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CAR-T on the road to market – if FDA follows ODAC advice

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By Mari Serebrov
Regulatory Editor

Ushering in what could be a new era of treatment for hard-to-fight cancers, members of the FDA's Oncologic Drugs Advisory Committee (ODAC) voted unanimously Wednesday in support of Novartis AG's CTL-019 (tisagenlecleucel), the first bespoke chimeric antigen receptor T-cell (CAR T) immunotherapy to be considered by the panel.

The vote was heralded by the Alliance for Regenerative Medicine as a major milestone. "We couldn't be more pleased and encouraged to see CAR T products and other cell-based immunotherapies moving ahead in the appropriately rigorous regulatory review process. These products offer extraordinary potential for patients and their families," the organization said following the meeting.

The next step is up to the FDA. If it follows ODAC's advice, it will approve the world's first CAR T therapy. Granted priority review as a breakthrough therapy, CTL-019 has an Oct. 3 PDUFA date.

As it would with any new product being developed while the technology itself is evolving, the panel had questions. The first part of the advisory committee meeting revolved around manufacturing consistency and quality in producing what Novartis and the FDA described as a "living drug" with each batch representing hope for a unique, distinct patient with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) – and producing it in time for that child or young adult.

ODAC members were convinced that Novartis, of Basel, Switzerland, was peddling something more than hope for a disease that has few options. Calling it a potential paradigm and transformational, they cited the positive benefits of the immunotherapy, which starts with a patient's own white blood cells, noting the testimony of parents, quality of life issues and Novartis' risk mitigation and long-term follow-up plans.

One of the parents testifying was Tom Whitehead, the father of Emily, who was the first patient to receive the immunotherapy. Five years later, Emily stood beside her father at the adcom as living proof that CTL-019 can work. For Emily and many other patients participating in the Novartis trials, the CAR T therapy was an alternative, rather than just a bridge, to a bone marrow transplant, which carries a 30 percent survival rate. Her father said his family was more afraid of the side effects of the full-body radiation that's used ahead of a transplant than of the experimental immunotherapy.

Slow down

Not everyone at the meeting was sold on Novartis' data. Speaking during the public hearing, Megan Polanin, a senior fellow at the National Center for Health Research who specializes in evidence-based mental health interventions, urged the FDA to take it slower in approving the CAR T therapy. She claimed the application was based on only three months of data from 63 patients, making it difficult to determine the efficacy of the treatment.

Following the hearing, Polanin told BioWorld that the FDA and Novartis had agreed to a one-year study as the basis for FDA approval, but that only three months of data were presented at the adcom. “Since remissions aren’t necessarily permanent and since the treatment has known risks,” she said they should look at the six-month data instead, adding that that most of the children in the trial had already been followed for at least six months.

Given the delay between when Novartis submitted the data in November and when the adcom was held, 10-month data should be available for all the patients, Polanin noted. “The company will need to analyze those data if they haven’t already, and it would provide the FDA with data that they will need to review anyway,” she said.

In her comments at the hearing, Polanin said licensing a product without significant data is an unnecessary risk and cautioned against approving new treatments on the hope that they will be shown to be effective. She also said that once the therapy is marketed, patients will be lost to the follow-up that's needed to determine long-term effects.

The pediatric oncologists on the committee called Polanin out on that comment, saying her follow-up fears were unfounded when it comes to children. Children with cancer are closely monitored for years in clinical practice, said Timothy Cripe, chief of the hematology/oncology division at the Nationwide Children's Hospital.

Noting that the FDA is requiring Novartis to monitor children and young adults who participated in the CTL-019 studies for up to 15 years, Cripe said pediatric oncologists typically follow their patients longer than that. Requiring extended monitoring once the therapy is on the market wouldn't be a problem, he told the FDA.

Handling the risk

Part of the meeting was spent discussing Novartis' risk mitigation plans to address the severe cytokine response syndrome (CRS) most patients encountered after the CTL-019 infusion, along with potential neurotoxicities. Initially, Novartis plans to make the treatment available at 30 to 35 cancer centers that have been trained and certified in administering the immunotherapy and providing follow-up care. Eventually, it will expand to other centers.

CRS may sound scary, Cripe said, but cancer centers that provide bone marrow transfers are used to dealing with the life-threatening complications on a daily basis and have developed strategies to manage CRS.

Novartis' risk mitigation also includes an education program for the sites providing the treatment and a registry, which the ODAC members and the FDA cited as essential to tracking long-term risks and better understanding of T cells. Echoing comments parents and a patient advocate made during the public hearing, the panel's patient representative, Gianna McMillan, said the education and monitoring results should be extended to the patient's caregiver, who should be seen as part of the health care team.

CTL-019 was first developed by the University of Pennsylvania, which partnered with Novartis in 2012 to further research, develop and commercialize CAR T-cell therapies. Novartis said it is planning additional filings for CTL-019 later this year in the U.S. and EU, including applications for the treatment of adults with relapsed/refractory diffuse large B-cell lymphoma.