It's extremely rare when a safe, very effective cancer drug that has saved many lives is dropped by a pharmaceutical company and simply disappears from the market. But that could happen to an innovative treatment for one of America's most common cancers.

Zevalin, a radio-immunotherapy drug approved 14 years ago by the Food and Drug Administration, may not be available much longer for patients with non-Hodgkin’s lymphoma.

That’s despite the fact that clinical trials and studies show Zevalin often provides longer complete remissions and lower toxicity for patients with non-Hodgkin's Lymphoma than other available drugs.

But with regulatory constraints, dipping sales, far more successful competitors, profound public misunderstandings about the drug, new treatments for lymphoma and even more in the pipeline, Zevalin may not be sustainable in the long term.

And that would send a troubling signal to the industry and to consumers that even good American medicines can die for reasons having nothing to do with their efficacy or safety.

Zevalin may be shelved ‘if this trend continues’

Spectrum Pharmaceuticals, Inc. (Nasdaq: SPPI), the American biotechnology company that produces Zevalin and several other notable cancer treatments, still has a dedicated sales team for Zevalin.
Its leadership says it remains committed to providing it to patients, and the company’s CEO has called Zevalin a competitive drug with a better response rate than the most used treatment, Rituximab.

But there are signs Zevalin’s future is in jeopardy. For one thing, demand for the drug in the US is steadily declining. According to Spectrum’s annual reports posted by the Securities and Exchange Commission, Zevalin’s 2012 sales were $30.3 million, 2013 sales were $29.4 million, 2014 sales were $22.1 million, and 2015 sales were $17.5 million – cut by almost half in just four years.

Compare that to Rituxan, the blockbuster lymphoma drug jointly marketed by Biogen and Genentech that earned more than $8 billion (with a B) in 2014, according to Research and Markets.

In 2014, fewer than 400 patients were treated with Zevalin, according to Spectrum.

“We may not be able to continue to market and supply this amazing drug to patients, if this trend continues,” Raj Shrotriya, Spectrum’s CEO, told Yahoo Finance.

He added that Zevalin’s downward trend continues “in spite of our efforts in doing additional trials and promotional activities.”

The Nuclear Regulatory Commission’s new mandate

Shrotriya said the biggest logistical hurdle for Zevalin is the 700-hour training and experience requirement mandated by the Nuclear Regulatory Commission (NRC) for doctors before they can administer all alpha- and beta-emitting drugs. The NRC changed that requirement from 80 hours in 2002.

Sales were never strong for Zevalin, which faced this new NRC requirement from its inception. While in the earlier years of the drug it was still showing some promise, the lack of interest among doctors and patients saw the sales eventually diminish.

As a result of the NRC change, Shrotriya said, “Most of the doctors who see and treat patients with non-Hodgkin’s lymphoma are not allowed to inject Zevalin. And those who are authorized to inject Zevalin, the nuclear medicine doctors, they don't see patients with non-Hodgkin’s lymphoma. A lot of young doctors have not even heard of Zevalin.”

For lymphoma patients, physicians, patient advocates, pharma executives and others who closely follow the lymphoma space, this frustrating scenario must feel all too familiar.

Just two years ago, the only other radioimmunotherapy for lymphoma, Bexxar, which was by also all accounts an effective and safe cancer fighter and saved this reporter’s life in 1999, was scrapped by GlaxoSmithKline because the company was not making enough money on the drug.

In a statement in August, 2013, Glaxo, among the largest drug companies in the world, said its decision to permanently shelve Bexxar the following February involved a “thoughtful and careful evaluation of patient needs and the clinical use of the therapy. The use of Bexxar has been extremely limited and is projected to continue to decline.”

The NRC issue was never brought up at the time of Bexxar’s fall. But industry analysts suggest it was certainly part of the problem for GSK, too. Oncologists and patients never embraced that drug in huge numbers, either.

When Glaxo shut down Bexxar, executives at Spectrum assured the nationwide lymphoma community the company would do all it could to keep selling Zevalin, the one remaining radioimmunotherapy for lymphoma.

Radioimmunotherapy, also known as RIT, couples monoclonal antibodies with radioactive materials called radiotracers to treat non-Hodgkin’s B-cell lymphoma and other types of cancer. The antibodies zero in on the cancer and drop their payload, with typically limit damage to surrounding healthy tissue that chemotherapy can often cause.

Lea Prevel Katsanis, a longtime pharmaceutical industry executive, industry analyst and professor of marketing at John Molson School of Business at Concordia University, called Zevalin’s situation “terrible” and said the NRC’s added training hours are “problematic.”

“It’s awful when a good drug is not made available to patients who need it,” said Katsanis, author of the 2016 book “Global Issues in Pharmaceutical Marketing.”

“Even if the drug company did everything right, and it appears they have, unless those rules are changed and even if they are I wonder how they can go forward with this treatment?” she said.

‘We don’t disagree that Zevalin is an effective drug’

Zevalin’s demise would make two lost cancer treatments in the same class, for the same patient population. That’s virtually unheard of, Katsanis and other industry analysts say, especially given how well these drugs work and how safe they are. Typically, when an FDA-approved cancer drug is shelved, it’s either because of intolerable toxicity or because it doesn’t work as well as it did in clinical trials.

But neither is the case with the two radioimmunotherapy drugs. While those drugs have proven to be safe and battle-ready cancer fighters, the radiation component means doctors are required to get special certification from the NRC before they can administer RIT to patients.

Critics of the NRC’s nearly 900% increase in required training hours to administer the drug 14 years ago say it has unfairly and unnecessarily limited the already small pool of doctors who can give this treatment to patients. The new mandate pressures doctors who are not certified to administer the drug to simply not tell their patients about Zevalin at all or risk losing the patient, critics say.

Shrotriya said he has reached out to Stephen Burns, the NRC commissioner in Washington, asking him to amend the training requirements for Zevalin.

For its part, the NRC insists the move to raise the training requirement was based on legitimate safety concerns.

“We don’t disagree that Zevalin is an effective drug. I’ve heard from nuclear medicine doctors who rave about it,” Douglas Bollock, chief of the medical safety branch at the NRC, told Yahoo Finance. “The safety of the drug is what we are concerned with. The change to 700 hours was made after public meetings and much public discussion from 1997 to 2000.”

Not all doctors are opposed to the increased hours. Gregg Franklin, an oncologist at the New Mexico Cancer Center, wrote the NRC in March on behalf of the American Society for Radiation Oncology (ASTRO) saying he does not believe the current data supports a reduction in the hourly training requirements for those who administer Zevalin.

Franklin said other factors influence the use of the drug, “most notably the availability of alternative treatments, including chemotherapy agents such as maintenance Rituximab [Rituxan]. It is unlikely that a change” in training hours will impact the use of Zevalin, he wrote, “but could instead have the unintended consequence of exposing patients, providers, and the public to risks that could otherwise be avoided.”

Is 700 hours ‘too onerous’ for community oncologists?

However, multiple oncologists, hematologists, patient advocates and lymphoma organizations insist a reduction in the hours required to administer Zevalin would not lead to any safety problems, and it could save this struggling therapy.

They cite the fact that the NRC's own Advisory Committee on the Medical Uses of Isotopes (ACMUI), which recommended the original hours change, recently described Zevalin’s safety record as “indisputable.”

In a letter last December, the American Society of Hematologists (ASH), which represents more than 15,000 clinicians and scientists, told the ACMUI’s Subcommittee on Training and Experience for Alpha and Beta Emitters that a reduced training and experience requirement is “appropriate” for Zevalin.

Dr. Jeffrey Vacirca, vice president, board of directors of the Community Oncology Alliance, told the NRC that the 700 hours is “too onerous for the practicing community oncologist to take on.”

The Lymphoma Research Foundation, the nation’s largest nonprofit organization devoted to funding lymphoma research, recently wrote to the NRC saying that the commission “must find balance between ensuring public safety during the administration of radiopharmaceuticals while not hindering access to potentially lifesaving treatment.”

Joseph Mace, an oncologist at Florida Cancer Specialists who’s been administering Zevalin since 2006, recently told the NRC that 80 hours is sufficient and that administering Zevalin is simple and “does not even require patient isolation or exposure measurements.”

A long-term effect on the cancer-drug industry

Several sources interviewed for this story said there is a public need for a cancer drug that is safe, achieves better results than any other treatment available for many patients, and often comes with far fewer harsh side effects than other available lymphoma treatments.

Lawrence Piro

, an oncologist in Los Angeles and president and CEO of the Angeles Clinic and Research Institute who’s treated such cancer patients as Farrah Fawcett, has been a staunch supporter of RIT and used it in his clinic. But Piro, whose pioneering work in lymphoma research helped lead to the approval of Rituxan, said RIT may have unfortunately run its course.

“When Bexxar became unavailable, it was unfortunate, but if Zevalin goes away there will be no radio-immunotherapy option available for lymphoma patients, and that is very sad,” Piro said. “I don’t want to see any patient situation limited by lack of access to  therapies that are effective and safe.”

Both Bexxar and Zevalin went through the hands of several drug companies before ending up at GSK and Spectrum, respectively. Piro is not surprised that Zevalin is on the decline.

“It has been a series of steps that have brought us to this point, one company buying [radioimmunotherapy], then selling it to another company,” he said. “Every company that has taken it has been invigorated that they would solve the problems, but they have not.”

If Zevalin is discontinued, Piro said it would reflect a game-changing trend in the oncology drug sector in which treatments like Zevalin that are more complicated to administer are phased out in favor of newer, simpler therapies that come in a pill – even if the older, slightly more complicated drugs show amazing results in patients.

“There was a lot of promise in the [RIT] field, and it’s really not that complicated, but it does involve more than just giving a patient a pill, and the energy for thinking about this as an effective treatment has gone away,” Piro said. “I think these kinds of therapies with a more complicated process of administering the drug are going against the grain of movement toward targeted and oral therapies.”

Piro said another “revolutionary” cancer treatment that has shown tremendous results in clinic but is also complicated to administer and has not been widely embraced is Provenge, a vaccine for advanced prostate cancer that boosts the body's immune system to help it attack prostate cancer cells.

“It’s a type of therapeutic cancer vaccine, and finally after years of cancer vaccines failing, not only was it approved, it affected survival in end-stage prostate cancer,” Piro explained. “Yet because you have to remove immune cells from the blood and send it to the lab and process it and send back to doctor who then administers it, the complexity is similar to radio-immnotherapy.”

Piro notes that Provenge is the “first therapeutic cancer vaccine to ever be effective and approved by the FDA and sold as a treatment, and the company filed for bankruptcy because of low adoption and the product is struggling.”

Alberto DeJesus, Spectrum’s vice president, strategic planning and advocacy, said there will be long-term consequences for the entire cancer drug industry if the current regulatory barriers are not removed for Zevalin.

“The net effect will be that Spectrum and other manufacturers will just not invest in new cancer research involving radio-isotopes,” said DeJesus.

‘I don’t want to lose this important option’

Lymphoma patients interviewed for this story who’ve been treated with Zevalin are upset that it could soon disappear. Betsy de Parry, a 14-year non-Hodgkin’s Lymphoma survivor who did not respond to chemotherapy, then tried Zevalin. It put her in complete remission.

"It would be a shame to lose a drug like [Zevalin],” she said “There needs to be a drug like this available to patients and doctors.”

Linda Groscurth, who also didn't respond to chemotherapy and then tried Rituxan without success, was finally treated with Zevalin in 2011, and, she said, “I believe it saved my life.”

Michael Werner, chairman of the board of directors for the Lymphoma Research Foundation, was also treated successfully with Zevalin.

"As a 10-year follicular lymphoma survivor, I know firsthand the importance of having access to the right treatment at the right time,” Werner said, “and RIT was an important part of my treatment plan.”

Lisa Swanson, who was diagnosed three years ago with follicular Non-Hodgkin’s Lymphoma but has not yet been treated for her cancer, said Zevalin is one of her first treatment options if her cancer grows or she develops more symptoms. That is, if the drug is still around when she needs it.

“It seems inconceivable that Zevalin, which has the potential to put non-Hodgkin’s lymphoma patients into a very durable remission that lasts a long time, would be discontinued,” Swanson said. “Some of the new treatments are proving to be ineffective for my type of lymphoma, some have proved to be somewhat dangerous, and Zevalin sounds like it might be a good course of treatment for me. I don’t want to lose this important option.”

Is there any way to save Zevalin at this point? Karl Schultz, a lymphoma patient advocate and founder of Patients Against Lymphoma (PAL), which provides evidence-based information on lymphoma and its treatments and is independent of health industry funding, said the NRC “can and should design a short module to train community oncologists to make it feasible for doctors to offer and administer this prepackaged and unique drug to their patients in the community setting.”

Despite the fervent call from patients, doctors, advocates and drug company executives to lower the training requirements, the NRC stands by its decision and insists the rule change has had no effect on patient access to the drug.

The commission did initiate a standing subcommittee in March to take another look at the issue. But, said the NRC’s Bollock, “This doesn’t mean going back to 80 hours. There is a reason why it was changed, but we are looking at this.”

Bollock, who noted during the interview that he is cancer survivor, said he's been speaking with federal lawmakers and others about Zevalin. He added, "It's an emotional issue."