From MIT’s Undark: More and More, New Drugs Clear the FDA With ‘Accelerated Approval’

Increasing reliance on this and other means of moving drugs quickly to market have many critics worried, given that drugmakers benefit most.

September 10, 2018 by Abigail Fagan & Mark Kaufman

On June 28, 2011, ten police cars descended upon the headquarters of the Food and Drug Administration. Scores of protesters carrying loudspeakers and donning pink shirts had attempted to enter the building, but were thwarted by the officers. One man held a sign that read: “My wife is not a statistic: Save Avastin.”

downloadAvastin was one of the world’s best-selling cancer drugs, first approved in 2004 to treat advanced colon cancer, with high expectations. The first drug of its kind, it was designed to block the blood supply of growing tumors, and it appeared to work well for colon cancer and lung cancer. Riding on a swell of optimism, the FDA decided in 2008 that Avastin could also be used to treat a certain type of advanced breast cancer — but just three years later, the agency seemed poised to reverse that decision.

Inside the building that June morning, a public hearing on that decision was being held. Some members of the audience shouted “Don’t take my drugs away!” Others came with photo albums in the hopes of showing the expert panel weighing the drug’s fate how the cancer drug had saved them from the ravages of breast cancer, and allowed them to live longer, fuller lives.

bhn deskThe pleas didn’t work. The panel concluded that Avastin didn’t improve chances for surviving breast cancer, and in fact, determined that the drug was so toxic — it sometimes caused high blood pressure, heart attacks, and ruptured intestines — that it could be more lethal than the cancer itself. Four and a half months later, the FDA officially rescinded the approval of Avastin for treating breast cancer. The FDA commissioner at the time, Margaret Hamburg, admitted that new evidence showed that the once-promising drug was not actually effective in treating breast cancer. “It is clear that women who take Avastin for metastatic breast cancer risk potentially life-threatening side effects without proof that the use of Avastin will provide a benefit… that would justify those risks,” Hamburg said at the news briefing.

The anger and disappointment of the gathered patients was palpable, but the stunning reversal, and Hamburg’s own words, raised a troubling question: If there was no evidence that Avastin was effective against breast cancer — and even some evidence that it was explicitly harmful — why was it approved as a breast cancer treatment in the first place, and why was the company that made the drug, Genentech, permitted to market Avastin to doctors and breast cancer patients for the better part of three years?

It’s a question that cuts to the heart of a program that allows the FDA to approve drugs using a lower standard of evidence. Under what’s known as the Accelerated Approval Program, the FDA can reduce the bar for approval in cases where there is an unmet medical need for a serious condition. In such cases, a drug manufacturer need not show that the drug works. It only needs to demonstrate some reasonable expectation that the drug ought to work.

By definition, that’s a much more subjective threshold, but according to Janet Woodcock, the director of the FDA’s Center for Drug Evaluation and Research, the benefits of accelerated approval more than justify the problems that might come with lowering standards of scientific evidence — particularly when desperate patients are willing to gamble on the additional risk. “It’s not unusual to have differences of opinions about accelerated approval because it’s more uncertain,” Woodcock said. “The patients are saying ‘we want to accept the tradeoffs, we’ll accept more uncertainty.’”

Today, the FDA is increasingly proactive in bringing drugs to market short of full approval and uses accelerated approval to get new drugs to people suffering from devastating diseases. Since 2003, more than 16 percent (66 of 404) of all new drugs were approved through the Accelerated Approval Program, and it seems to be a more popular option. Between 2003 and 2013, about three drugs were approved each year through this expedited route. But during each of the last three years (through 2016), that number has increased to more than seven drugs per year.



The FDA is candid about its commitment to expedited approval programs — in part to speed up what is often characterized as a notoriously drawn-out and bureaucratic approval process. The agency’s former head, Hamburg, wrote about the FDA’s intention of getting new drugs to people as “quickly” as possible, and the FDA’s new leader, doctor and cancer survivor Scott Gottlieb, bemoans the FDA’s slow-moving approval process. While a fellow at the conservative American Enterprise Institute in 2012, Gottlieb lamented the “increasingly unreasonable hunger for statistical certainty on the part of the FDA.” And at Gottlieb’s confirmation hearing last May, he rejected the idea that speeding up drug approvals would compromise their safety, calling it a “false dichotomy that it all boils down to a choice between speed and safety.”

But the increasing reliance on accelerated approval and other means of expediting drug approval have many critics worried — particularly given that the interests most readily served by fast-track approvals are those of the pharmaceutical industry. David Gortler, an associate professor of pharmacology at Georgetown University and a former FDA medical officer, is one such critic. He fears that the drive to get drugs out faster with weaker scientific evidence is already taking a toll — not just on consumers who are taking drugs that should never have been approved, but also on the agency’s credibility.

“I don’t really recognize the agency for which I once worked,” said Gortler, “because they’re making all these crazy decisions.”


The essential problem is that when it comes to drug approvals, speed and certainty are fundamentally at odds. It typically takes years of testing in large numbers of patients to determine if a drug provides a meaningful benefit — including improving an individual’s odds of survival. And it’s impossible to detect potential side effects until a sufficient number of patients have been monitored carefully, and for enough time, for such problems to truly surface. It’s extremely time-consuming to show, scientifically, that a drug really works — and to understand its risks.

But not all patients have the luxury of time. In the early 1980s, for example, an HIV infection meant certain death, as the virus devastated a person’s immune system, leaving them with wasting, sore-ridden bodies. Without drugs available to combat the virus, the afflicted were pushed toward desperate, ineffective treatments. Some tried cooking medicine themselves, while others heard stories of potent drugs and sought them out on black markets. None of it, of course, worked.

Responding to the crisis, the FDA began experimenting with what would formally be called accelerated approval. Instead of requiring ironclad evidence that a potential anti-HIV drug prolonged patients’ lives, the agency asked for indirect evidence that the drug was working as it was supposed to. In 1992, the anti-HIV drug ddC was approved because initial trials demonstrated that patients using it showed an increase in the number of a certain type of immune-system cells in their bloodstream. It wasn’t proof that the drug actually helped patients — the agency asked for a number of follow-up studies to establish that fact — but the consequences of the disease were so grave that the agency decided that it was worth the risk to approve ddC.

In this case, the gamble paid off. The drug worked. “We approved the AIDS drugs … and over time it came about that those were correct decisions and the epidemic was controlled,” Woodcock said. It also set a pattern for the future. Under certain circumstances — only having to do with serious diseases and unmet needs — the FDA can allow a drug to come to market with a lesser standard of evidence. Instead of proving that a drug prevents heart attacks, a pharmaceutical company might only need to show a reduction of fatty cholesterol molecules in patients’ bloodstreams. Instead of proving that a cancer drug extends lives, the company might have to show only that the chemotherapy delays tumor growth for a while. And instead of showing a direct benefit to a patient, an applicant might need only demonstrate that its drug meets a “surrogate endpoint” that suggests the drug is helping people who take it.

Using these surrogate endpoints saves time; it might take only weeks or months to show that a drug affects patients’ blood chemistry, whereas it takes years to gather enough data — and enough deaths — to determine whether a drug can actually extend a patient’s lifespan. The promise of surrogate endpoints is getting drugs to patients who are in desperate need of them quicker, but the downside is that there’s less careful testing of whether the drug actually works, or whether it kills patients instead of helping them.

“It is likely” said Vinay Prasad, a hematologist-oncologist at Oregon Health and Sciences University, “that many people are being treated with drugs that actually do not make them live longer or live better.”


In September 2016, the FDA approved the drug eteplirsen, designed to treat Duchenne muscular dystrophy (DMD), which primarily affects young boys. DMD is an invariably fatal disease that slowly destroys the muscles of its victims. None of the disease’s variants has a cure, although drug therapies like steroids can help slow muscle deterioration. Eteplirsen, however, is the first drug approved to target the root of the disease. Despite the huge expense — starting at around $300,000 per year — eteplirsen is the only real source of hope for children dying of DMD.

The root of the disease is a protein called dystrophin that is necessary for building muscle fibers; but those with DMD have a genetic mutation that interferes with the normal production of this protein. Eteplirsen can be used to specifically counter the effects of one of these mutations.

To speed up the approval process for struggling boys and hapless parents, the FDA put eteplirsen on the accelerated approval pathway. During the drug’s testing, the trials were too short to determine if the drug actually improved how long the boys lived, so “dystrophin production” was used as a surrogate endpoint. The study’s scientists reasoned that if they found increased levels of the protein, it was a good indication that the medication would ultimately improve the children’s condition.

As it was, evidence did suggest that eteplirsen increased the levels of dystrophin in patients’ muscles, but the increase was tiny — far below what would be expected to have any clinical effect. Scientists were baffled, in fact, by the miniscule quantity of dystrophin the drug produced.

“I find it difficult to conceive how a treatment effect of three parts per thousand could confer clinical benefit,” wrote Ellis Unger, the director of the FDA’s Office of New Drugs, and who oversaw eteplirsen’s scientific review. “If there were 10 inches of snow on a sidewalk that needed to be cleared, three parts per thousand would amount to 1/32nd of an inch.”

Unger wrote that a drug would need to increase dystrophin levels to around 10 percent of normal, healthy levels to even be considered “reasonably likely” to offer “measurable clinical benefit.” This means that even if dystrophin levels were 32 times higher than the trial results, there would still be big question marks about eteplirsen’s effectiveness.

Indeed, given that the drug didn’t even seem to meet the weakened standard of a surrogate endpoint, Unger and the other FDA scientists on the review panel wanted the FDA not to approve eteplirsen. Still, their recommendation was overruled by Janet Woodcock, who concluded the results met FDA effectiveness and safety standards for drugs on an accelerated pathway. (Two of the eteplirsen panel members resigned after this decision.) DMD patients across the country are now fighting with their insurance companies to get coverage for the expensive new drug.

“They may very well be paying $300,000 for some snake oil treatment,” says Gortler at Georgetown University. “It’s mean too, because these people are very desperate. They’ve been given a death sentence and they want to have hope.”


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Prasad also warns that the increasing reliance on surrogate endpoints risks eroding the overall standards of new drugs that are allowed to appear on the market. If the bar for approval becomes so low, he reasons, pharmaceutical companies aren’t incentivized to make any of them truly safe and effective. “We want A-plus drugs, not D-minus drugs. So why are we accepting it?”

Not everyone takes such a hard line on the risk-benefit calculations at the heart of accelerated approval processes. Mikkael Sekeres is an oncologist at the Cleveland Clinic who served on the FDA’s advisory committee for Avastin on whether or not it should be withdrawn. While approval for use of the drug in treating breast cancer was ultimately rescinded, Sekeres says the FDA is right to try certain drugs — based on surrogate endpoints — if a disease is bad enough. “If the risk of disease is awful, then [the FDA] might be willing to consider a drug with more risk than with a disease that isn’t as awful,” Sekeres said.

He pointed by way of another example to lymphoma where patients might survive only 10 years with the disease — a rather long disease course. Running a complete clinical experiment to see if a drug can prolong cancer patients’ survival might take 15 years, Sekeres noted, meaning many patients would be dead before they can ever try the drug.

“So you make an approval based upon a clinical maker,” he said. And if a drug does prove to be harmful, the FDA’s accelerated approval program is designed to pull the drug from use — just like the FDA did for Avastin. “It’s a demonstration that the system works when the FDA reserves its rights to recommend removing the drug from approval,” said Sekeres. “I think the evidence is working and the FDA is exercising its duty to protect the public.”


To be sure, the FDA emphasizes that accelerated approval is designed to help patients with no other options. “This pathway allows for flexibility in new drug approvals for serious diseases with no satisfactory therapies while meeting the appropriate standards for safety and effectiveness,” FDA spokesperson Sandy Walsh wrote in an email. “Accelerated approval recognizes that physicians and patients are generally willing to accept greater risks or side effects from products that treat life-threatening and severely-debilitating illnesses, than they would accept from products that treat less serious illnesses.”

As it stands, the FDA approved 86 cancer drugs in the 15 years prior to October 2017. Twenty-nine cancer drugs were granted accelerated approval in the same time frame, representing about a third of all cancer drug approvals. And cancer therapies are a substantial component of all drugs brought to market, accounting for nearly 22 percent in the last 15 years.

Of course, even under the best circumstances, Walsh noted, the accelerated approval process can lead to approvals that are later revoked. “These limitations are a reason accelerated approval is available only for a limited group of drugs,” Walsh said, including “those intended to treat serious or life-threatening illnesses when the drug is expected to provide a meaningful benefit over existing therapy.”

Companies (Sarepta included) that approve drugs based on a surrogate endpoint are still required to conduct clinical trials, called Phase 4 confirmatory trials, demonstrating that the medication provides the intended benefit, Walsh added.

Still, there is some evidence that this may well depend on the drug. The drug Mylotarg was originally granted accelerated approval in 2000 with a surrogate endpoint showing a decrease in patients’ leukemia. Following its approval, however, further trials revealed the drug was not only ineffective, but could also be lethal. So in 2001, the FDA issued a so-called black box warning — a notice appearing on a drug’s label that warns users of “life-threatening risks.” Nine years after that, in 2010, Pfizer withdrew the drug completely.

Despite this, Mylotarg is back. The FDA, designating a lower dose and new population for the drug, approved it to treat certain patients with acute myeloid leukemia. But the new approval still relied on surrogate endpoints, which critics say prioritizes speed over compelling proof. One of the Mylotarg clinical trials, for example, found that the drug increased event-free survival by nearly eight months, but did not impact overall survival at all.

“The problem with surrogate outcomes is they’re more convenient because you can observe them sooner, but it’s very, very easy to get a big difference in the surrogate outcomes that does not translate into a big difference in survival,” says Peter Thall, a biostatistician and expert in clinical trial design at the MD Anderson Cancer Center. “The whole game of saying ‘This is statistically significant’ is grossly misleading. This is done again and again and again in oncology.”

This is also what happened in the case of Avastin. The drug was brought to market for the treatment of colon cancer and then lung cancer specifically, and in both cases, there actually was clinical data showing the drug marginally extended patients’ lives. But the 2008 approval of Avastin for breast cancer didn’t have that sort of data, so the FDA put Avastin on the accelerated approval pathway. Early evidence showed that when Avastin was used in combination with the chemotherapy drug paclitaxel, patients experienced an improvement in progression-free cancer survival over those that took the chemotherapy drug alone. However, clinical tests on cancer patients didn’t show that breast cancer patients actually lived any longer overall. Rather, the surrogate endpoint “progression-free survival” only meant that patients lived longer with the tumor after treatment.

Patients taking Avastin did seem to do better on this particular measure, so the FDA took the gamble to let patients start taking the drug. But in this case, follow-up studies showed that the drug didn’t actually increase overall survival. What’s more, Avastin proved unacceptably toxic, including producing gastrointestinal perforations in some patients. The FDA rescinded the approval, much to the disappointment of scores of breast cancer patients who were convinced that Avastin had saved their lives.

The uncertainty that comes with a surrogate-endpoint-based approval is a huge problem when it comes to treating cancer, said Oregon Health and Sciences University’s Prasad. “If you look at big randomized studies in oncology over [the] last few decades, they used to look at survival more. But survival as the endpoint of randomized studies has fallen and it’s largely been replaced by surrogates like progression-free survival,” Prasad says.

What’s worse: These surrogate endpoints often don’t mean the patient benefits. Prasad and his colleague Chul Kim investigated drugs for 55 cancer indications approved by the FDA based upon surrogate endpoints and discovered that only about half of those drugs had any sort of proof that the surrogate endpoint really helped patients in any meaningful way. The analysis was published in the journal Mayo Clinic Proceedings in 2016. “For almost half of these established surrogates, there is no published study ever showing what their correlation is with survival or quality of life,” Prasad said. “We just can’t even find documentation.”

Kim, lead author on the report and an attending physician at MedStar Georgetown University Hospital admits to being surprised. “It was sobering to see,” he said. “I’d expect to see more high-level evidence to support the use of surrogate endpoints. Because progression-free survival and response rate have been used for a long time.”

This lack of proof creates a layer of uncertainty that is extremely hard to explain to patients, Prasad says. People with cancer come to him desperate to find a drug that will prolong their lives. When he explains that a drug was shown to slow tumor growth, patients immediately ask, “Does that mean I live longer?” Prasad simply can’t answer that. And thanks to surrogate endpoints, FDA approval of a cancer drug doesn’t quite mean that it is proven “effective” in the way that patients naturally think it is.

Nonetheless, accelerated approval is likely to become increasingly common, experts say, because patients, politicians, and pharmaceutical companies are all shouting for swifter drug approval. “There’s been an ongoing beating of the drum,” said Joseph Ross, an associate professor and physician at Yale University, “about the FDA needing to be faster,”

But Ross urges caution before the approval process is kicked into an even higher gear. “All evidence suggests that the FDA is reviewing and approving drugs faster than any other peer regulator in the world,” he said. “But we need to do more studies now to show what this means for safety and efficacy.”

About half of new drugs, Ross says, are now approved on standards that might look impressive in the laboratory but might not actually benefit patients. “These drugs are being approved on the basis of lab measures, but will they improve symptoms and mortality?” Ross asked. “We don’t know.”

That’s why Kim and other experts would like to see more study of the impacts of accelerated approval and surrogate endpoints overall. “If a drug is approved on a surrogate endpoint, we must do a follow-up study to make sure that it was not a false sign of efficacy,” Kim said.

“Cancer drugs can be toxic,” he added. “Without those hard outcomes, we may just cause harm to patients.”


This article was produced by students in the Science, Health & Environmental Reporting Program at the NYU school of journalism.

This article was originally published on Undark. Read the original article.

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Will 21st Century Cures Act benefit hospitals?

captureFirst: The Globe is getting some attention for its five-part narrative about a family that helped  start a drug company to keep their son on an experimental cancer treatment.

Nicely written narrative with illustrations and audio. We won’t give away the ending. 

Also, here’s what people were saying a year ago about the “21st Century Cure Act.” It’s been amended since then, but much of what they have to say still applies. My take was: What’s in it for hospitals? 

The drug development and approval elements in the proposed legislation are the centerpiece of a gift basket that has something for everyone: engaged patients, drug makers, FitBit fanatics, NIH-funded scientists, those faced with rare diseases, and those fighting antibiotic resistance.

What do hospitals get out of it? Of course, it depends on whom you ask. One side says it will clear out bottlenecks that are delaying access to better drugs and new, effective antibiotics. That’s good news for hospitals struggling to improve patient outcomes and prevent readmissions. The other side says it will lead to unsafe drugs and a flawed approach to dealing with antibiotic resistance. That’s bad news for hospitals struggling to improve patient outcomes and prevent readmissions.

John Powers, MD, is a former head of the FDA’s Antimicrobial Drug Development and Resistance Initiatives. He is now a clinical professor at the George Washington University School of Medicine and one of the bill’s critics. If the bill’s provisions regarding FDA approval become law, hospitals should be worried that they will be held responsible for drugs that are ineffective or worse, he said.

“If you have a new drug and it doesn’t make the patient better, what you actually end up doing is spending more money in the long run because they stay in the hospital longer,” Powers said. “Or you may have to administer additional treatment to deal with the side effects of that medicine — which costs money.”

Two Boston meetings look at the role of patient advocates. They offer two very different perspectives.

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Pharmaceutical manufacturers often  look to patient advocates for help winning approval for new drugs. Their most recent success in this area was the FDA’s approval of a new drug for Duchenne muscular dystrophy. That decision came despite recommendations against approval from FDA staff.

In an editorial, the Boston Globe questioned the FDA’s move while noting that eteplirsen’s “entry into the marketplace represents a major victory for the patient advocacy movement, and is bound to encourage more such engagement in the drug-approval process. Based on the infighting that went on over the Duchenne treatment, that’s going to be challenging for the FDA. It has to find a balance between public opinion and what’s truly in the public interest.” (The Globe also featured a story this week about one of those patient advocates.)

Today, drug makers in Boston are hosting a conference for patient advocates. The “Patient Advocacy Summit 2016 – Sharing Our Stories: Building a Patient-Centered Ecosystem” is underway at Novartis facility near MIT.

This event brings industry leaders together with patient advocates and other stakeholders to examine ways in which life sciences companies can more fully incorporate the patient voice into the work they do— not just approaching regulatory applications or at commercialization, but throughout the drug development cycle.

The day-long event will include panel discussions, case study presentations (spotlighting industry/patient partnerships), a keynote address, and awards ceremony, as well as a networking breakfast, lunch and cocktail reception. Expected attendance is 180 patient advocacy professionals, patient organizations and other stakeholders.

Worth noting that the same topic was the subject of  yesterday’s  panel at HUBweek, a  science/tech/arts series ongoing in Boston. The title: “The FDA and the Drug Approval Process: Is it Really Broken?”  Some made the point —  we should listen to the parents of sick children.  Others offered a different perspective: Patients might be better off in clinical trials with informed consent and free drugs,  rather paying  $300,000 per year for that same, unproven medication with unknown side effects.

Contacted after the panel, Zuckerman, president of the National Center for Health Research in DC,  offered these thoughts:

  1. Patient perspectives are crucial in helping us understand what scientific data mean, what the benefits and risks both mean to patients.  So patients should be part of the process – what should the outcome measures be and how can they be measured?
  2. The FDA is listening to patients who desperately want treatments but they are not listening well to patients who are harmed by ineffective or unsafe treatments.  That’s partly because the former are funded by Pharma to attend FDA meetings and to lobby Congress, but the latter are on their own, often don’t have the money to attend FDA public meetings, and wouldn’t even know about them if they don’t read the Federal Register, which is the only place they are announced in advance.

 A few more tweets worth noting.

 

April 26: Boston health news round up

Health writers on both ends of 135 Morrissey Boulevard have been busy — main Globe newsrofenway__1282224095_4483 (2)om to STAT down the hall:  From Stat;  from the Globe business desk. 

Stat shared this story with the print edition of Globe today: Lam, a 22-year-old aspiring doctor, is part of the fast-growing industry of medical scribes working in hospitals and clinics across the country. These scribes, often premed college students, help doctors with a dreaded task — checking boxes and typing words into electronic health records.

And both outlet covered yesterday’s disturbing FDA meeting. This is an ongoing story — desperate patients insist on FDA approval treatments despite lack of solid evidence of efficacy.

Video up soon: What are the public health implications of terrorism? This (Harvard School of Public Health) Forum — which took place a week after the 3rd anniversary of the Boston Marathon bombings — asked what makes a society resilient in the face of attacks or perceived threats. Experts in homeland security, psychological resiliency, crisis leadership, and disaster preparedness and response participated. 

 Dumb question award: Boston Magazine: Should the Media Report on Health Research?  A good topic, but a bit too much to bite off in a blog post. For a more thorough analysis, see Health News Review, which this week looks at what happens when the media doesn’t report on Research

Health Wonk Review: Lots of blog commentary and an invitation you to this afternoon’s “blab” on health policy.

Is female Viagra a scam? Boston women’s health group questions drug, supporters

indexThe non-profits pressuring the FDA to approve a drug billed as female Viagra do not quite make up a top ten list or women’s health advocacy organizations. This health writer has never heard of most of the groups cited in Sunday’s New York Times story.

But familiar women’s health groups, like Boston’s Our Bodies, Ourselves, are siding with the FDA on this one. From their response to an earlier review of the drug.

imagesWomen taking the drug had less than one additional “sexually satisfying event” (orgasm not required) than women taking a placebo. And in the meantime, the drug caused dizziness, nausea and fatigue, particularly with long-term daily use, in some women — hardly the recipe for sexual excitement.

The FDA also considered whether the drug had increased women’s desire — a crucial element of the HSDD diagnosis, which involves low or no sexual interest to the point of distress in people who are physically healthy and not depressed — and found that the drug failed in this area.

The FDA takes another look — and offers  a live webcast of the deliberations —  on Thursday.

In it’s report on the 2010 FDA rejection of the drug, the OBOS  website notes another Bay State-based critic of the drug:

According to Julia Johnson, the panel’s chairwoman and head of the department of obstetrics and gynecology at the University of Massachusetts Medical School, the impact of the drug flibanserin … was “not robust enough to justify the risks.”

More here from another independent, feminist women’s health group, The National Women’s Health Network:

Members of the campaign called “Even the Score” are challenging the FDA on what they claim is a perpetuation of a gender bias by virtue of the claim that the FDA is holding drugs that treat women’s sexual problem to a higher standard than those for erectile dysfunction.  Even the Score has engaged prominent women’s rights organizations, health care providers, the media and members of Congress in a public relations misinformation campaign to criticize the FDA.  There are Female Sexual Dysfunction drugs currently under FDA review, and Even the Score is attempting to move the discussion away from the safety and effectiveness of these drugs and towards controversy about gender bias. 

The reality is that no amount of public relations or slick marketing can get around the fact that the drugs currently being proposed for Female Sexual Dysfunction simply don’t work and may be quite dangerous. Poor efficacy, a strong placebo effect, and valid safety concerns have plagued all of the drugs that have been tested so far. There are many reasons why the proposed drugs may not have been effective in increasing women’s sexual enjoyment; chief among them is the heterogeneity of female sexuality and, of course, research demonstrating that sexual problems are mostly shaped by interpersonal, psychological, and social factors. Nevertheless, pharmaceutical executives will continue to drum up hype over the possibility of a “pink Viagra” because the profit market for this type of drug is estimated to be over $2 billion a year.

Note that neither of these groups accept funding from the pharmaceutical industry. Even the score supporter include Sprout, the company seeking approval for the drug and Trimel Pharmaceuticals, a company testing a nasal testosterone gel for “female orgasmic disorder.”

Should the FDA approve Vertex’s new cystic fibrosis drug?

The scene at the FDA hearing was familiar. All the  advisory committees have seen it play out again and again. Yesterday, it was the Pulmonary-Allergy Drug committee: The pharma doc with the convincing statement. The weeping patients. The drug likely to cost a couple thousand a month offering a slim  benefit over an existing drugs. But it works, and it’s safe.

From the Globe:VertexLogoSOP

“I think this is a much-needed advance for patients with cystic fibrosis,” said committee member Dr. Michelle S. Harkins, associate professor of medicine at the University of New Mexico Albuquerque, one of the majority voting to recommend approval.

The lone dissenter in the 12-1 vote recommending approval of the drug, Dr. Yanling Yu, the president and cofounder of Washington Advocates for Patient Safety in Seattle, said she was not convinced the data generated by the Vertex testing supported the approval of Orkambi.

“I really understand the patients critically need a new drug, but sometimes a new drug does not provide [the needed effectiveness],” she said.

From The New York Times story:

An issue for the advisory committee was that Orkambi had what the F.D.A. said was only modest effectiveness, improving lung function by only about 3 percentage points relative to placebo.

Some family members or advocates, some of them crying, pleaded with the committee to endorse the drug.

Some patients who took the drug in clinical trials said it had made a huge difference in their lives, reducing their coughing, allowing them to exercise better, helping them gain weight or reducing how often they ended up in the hospital…

Michael Yee of RBC Capital Markets, for instance, expects the price will be $225,000 to $250,000 a year.

The vote is advisory. The FDA staff will make the final call.

More here:

The financial stakes for Vertex.

FDA briefing for meeting.

Vertex briefing for the meeting

Avandia, the Duke Clinical Research Institute and conflict of interest

The  debate over potential bias at the Duke Clinical Research Institute emerging fro  this morning’s Avandia hearing inspired a trip to the archives. This story looked at many of the same issues, which came up when  the Duke clinical trials operation was young.

By Tinker Ready

from The Raleigh News & Observer

Genentech and university researchers wanted to ensure that a study of the comparative effectiveness of  tPA was definitive. Critics say they failed.

By TINKER READY and TRISH WILSON

STAFF WRITERS

THE NEWS & OBSERVER

 3/31/1994  

All corporate research spending on campus isn’t aimed at inventions. Sometimes the goal is to torpedo a competitor.

That was the hope of Genentech, a San Francisco biotechnology company. It paid $55 million for a study comparing its heart attack drug to a far cheaper drug cornering the market for thrombolytics. The drugs dissolve blood clots and reopen arteries after a heart attack.

The study — completed last year — was coordinated at Duke University, where researchers said their goal was to determine which method of using the two drugs would save more lives.

Genentech’s sponsorship of the massive study raised eyebrows, but the company tried to reassure the medical community that the study would be unbiased. A previous tPA study had been dogged by charges of conflict of interest, and Genentech wanted to avoid a replay.

The company chose Duke University to coordinate the research because it had a relationship with Duke scientists and their collaborators, who had worked with tPA in the past.

“If Genentech was forking over the money, they wanted someone to run the study who they trusted, ” said Robert Califf, a Duke cardiologist and the study’s clinical director.

The company also had reason to trust Ralph Snyderman, the top administrator at Duke’s medical center and former Genentech executive. Snyderman left Duke to join Genentech in 1987 as director of research and development. While there, he successfully ushered tPA through a long and contentious Food and Drug Administration approval process before returning to Duke in 1989.

In the end, Genentech’s study paid off. After examining medical records of 41,000 heart attack patients in 15 countries, researchers announced that Genentech’s tPA (about $2,200 a dose) was superior to streptokinase (about $300 a dose). They concluded that the prompt use of tPA could reduce by 14 percent the number of people who died from heart attacks.

Eric J. Topol — a cardiologist at the Cleveland Clinic Foundation and chairman of the study — claimed victory for tPA.

“We have to put to rest this battle of the thrombolytics, ” Topol said at an April 1993 news conference in Washington. “Accelerated tPA was significantly better.”

That day, the price of Genentech stock jumped $4.75 a share to $37.50.

Not everyone shared the stock market’s optimism. Some doctors thought the results were ambiguous and failed to reflect tPA’s risks, particularly a higher incidence of stroke among users.

One member of the steering committee — streptokinase advocate Victor Marder — said Genentech had generated what it wanted.

“On the face of it, Genentech was not part of the decision-making apparatus, ” said Marder, the chief of hematology at the University of Rochester medical school.

On the other hand, he said, the test was not a fair comparison. It compared a hyped-up dose of tPA to a standard dose of streptokinase, Marder said. In addition, he said, he did not think the study properly accounted for the disproportionate number of tPA patients who might have done better because they had undergone heart bypass operations.

When he tried to raise these issues to the steering committee, “everybody got really angry, ” Marder said.

Marder thinks the study fails to prove that tPA is better.

“I don’t think it’s dishonest, he said. “I think it was an exaggerated conclusion made to influence people.”

Califf said that Marder is off the mark. The comparison between the two drugs was valid, he said, and the study accounted for the bypass operations.

Soon, Marder and other critics will be able to see that for themselves, because all the data is about to be published in 40 manuscripts.

“Anyone can look at it and draw their own conclusions, ” Califf said.

Califf doesn’t deny that Genentech had a huge stake in the outcome. But he vehemently denies that the study was designed with a foregone conclusion.

The project began when Califf and Topol — who had done research with tPA — began talking to Genentech about a larger study. At the time, the company was trying to cope with 1990 Italian study that found no significant difference in tPA and streptokinase.

By the time a second damaging European study came out in 1992, Genentech was ready. The company promised that a new, bigger study would definitively prove whether tPA was safer and more effective than its low-cost rival.

That study — know as GUSTO for Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries — was headed by Topol. Duke, with its massive cardiac computer data bases, served as a data clearinghouse.

“They needed to do this study, ” Califf said. “They were losing market share. We were very concerned that the European studies had missed the point.”

Both the company and the researchers wanted to make sure the findings were above question, he said.

The company had good reason to expect skepticism. In 1989, a congressional investigation found that 11 of the researchers involved in the original, federally sponsored studies of tPA owned Genentech stock. That stock became much more valuable when the FDA approved the drug.

So, when GUSTO trials came along, Genentech set up an independent steering committee to run them. None of the researchers could own Genentech stock, nor could they consult for the company until at least a year after release of the final results.

Genentech staff say that Snyderman played no role in bringing the study to Duke. Snyderman said in a recent interview that he still consults for Genentech and will continue to do so for the next couple of months.

“There was absolutely no conflict of interest, ” Snyderman said.

Califf called GUSTO’s ethical precautions “draconian.” Genentech staff saw none of the data and had no role in running the study, he said.

“The risk that Genentech had to take is that they had no control over this trial, ” he said.

Califf said his goal was not to compare the clot busters — it was to find out if a doctor can save more lives if he moves faster to open arteries after a heart attack.

Still, if the study also proved that Genentech makes a better drug, and its corporate fortunes turned around, more power to the company.

“I will not make apologies for industry being involved, ” Califf said. “That’s the American way.”