for withdrawal, avoiding what has often become a prolonged period of market availability of accelerated approval drugs in the absence of clinical benefit confirmation.
On 25 April, Lilly announced plans for worldwide withdrawal of olaratumab after the platelet-derived growth factor receptor alpha blocking antibody failed to demonstrate a survival benefit in the 460-patient ANNOUNCE confirmatory trial.
The withdrawal announcement, which was not entirely unexpected, came just three months after Lilly disclosed the ANNOUNCE study results and two and a half years after the FDA granted accelerated approval for use in combination with doxorubicin in adults with advanced soft tissue sarcoma. (Also see "Keeping Track: Bad News For Bristol And Lilly, Good News For TG Therapeutics" - Pink Sheet, 27 Jan, 2019.)
Fastest Withdrawal Under Accelerated Approval
The interval between olaratumab’s licensure and withdrawal is the narrowest margin among the 10 accelerated approval drugs and indications that later came off the market for failure to either verify clinical benefit or complete mandatory postapproval trials, according to FDA data compiled by the Pink Sheet.
For other accelerated approval drugs and indications, the interval between approval and withdrawal has ranged from three years to more than a decade. (See infographic.)
FDA officials and other stakeholders have raised concerns about the amount of time that accelerated approval drugs remain on the market, either because sponsors have not completed confirmatory trials or, in the case of Genentech Inc.'s Avastin (bevacizumab), because the sponsor disagreed with the agency’s request for withdrawal.
The dispute over Avastin’s metastatic breast cancer claim, which was added to the VEGF-inhibitor’s label under accelerated approval, marked the first time that a sponsor had requested a hearing on withdrawal under the expedited regulatory pathway.
The two-day hearing in June 2011 was a resource-intensive experience for both the agency and Genentech. Ultimately, then-Commissioner Margaret Hamburg ordered the breast cancer claim removed from the label in November 2011, a decision that Genentech did not challenge further.
The Avastin experience led FDA officials to call for a more expedited process to get accelerated approval drugs and indications removed when clinical benefit is not confirmed. (Also see "Avastin’s Legacy May Be Quicker Withdrawal Process For New Approval Pathways" - Pink Sheet, 19 Dec, 2011.)
Oncology Center of Excellence Director Richard Pazdur has previously suggested that any efforts aimed at making it easier for sponsors to pursue accelerated approval should also come with an “easy off” mechanism when post-approval trials fail to confirm clinical benefit. (Also see "Lessons From Avastin: Accelerated Approval Needs “Easy On, Easy Off” Mechanism, Pazdur Says" - Pink Sheet, 26 Nov, 2012.)
Taking A Regulatory Risk
In recent years, the oncology review division generally has insisted that a confirmatory trial be underway, or at the very least its design agreed upon, before accelerated approval is granted to shorten the interval that a drug is on the market absent a confirmation of clinical benefit.
Such was the case with Lartruvo, which was approved on the basis of a 133-patient Phase II study in which olaratumab with doxorubicin demonstrated a statistically significant 11.8-month improvement in overall survival compared to doxorubicin alone. (Also see "Lilly's Lartruvo Scores Broad FDA Approval In Orphan Sarcomas" - Pink Sheet, 19 Oct, 2016.)
FDA staff felt comfortable granting accelerated approval because the ANNOUNCE confirmatory trial was at an advanced stage of enrollment. In addition, the study’s design assured that enrolled patients would receive at least standard of care because it tested olaratumab and doxorubicin versus doxorubicin alone. (Also see "‘Regulatory Risk’: A New Factor In Risk/Benefit Equation At US FDA?" - Pink Sheet, 30 Nov, 2016.)
FDA officials have made no secret of their expectation that some accelerated approval drugs ultimately will fail to verify clinical benefit and inevitably be withdrawn – which is, in essence, the regulatory risk that comes with the pathway. (Also see "FDA “Regulatory Flexibility” On Accelerated Approval Must Result In Some Withdrawals" - Pink Sheet, 15 Apr, 2013.)
From strictly regulatory sense then, use of the accelerated approval pathway for olaratumab might be characterized as a success; the drug came to market sooner than it would have under full approval but was withdrawn relatively quickly after the failed confirmatory trial.
Nevertheless, the olaratumab withdrawal has renewed criticism that while accelerated approval poses no downside for sponsors, it can be to the detriment of insurers who are paying for unproven drugs and patients who are expecting to gain therapeutic benefit. (See sidebar for story.)
Continued Access For Current Patients
Lilly said it is working to establish an access program for patients who currently are receiving olaratumab, which it estimates at approximately 1,000 worldwide. No new patients should receive Lartruvo outside of participation in ongoing clinical trials, the company said.
Following Lilly’s disclosure in January that the ANNOUNCE study failed its primary endpoint, the FDA recommended Lartruvo not be started in new patients outside of a clinical trial. The agency said patients who were currently receiving the drug should consult with their healthcare provider about whether to remain on treatment. (Also see "No New Patients For Lartruvo In EU After Trial Failure" - Pink Sheet, 23 Jan, 2019.)
Similarly, the European Medicines Agency said no new patients should be started on olaratumab therapy. (Also see "No New Patients For Lartruvo In EU After Trial Failure" - Pink Sheet, 23 Jan, 2019.)
Lartruvo holds a conditional marketing authorization in Europe. The Committee for Medicinal Products for Human Use was expected finalize its review of Lartruvo’s benefit/risk profile in the wake of the ANNOUNCE results during its April 23-26 meeting.
Lilly said ongoing clinical trials with olaratumab will continue as planned and are not affected by the market withdrawal. The ClinicalTrials.gov database lists three ongoing studies that are still recruiting patients – two in soft tissue sarcoma and one in pancreatic cancer.