By Paul Goldberg

The job interview wouldn’t last more than 15 minutes, Richard Pazdur believed.

So, on a June morning in 1999, his wife Mary settled down to wait at a restaurant near the FDA buildings alongside Rockville Pike.

The restaurant turned out to be Hooters, and Mary ended up spending three hours at the joint known for all-you-can-eat chicken wings served by scantily clad waitresses known as Hooters Girls.

“How much Hooters coffee can you drink?” Mary said frequently, retelling the story of her introduction to FDA, Washington and cancer politics.

Rick got the job, and over 16 years, he shaped the FDA approach to drug approval, setting forth a set of criteria accepted by drug companies, academics and NCI. Mary was by his side, supportive, practical, compassionate, intuitive, and intolerant of nonsense. For most of these 16 years, she was an oncology nurse practitioner at the NIH Clinical Center. She eventually took the therapies she had worked on.

Mary died of ovarian cancer Nov. 24. She was 63.

Her death and the three-year struggle that preceded it appears to have launched Rick, director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research, into a new career phase, one where he infuses an advocate’s urgency into his unchallenged power—he’s the closest thing America has to a cancer czar.

“This three-year period of time has given us the opportunity for observation of the healthcare system from the other side of the stethoscope,” Pazdur said Nov. 17, at a Washington conference sponsored by Friends of Cancer Research. “You see the worst of the system; you see the fact that you’re not immune just because you’re a doctor or a member of a doctor’s family.”

At the time Rick uttered these words, Mary was at the Casey House of the Montgomery County Hospice.

The FOCR talk—an onstage conversation with the group’s chair and founder Ellen Sigal—is posted here.

A few weeks earlier, the Pazdurs sat down for a chat with Ellen Stovall, senior health policy advisor with the National Coalition for Cancer Survivorship. The hour-long interview, filmed at the Pazdurs’ house in Bethesda, is available below. A shorter version was published on the NCCS website and in the Oct. 23 issue of The Cancer Letter.

The two conversations address the FDA approval criteria, accrual to studies, reporting of toxicities, difficulties of getting treatments on compassionate basis, and the need to complete consolidation of the FDA oncology functions.

Sigal appears to have launched the buzzword “integration” to describe this proposed reorganization of FDA. As it is, Pazdur’s office doesn’t regulate cancer vaccines, cellular therapies, assays and devices.

The conversations also depict the couple’s coming to terms—publicly—with impending loss. And they record oncology’s principal rainmaker adopt the language of advocacy.

Consider this statement, made in his conversation with Sigal:

“I have morphed from ‘the regulator’ to the unique position of ‘regulator/advocate.’

“What we’re seeing now is not a patient voice but a patient cry—wanting to have their position heard.

“The position of a patient should be defined by the patient—not by somebody else. Certainly not by the FDA, and not by the pharmaceutical industry nor the clinical trial enterprise—a multi-billion dollar enterprise. Rather than the patients being asked to come and comment about a predefined issue, patients need to direct the show.

“So the question I have for the patients is ‘what do you want?’ You need to run the show—not the FDA, not the NCI, and not the pharmaceutical companies. Ultimately, the clinical trials are about you.”

Advocates and bureaucrats aren’t easily hybridized. Advocates, if they are genuine, are focused on a single, defined set of issues. Under normal circumstances, advocates work on behalf of constituents, and they couldn’t care less about competing priorities. Bureaucrats usually move with caution, considering institutional interests and practicing the art of the possible.

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An interview with Rick Pazdur and his wife, Mary. The interview was conducted by Ellen Stovall, senior health policy advisor of the National Coalition for Cancer Survivorship. Filming and production courtesy of Beckstein Productions, LLC. 

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What should one expect from a “regulator/advocate”?

Expect a sense of urgency. Expect impatience. Indeed, if you know where you are going, why not move fast?

Consider this recent action on the part of the agency:

On March 4, FDA announced approval of the Bristol-Myers Squibb drug Opdivo (nivolumab) in metastatic squamous non-small cell lung cancer. The action was almost certainly unprecedented, because the agency received the data and sprung into action—read this carefully—before the results were unblinded to the sponsor.

“With regard to the impetus for this rapid action, we began working immediately on this review and submission strategy after being informed of the survival results. This was prior to BMS having been informed of the results since they were still blinded,” Pazdur said matter-of-factly to The Cancer Letter (The Cancer Letter, June 2). “Patients and physicians need to be informed about these findings and this was the impetus for the rapid inclusion of the survival data in product labeling.”

Some changes are hard to miss, and people who know the Pazdurs pretty much uniformly note the change of tone in Rick’s remarks and a new sense of urgency in his actions.

“It’s a huge loss, and I think he has been using this experience—I don’t know whether consciously or subconsciously—to impact major changes in such a short period of time as to how we are redefining drug development and drug approval. It’s very outside the box,” said Patricia LoRusso, associate director of innovative medicine at Yale Cancer Center and one of Rick’s former trainees.

“Rick—as many caregivers of cancer patients—realizes the urgency. He may speak as an activist, but I think he also thinks as a brilliant drug regulator. He may come across as an activist, but I think his brilliance always made him an activist. It could look like he is an activist, but when you know Rick, you know a very outside-the-box thinker,” said LoRusso.

“He is the kind of person who can solve the problems.”

FOCR’s Sigal, too, sees the new urgency. “I think he has changed. I don’t think that he is prepared to put junk products on the market, to loosen standards,” said Sigal. “I think the toxicity, and the urgency, and the quality of life issues change you when you see them first-hand.”

Same goes for NCCS’s Stovall: “Mary’s diagnosis heightened Rick’s interest in the way cancer patients are treated in our healthcare system and that no matter who you know or how much you know, the limitations of the science are the harsh realities he an others have to face when a loved one has cancer,” she said to The Cancer Letter.

“Both Rick and Mary expressed to me that they didn’t want or expect any special treatment simply because of his position with the FDA. I do think because of Mary’s professional role as an oncology nurse at NIH, and Rick’s distinctive knowledge of emerging therapies, that their mutual respect for the science gave them a lens through which to view the realities of what would be in store.

“Did these realities change Rick and alter his views of regulatory processes? I don’t believe so. I do believe that his sense of urgency about getting promising drugs through the regulatory system expediently, but responsibly, was top of mind for him throughout his career and remains his steadfast goal.

“I do believe that Mary’s diagnosis widened his awareness of what families experience when treatments become futile, and how frustrating it is that we can do so little for someone with advanced cancer.

“I feel certain that his awareness will serve to strengthen his resolve to continue to reform the FDA to best serve the interests of all of us who rely on that agency to be a standard-bearer for excellence in expediting well designed drug development plans and approval of effective new oncology therapies.”

 

Where Detroit Is

Rick and Mary met in June 1979, on the first day of his oncology fellowship at Rush Presbyterian Hospital in Chicago, where Mary Patricia Bagby was a nurse.

Both were as Chicago as it gets. Rick comes from a Polish family in the grimy, industrial Calumet City, Mary from a large Catholic family in Tinley Park, also south of the city.

“If she had my mother, she would be chief of neurosurgery at Mass General,” said Rick recently. But nursing was the traditional occupation for women in the Bagby family. Mary’s mother, Shirley Bagby, was a nurse, as are her three sisters. “She won academic awards,” said Pazdur. “She could have done anything she wanted to, and she chose nursing, because she wanted to help people.”

“It’s hard for me to talk about her without crying,” said Arthur Rossof, who worked with Mary and Rick when he was a junior attending physician at Rush. “Mary was always a tranquil, anchoring voice, she was always in control, she always had nice things to say about people, projecting the attitude of we’ll get through this, and we will get it right, and everybody will be taken care of.”

Mary and Rick started dating two years after they met, and were married in 1982, as Rick was preparing to move to Wayne State University.

“You don’t even know where Detroit is,” said Mary at the time.

“Yeah, it’s someplace east of South Bend,” Rick conceded. Their honeymoon was in Detroit.

“When Mary smiled, she always had that sparkle in her eyes, it was just so special,” said LoRusso, who was trained by Pazdur at Wayne State. “She was such a basically positive person. She had such a gentle soul.”

Six years later, in 1988, the Pazdurs moved to MD Anderson Cancer Center, and in the mid-nineties, in interactions with FDA over clinical trials of the drug UFT, an oral version of 5-fluorouracil, Rick realized that the agency might be an interesting place to work.

Roy Herbst got to work with Mary when he was a junior attending physician and she ran the practice of Waun Ki Hong, chair of the Department of Thoracic/Head & Neck Medical Oncology at MD Anderson.

“Mary was sort of the dean of our nurse practitioners there,” said Herbst, now chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven.

Rick applied for the job to head the oncology division at the FDA Center for Drug Evaluation and Research, but didn’t get hired on the first try. The job went to Robert DeLap instead. In 1999, the job opened again after DeLap moved to regulation of over-the-counter drugs.

“I don’t want to get Rick mad, but I remember when Rick left, we all missed him at MD Anderson, but we missed Mary at Thoracic/Head & Neck more,” said Herbst.

“And here at Yale, I have just recently recruited a fellow from NCI who had trained under her,” Herbst said. “I knew that if he worked with Mary, he must have had some good training.”

Politics of cancer wasn’t Mary’s world, but after the couple’s moved to Bethesda and she took a job at the Clinical Center, she relied on her God-given intolerance of nonsense to become a clear-headed observer and advisor to Rick.

“She was the sounding board,” Rick said. “How could she not be? You discuss things. During the hard times she was there.”

Paul Kluetz, who is now the acting deputy director at the FDA Office of Hematology and Oncology Products, met Mary in the beginning of his fellowship at NCI in 2008.

“I was eager to learn what it takes to become a great oncologist, how to confront the challenge of providing empathy and compassion while taking care not to allow the inevitable losses to hit too hard, derailing my mission to continue to help the next patient. This is a continuous balancing act,” Kluetz said.

“At the time, Mary worked with Bill Dahut’s group [the Prostate Cancer Clinical Research Section], and I had gravitated toward his busy clinic at the NCIs Clinical Center. As a new fellow, I remember getting to know Mary—and being struck by her combination of efficiency and great humanity, her compassion and strength.

“She frequently saw more patients than any other nurse in the clinic. The patients and their families loved her. She cut to the chase, she had a great sense of humor and an infectious laugh—and she cared. Deeply.”

 

FDA, 16 Years Ago

In 1999, FDA’s cancer portfolio was splintered, with small-molecule drugs going to one division and biologics to another.

The word in the street was that to get your drug approved you needed two randomized trials showing an improvement in survival.

There was a de facto shortcut—accelerated approval, which allowed the use of surrogate endpoints, primarily tumor shrinkage. The best way to get an accelerated approval was to conduct a large, usually single-arm, phase II study, enrolling 100 patients or more.

Many times, these trials demonstrated small, marginal response rates that raised questions about their utility. But the advantage of accelerated approval was a fast route to approval with a small data set that didn’t require a large randomized trial of hundred of patients.

In what could be described as the first phase of his career at the agency, Pazdur combined an emphasis on randomization with the search for endpoints other than survival. This met with protests on the part of groups that opposed randomization, some for ideological reasons.

The Wall Street Journal’s editorial pages singled out Pazdur as FDA’s “Dr. No,” building on a theme of opposition to the efficacy standard and the IND requirements.

Editorial pages included stories titled “Pazdur’s Revenge,” “Pazdur’s Cancer Rules,” and “Pazdur is What the Doctor Ordered.” The newspaper’s editorialists described the oncologist as a “hyper-cautious” man of “anti-industry views” who insists on costly and unethical placebo-controlled trials, and is determined to use mind-numbing minutiae to drive American’s cancer sufferers into the grave by denying them access to life-saving drugs.

Decisions attributed to Pazdur triggered demonstrations, vicious posts on the Web, and lawsuits. All of this made friends worry about the Pazdurs’ physical safety (The Cancer Letter, Aug. 5, 2005).

Yet, even in situations where others accepted protection, the Pazdurs did not. Threats notwithstanding, they continued with their routines, which included buying cool stuff and useless tchotchkes at estate sales, taking care of their garden and playing with their tiny, snow-white Maltese dogs.

One of them, a rescue Maltese named Moshe, loved Mary, but, akin to The Wall Street Journal editorialists, took every opportunity bite Rick.

 

Tag-Team Storytelling

Yale’s Herbst says that Pazdur’s achievements at FDA include building a strong team of medical reviewers. This required making regulatory science into an exciting career path for young oncologists.

Over the past five years, Pazdur’s office hired many former NCI fellows, all of them unofficially pre-screened by Mary.

“I remember someone at NCI saying to me, ‘Don’t you know who Mary’s husband is? It’s Rick Pazdur!’” Kluetz recalled. “Not being familiar with the FDA at the time, I didn’t really know who the guy was.

“As I began to work closely with Rick at FDA, my relationship with Mary changed a bit. I got the opportunity to get to know her outside the clinic as a friend. It has really been a pleasure to get to see how Mary and Rick were as a couple, the way they looked at each other knowingly and smiling during conversation, how they reminisced about great trips and adventures they had taken. They were complementary, and they were tag team storytellers.

“Mary would set the scene, Rick would flesh out the characters and play out the events, taking it to the extremes of appropriateness and beyond, and the story would be punctuated by a Mary Pazdur laugh, usually a half-hearted reprimand—‘Oh Rick!’—and a knowing smile.”

 

“Integration”

Pazdur’s emphasis on randomization has made it possible to change the endpoints for some diseases from survival to slowing down disease progression, and with the industry mostly pleased, the protests haven’t been heard in recent years.

And as science changed and drugs became more precise, Pazdur’s office found a methodology to approve them quickly.

Because of the new crop of drugs over the past few years have far more impressive response rates, single arm trials have come back into vogue. “The drugs just got better,” Pazdur said to The Cancer Letter. “We are no longer taking about response rates of 10-15 percent, but rate exceeding 50-60 percent.”

So far this year, the hematology and oncology office approved 15 new molecular entities—and almost 40 percent of breakthrough therapies are in oncology.

At the recent FOCR meeting, Pazdur said he believes that FDA’s oncology portfolio needs to be further consolidated.

“Our orientation toward a specific problem is a reflection of legislation—much of that emanated from the 1960s,” he said. “I ask each one of you, have you changed since 1962? And I think if you haven’t, there’s something fundamentally wrong with you.

“I’ll use a phrase that my wife uses. And I’ll answer it as she would answer this question. Who likes change? A baby with a wet diaper.

“The purpose of the FDA is ultimately to serve the American public and get these drugs out in the most efficient means as possible… People need to have the structure and the foresight to see that this is coming. Whether it’s in my lifetime or not, it will be done because it’s the right thing to do.”

Sigal agrees. FDA needs to integrate its cancer portfolio, she said to The Cancer Letter.

“You don’t go to a doctor for CDRH or CDER. You go to a doctor for your disease. When you are regulating this disease, the integration of disciplines is extremely important,” she said. “I have never gone against FDA—ever. I have always worked with them. And I have always been genuine partners with them. But this time I am willing to make a lot of noise.”

Exactly a week after Pazdur spoke at the FOCR event, Mary succumbed to her disease.

The funeral service at St. Jane de Chantal Catholic Church on Dec. 1, a few blocks from the couple’s house, was followed by a gathering in the church basement. The food was Middle Eastern, prepared by the Syrian immigrant who cooks at the Montgomery County Hospice.

Mary hired her to make sure that the last arrangements she will ever make would help someone establish a new life in a new country.

She will miss the next act in Rick’s career, the phase that her illness inspired.

In addition to Rick, she is survived by father David Bagby and siblings Michael Bagby, Larry Bagby, Debbie Brower, Patty Ortiz, Peter Bagby, Martha Baggetto and Joseph Bagby.

In lieu of flowers, memorial donations can be made to Marcella Niehoff School of Nursing, Loyola University of Chicago, Health Sciences Campus, 2160 S. First Ave., Building 120, Suite 300, Maywood, IL 60153—or to the Christ Child Sodality of St. Jane’s Church.