The Pills of Last Resort: How Dying Patients Get Access to Experimental Drugs

October 31, 2013

The Pills of Last Resort

How Dying Patients Get Access to Experimental Drugs


It was shortly after the breadbasket arrived last year at the Temple Bar near Harvard Square that Sarah Broom first told me about the last-ditch plan to save her own life. Broom’s mere presence that evening was something of a miracle. Several years earlier, in 2008, while pregnant with her third child, she received a harrowing diagnosis. A 35-year-old English lecturer and poet living in New Zealand, Broom developed a persistent cough. She saw doctors in Auckland repeatedly over the course of a few months, but they didn’t want to do an X-ray on a pregnant woman. Finally, her shortness of breath became so severe that they relented, and 29 weeks into her pregnancy, she was found to have a large mass on her lung. She underwent a cesarean section — her daughter was born almost three months early — and a biopsy.Broom had advanced-stage lung cancer. “I was told nothing could be done to cure the cancer, but that various treatments could give me time,” she recalled. Less than 1 percent of patients live more than five years.

She endured chemotherapy for weeks but then developed severe pelvic pain. To her horror, tests showed there was a new plum-size tumor on her ovary that wasn’t present at her C-section. The cancer was spreading relentlessly. Broom’s doctors predicted she had only a few months to live. She worried about her two sons, Daniel and Christopher, ages 5 and 2; her husband, Michael, whom she’d been with since they were teenagers; and her premature baby, Amelia, who was still hospitalized in the newborn unit. “My determination was to live, to live a long time — what else could I do, with three little kids depending on me — but at this time, it was clear that the situation looked pretty dire indeed,” Broom told me.

In desperation, she called friends around the world, including Meghan O’Sullivan, a former deputy national security adviser in the Bush administration, who contacted Bruce Chabner, the director of clinical research at Massachusetts General Hospital Cancer Center in Boston. Chabner asked Broom to send him her biopsy, so he could analyze its DNA. Her tumor had a mutation in a gene called anaplastic lymphoma kinase, or ALK, which occurs in about 5 percent of lung cancers. A Japanese group discovered it only a year earlier. Chabner knew that the drug company Pfizer was developing a new compound called crizotinib that might treat this mutation. The trouble was, it had been given to only two ALK-positive people before, and one died anyway. Still, it was Broom’s only hope, and Pfizer agreed to enroll her in a trial in Australia.

Incredibly, the tumors shrank by half, and Broom led an almost normal life for two years. Then the cancer returned. Various drugs were tried; none worked. Through Chabner, Broom ultimately got in touch with Alice Shaw, an oncologist who knew of two promising new compounds, AUY922 and LDK378, from Novartis, that might treat ALK-mutated lung cancers. They were two of the 23 Novartis anticancer drugs that were so early in development that they weren’t yet named or on the market. Because the company had no sites for the trial near New Zealand, Broom left her family and flew to Boston in late 2011 so that Shaw could treat her with AUY922.

But Broom did not respond to the drug and instead developed large new metastases in her brain. Her final hope was LDK378, but Broom was worried that she’d soon be too sick to travel. She decided to return home even though she would have no access to the drug.

Shortly before she left, O’Sullivan invited her out with a few other friends to the Temple Bar, where I met her. As we spoke, we discovered an unexpected connection: Alice Shaw was a college classmate of mine. Broom explained her and Shaw’s master plan to get Novartis to release the drug. It was simple, really. Broom would send a letter begging the Swiss pharmaceutical giant for compassion.

“Dear Novartis,” she wrote. “I am writing to plead with you for compassionate access to LDK378. . . . I have three small children, and I cannot yet give up.” Couldn’t the company, she asked, just sidestep the clinical trial and send her the medicine that could save her life?

Before drugs in the United States can be prescribed by doctors and bought by patients, they must undergo three stages of rigorous clinical trials and approval by the Food and Drug Administration. This safety requirement dates back to 1962, when the sedative thalidomide was revealed to have caused thousands of birth defects. This policy has helped cause drug-development costs to skyrocket to hundreds of millions of dollars and drug approval to take up to 10 years, but it has also protected the public from untold risks and side effects.

Circumventing the deliberate pace of clinical trials can be dangerous, as my own father’s story attests. Short of breath for years and told he had asthma, he actually had idiopathic pulmonary fibrosis, a disease in which the lungs quickly and fatally scar. The New England Journal of Medicine reported that interferon gamma-1B could help, but the 1999 report included only nine treated patients. The F.D.A. approved the drug a few years earlier, but for only a rare genetic bone disease or an immune-system disorder, and it could cost tens of thousands of dollars for a course of treatment. My sister and I, both doctors, wrote a letter to my father’s insurer pleading for them to cover this off-label use. Amazingly, the insurer agreed.

Three times a week, my father gave himself an injection of interferon gamma. Not only did the drug not improve his condition, but it also caused raging fevers that left him confined to bed in terrible pain. He died in 2001. Three years later, N.E.J.M. published a far more thorough study with 330 patients that concluded interferon gamma was not only ineffective against the scarring disease but also caused respiratory infections. It would have been better if my father never took it. And because we had found a backdoor way of getting it — he never joined any study — no drug company or regulator learned anything constructive from his death.

Consider what might have happened if more people with idiopathic pulmonary fibrosis followed my father’s path: 330 people may never have enrolled in the study that clearly showed that the drug was useless for his condition. Which is why last year, after the journal Science reported that the drug Targretin, already approved to treat skin cancer, reversed Alzheimer’s disease in mice within three days, federal experts writing in N.E.J.M. warned that “even if patients and families are willing to take the risks [of Targretin] for the potential benefit, the physician’s answer should be no.” Doctors, in other words, should instead tell patients to enroll in placebo-controlled trials, not least so we can learn whether Targretin really helps fight the disease.

Nevertheless, for desperate patients like Broom, the pace of clinical trials can be lethally slow, and patients have successfully argued for “compassionate access” to unapproved drugs. The first compassionate access was granted for a drug called AZT, originally created to treat leukemia, then shelved. In 1985, the Burroughs Wellcome lab sent it to the National Cancer Institute, where, incidentally, Chabner was director of the treatment division. AZT was the 11th drug tested in a shotgun approach against a new virus soon known as H.I.V., and it worked. By 1986, a key study showed the drug saved lives, but final F.D.A. approval would normally take a year. Dying AIDS patients couldn’t wait. So Robert Yarchoan, along with other N.C.I. investigators who helped develop AZT, worked with Wellcome, the F.D.A. and other federal agencies to create an “open-access clinical trial,” which served as a way to release the drug free to almost one-third of all AIDS sufferers in the country. It was a shrewd way to bypass the usual F.D.A. timeline for drug approval.

Pushed by the advocacy group Act Up, the F.D.A. agreed to allow pharmaceutical companies to offer compassionate access to other promising AIDS drugs. The activists for patients with Alzheimer’s and cancer soon demanded access to promising drugs as well. “AIDS created a terrible, wonderful model for us all,” one activist told The New York Times in 1991. In 1999, a 19-year-old college student named Abigail Burroughs unsuccessfully fought for compassionate access to experimental drugs owned by ImClone and AstraZeneca to treat her head-and-neck cancer. After her death in 2001, her father founded the Abigail Alliance, which sued the F.D.A., arguing for a constitutional right to early-phase drugs. Though the courts ultimately ruled against the family, the F.D.A. did recently create a program that would make it easier for companies to release experimental medicines — if the companies agreed to do it.

But not all companies willingly allow compassionate access to drugs in their pipelines, and ImClone’s and AstraZeneca’s reluctance makes sense on some level. Only 6 percent of early-stage cancer drugs ever come to market, because many are found to have severe side effects or simply don’t work. Given those odds, companies hesitate to do anything to jeopardize a product too soon. If they give drugs away, a disastrous side effect or other poor outcome could spur bad publicity and extra scrutiny from regulators. Even more important, if doctors simply let people take untested medicines without going through all the clinical trials, drug companies would most likely never get anyone to enroll in them, never get the data on safety and efficacy for F.D.A. approval and never pass the gateway to big sales. “Even if patients with cancer are willing buyers,” writes George Annas, a Boston University expert on medical law, “drug manufacturers are not willing sellers.”

As a public-health advocate, I know that if we simply let people have access to untested medicines without those trials, we will never learn which ones are effective and how best to use them. But to a physician coming face to face with frightened and desperate patients in the clinic, the case for the greater good seems less compelling. After all, the promising drug may be the patient’s last and only chance. Every now and then, desperation leads to success. That’s the hope that led Broom to write to Novartis.

Not long after our dinner, Novartis responded to Broom’s letter begging for LDK378, denying her request but giving no reason. Shaw decided to make a more personal appeal. She asked Broom to have her three children and husband hand-write letters. Daniel’s letter read: “Dear Drug Company . . . Mummy needs to finish reading ‘The Lord of the Rings’ to Christopher and I, we are at ‘Return of the King,’ siege of Gondor, page 853. There are 1,069 pages. . . . I love my mum, please help her to get better.” Shaw topped it off with a montage of photos: Broom holding her daughter, Amelia, in an angel costume; Broom wading with her kids in a lake. In her own letter, Shaw made the detailed scientific case for LDK378 and referred to her authority as a Harvard Medical School professor and the lead recruiter for major cancer trials.

She gathered the packet and sent it to Barbara Weber, Novartis’s head of early-development oncology and senior vice president, who had the authority to release LDK378. “I apologize for e-mailing you directly,” Shaw wrote, “but I have exhausted all other options.” She also sought Weber out in person at an oncology conference in California. Weber was so moved by the packet that she decided to give Broom the LDK378.

Right now, there are no specific guidelines that determine who is eligible for compassionate access. Weber told me that she gets only a handful of requests and that she usually approves them. (Shaw told me she made numerous requests for Broom to get compassionate access to Novartis’s LDK378 but was repeatedly denied. Weber said she was not aware of those requests.) The fact that Broom’s appeal was so personal and got directly into Weber’s hands made the difference, but few patients actually have the resources and connections to make that happen.

Novartis mailed Broom a package of LDK378, and she began taking the pills. Within weeks, her headaches were gone, and scans showed that her tumor almost entirely disappeared. In August 2012, she was on vacation with her family at a national park near her home when I reached her by Skype. We talked about a children’s-book character she created named Freya Fantail, a small bird who helped ill animals. Broom was particularly grateful that a close friend had illustrated the manuscript with vivid crayon drawings. She’d resumed reading “The Return of the King” to her sons.

To be sure, the events leading to Broom’s miraculous improvement arose from a series of advantages. She was a well-connected, highly literate Oxford graduate who could afford to travel to Boston from New Zealand. She happened to know O’Sullivan, who in turn knew Chabner, a globally respected cancer researcher. And of course, Shaw, her oncologist, wouldn’t accept Novartis’s initial denial of LDK378 and knew how best to navigate the system. Few people are so lucky, as Broom was the first to admit.

Still, access to unproven medicines cannot be an absolute right; it must depend on review by an experienced doctor, like Shaw, who can weigh complex medical data to make educated guesses for treatment. Otherwise, patients are too vulnerable to charlatans. Recently, Shinya Yamanaka, who won the 2012 Nobel Prize in Medicine for his work on human stem cells, described to me the pleas he and his colleagues receive. His work has created the possibility of one day growing new organs, and patients come to him asking for all sorts of unproven treatments. When they’re inevitably denied, they may seek out people like the Beijing neurosurgeon who treats paralysis by injecting aborted fetal tissue into the spine, even though there is no conclusive testing to suggest it works.

This is where patient-advocacy groups could make an impact: by creating easily accessible tools to help such patients better understand their options, connect them with the latest science and point them to promising drugs under development. The fact that Barbara Weber gets only a half-dozen or so requests for compassionate use each year suggests that very few patients know the possibility even exists. Advocacy groups could also ensure that companies price new therapies fairly. (Last fall, after doctors from Memorial Sloan-Kettering hammered Sanofi and Regeneron for the high price of one of their cancer drugs in a New York Times Op-Ed, the companies dropped their price by half.) Government resources like could better organize and curate studies for patients and disclose which drugs are in the development pipeline. In these ways, compassionate access could become less about luck and more about what’s best for patients and for science.

Broom’s cancer responded to treatment with LDK378. But her reprieve again proved temporary. After almost a year, LDK378 stopped working, and Broom truly was left with no options. Earlier this year she stopped responding to my e-mails. She died on April 18 in Auckland, surrounded by her family.

Around that time, her husband, Michael, had taken to wearing three bracelets carved from bone. An American woman named Linnea Duff had given Broom the bracelets to symbolize that she was the third person to get crizotinib, the cancer drug Chabner first prescribed. Duff was the fourth to get it, for her advanced-stage lung cancer, and she bought four bracelets for herself. Like Broom, Duff had a remarkable response, and the drug kept her cancer at bay for years. She recently began a trial of LDK378 after having a relapse, but she has already survived almost seven years since her diagnosis, longer than even the best prognosis.

Broom, too, survived for years beyond what doctors first told her she could expect. She wasn’t supposed to see Amelia’s first birthday, and instead she was able to celebrate her fourth. For long stretches of that time, Broom was able to live a normal, relatively healthy life. All this was undoubtedly due to the various drugs she was able to get through compassionate access.

Duff and Broom used to playfully refer to each other as “No. 3” and “No. 4,” Duff told me, but now only No. 4 is left. “I resolve to never give up,” she said, “and I start each day saying, ‘I’m alive, I’m alive, I’m alive.’ ”

Darshak Sanghavi, a pediatric cardiologist, is a fellow at and managing director of the Brookings Institution. His last article for the magazine was about doctors’ work hours.

About bambooinnovator
Kee Koon Boon (“KB”) is the co-founder and director of HERO Investment Management which provides specialized fund management and investment advisory services to the ARCHEA Asia HERO Innovators Fund (, the only Asian SMID-cap tech-focused fund in the industry. KB is an internationally featured investor rooted in the principles of value investing for over a decade as a fund manager and analyst in the Asian capital markets who started his career at a boutique hedge fund in Singapore where he was with the firm since 2002 and was also part of the core investment committee in significantly outperforming the index in the 10-year-plus-old flagship Asian fund. He was also the portfolio manager for Asia-Pacific equities at Korea’s largest mutual fund company. Prior to setting up the H.E.R.O. Innovators Fund, KB was the Chief Investment Officer & CEO of a Singapore Registered Fund Management Company (RFMC) where he is responsible for listed Asian equity investments. KB had taught accounting at the Singapore Management University (SMU) as a faculty member and also pioneered the 15-week course on Accounting Fraud in Asia as an official module at SMU. KB remains grateful and honored to be invited by Singapore’s financial regulator Monetary Authority of Singapore (MAS) to present to their top management team about implementing a world’s first fact-based forward-looking fraud detection framework to bring about benefits for the capital markets in Singapore and for the public and investment community. KB also served the community in sharing his insights in writing articles about value investing and corporate governance in the media that include Business Times, Straits Times, Jakarta Post, Manual of Ideas, Investopedia, TedXWallStreet. He had also presented in top investment, banking and finance conferences in America, Italy, Sydney, Cape Town, HK, China. He has trained CEOs, entrepreneurs, CFOs, management executives in business strategy & business model innovation in Singapore, HK and China.

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