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Cancer patient Darcy Doherty. (Kevin Van Paassen/The Globe and Mail)
Cancer patient Darcy Doherty. (Kevin Van Paassen/The Globe and Mail)

Drug trials on trial: Is it really greed versus good? Add to ...

They tried for months. Petitions, e-mails, phone calls, videos, personal pleas, all with a simple message aimed at drug giant Bristol-Myers Squibb: “Help Save Darcy.”

Darcy Doherty was a 48-year-old Toronto businessman and father of three who was dying of melanoma, a type of skin cancer. Bristol-Myers had actually kept Mr. Doherty alive for a good part of the past four years: It included him in a trial for a new drug it was developing in 2007, just after doctors discovered that his cancer had spread and he had only a few months to live.

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The drug, now on the market as Yervoy, proved effective and Mr. Doherty thrived. But he stopped responding at the end of 2011.

Still, there was still hope. Bristol-Myers had started early testing of a new version of Yervoy called BMS-936558, and it also looked promising. If Mr. Doherty could get into those trials, maybe he would get a few more years. But he was medically disqualified because the cancer had spread to his brain, and companies prefer not to enroll test subjects who may become gravely ill or die before the study is complete.

Mr. Doherty’s family asked Bristol-Myers: Give him the drug anyway. We’ll take our chances. We’ll sign off on all liability. We’ll try anything. The company said no. It was too early in development. Too risky, even for someone who was dying.

So Mr. Doherty’s wife, Rebecca Cumming, went public. She organized petitions, sent e-mails, contacted journalists and posted videos online. The company had an ethical obligation to help Mr. Doherty, she argued. The message resonated and within weeks nearly 200,000 people signed an online petition. E-mails flooded inboxes at Bristol-Myers. Mr. Doherty’s story was featured in newspapers and on television across the country.

Bristol-Myers held firm. While the drug had shown potential in early testing, “we believe there is not enough information on its use in humans at any given dose to allow use outside of a well-controlled clinical trial at this time,” company spokeswoman Monica Flores said.

Mr. Doherty died on Tuesday.

“We always remained hopeful that [Bristol-Myers] would change its mind and Darcy would have another miracle,” Ms. Cumming said in a statement. “Sadly, that did not happen.”

The sad case has given new urgency to a long-standing, gut-wrenching debate: What obligation, if any, do drug companies have to terminally ill people? Should they help very sick individuals even if that could jeopardize clinical trials and delay the introduction of a drug? What about the testing process over all? Why does it take more than a decade and as much as $1-billion to bring a new drug to market? And should these questions be left in the hands of drug companies in the first place?

This case “is sort of illustrative of the tension that arises during drug development,” said David Hogg, an oncologist at Toronto’s Princess Margaret Hospital specializing in melanoma, who treated Mr. Doherty. “We all want things to go really fast and we all want things to be very safe.” But sometimes you can’t do both.

“I don’t think it’s an issue that’s ever going to be resolved completely,” Dr. Hogg said, “because the objectives of pharmaceutical companies and the objectives of an individual patient are not congruent.”

It’s an age-old problem – how to balance the rigour and rationality of scientific advancement with the all-too-human emotion of compassion. Must we look beyond saving one life now for the greater good of society in the future? Scientists, drug companies, advocates, governments and ethicists have been seeking that balance for more than a century, to the earliest attempts to control the proliferation of new drugs.

Some of the first drug-control measures were adopted by British officials in the mid-1800s after a series of deaths caused by questionable pills and potions. In one case, a drug maker accidentally substituted arsenic for sulphate of lime in peppermint lozenges, killing 400 people. Canada and the United States followed suit in the early 1900s, also in response to deadly outbreaks of contaminated food and medicine.

Even then, though, there was no formal approval process for new drugs. That came in the late 1930s after S.E. Massengill Co., a Tennessee-based drug maker, created a new liquid version of a popular medicine for strep throat. The company used diethylene glycol as a solvent, not understanding it was toxic. When it hit the market in 1937, 108 people died. The chemist who came up with the lethal formula used the medicine as well – to kill himself.

After that, U.S. and Canadian officials began requiring drug companies to seek government approval for new products. Even bigger changes came in the 1960s, after another tragedy – thalidomide. What looked like a safe, effective medication for morning sickness in pregnancy proved, as it took researchers years to discover, to cause severe birth defects. The public outcry led to an overhaul of the drug-testing process around the world and created a regulatory system that is still used today in most developed countries.

Drugs now go through a three-phase testing process. Phase 1 – which tests toxicity, but not whether the drug actually works – typically involves a handful of patient volunteers; they all receive varying doses of the medicine and are closely monitored for their responses. The vast majority of new drugs never get beyond Phase 1, which takes about a year.

If a drug passes, it goes to Phase 2, in which researchers start to measure the drug’s effectiveness on several hundred volunteers over about two years or more.

Then, if the drug gets to Phase 3, more tests are done on as many as a thousand volunteers and information is gathered over at least three years about the drug’s efficacy and safety.

Phase 2 and 3 trials both rely on “randomized controlled testing,” in which volunteers are selected by lottery to get either the new drug or a placebo. To avoid bias, often neither the volunteers nor the testers know which version the volunteer is receiving.

Only after Phase 3 will regulators such as Health Canada and the U.S. Food and Drug Administration begin to assess whether the drug can be sold. And even then the drug can be rejected.

This is why the process of getting a drug from development to market can take 14 years and cost as much as $1-billion – nearly all of it funded by drug companies.

That system remained largely unchallenged until the 1980s and the advent of AIDS. As people began to die, and research went into high gear, activists mounted an aggressive campaign against the medical and pharmaceutical establishments. It was the first time people openly challenged the drug-testing system.

There were demonstrations for earlier access to drugs in development and protests against the use of placebos. Why, the advocates demanded, should terminally ill people volunteer for a trial where they only had a 50-per-cent chance of getting the new drug, especially if it showed promise?

AIDS activists “were not willing to accept doctors’ views on these matters at face value and just take it lying down,” said Udo Schuklenk, a professor at Queen’s University who specializes in bioethics. “‘Why should I not have the last say?’ they argued. ‘Why not throw the dice one last time?’”

 

Experts argue early access can be hazardous

 

Yet many medical experts resist such emotional appeals. They argue that opening more access to drugs can be dangerous, even to terminally ill people: They could end up dying faster, more miserably, enduring painful side effects. Some early recipients of artificial hearts, for example, came to regret it because of the suffering that followed.

“There is a tendency of people to simply believe that new drugs are better than the older ones,” said Trudo Lemmens, an associate professor of health law at the University of Toronto.

In the case of AIDS, the activists’ campaign had some success. Certain drugs were released during later-stage testing and the approval time for others dropped significantly. Cancer patients took note and pushed for similar measures. By the 1990s, the FDA and Health Canada developed “compassionate access” policies, allowing drug companies to release some promising medication to terminally ill people during Phase 2 and 3 testing.

But that still did not go far enough for people like Steve Walker.

Mr. Walker is a Florida-based scientist who lost his wife to colon cancer. He is also a co-founder of the Abigail Alliance, a Vermont-based organization named after 21-year-old Abigail Burroughs, who died of cancer in 2001 after her family spent years trying to get her early access to a promising drug.

The alliance sued the FDA in 2003, arguing that the agency’s compassionate-access programs were too restrictive, excluding far too many sick people and violating the constitutional right of terminally ill people to live. The group lost the legal action but the case sparked widespread debate and the organization is now pushing Congress to change how the FDA operates, by increasing early access to drugs and streamlining the overall approval process.

“Our position has always been that the data you need to make these types of decisions emerges when it emerges, and has nothing to do with phases,” Mr. Walker said. “If you have a drug that is either helping a small number of patients dramatically or a large number of patients somewhat or dramatically, then, for patients who have a terminal disease and no other options, that’s enough. And they should be allowed to make that decision.”

James Gowing, an oncologist in Cambridge, Ont., and past chairman of the Cancer Advocacy Coalition, has sympathy for people like Mr. Doherty, but he rejects the idea of allowing access to drugs as early as Phase 1.

“What are the chances that it will be effective? Almost zero,” he said. “It’s way too early.”

Drug companies are also leery about handing out too many drugs too early. It’s already hard enough to get terminally ill people to volunteer for some cancer-drug trials and it would become even more difficult if drugs were given away.

That would delay the already lengthy approval process and cost companies more money. As a result, most drug manufacturers have their own, and differing, policies on compassionate access.

“They are not easy calls,” said Edward Lang, a spokesman for San Francisco-based Genentech Inc., a division of Hoffmann-La Roche Ltd. “It really comes down to a company decision.”

Mr. Lang explained that compassionate access is easier during Phase 3 trials, when drugs are close to being approved. Most companies will open up a special trial for some terminally ill people in Phase 3 and essentially make the drug available to them (on approval of regulators). But every company has a different policy and some do not open early access at all.

To level the field, the University of Toronto’s Prof. Lemmens and others have proposed removing drug companies from testing altogether – by creating a national drug agency. Funded by a tax on drug products, the agency would manage testing and compassionate access.

“There should be an arm’s-length relationship between companies testing the drugs and the industry itself,” Prof. Lemmens said.

Meanwhile, though, companies such as Genentech have to decide what to do when they hear public pleas for special access. One came in April from Darlene Gant, a 46-year-old Florida mother. Ms. Gant had been told by doctors that her breast cancer had returned and was spreading rapidly. She did not have long to live, but she knew Genentech was in the final stages of testing a new breast-cancer drug called Pertuzumab. Ms. Gant made a tearful 20-minute YouTube video begging Genentech to give her access to the drug.

“So many women are dying of ovarian and breast cancer and they won’t release the drugs for compassionate use,” she said on the video. “My dream is hopefully that this video would wake somebody up.”

The video sparked a public appeal and Genetech relented – it managed to include Ms. Gant in a trial, Mr. Lang said.

Meanwhile, the drug industry and regulators are facing another kind of challenge: The whole concept of randomized controlled testing for cancer drugs has begun to change because of an ethical storm that erupted in 2010 over a melanoma drug known as PLX4032.

During Phase 2 testing of the drug by Roche, half the melanoma-suffering volunteers received the new drug; the others, the control group, were treated with chemotherapy, using a drug many doctors no longer felt was effective. The idea was to compare the new drug against one that had been in use for decades.

Two California cousins in their 20s, both with melanoma, came to illustrate the controversy. One, Thomas McLaughlin, joined the trial at the University of California at Los Angeles and got the new drug. As he watched his tumour shrink, Mr. McLaughlin encouraged his cousin, Brandon Ryan, to join the trial as well. But Mr. Ryan was put into the control group, and he died.

The drug was eventually approved, but the controversy remained, fed by New York Times coverage, over the ethics of knowingly giving patients a treatment that many felt did not work. Defenders said it was the only way to properly assess the new drug. Critics called for a new way of testing.

“Those of us involved in the trial were very unhappy because we thought [the chemotherapy treatment] was worse therapy,” Princess Margaret Hospital’s Dr. Hogg said. “And we’re not going to do that again.”

Now, those selected for control groups in similar trials receive the best available therapy (aside from the drug in question).

Mr. Doherty’s case pushes some of the limits further, raising questions about how early drugs should be released.

“There’s no bad guy here at all,” Dr. Hogg said. Bristol-Myers, he said, was concerned about accidentally hastening Mr. Doherty’s death, “and there’s the potential of doing that. And Darcy [was] worried about not getting a drug that might prolong his life.”

Ms. Cumming, Mr. Doherty’s wife, knew that she was breaking new ground. “I think this is new territory for everyone and that’s why we are really pushing compassionate access,” she said in an interview before her husband died. “It’s hard to see a drug that you know your husband has a really decent chance of responding to is just outside of your grasp. We are just so close and yet can’t get it.”

The question is whether there’s any way to answer that kind of pain and frustration without putting much more at risk.

Paul Waldie is a reporter with Report on Business.

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