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Pink Sheet – Supplemental Oncology Approvals: 'Reverse Accelerated Approval,' Not Lowering The Bar

Pink Sheet – Supplemental Oncology Approvals: 'Reverse Accelerated Approval,' Not Lowering The Bar

Executive Summary

Sometimes data supporting drug’s initial approval can serve as confirmatory evidence for full approval of a subsequent indication based on an intermediate endpoint, US FDA Oncology Center of Excellence Director Pazdur says; proposed framework discussed at Friends of Cancer Research meeting would establish more systematic approach to streamlining supplemental approvals.

Granting regular approval to a supplemental oncology drug or biologic application based on an intermediate or surrogate endpoint can be a form of “reverse accelerated approval” and should not be seen as lowering the bar for demonstrating efficacy, the US FDA’s top oncology drug official believes.


In some circumstances, it is appropriate to grant full approval for a supplemental indication because the initial approval essentially serves as the confirmatory evidence, Richard Pazdur, director of FDA’s Oncology Center of Excellence said at the Friends of Cancer Research’s (FOCR) annual meeting Nov. 15.


Pazdur’s comments may be viewed as an oncology regulator’s spin on that age-old question about the chicken and the egg: Which came first, the approval or the confirmatory evidence?


Granting full approval for supplemental indications based on an intermediate or surrogate endpoint may prompt some critics to accuse the agency of lowering its approval standards, Pazdur acknowledged.


Critics will say “‘you’re throwing a window open here. You’re not asking for any confirmatory study,'” Pazdur said. “Well the confirmatory study has been done” in the form of the data need to establish the initial indication.

Pazdur’s comments may be viewed as an oncology regulator’s spin on that age-old question about the chicken and the egg: Which came first, the approval or the confirmatory evidence?

Changing The Sequence For Confirmatory Evidence

Pazdur spoke from the audience during a panel discussion on FDA’s case-by-case approach to granting regular approval to supplemental indications based on an intermediate endpoint. The panel also weighed how to further standardize and operationalize this approach through a proposed framework that considers the unmet clinical need in a given patient population while also leveraging the totality of evidence available for an approved drug. (See framework, below.)


Pazdur said that when FDA internally discussed this approach to granting full approval, he coined the term “reverse accelerated approval.”


“People didn’t like that term because it sounded like we were moving away from accelerated approval, but at the end of the day you have the same information. It’s the sequence that you’re doing it” that is different, he said.


“You’ve already shown the clinical benefit in another setting. And that’s what we’ve done in most of the accelerated approvals is we have always asked for a trial to be done in a related disease setting. So we’re really not lowering the standard here, it’s just [a] sequential difference of how we go about really showing clinical benefit has been demonstrated for a particular drug.”

Darzalex, Xalkori Case Studies

FDA cited several recent examples in which it has granted regular approval for a supplemental indication based on response rate or another intermediate endpoint that traditionally has been used to support accelerated approval.

In June, FDA granted regular approval to Janssen Biotech Inc.’s Darzalex (daratumumab) for use with Celgene Corp.’s Pomalyst (pomalidomide) and dexamethasone for third-line treatment of refractory multiple myeloma based on a 59.2% response rate in an open-label, single-armed trial, with a 13.6-month median duration of response.


“These efficacy outcomes were considered substantial in this unique population and supported the full approval of this combination therapy in the absence of further therapies for patients with relapsed or refractory disease,” states a draft discussion paper developed for the FOCR meeting by a multi-stakeholder group.


The indication was the third for daratumumab, which initially received accelerated approval in November 2015 for fourth-line monotherapy treatment and regular approval a year later for use in combination with Celgene’s Revlimid (lenalidomide) and dexamethasone or Takeda Oncology’s Velcade (bortezomib) and dexamethasone for second-line treatment in multiple myeloma.


In March 2016, FDA granted regular approval to Pfizer Inc.’s Xalkori (crizotinib) in patients with metastatic ROS-1 positive non-small cell lung cancer (NSCLC) based on response rate in a single-arm trial. This marked the drug’s second indication – it originally came to market under an August 2011 accelerated approval in patients with ALK-positive NSCLC, which was converted to regular approval in November 2013.


“Since crizotinib had already demonstrated substantial evidence of safety and efficacy in the same tissue type and stage (metastatic NSCLC), and there were no treatment options available for this small and unique group of patients, the FDA fully approved this drug for the treatment of patients with metastatic ROS1+ NSCLC using [objective response rate and duration of response] as the efficacy outcomes, which were measured in a single-arm trial with 50 patients,” the discussion draft states. “Due to a clear understanding of the role of receptor tyrosine kinases in the growth and metastatic progression of NSCLC, there was increased confidence that crizotinib would have a similar therapeutic effect on both indications.”

Keytruda’s tissue-agnostic indication potentially could have received regular approval but “what we really wanted was longer term follow-up.” – FDA’s McKee

Amy McKee, supervisory associate director in FDA’s Office of Hematology and Oncology Products, said that while the agency has already used the proposed framework in select situations for supplemental indications, it wants feedback on whether the approach is appropriate for all oncology supplements and stakeholders, and whether it can be applied across diseases and for tissue-agnostic indications. She noted that the data currently are not sufficient to support use of this approach with some earlier endpoints, such as minimal residual disease.


McKee was asked why the indication for Merck & Co. Inc.’s Keytruda (pembrolizumab) in patients with microsatellite instability-high or mismatch repair deficient solid tumors was awarded under accelerated approval rather than regular approval. The PD-1 inhibitor’s supplemental approval marked the first time that FDA has granted an indication without regard to tumor location. (Also see “Biomarker-Led Claim Is Small Step For Merck’s Keytruda, Giant Leap For Cancer Indications” – Pink Sheet, 23 May, 2017.)


For FDA, the decision on the appropriate approval pathway came down to response durability.


“We know the science is behind it, so that gave us some confidence in getting this first tissue-agnostic approval. What we really wanted was longer-term follow-up,” McKee said. “We wanted to make sure that the responses in this population were as durable as the responses we ‘ve seen in other populations with these agents, so that was the primary reason behind giving the accelerated approval rather than a regular approval.”


“It could have potentially received a regular approval,” McKee continued. “The evidence was there based on response rates, but we really felt like to give the whole description of what a patient may expect from it that we wanted more follow-up on the patients and to see how long responses potentially last.”

Global Demands For Randomized Trials

Shanthi Ganeshan, vice president and US head of oncology regulatory affairs at Novartis AG, said the proposed framework provides a streamlined and systematic approach for bringing new indications onto the label, enabling rapid, full approval and expediting the availability of drugs for patients with unmet need.


Since approval under this framework potentially could be based on single-arm studies, these would require fewer patients and less time to complete than a traditional clinical development program. The lack of requirement for post-approval confirmatory studies also would save considerable time and resources, she said.


Nevertheless, companies also must consider the requirements of other global regulatory authorities, including health technology assessment bodies, in their development programs, Ganeshan said. Even though FDA may be willing to accept a single-arm study for full approval of a supplemental indication, a company still might have to conduct a randomized study to secure approval and reimbursement outside the US, she said.

Ramifications For Other Sponsors

Speaking from the audience, Josephine Torrente, a director at Hyman, Phelps and McNamara, asked whether FDA had considered how full approval based on an intermediate endpoint for one sponsor might impact the ability of another company seeking accelerated approval of a new molecular entity in the same therapeutic setting.


Granting an indication full approval, rather than accelerated approval, makes it “available therapy,” a term that has implications when it comes to the availability of FDA’s expedited regulatory pathways. (Also see ““Breakthrough” Designation: FDA Clarifies How To Get It – And How It Can Be Lost” – Pink Sheet, 29 May, 2014.) For example, a sponsor of a product with breakthrough therapy could lose the designation if a competitor with accelerated approval successfully completes confirmatory trials. (Also see “Accelerated Approval Conversion Could Mean ‘Breakthrough’ Loss” – Pink Sheet, 11 May, 2015.)


Particularly for smaller companies, “there’s a lot of math that goes into my new NME and how I’m going to try to get it to approval,” Torrente said. “And FDA can’t tell the company, ‘Hey, that’s a really bad idea because I think the product ahead of you is going to get full approval.'”


She questioned whether an NME sponsor that conducted a study based on overall response rate to support accelerated approval would be sent back to the drawing board and required to do a randomized study that takes into account the new supplemental indication for the previously approved product.


“I just think that’s a challenge that might come up, just because I see how much companies try to predict what approval the guy ahead of them is going to get in designing their study for their accelerated approval,” Torrente said.


“I really would not look at that as a reason not to proceed with this,” Pazdur responded, noting that some oncology patient populations are so small it would not be possible to conduct a randomized trial.


This concept of “looking at accelerated approval as not an available therapy basically is one that we developed decades ago,” Pazdur said.


“The whole reason behind that was not to block other drugs, but to make people do their confirmatory studies in a timely fashion. And it got used in a somewhat unintended consequence in that whole design,” he said. “There’s unintended consequences to every good action here.”…