publication date: Feb. 19, 2016

Rejected Therapy Reveals Inconsistency of FDA Procedures for Drugs, Immunotherapies 


Reform of the FDA oncology program is emerging as the immediately tangible element of the Obama administration’s moonshot program.

With a modest $75 million commitment, the administration may be able to standardize the manner in which elements of modern cancer care are reviewed and approved by the regulatory agency (The Cancer Letter, Feb. 12).

As it stands, immunological and cellular cancer therapies as well as diagnostics don’t go through the same review procedures as cancer drugs and biologics.

The administration is proposing to address this inconsistency by creating a “virtual” oncology center at the agency, but no one seems to be able to understand how a virtual center would be defined and whether it would be able to synchronize the agency’s functions in oncology.

In today’s FDA, the type and quality of review can vary dramatically. The pathways to which a therapeutic or diagnostic is assigned can determine:

• The type and quality of guidance received through the development process,

• The chances of the application being referred to an advisory committee,

• The level of expertise of the advisory committee, and

• The chances that committee members would be asked to vote on an application.

Consider the recent application by Telesta Therapeutics Inc. for the approval of Mycobacterium phlei Cell Wall-Nucleic Acid Complex, or MCNA, for intravesical use in the treatment of non-muscle-invasive bladder cancer at high risk of recurrence or progression in adult patients who failed prior bacillus Calmette-Guérin immunotherapy—i.e., in patients who are BCG refractory or BCG relapsing.

Earlier this month, the company got bad news from the agency: an additional phase III clinical trial for MCNA would be necessary to adequately establish MCNA’s efficacy and safety.

“We are very disappointed with the FDA’s decision,” Michael Berendt, the CEO and chief scientist, said in a statement. “Since we began our dialogue with the FDA in February 2014, we have clearly communicated that we believe that MCNA is a safe and efficacious agent for the treatment of high risk non-muscle invasive bladder cancer patients who have failed front line BCG therapy. The FDA decision, at this point, to require an additional clinical trial, is a setback for under-served bladder cancer patients, our dedicated staff, and our investors who have funded our efforts to obtain MCNA approval in the U.S.”

The agency’s decision follows on a meandering all-day meeting of an advisory committee, which voted 18-6 against approval (The Cancer Letter, Nov. 20, 2015).

Publicly available information doesn’t make it possible to assess the quality of guidance the company received from the FDA Center for Biologics Evaluation and Research and compare it with the type of guidance it would have received at the agency’s Center for Drugs Evaluation and Research.

However, when the matter came to the attention of the advisory committee, the lack of focus in the presentations by the company and the agency was difficult to miss.

Had the drug gone to CDER’s Office of Hematology and Oncology Products, the application would have been a candidate for being bounced to the FDA Oncologic Drugs Advisory Committee, which usually consists of about a dozen members, most of whom are focused on cancer drugs.

The CBER group formed a massive advisory committee that included all of ODAC and the entire Cellular, Tissue, and Gene Therapies Advisory Committee. That’s 25 voting members.

With the committee taking a vote, people who don’t know cancer could have easily drowned out those who understand the disease. This method of soliciting advice differs from what would have happened before the agency took the first stab at consolidating its oncology units more than a decade ago.

Before that consolidation, small-molecule compounds went to one administrative unit—CDER—and biologics, including monoclonal antibodies and growth factors, went to another—CBER.

Nonetheless, both small-molecule drugs and biologics went to the same advisory group: ODAC.

One might have surmised that by the time FDA asks an advisory committee to vet an application, the questions would deal primarily with clinical utility of the therapy in question. By that stage in the game, advisors would be asked to discuss the outcomes, as opposed to the biological mechanisms for achieving them. Yet, the biological mechanism was very much on the table.

It’s unlikely that MCNA would have made it to an advisory committee at CDER. The company’s single-arm trial missed its primary endpoint and was stopped prematurely.

Worse, it was unclear what kind of patients benefited and what the characteristics of their disease were.

“At the end of the day, I thought there was a handful of patients, maybe even less than the number of committee members [here], that we could say had clear and durable benefit from the drug,” said ODAC member Brian Rini, associate professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.

ODAC appears to have moved away from asking its advisors to vote. The latest thinking at the oncology office suggests that a committee vote can be misleading and a discussion has greater value.

Also, at ODAC meetings, committee members who exhibit a lack of understanding of laws and regulations are given quick reminders. This didn’t happen at the MCNA deliberations, when the chair of the joint committee, Timothy Cripe, professor of hematology, oncology and bone marrow transplantation at Nationwide Children’s Hospital at Ohio State University, expressed disappointment with the outcome.

“We’re still losing the war on cancer in general, and we need all the help we can get,” Cripe said. “And with immunotherapies on the rise, if this were approved, I’m sure there would be a lot more trials and combinations that would augment its activity.”

Actually, FDA’s functions don’t include encouraging development of approaches to therapy. The agency’s function is to approve indications for therapies.

Before the vote was taken, Cripe floated a proposal to take an informal straw poll before the binding vote, presumably to determine how many committee members were opposed to the application.

And when a voting patient representative noted that approval is important because it would lead to reimbursement, neither Cripe nor FDA staff members stepped in to point out that FDA has no authority to consider the cost of therapies.

Over the past decade, the agency has been pushed by oncology groups to consolidate its cancer operations, thus making it possible to place cancer drugs, biologics, vaccines, diagnostics and devices all under the same regulatory roof (The Cancer Letter, July 9, 2004, July 23, 2004, Feb. 18, 2005, March 4, 2005, April 22, 2005).

This drive is visibly intensifying as the agency’s Office of Hematology and Oncology Products is changing the structure of drug development—and approving more drugs than any other part of FDA (The Cancer Letter, Feb. 14, 2014).

This is happening in part because, likely more so than at any other time in the history of oncology, all participants understand the approval criteria and as the Obama administration is seeking to make progress against cancer.

“The moonshot creates a framework that builds upon the incredible oncology research taking place all across the country,” Ellen Sigal, chair of Friends of Cancer Research, a Washington group spearheading FDA reform, said to The Cancer Letter last week (The Cancer Letter, Feb. 12)

“By finding ways to streamline the FDA it creates a more collaborative ecosystem across all sectors to expedite scientific discovery. Specifically, it calls on Congress to update FDA’s structure to better reflect 21st century science by creating Centers of Excellence within FDA. The centers will improve coordination within and between FDA medical product centers and break down decades-old silos within FDA and make for a more efficient agency. This coordination will allow the agency to expedite the development of novel combination products, as well as support an integrated approach in product evaluation, support continued development of combination products, and develop and promote precision medicine methods.

“Most importantly, the proposal enhances FDA’s ability to execute their vital role in translating scientific discovery into new therapies for patients.”

The most spectacular snag in CBER’s operations involved the drug Provenge, which was approved by the advisory committee in 2007, only to encounter a backlash from cancer experts who had been outvoted by non-oncologists on the committee (The Cancer Letter, April 13, 2007, April 27, 2007, May 4, 2007).

Copyright (c) 2020 The Cancer Letter Inc.