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What the FDA’s approval of “pink Viagra” tells us about the problems with drug regulation

Critics worry the agency is now approving marginal drugs with troubling side effects. Has the FDA become too lax?

In the late 1980s, with the AIDS crisis in full swing, HIV-positive patients accused the Food and Drug Administration of hindering access to lifesaving drugs. At the time, the FDA was notoriously conservative and sluggish in approving new treatments, with scientists requiring endless piles of data before making a decision. The activists argued this was untenable. Patients couldn't wait for data on every last side effect. They were dying. They were willing to take big risks.

It took an incredible lobbying effort — at one point in 1988, activists stormed the FDA's headquarters in Maryland — but the agency eventually relented. The FDA began listening more closely to patients as part of its deliberation process for new drugs. By many accounts, these changes were successful. An HIV diagnosis is no longer a death sentence today, in part because those activists pushed the regulator to be less hidebound. The FDA now oversees one of the speediest drug-approval processes in the world.

But fast-forward 30 years, and many observers think the pendulum has swung too far in the opposite direction. Instead of being too conservative, critics nowadays worry the FDA has become too lax. So far in 2015, the agency has approved a stunning 96 percent of drug applications considered, according to data from Forbes. The big concern is that the FDA is waving through ineffective and potentially harmful drugs too quickly — sleep drugs with marginal benefits that can cause car accidents, for example.

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One place to see the massive changes in the way the FDA approves drugs — and the increasing sophistication of the pharmaceutical industry efforts to influence their regulator — is the fight over "pink Viagra."

Over the past year, patient advocacy groups and the drug industry engaged in yet another massive lobbying effort: this time, to get the FDA to approve flibanserin ("pink Viagra"), a pill intended to fix female sexual dysfunction. One outside researcher called the drug "a mediocre aphrodisiac with scary side effects" that can cause women to randomly pass out. Other doctors said the FDA's approval was a mistake.

The episode raised hard questions about the changes wrought by the patient movement and other reforms that have followed. There were excellent reasons for the FDA to bring HIV-positive patients into its deliberations in the 1980s — they provided a crucial perspective that the agency's in-house scientists and officials lacked. But these days, some critics argue that those listening sessions have been hijacked by drug companies. As I found in my reporting, the patients who had lobbied the FDA to approve pink Viagra were often sponsored by the drug's manufacturer.

"The role of pharma in patient groups in the contemporary era is entirely fraught," says Yale Law School's Gregg Gonsalves, who was once one of those HIV activists in the 1980s. "[Drug companies] learned from the early days of the AIDS epidemic that the patient community could be useful allies, and they've poured money into patient groups here in the US and around the world."

So is the FDA approving drugs too easily? Has the push for speed and efficiency now undermined the agency's ability to protect public health? To find out, I took a closer look at the approval of "pink Viagra," which offers a vivid illustration of just how much the FDA has transformed over time — and why those changes worry many experts.

Pink Viagra: How a "mediocre aphrodisiac" got approved despite scientific skepticism

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Flibanserin, which will be sold under the brand name Addyi. (Sprout Pharmaceuticals)

In June 2015, the FDA convened a public meeting at its campus in Silver Spring, Maryland, to talk about the sex lives of American women. Specifically, a group of industry representatives, scientists, and patients came together to discuss whether a drug designed to treat women with sexual dysfunction should be approved for market.

Though you might imagine such a meeting would be a sober and scientific accounting of clinical trials and patient data, the people in the room that day said it seemed more like a football match.

There was clapping, booing, and high-fiving. There were tear-filled testimonials from sufferers of hypoactive sexual desire disorder (HSDD) — the term used for a sudden and unexplained loss of libido. Husbands and wives got up to say that their marriages had nearly been destroyed, that they’d lost an essential part of their lives to a disorder. Doctors who treat the disorder said they needed a cure. Consumer advocates and women's rights groups accused the FDA of sexism, of not taking seriously enough a condition that affected many women.

The sentiment in the audience was clear: Female sexual dysfunction was a genuine medical condition that needed a medical treatment. Patients had the right to decide whether or not they want to try flibanserin — even if it had serious side effects, such as spontaneous fainting (which can be deadly if, say, you're driving).

Everyone I spoke to, including FDA officials, said this gathering was highly unusual. "This was a really unprecedented meeting," Richard Klein, director of the FDA patient liaison program, told me. "From the agency perspective, the decision should be made on evidence of safety and effectiveness for the clinical trial. But if you went through the transcript, members of the [FDA advisory] committee were really over-barreled."

"There was a lot more rowdiness than usual," said Liz Canner, director of the documentary Orgasm Inc., who was present at the meeting. There were hundreds of people there that day, she said, clapping when people said something positive about flibanserin and booing when something critical was uttered. "You felt there was a team trying to win, as opposed to, ‘Let’s look at the science and see what’s best for the public.'"

After the meeting, an FDA advisory committee appointed to weigh in on the day’s events recommended that the agency approve the drug. In August, the FDA announced that it would follow the committee’s advice. Addyi, the drug’s brand name, will hit store shelves this fall. Public pressure had won out. Cindy Whitehead, the CEO of Sprout Pharmaceuticals, which manufactures the drug, told me that its passage "was a triumph of science, and in turn, women won."

If flibanserin worked wonders, the FDA’s decision might be cause for celebration. But according to the best evidence, the pink pill doesn't actually work all that well and can be quite harmful.

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Flibanserin started life as a failed antidepressant. It was then repurposed as a libido enhancer, and the FDA rejected the drug twice before, out of concerns that flibanserin's benefits to the libido (about half an additional sexual encounter each month above a placebo for a small subset of users) didn’t outweigh the potentially dangerous risks. One in five women experienced side effects including drowsiness, dizziness, nausea, and less commonly, extremely low blood pressure and spontaneous fainting — all worsened by alcohol, which many women drink.

I asked the Dartmouth Institute's Steven Woloshin and Lisa Schwartz, independent researchers who analyzed the flibanserin data, to help me contextualize the drug's relative harms and rewards. They noted that with any treatment, there's a trade-off between benefits and risks. Based on the available data, they estimated that 9 percent of women who take flibanserin will feel noticeably better over a placebo control group.

"The problem is that most women will not get a benefit," Woloshin and Schwartz said by email. Yet those women are still susceptible to quite serious side effects. "Some women will be hurt from low blood pressure causing fainting and drowsiness," they wrote. "And other people may be hurt if there are car accidents. The main way to mitigate the potential harms — avoiding any alcohol — is unrealistic."

The company's "alcohol interaction study" — to see how the drug works while taken with alcohol — involved 25 participants, but only two were women, even though the drug will be prescribed exclusively to women.

Strangely enough, the drug company had presented no new research on flibanserin’s efficacy since the FDA last rejected it in 2013. (The company's new data included two pharmacology studies to see how women metabolized the drug, and research on whether women could drive safely while taking flibanserin.)

"This was not a decision based on the science," Woloshin added in a follow up call. "There was no new evidence. The FDA had made the decision twice that they didn't think the benefits outweighed the harms."

So by all appearances, it was the rowdy meeting that had changed the FDA's mind.

How the drug industry worked with patient groups to bring "pink Viagra" to American women

To find out more about the patients who had lobbied the FDA to approve flibanserin, I called some of them up. They were generally sincere in their advocacy. But I also learned that Sprout, the drug's manufacturer, had paid for some of them to push for the drug's approval.

Katherine Campbell is an Indiana resident and a new mom who spoke at the June meeting with her husband because she's desperate for a treatment for her very low sex drive. "I've been dealing with HSDD for over three years now," she told me. She initially thought it was just the exhaustion that comes with having a child. But long afterward, her sex drive still hadn't returned. Chocolate, romantic holidays, glasses of wine — nothing worked. And she had no other medical or marital issue that might explain the lack of desire.

So, following a particularly unhelpful doctor's appointment, Campbell did some research online and came across Sprout's homepage. She contacted the drug company about participating in a clinical trial. A representative wrote back saying that they were finished with the trials, but encouraged her to get involved with patient advocacy. "I thought if there's anything I can do to get treatment, that would be amazing," she told me.

There were 38 people who got up to speak. At least six were paid by Sprout to be there.

Sprout paid for flights and expenses to get Campbell and her husband to an FDA meeting in 2014 about HSDD, and to return to Washington, DC, for the June meeting. Campbell viewed the funding as a fortuitous alignment of interests, rather than a conflict.

As it turns out, Sprout was behind a number of voices like Campbell's at that approval meeting. There were 38 members of the public who got up to speak. At least six were paid by Sprout to be there, according to the company. Still other attendees had either participated in the flibanserin clinical trials or worked with Sprout in other capacities. Some of the consumer groups that spoke, such as the National Consumers League, receive funding from the drug industry.

This potential conflicts of interest weren't obvious from the meeting itself. Seventeen of those who didn't disclose travel payments made statements like, "I have no financial stake in the outcome of this meeting." But, oddly, that included at least two Sprout consultants and a Sprout advisory board member.

"I had never seen a company go so far in their cultivation of patients to speak in a way that would help the company," said Cindy Pearson, the executive director of the National Women's Health Network, which does not receive any funding from the pharmaceutical industry.

To be clear, it's unlikely that anyone paid by Sprout to attend the meeting changed her mind because he or she received airfare. They all seemed to believe the drug should be approved, and Sprout simply gave them a platform. But the funding undoubtedly skewed the mix of voices present at that meeting. No one was paying to bring in women who may have been harmed by flibanserin at trial, for example, or other detractors.

That put the FDA advisory committee — which had to vote on whether to approve the drug — in a difficult position. "There was this consistent and passionate heartfelt testimony from women who had experienced a change in desire," says Pearson. "And I think it was just emotionally hard for most of the advisory committee to not respond to that with compassion and vote for approval."

How pharmaceutical companies can skew the drug approval process

pink viagra pills

(Shutterstock)

If pink Viagra were the only questionable drug making it past the gatekeepers, that might not be such a big deal. Arguably, flibanserin might not affect that many people, for better or worse. The bigger worry is that the process illustrates how companies can get drugs with marginal benefits and serious risks through the FDA. What happens if the agency ends up waving through another Vioxx — the anti-inflammatory that had to be withdrawn in 2004 after killing an estimated 60,000 patients?

What's more, the pink Viagra case shows how sober scientific decisions about new medicines can now be gamed by savvy advocates, turned into emotive spectacles.

The result, said Yale's Gonsalves, is that "
we'll be more and more unsure if a drug is safe, we won't know how to make treatment choices when faced with a new drug and an old one. Without rigorous evidence of new treatments in comparison with standard of care, we won't know what will help us, what will make us better."

Ever since the early days of AIDS activism, the FDA has steadily become more open to the public. Most recently, since 2007, the agency has convened public advisory committee meetings to discuss almost every new drug pending approval (unless there's no reason to do so, as when the data is clear-cut). These meetings typically feature industry representatives giving a presentation, FDA scientists analyzing the data, and an hour for public comment.

In the past, Pearson explained, these sessions usually featured individual clinicians who cared about a certain issue, consumer groups, and a handful of patients. "But as time went on, companies started to spread the word and encourage patients to come," she says. "And then advocacy groups started to encourage people to come to FDA meetings."

"FDA's public hearings are being stacked by pharmaceutical companies who are flying in patients"

Adriane Fugh-Berman, a professor at Georgetown University who studies pharmaceutical marketing, agrees that this is a concern: "The open public hearing is now being stacked by pharmaceutical companies who are flying in patients. It's not just Sprout." She adds that these patient testimonies can often be incredibly persuasive and move advisory committees.

Technically, the FDA asks that members of the public reveal potential conflicts of interest before speaking. But they aren’t required to do so, and the FDA has no ability to enforce transparency. "What goes on between the company and their public that they work with is out of our control," says the FDA's Richard Klein. "Unless Congress were to change laws, I don't see us having any jurisdiction."

On the flip side, Klein added, "You don't want to restrict that speech, either." After all, it doesn't seem right to bar people who suffer from rare diseases or unmet medical conditions from speaking at these events.

So that's one dilemma: How can the FDA incorporate outside views without falling prey to conflicts of interest? Klein, for his part, suggested the FDA's advisory committees are capable of sorting this out by itself. "If the evidence is really against the product in terms of benefit and that risk balance, then the decision probably couldn't be swayed so easily at any meeting by a concerted effort," he said.

That's not entirely comforting, however. What about when the risk-benefit calculus is a little unclear and there are no alternatives on the market, as with flibanserin? Or when, as this case shows, public meetings are overwhelmed by industry allies, drowning out independent voices?

This question also extends beyond public advisory meetings. Experts think drug companies exert influence in all sorts of subtle ways — often in favor of lower standards and faster approvals. Dan Carpenter, a professor of government at Harvard who wrote a history of the FDA, recalls going to a public meeting this summer about reauthorizing the Prescription Drug User Fee Act (PDUFA), the law that allows the agency to collect fees on pharmaceutical companies in order to fund the drug approval process.

This meeting was supposed to include academics, industry representatives, and patient and consumer groups — a mélange of diverse perspectives. But Carpenter noticed that the room was rife with conflicts of interest. One consumer group was funded by pharma. Another academic had worked as an industry consultant.

"The meeting was very tilted toward industry-backed views," Carpenter said. "Overwhelmingly the discussion was focused on how we can make drug approval even easier, how to get drugs even more quickly to patients with less testing, and an atmosphere in the room that suggested the consensus should be that the wheels of drug approvals should be greased as much as possible."

The FDA now approves almost every drug

Nowadays, the FDA is considered the fastest drug approval agency in the world. It takes between six and 10 months to approve drugs — down from about three years, on average, in 1975. So far this year, the agency has approved 96 percent of the new drugs it considered. Nearly everything gets through.

The hard question is whether this is happening because the FDA is especially efficient — or because the agency has been captured by industry and is approving dubious drugs more rapidly.

There's actually a good case that the FDA has become efficient for largely positive reasons. Peter Barton Hutt, a DC-based lawyer who specializes in pharmaceutical regulatory affairs, explained that the agency went from being a "black box" in the 1960s, leaving drug companies guessing about what requirements they needed to meet for approval, to being "one of the most transparent regulatory agencies that has ever existed."

Today it's easy for companies to find out what the FDA requires for approval — what sorts of studies, what sorts of data analyses — which in turn makes the whole process smoother. Pre-approval meetings with the agency are also now common. Drug companies are "no longer groping in the dark," Hutt says.

Other reforms have also sped up the process: Open advisory committee meetings are helpful for drug companies, Hutt said, because industry representatives can easily find out how other similar drugs have fared.

Add it up, and there may be a perfectly benign reason why the approval rate is so high: Companies no longer submit applications for drugs that are likely to get rejected. As Harvard researcher Aaron Kesselheim put it: "It’s actually a minority of drugs that make it all the way to the point of FDA submission and then end up never making it to the market — in part because many drug companies would not spend the resources on doing the pivotal trials and organizing the FDA submission unless they had a strong impression that their drug would be approved."

But that's not the end of the story, either. There are a few other reasons the FDA's drug approval process has sped and opened up — and these are the things critics worry about because they raise the specter of conflicts of interest.

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In 1992, Congress originally enacted the Prescription Drug User Fee Act (PDUFA), which allows drug companies to pay user fees to the agency in exchange for speedier reviews of their products. Before the law passed, taxpayer money funded the FDA's programs related to human drug development. Nowadays, about two-thirds of that budget comes from drug companies.

"[This law] dramatically changed the dynamic from regulated industry and FDA," says Michael Carome, the director of Public Citizen's Health Research Group. "The agency became a client of industry. And too often we think the agency is approving products where the standards for demonstrating that a drug is safe and effective — do the benefits outweigh risks — frequently in our view aren’t being met."

There may be something to those concerns: The average review time for a drug dropped from three years down to one year after the law came into effect, according to a study in Health Affairs. But that research also found that the FDA seemed to be approving riskier drugs following PDUFA. With the passage of the act, there was a 25 percent increase in medicines that needed to be pulled from the market out of safety concerns or that received a new black box warning (which signal that the drug carries very serious side effects).

Other drugs with marginal benefits and potentially dangerous side effects have recently made it through the FDA: Belsomra for insomnia, Contrave for weight loss. A 2010 study in the European Journal of Clinical Pharmacology looked at 122 new drugs approved between 1999 and 2005. Only 10 percent performed better than drugs that were already available. Similarly, a number of studies that have found that since the mid-1990s, about 85 to 90 percent of new drugs don't offer any clinical advantages for patients.

Harvard's Kesselheim is quick to caution that it's hard to tease out causation here, and there's a real debate among academics as to the pros and cons of PDUFA. "I think most rational people recognize that having industry fund the FDA is suboptimal for many reasons," he says. "But having an FDA that isn’t starved for funds as it was in the 1980s is also vitally important."

When I asked an FDA spokesperson about the potential for conflict of interest, she said reviewing thousands of applications for new drugs is extremely labor-intensive work. "It takes steady and reliable funding to maintain and support a staff of trained reviewers capable of accomplishing this vital task," she wrote in an email. "We’re gratified that Congress agrees and has continued to reauthorize the program over the years."

But there have been another unexpected side effect of PDUFA. It gets Congress more involved in shaping the FDA's approval process, which opens another door for pharma lobbying. After all, the law's user fees have to be renewed every five years. And, Carome said, lawmakers frequently tack on provisions to reauthorization bills that are only loosely related to the fees — but are often favorable to the drug industry, like pathways for speedier approval of "breakthrough" or innovative drugs for serious conditions.

Another example: In 2007, as part of PDUFA reauthorization, Congress enacted the Risk Evaluation and Mitigation Strategies (REMS) program. This program allows the FDA to approve drugs that might prove risky for some populations, albeit with controls on how the drug is used. So, for instance, flibanserin will be available through specially certified health-care professionals and pharmacies that have gone through some training. Doctors will need to assess the ability of patients to stay away from drinking while on flibanserin, and women who take it will have to acknowledge they understand the risks.

"I think that has made the FDA a lot more comfortable approving drugs," says Matthew Herper, a Forbes researcher who compiled data on the FDA's faster approval process.

These changes aren't necessarily a win for patients. In 2012, researchers in JAMA looked at the various new pathways for expedited approvals of innovative drugs and worried that some of the medicines offered a small benefit "with substantial risks not yet fully understood." They warned doctors that the "FDA's emphasis on rapid drug approval" underscored the need to be ultra-conservative in their prescribing practices.

"In an ideal world," said physician and author Ben Goldacre, "it wouldn't matter that the FDA had a low bar, because doctors and organizations like NICE [which review evidence and advise governments on which drugs to purchase] would demand high-quality evidence of effectiveness on real-world outcomes before prescribing drugs to patients. Unfortunately, the reality is that this vital filter is patchy."

The FDA may soon be approving more drugs — and faster

Congress is now considering yet more legislation to speed up the FDA approval process even further — and lower the standards for data that the regulator uses to make clinical decisions.

In July, the House passed the 21st Century Cures Act by an overwhelming 344-77 vote. The pharma-backed bipartisan effort actually has a chance of passing through the Senate and getting signed into law.

Critics have pointed out that hidden in the bill's 352 pages is language that could erode the quality of evidence the FDA uses to evaluate new drugs and devices, making it easier for companies to bring substandard or dangerous medicines and medical devices to patients. Rather than fixing certain regulatory problems researchers have flagged, this bill could open the floodgates.

The underlying premise of the 21st Century Cures Act is that the FDA is slowing down the passage of lifesaving cures to people who need them. Again, patients are advocating for the bill's passage. Yet, as a number of observers have pointed out, the problem isn't the FDA. It's that drug companies themselves aren't developing innovative drugs. The problem, in other words, is the pipeline.

"There's no evidence the FDA blocks innovation or makes innovation harder or makes it more costly," said Kesselheim. "The goal in drug development isn't merely innovation, it is innovation that works to help patients. When drugs are shown to be effective and safe, the FDA is the fastest regulatory agency in terms of approvals of new drugs in the world."

Drug companies are also pressuring the FDA to become more lenient on another aspect of regulation: marketing. In the US, companies can only advertise their drugs for FDA-approved indications, not so-called "off label" uses (as when doctors prescribe, say, birth control for acne). But recently, two pharmaceutical companies have turned this into a First Amendment issue, suing the FDA for violating their right to free speech. If others follow, this will hamper the FDA's power to crack down on misleading marketing practices and encourage companies to make all kinds of claims about their products, not necessarily evidence based.

Yale's Gonsalves argued that we already have a far weaker FDA today. "We've tipped the balance far away from rigor now, and patients will pay the price, because they will now become more and more unsure of what the drugs they put in their bodies are actually doing in the most essential sense: Do they extend health and life?"

Gonsalves learned about the dangers of lobbying the FDA early on, during his years as an HIV activist.

"At the start, we were under some illusions about the FDA and drug development, and thought that the agency had lots of drugs in the queue for approval for study or marketing and they were depriving us of life-saving medicines," he said. "We wanted access as soon as we saw some promising data."

A year or two later, activists realized they were wrong. "We had pushed the FDA to approve based on the slimmest of data and at great speed, and really didn’t know much about how or if these drugs were doing any good at all."

Correction: A previous version of this article said the flibanserin alcohol interaction study was submitted to the FDA after the agency's last rejection in 2013. (It was submitted before.)


Editor: Brad Plumer
Visuals: Javier Zarracina

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