Category Archives: News Analysis: Interviews, Op-eds, & Editorials

New Drugs So Pricey They Need New Payment Plans

Sarah Owermogle, Politico: August 13, 2018.


[…] FDA LOOKS TO MODERNIZE CANCER TRIALS — The FDA issued guidance on Friday intended to speed up certain early and mid-stage clinical trials for oncology drugs by merging elements typically found in phase 1 and phase 2 trials. Studying multiple patient groups separately for criteria like safety and efficacy has the potential to lower costs and add efficiency, Commissioner Scott Gottlieb said in a statement.

Initial reviews were positive: “There is no tablet that got handed down from God to Moses that said drug trials must be conducted in three conventional phases,” said Dana-Farber’s George Demetri, who chairs the American Association for Cancer Research’s government affairs committee. The new approach, known as expanded cohort trials, could allow researchers to be more nimble, Demetri said — more easily spotting a drug’s effect on specific cancers or realizing earlier that it isn’t working.

Vanessa Lucey said the Cancer Research Institute, where she directs the venture fund and clinical accelerator, has itself moved toward these kinds of studies.

The costs: But while the proposed changes could streamline certain cancer trials — the guidance is limited to cases in which a drug’s benefits justify an increased risk, like for cancers that have no cure — there still could be additional costs. In the guidance, the FDA warned that trial sponsors would need to streamline logistics and data collection, and incorporate plans to assess data in real time.

“What’s important about this guidance is it’s trying to come to some kind of political compromise,” said Diana Zuckerman, president of the National Center for Health Research. “It’s trying to do two things that usually conflict — speed and safety don’t go together, usually.” She added: “It’s OK to say they’re going to do this to speed up drug development, but some patients are definitely going to get harmed.” […]

Read the full story here.

The Human Tragedy of Poorly Regulated Medical Devices Gets the Spotlight in a Netflix Film

Amy Martyn, Consumer Affairs: July 27, 2018.


The motel where Ana Fuentes arrives one evening with her young daughters charges $110 for a single night and doesn’t offer weekly discounts. Fuentes asks the cashier for a moment so she can think about it.

Outside, the camera captures an anguished look on her face. It’s clear she can’t afford the expense. She books the room anyway. “Do you like it?” she asks her girls as they excitedly unpack their bags.

The family used to have an apartment, but Fuentes had to visit the emergency room so often that she lost her job, her daughters explain on camera.

Such situations aren’t rare in the United States, where experts have repeatedly warned that millions of Americans have almost nothing in savings and are a single medical disaster away from financial ruin. The problem is compounded nationwide by costly healthcare, lack of access to paid sick leave in the workforce, or a combination of the two.

But Fuentes’ story, like dozens of others featured in an upcoming expose about the medical device industry, has a particularly cruel twist. She says in the film that she was healthy until a doctor convinced her to undergo what was supposed to be a routine, non-surgical medical procedure — getting small birth control implants permanently embedded into her fallopian tubes.

The $155 billion medical device industry has mostly avoided the type of scrutiny that drug companies and health insurers sometimes face from elected officials and others. On Friday, a documentary about the device industry and patients like Fuentes called The Bleeding Edge is set to go live on Netflix, bringing what advocates hope will be widespread attention to an industry increasingly characterized by lax safety standards, enormous power in the operating room, and horrific side effects.

“If you’re going to have something implanted in your body for potentially the rest of your life, wouldn’t you like it to be really well-tested beforehand? Is that really too much to ask?” says Dr. Diana Zuckerman, a health policy analyst who has worked in the White House and as a staffer in Congress.

The current president of the National Center for Health Research, Zuckerman and the other researchers at her non-profit are among the few to have taken interest in faulty medical devices.  

Diving into the medical device industry

Hollywood directors Kirby Dick and Amy Ziering knew they wanted to make a documentary film about preventable medical injuries, Dick tells ConsumerAffairs, but that was about it.

Sitting in on one patient advocacy meeting for research, they caught a presentation that Zuckerman gave about the medical device industry and the ease with which questionable products get on the market. They decided that they had found their story.

The team interviewed approximately 70 patients to make their film, Dick tells ConsumerAffairs. The film also includes interviews with numerous whistleblowers, such as doctors, former Food and Drug Administration (FDA) researchers, and one medical device sales rep who requested anonymity in exchange for speaking on camera.

Dick and Ziering were previously nominated for an Oscar for The Hunting Ground, their documentary about sexual assault on college campuses. Another earlier film, The Invisible War, is an expose about sexual assault in the military.

But persuading people to speak out against the device industry made for the most challenging interviews they’ve done, Dick tells ConsumerAffairs. (A medical device industry lobbyist touts in one scene that the industry is more powerful than some national governments.)

The “E-sisters”

As the film and the research it is based on shows, the problem is bigger than any single device. The Bleeding Edge captures the story by focusing  on four implants — three of which were used exclusively women’s reproductive organs.

The narrative is driven forward by the story of the “E-sisters,” or the activists who say that they suffered debilitating side effects after receiving the permanent birth control implant Essure.

For years, the “E-sisters” have organized a grassroots campaign to convince regulators to ban Essure from doctors’ offices. That goal seemed like an uphill battle until last week, when Bayer suddenly released an announcement that Essure will no longer be sold in the United States by the end of the year.

Bayer frames the move as a “business decision.” The announcement came one week before the Netflix documentary was scheduled for release.

“I’m very glad that these issues are getting this kind of attention, and I hope that Bayer’s decision to take Essure off the market won’t take away from the bigger message of the film,” says Zuckerman, “which is the whole process for devices that makes no sense at all.”

“Why in the world would you want to have a regulatory agency in our government, the FDA, having much lower standards for devices than they do for prescription drugs?”

Essure implants

The story of Essure, in particular, only saw the light-of-day thanks to the “E-sisters,” who count 30,000 people in their Essure Problems Facebook group and have convinced numerous elected officials, doctors, and even early clinical trial participants to join their cause.

“One of the things that is disturbing to me is that these issues only came to light because of the work of victims,” former Representative Mike  Fitzpatrick (R-Pa.) said in an interview several years ago.

Women who agreed to participate in clinical trials for Essure in the late 90s have said that they there were sold on a pitch to get a free, non-hormonal, and permanent birth control that was already proven safe.

A nickel coil, the size of a ballpoint pen, would be placed in each fallopian tube. That was designed to create an inflammatory response so that the coils would become permanently encased in the resulting scar tissue.

Regulators with the FDA approved the device in 2002, despite admitting that they knew little about the long-term side effects of such a procedure, as footage that the E-sisters had obtained captures. What’s more, numerous clinical trial participants later said that their painful side effects were not included in the company’s official data.

Doctors not long after began using the devices without questioning potential risks. “For some reason we did that to women. And I did that, too,” Dr. Shawn Tassone, an Austin-based gynecologist, tells ConsumerAffairs.

Insurance and profit margins

The sales representatives who taught doctors how to place the devices — something that Bayer has defended as a common industry practice — offered no instructions on how the device should be removed if there were side effects.

“We were just told from the very beginning that even if they’re misplaced, you don’t have to remove them,” Tassone remembers.

The role that insurance coverage may have played isn’t examined specifically in The Bleeding Edge, but testimony from patients and doctors suggests that getting insurers to cover Essure proved much easier than getting them to cover removal.

Tassone remembers that both private plans and Medicaid paid fairly generously for the Essure procedure, especially considering that inserting Essure was much cheaper and less labor-intensive than tubal surgery, the older sterilization procedure.

“If you think about a tubal ligation where you go to the operating room, it’s $400 [in profit] give or take,” he say. “Essure in the office, after you subtract the amount of the device, it’s probably $1100.”

Treating any resulting side effects proved impossible for women navigating unfamiliar territory. Angie Firmalino, the New York City mail carrier who founded the E-sisters network, initially seeked help from a doctor who morcellated the coils into small pieces — sending the nickel elsewhere in her body.

Connecting patients with doctors who are willing and able to properly remove the devices, as well who are able to code it correctly so that insurance will pay, has since become one of the E-sister’s major tasks.

Tassone, for his part, implanted his last Essure device in 2013. He says it was a call from another doctor who convinced him not to perform the procedure anymore; a woman with Essure apparently had gotten pregnant, he was told, which can be extremely dangerous for both the baby and the mother. One researcher has counted 303 fetal deaths linked to the device.

Tassone has since switched sides, counseling the E-sisters online and in the operating room. He estimates that he has conducted 600 Essure removal surgeries.

Trust remains despite ban

In recent years, the advocates have convinced the FDA to add a black box warning to Essure. Later on, they were able to help pass a rule which requires doctors to give patients more detailed warnings about the product.

But that didn’t appear to stop most doctors from trusting the device. The American College of Obstetricians and Gynecologists continues to say on its website that lasting pain from the procedure is “rare.” By contrast, nearly 27,000 reports have been filed to the FDA’s “adverse event” report database describing health problems caused by Essure and 16,000 lawsuits have been filed here. An estimated 750,000 women worldwide have undergone the procedure.

Now that Essure is off the market, doctors may be more willing to attempt removal surgery, Tassone says, something he thinks is necessary but frightening

“They’re going to think its not a big deal to take out,” he worries. (More detailed advice about removal surgeries is offered on the Essure Problems page).

Generally, before any major surgery involving a permanent implant, researchers advise patients to press doctors on the specific devices that will be used. Zuckerman, the health policy analyst who helped inspire the Netflix film, recalls that even she struggled to get specific answers when she asked a doctor what brand of hip he would choose for her own surgery.

The procedure ultimately went well, she says, but trying to search for good data comparing brands beforehand was nearly impossible.

“In the vast majority of cases, the surgeons are still quoting the company data,” Zuckerman says. “The company’s data on humans is nonexistent —  at least publicly.”

FDA Expedited Approval Process Raises Concerns About Risks

Roxanne Nelson, Medscape: July, 20, 2018


The Breakthrough Therapy designation created by the US Food and Drug Administration (FDA) expedites the approval of drugs intended to treat serious or life-threatening conditions, thus allowing patients quicker access to therapies. But the shorter approval process leads to great uncertainty about safety and efficacy. Are the risks greater than the benefits?

These concerns have been raised again in a new study published online July 17 in JAMA and in an accompanying commentary in the JAMA Forum.

The findings from this study “suggest that the FDA’s expedited review programs may invite greater risks than benefits,” writes Austin B. Frakt, PhD, director of the Partnered Evidence-based Policy Resource Center, Veterans Health Administration, Boston, Massachusetts, in the commentary.

“The idea that doing something more quickly means it is not done as well has considerable face validity,” he comments.

Shorter Trials Lacking Controls  

The new study reviewed all FDA approvals given Breakthrough Therapy designation from 2012 through 2017 and found that the pivotal trials used as a basis for these approvals more often than not lacked randomization, double-blinding, and control groups. They also tended to use surrogate markers as primary endpoints and had small patient cohorts.

In addition, over half of the approvals were based on the results of a single trial.

This leads to greater uncertainty, say the authors, led by Joseph S. Ross, MD, MHS, an associate professor of medicine at Yale University School of Medicine, New Haven, Connecticut.

It is not known whether the effect observed in the single small trial will be observed in a larger population or replicated in another trial, or whether the effect observed over the short term will persist over the longer term.

“There is also uncertainty over whether the effect observed on the outcomes used in these shorter trials, such as surrogate markers of disease, will be confirmed by eventual demonstration of benefit and safety based on clinical outcomes like improved mortality or improved symptoms,” Ross told Medscape Medical News.

Ross said that the FDA “is doing everything it can to expedite the development and review of drugs that treat serious and life-threatening conditions.”

“My expectation is that this is what the public and clinicians — and Congress — want,” he told Medscape Medical News. “More novel therapies coming to market as quickly as is reasonably possible, while still assuring drug safety and efficacy.”

But their research suggests that FDA approval of these breakthrough therapies is generally based on shorter and smaller clinical trials than those that support FDA approval of non–breakthrough therapy drugs.

If this “trade off” is going to be made, with novel drugs entering the market on the basis of evidence that is generally accompanied by greater uncertainty, “we must be committed as a clinical and scientific community to ensuring that high-quality, rigorous postmarket trials are conducted within a reasonable period of time,” he added. “This will resolve some of this uncertainty and ensure that the drugs are associated with the benefit/safety profile that we expect based on the initial clinical studies, allowing clinicians and patients to make fully informed decisions about whether to use these novel treatments.”

Minimal Evidence

In this study, Ross and colleagues reviewed all new FDA approvals that had been granted Breakthrough Therapy designation, looking at the pivotal clinical trials that serve as the basis for approval as well as pre-market development and review times.

They identified 46 agents that had received Breakthrough Therapy designation between 2012 and 2017, based on 89 pivotal trials. Of these, more than half were for oncologic indications (n = 25 [54.3%]), followed by infectious disease (n = 8 [17.4%]); just over half the drugs (n = 25 [54.3%]) were considered to be first in class.

In addition, nearly two thirds of these agents were designated as orphan products (n = 30 [65.2%]) and qualified for Fast Track review (n = 24 [52.2%]) and Accelerated Approval (n = 18 [39.1%]).

Many of these drugs had only one clinical trial (median, 1; interquartile range [IQR], 1 – 2), while the median number of patients enrolled in these trials was 222 (IQR, 124 – 796). Roughly half of all approvals were made on the basis of a randomized trial (n = 27 [58.7%]), while 21 studies used double-blind allocation (45.7%), 25 had an active comparator or placebo control group (54.3%), and 10 had a clinical primary endpoint (21.7%).

Clinical trials that supported breakthrough approvals with Accelerated Approval status were less likely to be randomized than those without Accelerated Approval (3 trials with Accelerated Approval [16.7%] vs 24 trials without Accelerated Approval [85.7%]; P <  .001).

The median time to FDA approval was 4.9 years (IQR, 2.7 – 7.6 years), and all eight agents (100%) that received accelerated approval had at least one clinical safety or efficacy-focused postmarketing requirement, as did 18 (64.3%) without Accelerated Approval designation.

Information Lost

Approached for comment, Diana Zuckerman, PhD, president of the National Center for Health Research, noted that historically, the FDA required two clinical trials with clinically meaningful endpoints, and for cancer, that was survival.

“That was the standard, and it did result in complaints,” she told Medscape Medical News. “There were complaints that trials take too long and are too expensive, and complaints from patients and physicians that the drugs weren’t available.”

“This research letter in JAMA is important, as it is a very well done reminder what you lose when you speed things up,” Zuckerman added.

The FDA required two studies because the second study shows replication of the results, and that is the keystone to research. “You need to replicate the results,” Zuckerman commented.

“This paper also shows that we have lost double-blinding and active comparators and placebo groups half of the time,” she said. In addition, “very few trials had a clinical endpoint.”

“We lost a lot of information, and this means that patients are using drugs that may not be as effective as older treatments, but yet are much more expensive,” she said.

Zuckerman pointed to a study that she coauthored in 2016, which found that many new cancer drugs approved on the basis of surrogate endpoints retain their approval status and remain available to prescribing physicians even though postmarketing studies show no survival or quality-of-life (QoL) benefit compared with placebo or observation groups.

Of 36 drugs that were approved between 2008 and 2012, 18 did not significantly prolong overall survival in postmarket studies. QoL information was available for 7 drugs, and compared with placebo or observation groups, 2 drugs demonstrated worse effects on QoL, 4 drugs showed no statistical difference, and 1 drug had mixed results. In addition, 1 drug reduced overall survival and 6 offered no survival benefit compared with placebo or observation groups.

“These drugs are very expensive,” Zuckerman explained, noting that they ranged in price from $20,237 to $169,836 per year. “There is no relationship between cost and evidence.”

The FDA does allow access to experimental drugs, and with the Right to Try law, it is now easier for patients to gain access, she said. “At least patients know that they are getting an experimental treatment, and that long-term safety and efficacy are unknown. But with expedited approval, they believe they are getting something backed by evidence.”

Right now, the model is “unsustainable,” she said.

Zuckerman also added that the FDA is not responding to these concerns by enforcing requirements for postmarketing studies, and those that are completed are not giving useful results.

Greater Risks Than Benefits?

In the related commentary, Frakt says the findings suggest that the FDA’s expedited review programs may invite greater risks than benefits.

He notes that most of the new drugs are approved even though information concerning long-term outcomes is limited, and more than two thirds are approved on the basis of clinical trials lasting under 6 months.

In addition, the median approval for cancer drugs in the expedited process is 6 months, which is much quicker than in Europe and Canada.

However, it remains an “empirical question” as to whether the drugs that receive an expedited approval have a worse or better benefit/risk balance compared with drugs that receive standard approval.

Frakt points out that over time, safety concerns may arise for drugs with expedited approval. “Drugs subject to less FDA scrutiny are more likely to exhibit safety problems, be withdrawn from the market, or carry black box warnings,” he says. “We should therefore continue to monitor these drugs and update the performance of expedited approval programs as more information is available.”

But another concern, he adds, is that from 2009 through 2013, only a minority of drugs with expedited approval had their efficacy tested in a postmarket trial within 3 years, as previously reported by Medscape Medical News.

Accepting greater risks may be “reasonable and consistent” with patient preferences, as the expedited review programs are for new agents designed to treat serious conditions and address unmet medical needs. But because many of these new drugs are quite costly and are paid for with public funding through Medicare, Medicaid, and other programs, Frakt notes that “the patients’ point of view is not the only one of relevance. A consideration of cost is also reasonable from the point of view of taxpayers.” […]

Read the original article here.

To Improve Treatments, Researchers Want To Hunt For Clues In Medical Records

Richard Harris, NPR: July 16, 2018


When you go to your doctor’s office, sometimes it seems the caregivers spend more time gathering data about you than treating you as a patient.

Electronic medical records are everywhere – annoying to doctors and intrusive to patients.

But now researchers are looking to see if they can plow through the vast amount of data that’s gathered in those records, along with insurance billing information, to tease out the bits that could be useful in refining treatments and identifying new uses for drugs.

For instance, when the Food and Drug Administration approves a new drug, doctors often don’t know the optimal dose, the ideal length of treatment or who is most likely to benefit – or be harmed – by the medicine.

Especially when it comes to drugs fast-tracked through the process, “there are so many questions that remain when a drug is approved,” says Dr. Janet Woodcock, who heads the FDA’s drug-approval branch. “Many of the questions are not interesting to academics so they’re not done in the academic setting, and companies are not compelled to do them… so nobody does them. I’ve been raving about this for years!” she said Wednesday at a meeting on the subject convened by the Friends of Cancer Research, a nonprofit organization that builds collaborations between government, industry and advocacy groups.

Relevant information is buried – somewhere – within medical records and billing information. The question is whether it’s practical to extract it from these systems, which weren’t designed to be used for research.

It’s an uphill climb. Researchers involved in an experiment to explore medical records to study cancer treatment discovered that these data sources lack some very basic information.

For example, these records don’t typically even show whether a patient is alive or dead.

“Physicians are spending a tremendous amount of time entering information into electronic systems to the point they can hardly find time in their day to look patients in the eye,” says Dr. Andrew Norden, chief medical officer of Cota, a company that crunches digital medical data gleaned from these records. “Yet to date, we’ve not been able … to drive knowledge forward much from that information.”

Cota joined five other organizations recently in an experiment to explore the value of electronic medical records to improve cancer treatment. Friends of Cancer Research asked these six firms to plumb their databases to see what they could conclude about the value of various treatment options for a type of lung cancer.

The results of this pilot study, unveiled at the Friends of Cancer Research meeting, showed that the six independent dives into the data came up with roughly consistent answers. That suggests that this information gathered about patients, dubbed real-world data, is potentially useful for research.

But there are plenty of challenges. Take death. Doctors and insurers rarely add this information into the record of a patient who has died. Researchers have to find that critical piece of information elsewhere.

“We do have a national death index,” says Nancy Dryer, at the medical data firm called IQVIA. “It’s phenomenal, but it’s slow.” It can take more than a year for a death to be recorded there, which means people trying to study medical records have to deal with a difficult time lag. There are other faster ways to glean this information – for example from credit bureaus. “They actually know if you’re dead!” Dryer says. But medical researchers can’t readily access that information because of privacy concerns.

Another challenge is using medical records to measure whether a disease has progressed. Researchers who run formal clinical trials of a potential new drug define disease progression carefully. But that’s not usually the case in medical records. Researchers have to figure out ways to infer that from the medical records and in billing information, and that’s dodgy.

Sometimes it’s even hard to tell a patient’s exact diagnosis from an electronic medical record. “Apparently that’s a very big barrier, to get the diagnosis correct in the patient’s own chart!” Woodcock says. “So you can see how far we have to go.”

Nevertheless, Woodcock says this is an avenue well worth exploring. Much of medical research now depends on formal clinical trials – typically tests that pit a new treatment against a placebo or one that is already on the market.

The traditional system provides the most reliable data, but “it’s incredibly, ridiculously and unsustainably expensive,” Woodcock says. She laments that clinical trials operate largely in isolation from routine clinical care, “and we must bring them back together if we’re going to investigate interventions rapidly and thoroughly.” Figuring out how to use real-world evidence “is the key to making that happen,” she says.

But data from individual patient records is never going to be consistent or error-free. The balancing act is to figure out when a finding extracted from this noisy information is good enough to make judgments that affect clinical practice.

Insurers and drug companies are already interested in using this information to help establish the value of a particular treatment, which can affect whether a new treatment is covered, and at what price. But drug companies would also like to use this information to identify new or expanded uses for drugs already on the market.

Diana Zuckerman, president of the National Center for Health Research, is concerned about that use of real-world data. “You can pretty much make the data show whatever you want it to show,” she says in a telephone interview. So if you put the data into the hands of drug companies, who have a financial incentive to find new uses for their drugs and improve their market share, “you can’t expect they’re going to be conducting unbiased research if nobody’s monitoring that.” […]

Read the original article here.

FDA Repays Industry by Rushing Risky Drugs to Market

Caroline Chen, ProPublica. June 26, 2018.


Nuplazid, a drug for hallucinations and delusions associated with Parkinson’s disease, failed two clinical trials. In a third trial, under a revised standard for measuring its effect, it showed minimal benefit. Overall, more patients died or had serious side effects on Nuplazid than after receiving no treatment.

Patients on Uloric, a gout drug, suffered more heart attacks, strokes and heart failure in two out of three trials than did their counterparts on standard or no medication.

Nevertheless, the U.S. Food and Drug Administration approved both of these drugs — with a deadly aftermath. Uloric’s manufacturer reported last November that patients on the drug were 34 percent more likely to die from heart disease than people taking an alternative gout medication. And since the FDA fast-tracked approval of Nuplazid and it went on the market in 2016 at a price of $24,000 a year, there have been 6,800 reports of adverse events for patients on the drug, including 887 deaths as of this past March 31.

The FDA is increasingly green-lighting expensive drugs despite dangerous or little-known side effects and inconclusive evidence that they curb or cure disease. Once widely assailed for moving slowly, today the FDA reviews and approves drugs faster than any other regulatory agency in the world. Between 2011 and 2015, the FDA reviewed new drug applications more than 60 days faster on average than did the European Medicines Agency.

Europe has also rejected drugs for which the FDA accelerated approval, such as Folotyn, which treats a rare form of blood cancer. European authorities cited “insufficient” evidence of health gains from Folotyn, which shrinks some tumors but hasn’t been shown to extend lives. It costs more than $92,000 for a seven-week course of treatment, according to research firm SSR Health.

As patients (or their insurers) shell out tens or hundreds of thousands of dollars for unproven drugs, manufacturers reap a windfall. For them, expedited approval can mean not only sped-up sales but also — if the drug is intended to treat a rare disease or serve a neglected population — FDA incentives worth hundreds of millions of dollars.

“Instead of a regulator and a regulated industry, we now have a partnership,” said Dr. Michael Carome, director of the health research group for the nonprofit advocacy organization Public Citizen, and a former U.S. Department of Health and Human Services official. “That relationship has tilted the agency away from a public health perspective to an industry friendly perspective.”

While the FDA over the past three decades has implemented at least four major routes to faster approvals — the current commissioner, Dr. Scott Gottlieb, is easing even more drugs’ path to market. The FDA okayed 46 “novel” drugs — whose chemical structure hadn’t been previously approved — in 2017, the most in at least 15 years. At the same time, it’s rejecting fewer medications. In 2017, the FDA’s Center for Drug Evaluation and Research denied 19.7 percent of all applications for new drugs, biologics, and efficacy supplements, down from a 2010 peak of 59.2 percent, according to agency data.

President Trump has encouraged Gottlieb to give patients faster access to drugs. “You’re bringing that down, right?” Trump asked the commissioner at a May 30 event, referring to the time it takes to bring drugs to market. “You have a lot of good things in the wings that, frankly, if you moved them up, a lot of people would have a great shot.”

Faster reviews mean that the FDA often approves drugs despite limited information. It channels more and more experimental treatments, including Nuplazid, into expedited reviews that require only one clinical trial to show a benefit to patients, instead of the traditional two.

The FDA also increasingly allows drugmakers to claim success in trials based on proxy measurements — such as shrunken tumors — instead of clinical outcomes like survival rates or cures, which take more time to evaluate. In return for accelerated approval, drug companies commit to researching how well their drugs work after going on the market. But these post-marketing studies can take 10 years or longer to complete, leaving patients and doctors with lingering questions about safety and benefit.

“Clearly, accelerated approval has greater uncertainty,” Dr. Janet Woodcock, head of the FDA’s Center for Drug Evaluation and Research, said in an interview. When only a single trial is used for approval, “in some cases, there may be more uncertainty about safety findings or with the magnitude of effectiveness.”

She attributed the increased use of expedited pathways to more drugmakers developing treatments for rare diseases, “where there’s unmet need, and where the patient population and providers are eager to accept more uncertainty.”

The FDA’s growing emphasis on speed has come at the urging of both patient advocacy groups and industry, which began in 1992 to contribute to the salaries of the agency’s drug reviewers in exchange for time limits on reviews. In 2017, pharma paid 75 percent — or $905 million — of the agency’s scientific review budgets for branded and generic drugs, compared to 27 percent in 1993.

“The virginity was lost in ’92,” said Dr. Jerry Avorn, a professor at Harvard Medical School. “Once you have that paying relationship, it creates a dynamic that’s not a healthy one.”

Industry also sways the FDA through a less direct financial route. Many of the physicians, caregivers, and other witnesses before FDA advisory panels that evaluate drugs receive consulting fees, expense payments, or other remuneration from pharma companies.

“You know who never shows up at the [advisory committee]? The people who died in the trial,” lamented one former FDA staffer, who asked not to be named because he still works in the field. “Nobody is talking for them.”

The drug industry’s lobbying group, Pharmaceutical Research and Manufacturers of America, continues to push for ever-faster approvals. In a policy memo on its website, PhRMA warns of “needless delays in drug review and approval that lead to longer development times, missed opportunities, higher drug development costs and delays in treatments reaching patients.”

The agency has internalized decades of criticism that painted it as an obstacle to innovation, said Daniel Carpenter, a professor of government at Harvard and author of a 2010 book on pharmaceutical regulation at the FDA. “They now have a built-in fear of over-regulation that’s set in over the last 20 years.”

To be sure, nobody wants the FDA to drag out drug reviews unnecessarily, and even critics acknowledge that there’s no easy way for the agency to strike the perfect balance between sufficient speed and ample information, particularly when patients have no other treatments available, or are terminally ill.

“I think it’s reasonable to move drugs faster particularly in the case where you’re dealing with an extremely promising new product which treats a serious or life-threatening disease,” said Dr. Aaron Kesselheim, an associate professor at Harvard Medical School. “The key, though, when you do that is that you’ve got to make sure you closely follow the drug in a thoughtful way and unfortunately, too often we don’t do that in the U.S.”

Gregg Gonsalves used to be a member of ACT UP, the HIV advocacy group that tried to take over the FDA’s headquarters in Rockville, Maryland, in 1988, accusing the agency of holding back cures. While he didn’t storm the FDA building, Gonsalves participated in other protests that led the FDA to accelerate approvals. Now an assistant professor of epidemiology at Yale School of Public Health, he said he fears HIV activists “opened a Pandora’s box” that the industry and anti-regulation think tanks pounced on.

“We were desperate. We naively had the idea that there were hundreds of drugs behind a velvet curtain at the FDA being held back from us,” he said. “Thirty years of our rash thinking has led us to a place where we know less and less about the drugs that we pay more and more for.”

After thalidomide, taken by pregnant women to prevent nausea, caused thousands of babies in the early 1960s to be born with stunted limbs, Congress entrusted the FDA with ensuring that drugs going on the market were both safe and effective, based on “substantial evidence” from multiple trials.

Assembling this evidence has traditionally required three stages of clinical trials; the first in a small cohort of healthy volunteers to determine a safe dosage; the second to assess the drug’s efficacy and side effects; and then, if results are positive, two larger trials to confirm the benefit and monitor for safety issues. An FDA team of in-house reviewers is then assigned to analyze the results and decide whether the agency should approve the drug. If reviewers want more input, the agency can convene an advisory committee of outside experts.

As the FDA’s responsibilities expanded in the 1970s, review times began to lag, reaching more than 35 months on average in 1979. The AIDS crisis followed soon thereafter, prompting complaints from Gonsalves and other activists. Their protests spurred the Prescription Drug User Fee Act in 1992, which established industry fees to fund FDA staff salaries. In return, the FDA promised to review drugs within 12 months for normal applications, and 6 months for priority cases.

The more that the FDA relied on industry fees to pay for drug reviews, the more it showed an inclination towards approval, former employees say.

“You don’t survive as a senior official at the FDA unless you’re pro-industry,” said Dr. Thomas Marciniak. A former FDA medical team leader, and a longtime outspoken critic of how drug companies handle clinical trials, Marciniak retired in 2014. “The FDA has to pay attention to what Congress tells them to do, and the industry will lobby to get somebody else in there if they don’t like you.”

Staffers know “you don’t get promoted unless you’re pro-industry,” he added.

This tilt is reflected in what senior officials choose to highlight. The agency’s Center for Drug Evaluation and Research gives internal awards to review teams each year, according to Marciniak and the former FDA employee who requested anonymity. Both said they had never seen an award granted to a team that rejected a drug application. The FDA did not respond to ProPublica’s request for a list of award winners.

Higher-ups would also send congratulatory emails to medical review teams when a drug was approved. “Nobody gets congratulated for turning a drug down, but you get seriously questioned,” said the former staffer, adding that the agency’s attitude is, “Keep Congress off your back and make your life easier.”

Dr. Peter Lurie, a former associate commissioner who left the FDA in 2017, recalled that John Jenkins, director of the agency’s Office of New Drugs from 2002 to 2017, gave an annual speech to employees, summing up the year’s accomplishments. Jenkins would talk “about how many approvals were done and how fast they were, but there was nothing in there saying, we kept five bad drugs off the market,” said Lurie, now president of the nonprofit Center for Science in the Public Interest in Washington, D.C. Jenkins declined to comment.

“I personally have no interest in pressuring people to approve things that shouldn’t be approved — the actual person who would be accountable would be me,” Woodcock said. She added that the FDA’s “accountability to the public far outweighs pressure we might feel otherwise.”

Congress has authorized one initiative after another to expedite drug approvals. In 1988, it created “fast track” regulations. In 1992, the user fee law formalized “accelerated approval” and “priority review.” When the law was reauthorized in 1997, the goal for review times was lowered from a year to 10 months. In 2012, Congress added the designation, “breakthrough therapy,” enabling the FDA to waive normal procedures for drugs that showed substantial improvement over available treatments.

“Those multiple pathways were initially designed to be the exception to the rule, and now the exceptions are swallowing the rule,” Kesselheim said.

Sixty-eight percent of novel drugs approved by the FDA between 2014 and 2016 qualified for one or more of these accelerated pathways, Kesselheim and his colleagues have found. Once described by Rachel Sherman, now FDA principal deputy commissioner, as a program for “knock your socks off, home run” treatments, the “breakthrough therapy” label was doled out to 28 percent of drugs approved from 2014 to 2016.

Nuplazid was one of them. It was created in 2001 by a chemist at Acadia Pharmaceuticals, a small biotech firm in San Diego. Eight years later, in the first of two Phase 3 trials, it failed to prove its benefit over a placebo.

The company, which had no approved drugs and hence no revenue stream, halted the second trial, but wasn’t ready to give up. Acadia executives told investors that the trials failed because the placebo patients had a larger-than-expected improvement. They asked the FDA for permission to revise the scale used to measure benefit, arguing that the original scale, which was traditionally used for schizophrenia assessments, wasn’t appropriate for patients with Parkinson’s-related psychosis. The agency agreed to this new scale, which had never been used in a study for drug approval.

Since there were no treatments approved for Parkinson’s-related psychosis, the FDA also granted Acadia’s request for the breakthrough therapy designation, and agreed that Nuplazid needed only one positive Phase 3 trial, instead of two, for approval.

In 2012, Acadia finally got the positive trial results it had hoped for. In a study of 199 patients, Nuplazid showed a small but statistically significant advantage over a placebo.

FDA medical reviewer Dr. Paul Andreason was skeptical. Analyzing all of Nuplazid’s trial results, he found that you would need to treat 91 patients for seven to receive the full benefit. Five of the 91 would suffer “serious adverse events,” including one death. He recommended against approval, citing “an unacceptably increased, drug-related, safety risk of mortality and serious morbidity.”

The FDA convened an advisory committee to help it decide. Fifteen members of the public testified at its hearing. Three were physicians who were paid consultants for Acadia. Four worked with Parkinson’s advocacy organizations funded by Acadia. The company paid for the travel of three other witnesses who were relatives of Parkinson’s patients, and made videos shown to the committee of two other caregivers. Two speakers, the daughter and grand-daughter of a woman who suffered from Parkinson’s, said they had no financial relationship with Acadia. However, the granddaughter is now a paid “brand ambassador” for Nuplazid. All begged the FDA to approve Nuplazid.

“Acadia or its consultants interacted with some of the potential speakers to facilitate logistics and reimburse for travel, as is common practice,” Acadia spokeswoman Elena Ridloff said in an email. “…All speakers presented their own experience in their own words.”

The only speaker who urged the FDA to reject the drug was a scientist at the National Center for Health Research who has never had any financial relationship with Acadia.

The witnesses’ pleas affected the panel members, who voted 12-2 to recommend accelerated approval. “If there were a safe and effective alternative on the market, I would not have voted yes,” said Almut Winterstein, a professor of pharmaceutical outcomes and policy at the University of Florida. “But I think that, in particular, the public hearing today was very compelling. There clearly is a need.”

Dr. Mitchell Mathis, director of the FDA’s division of psychiatry products, sided with the advisory panel, overruling Andreason. “Even this small mean improvement in a disabling condition without an approved treatment is meaningful,” Mathis wrote, adding that its safety profile was no worse than other antipsychotics on the market. Like other antipsychotics, Nuplazid carries a warning on the label of increased deaths in elderly patients with dementia-related psychosis. Since Nuplazid’s approval in 2016, Acadia has raised its price twice, and it now costs more than $33,000 a year.

As Nuplazid began to reach patients, reports of adverse events poured in. While it’s impossible to ascertain whether the treatment was responsible for them, the sheer numbers, including the 887 deaths, are “mind boggling,” said Diana Zuckerman, president of the National Center for Health Research.

In more than 400 instances, Nuplazid was associated with worsening hallucinations — one of the very symptoms it was supposed to treat.

That’s what happened to Terrence Miller, a former Hewlett Packard and Sun Microsystems employee who was diagnosed with Parkinson’s in the early 1990s. About five years ago, Miller began to experience mild hallucinations, such as seeing cats and dogs in his home in Menlo Park, California. At the time, he realized that the animals weren’t real, and the visions didn’t bother him, so he didn’t take any medication for them. But two years later, after surgery for a hip injury, the hallucinations worsened.

“He was convinced that he hadn’t had the surgery yet and people were going to harvest his organs,” recalled his wife, Denise Sullivan. “He’d see spaceships outside the window and they had to call security to help restrain him.”

In 2016, Dr. Salima Brillman prescribed Nuplazid. Miller tried Nuplazid twice, for a few months each time. His hallucinations became darker. “I’d say, ‘Who are you talking to?’ and he said, ‘They’re telling me to do bad stuff,’” Sullivan said. Afraid “he might hurt me because of what his evil ‘friends’ were telling him,” Sullivan, who was paying more than $1,000 a month for the drug out of her own pocket, then stopped the treatment.

What Sullivan and Miller didn’t know is that Brillman earned $14,497 in consulting fees from Acadia in 2016, ranking as the company’s seventh highest paid doctor, government records show. The top five prescribers of Nuplazid in Medicare, the government’s health program for the elderly, all received payments from Acadia. Dr. David Kreitzman of Commack, New York, prescribed the most: $123,294 worth of Nuplazid for 18 patients in 2016, according to data company CareSet. He was paid $14,203 in consulting fees.

Brillman and Kreitzman didn’t respond to multiple requests for comment.

Miller’s new doctor switched him onto Seroquel, an old drug long used off-label for Parkinson’s-related psychosis. With it, he’s sleeping better and the hallucinations, while remaining, have become more benign again, Sullivan said. Patients like Miller, whose hallucinations worsen, may not have been on Nuplazid for long enough, said Ridloff, the Acadia spokeswoman.

The 887 reported deaths of Nuplazid patients may be an undercount. A nurse in Kansas, who specializes in dementia care, said a resident in one of the facilities she worked at had no history of cardiac issues, yet died from congestive heart failure within a month of starting on Nuplazid. The nurse requested anonymity because she continues to work in nursing care facilities.

“We questioned the ordering physician whether this should be reported to the FDA in relation to Nuplazid and he said, ‘Oh no, the drug rep said this couldn’t have happened because of Nuplazid,’ and it was never reported,” she said.

Acadia’s Ridloff said such behavior by a sales representative would be “absolutely not consistent with our protocols, policies and procedures.”

She said that deaths are to be expected among patients who are elderly and in an advanced stage of Parkinson’s, and that Nuplazid does not increase the risk of mortality.

“Acadia’s top priority has been, and continues to be, patient safety,” she said. “We carefully monitor and analyze safety reports from clinical studies and post-marketing reporting to ensure the ongoing safety of Nuplazid. Based on the totality of available information, Acadia is confident in Nuplazid’s efficacy and safety profile.”

After a CNN report in April about adverse events related to Nuplazid prompted lawmakers to question the FDA, Gottlieb said he would “take another look at the drug.” Agency spokeswoman Sandy Walsh confirmed that that an evaluation is ongoing, and the FDA “may issue additional communications as appropriate.”

Nuplazid isn’t the only drug approved by an FDA senior official against the advice of lower-level staffers. In 2016, internal reviewers and an advisory committee called for rejecting a drug for a rare muscular disease called Duchenne muscular dystrophy. Only 12 patients participated in the single trial that compared the drug, Exondys 51, with a placebo. Trial results showed that Exondys 51 produced a small amount of dystrophin, a protein Duchenne patients lack. But the company didn’t show that the protein increase translated into clinical benefits, like helping patients walk.

Woodcock approved the drug. Internal FDA documents later revealed that she was concerned about the solvency of the drugmaker, Sarepta Therapeutics in Cambridge, Massachusetts. A memo by the FDA’s acting chief scientist recounted Woodcock saying that Sarepta “needed to be capitalized” and might go under if Exondys 51 were rejected. Exondys 51 went on the market with a price tag of $300,000 a year.

“We don’t look at a company and say they’ll have a lower standard because they’re poor, but we’re trying to recognize that, small or large, companies will never work on developing a drug if they won’t make a profit,” said Woodcock. “Our job is to work with the field, and with the firms to try and find a path forward,” especially on rare diseases where a large trial is impractical, she said.

Last month, the European Medicines Agency’s advisory committee recommended rejection of Exondys 51’s application, saying “further data were needed to show … lasting benefits relevant to the patient.”

Sarepta is asking the committee to reconsider, the company said in a June press release.

The debate over Exondys 51 centered on the value of a so-called surrogate endpoint, a biological or chemical measure that serves as a proxy for whether the drug actually treats or cures the disease. Surrogate measures speed drug development because they’re easier and quicker to measure than patient outcomes.

Some surrogate measures are well-established. Lowering cholesterol has been proven repeatedly to help reduce heart attacks and strokes. But others aren’t, like how much dystrophin needs to be produced to help Duchenne patients, raising concerns that drugs may be approved despite uncertain benefits.

The jury is still out on two other drugs, Folotyn and Sirturo, which received expedited approval based on surrogate measurements. There’s no proof that Folotyn helps patients with a rare cancer — peripheral T-cell lymphoma — live longer, while Sirturo, an antibiotic for multi-drug-resistant tuberculosis, has potentially fatal side-effects. Yet since both drugs were aimed at small or under-served populations, the FDA rewarded their manufacturers with valuable perquisites.

In a clinical trial, Folotyn reduced tumors in 29 of 107 patients, but the shrinkage lasted longer than 14 weeks in only 13 people. Since everyone in the study got Folotyn, it wasn’t apparent whether the drug would help patients do better than a placebo or another drug. Meanwhile, 44 percent of participants in the trial suffered serious side effects, including sores in mucous membranes, including in the mouth, lips and digestive tract, and low levels of blood cells that help with clotting. One patient died after being hospitalized with sores and low white blood-cell counts.

While tumor shrinkage is a commonly used surrogate measurement in cancer trials, it often has a low correlation with longer life expectancy, according to a 2015 study. “I would say to a patient, this drug may be more likely to shrink a tumor either partially or even completely, but that may in fact be a pyrrhic victory if it doesn’t help you live better or longer,” said Mikkael Sekeres, director of the leukemia program at the Cleveland Clinic Cancer Center, who voted against approving Folotyn at the FDA’s advisory panel discussion in 2009. He was out-voted 10 to four. Three years later, the European Medicines Agency rejected the drug.

Because peripheral T-cell lymphoma only affects about 9,000 Americans each year, the FDA designated Folotyn as an “orphan” drug, giving its manufacturer, Allos Therapeutics, tax incentives and at least two extra years of patent exclusivity. Nevada-based Spectrum Pharmaceuticals acquired Allos in 2012. At more than $92,000 per course of treatment, Folotyn is Spectrum’s top-selling product, earning $43 million in 2017.

Dr. Eric Jacobsen, clinical director of the adult lymphoma program at Dana-Farber Cancer Institute in Boston, has become disillusioned with Folotyn since he helped Allos run the original trial. “Enthusiasm for the drug has waned,” he said. “It’s been on the market for a long time, and there’s no additional data suggesting benefit.” He now prescribes other options first, particularly because of the mouth sores Folotyn can cause, which make it painful to eat or drink.

The FDA approved Sirturo in 2012 without requiring Johnson & Johnson, the manufacturer, to demonstrate that patients on the drug were cured of tuberculosis. Instead, Johnson & Johnson only had to show that the treatment, when added to a traditional drug regimen, killed bacteria in the sputum faster than did the regimen alone. Sirturo was successful by that measure, but 10 patients who took it died, five times as many as the two in the group on placebo.

Dean Follmann, a biostatistics expert at the National Institutes of Health, voted as an FDA advisory committee member to approve Sirturo but wrestled with how to read the sputum data in light of the higher death rate: “The drug could be so toxic that it kills bacteria faster, but it also kills people faster.”

The imbalance in deaths during the trial “was a safety signal” that led the FDA to require “its most serious warning in product labeling,” known as a boxed warning, said agency spokeswoman Walsh. The packaging, she added, specified that Sirturo “should only be used for patients for whom an effective TB regimen cannot otherwise be provided. Thus, current labeling provides for a safe and effective use.”

Under a 2007 provision in the user-fee law, aimed at spurring treatments for developing nations, Sirturo’s approval qualified Johnson & Johnson for a voucher given to manufacturers who successfully get a tropical disease drug to market. The voucher can be used in the future, for any drug, to claim priority review – within six months instead of the usual 10. Time is money in the drug industry, and beating your competitor to market can be worth hundreds of millions of dollars. Vouchers may also be sold to other drugmakers, and have garnered up to $350 million. Sarepta received a voucher under a similar program for pediatric rare diseases when the FDA approved Exondys 51.

In South Africa, where Sirturo is mainly used, the drug is seen as a helpful option for highly drug-resistant patients. A study at one South African hospital by Dr. Keertan Dheda found that 45 out of 68 patients who took Sirturo were cured, as against 27 out of 204 before the drug was available. That doesn’t rule out the possibility that Sirturo may be killing a small subset of patients, said Dheda, but the risk is “very minor compared to the disease itself.”

Adrian Thomas, Johnson & Johnson’s vice president of global public health, said in an interview that observational results since the drug went on the market make him “much more confident that there is no more unexplained imbalance in mortality” and that the “benefit/risk in drug-resistant tuberculosis is incredibly reasonable when you don’t have other treatment choices.”

Still, the World Health Organization said in a 2016 report that the “quality of evidence remains very low” regarding Sirturo. “There is still some residual uncertainty for mortality,” the group said, and “specific harms” to the respiratory system “continue to be observed.”

While the FDA expedites drug approvals, it’s content to wait a decade or more for the post-marketing studies that manufacturers agree to do. Definitive answers about Sirturo are likely to be lacking until 2022, when Johnson & Johnson is expected to finish its study, a full decade after the drug was approved. Studies of Nuplazid and Folotyn aren’t expected until 2021. Spectrum has missed two FDA deadlines for post-marketing studies on Folotyn. Spectrum spokeswoman Ashley Winters declined comment.

Post-marketing studies often take far longer to complete than pre-approval trials, in part because it’s harder to recruit patients to risk being given a placebo when the drug is readily available on the market. Plus, since the drug is already on the market, the manufacturer no longer has a financial incentive to study its impact— and stands to lose money if the results are negative. Of post-marketing studies agreed to by manufacturers in 2009 and 2010, 20 percent had not started five years later, and another 25 percent were still ongoing.

And, despite taking so long, most post-marketing studies of drugs approved on the basis of surrogate measures rely on proxy criteria again rather than examining clinical effects on patients’ health or lifespans. In fact, Folotyn’s post-marketing trials will measure what’s known as “progression-free survival,” or the time it takes before tumors start growing again, but not whether patients live longer.

Proving that a drug extends survival is especially hard in cancer trials because patients don’t want to stay in a trial if their disease gets worse, or may want to add another experimental treatment. “In cancer, we’re probably not going to get a clean answer,” Woodcock said. Instead, the best evidence that cancer drugs are effective would be an increase in national survival rates over time, she said.

By law, the FDA has the authority to issue fines or even pull a drug off the market if a drugmaker doesn’t meet its post-marketing requirements. Yet the agency has never fined a company for missing a deadline, according to Woodcock.

“We would consider fines if we thought companies were simply dragging their feet, but we would have the burden to show they really weren’t trying, and it’d be an administrative thing that companies could contest,” said Woodcock.

Even when post-marketing studies belatedly confirm that drugs are dangerous, the agency doesn’t always pull them off the market. Consider Uloric, the gout treatment. Even though it consistently lowered uric acid blood levels, the FDA rejected it in 2005 and again in 2006, because trials linked it to cardiovascular problems. But a third study by the manufacturer, Takeda Pharmaceutical of Osaka, Japan, didn’t raise the same alarms. So the agency decided in 2009 to let the drug on the market, while asking Takeda for a post-marketing study of 6,000 patients to clarify the drug’s cardiovascular effects.

Takeda took more than eight years to complete the study. It found that patients on Uloric had a 22 percent higher risk of death from any cause and a 34 percent higher risk of heart-related deaths than patients taking allopurinol, a generic alternative. The FDA issued a public alert in November 2017, sharing the results of the trial, but left Uloric on the market.

Public Citizen has warned patients to stop taking Uloric. “There is no justification for using it,” said Carome. “If the results of the most recent study had been available prior to FDA approval, the FDA likely would have rejected the drug.”

FDA spokeswoman Walsh said it is “conducting a comprehensive evaluation of this safety issue and will update the public when we have new information.”

Takeda is working with the FDA to “conduct a comprehensive review,” spokeswoman Kara Hoeger said in an email. The company wants to ensure that “physicians have comprehensive and accurate information to make educated treatment decisions.” Thomas Moore, senior scientist of drug safety and policy at the Institute for Safe Medication Practices, warned that future post-marketing findings on Nuplazid could be similarly bleak. Uloric “is the story of [Nuplazid] but a few years down the pike,” he said.

Nevertheless, FDA Commissioner Gottlieb is forging ahead with more shortcuts. In May, he announced plans to approve gene therapies for hemophilia based on whether they increased the level of clotting proteins, without waiting for evidence of reduced bleeding.

Two years ago, a prescient Dr. Ellis Unger, FDA’s Director of the Office of Drug Evaluation, had warned against precisely this initiative. After Woodcock approved Exondys 51 in 2016, Unger wrote, “A gene therapy designed to produce a missing clotting factor could receive accelerated approval on the basis of a tiny yet inconsequential change in levels of the factor…The precedent set here could lead to the approval of drugs for rare diseases without substantial evidence of effectiveness.”

Gottlieb seems less worried than Unger.

“For some of these products, there’s going to be some uncertainty, even at the time of approval,” Gottlieb said when announcing the plan. “These products are initially being aimed at devastating diseases, many of which are fatal and lack available therapy. In these settings, we’ve traditionally been willing to accept more uncertainty to facilitate timely access to promising therapies.”

His decision pleased investors. That day, while biotechnology stocks overall fell, shares of hemophilia gene therapy manufacturers rose.

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Trump Is Promising To Lower Drug Prices, But Experts Doubt It Will Happen

Dan Vergano, BuzzFeed: May 11, 2018

President Trump promised to lower drug costs through more generic drugs, improved Medicare rules, and less “foreign freeloading” on US companies’ research.

President Donald Trump unveiled his “American Patients First” proposal to lower drug prices on Friday, in a long-awaited speech on an issue he campaigned on.

“We will have tough negotiations, more competition, and much lower drug prices,” said Trump in the speech held at the White House Rose Garden. “Very soon.”

Prescription drugs cost the US some $329 billion in 2016, according to federal estimates. Price hikes — for EpiPenscancer drugs, and an antiparasitic medication that jumped from $13.75 to $750 per pill — have raised the political profile of the issue.

The speech comes days after revelations that pharma behemoth Novartis paid Trump’s personal lawyer, Michael Cohen, some $1.2 million last year for access to the president and his administration.

During the presidential campaign, Trump said he would force the government to negotiate lower drug prices. During his presidential transition, he said drug companies were “getting away with murder,” comments that caused panic in the industry.

In his Friday speech, he criticized pharmaceutical industry lobbying, which outmuscles many other industries, and outlined his new “blueprint” for lower drug prices. But Trump stopped short of letting the US government agencies directly negotiate drug prices, including the $675 billion Medicare program. The president described such negotiation as “foreign freeloading” when done overseas, leaving the US with the world’s highest pharmaceutical prices.

Instead, Trump focused on four areas:

—increasing the transparency of drug prices seen in ads and by Medicare patients;

—preventing the manipulation of FDA, Medicaid, and the Affordable Care Act drug quality rules to force cheaper drugs out of patients’ hands;

—promoting lower-cost drugs for Medicare and Medicaid patients;

—and stopping foreign countries from negotiating lower drug prices with pharma, which the administration has argued forces US consumers to pay higher prices…

And some health analysts are critical of Trump’s approach.

“The action plan is too vague. Better negotiation of prices could mean almost anything,” Diana Zuckerman, president of the nonprofit National Center for Health Research, told BuzzFeed News. Focusing on out-of-pocket patient expenses instead of lower prices for the drugs themselves will lead to higher health insurance costs, she said. For example, when drugs cost more than $100,000 per year, as many do now, taxpayers and people buying insurance bear the cost, not just the patients taking the drugs…

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US Regulators Float Ideas for Boosting Medical Device Safety

Matthew Perrone, The Associated Press: April 17, 2018

U.S. health officials on Tuesday proposed steps to improve the government’s system for overseeing medical devices, which has been criticized for years for failing to catch problems with risky implants and medical instruments.

The plan from the Food and Drug Administration includes few immediate changes, but lists a number of ideas and proposals with the goal of improving safeguards on pacemakers, artificial joints, medical scanners and other devices.

Among other measures, the FDA will consider requiring more training for doctors who implant certain high-risk devices. But that step, like others floated by the agency, might require new guidelines or regulations. Other proposals may require additional money from Congress.

The FDA has repeatedly been forced to issue safety alerts about unexpected problems with devices that only appeared years after they were approved for use in patients. In the last decade, those have included hip replacements that failed prematurely, faulty wiring in implanted defibrillators, surgical mesh linked to pain and bleeding and a surgical instrument that inadvertently spread uterine cancer.

“We want to have better tools for detecting issues that occur post-approval,” FDA Commissioner Scott Gottlieb said Tuesday. “But we also want to have better policies to quickly intervene and better inform patients and providers if we see adverse events happening.”

An agency critic said the report contains few concrete changes and “many sections that will please the device industry.”

“FDA’s safety strategies for medical devices are still years away from effective implementation,” said Diana Zuckerman, president of the National Center for Health Research, a consumer advocacy group. “Overall, the report indicates that the FDA’s approval standards for medical devices remain completely inadequate.” […]

Among other proposals laid out in the FDA’s “Medical Device Safety Action Plan,” the FDA will consider:

— How to quickly require additional safety requirements for certain devices, including training for doctors who work with the complex devices.

— Extra scrutiny of devices for women, following recent problems with vaginal mesh, the birth control implant Essure and surgical tools.

— New ways to encourage manufacturers to improve safety, including quicker approval for devices that appear safer than what’s available.

— Requiring cybersecurity features for electronic devices like implantable heart pacemakers and defibrillators.

The agency will also ask Congress for more money for a public-private system intended to monitor insurance claims, electronic health records and other data sources for early signs of device problems. The project is estimated to cost $250 million over five years to become operational; it is now slated to receive $30 million from device manufacturers.

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CMS Payment Rule Seen as Bad for Some Patients

Joyce Frieden, MedPage Today, April 10, 2018

New final regulations on the Affordable Care Act (ACA) health insurance exchanges issued by the Centers for Medicare & Medicaid Services (CMS) have drawn mixed reactions from health policy experts and others.

The rule makes a number of changes to the exchanges, including:

  • Expanding the number of “benchmark” plans from which states can choose to model their coverage of the 10 “essential health benefit” (EHB) categories included in the ACA, potentially allowing states to choose plans with more generous or skimpier coverage than is currently offered on their exchanges.
  • Adding several new “hardship exemptions” to allow consumers to avoid paying a penalty for not buying health insurance. One exemption is for consumers who live in an area in which there are no health plans offered for them on the exchange, or only a single plan offered which is unaffordable. Another exemption is for consumers who live in an area in which the only health plans offered provide coverage of abortions, in cases where that conflicts with the consumer’s personal beliefs.
  • Allowing states to adjust the “medical loss ratio,” which determines what percentage of a health insurer’s revenue must be used for paying healthcare costs. Currently, according to the ACA, health insurers must spend at least 80% of their revenue on healthcare claims and quality improvement, with the rest going toward overhead and profit.
  • Increasing the percentage premium increase which requires review by insurance regulators. Under current ACA rules, review is triggered if an insurer requests to increase rates by an average of 10% or more; the new regulations increase that threshold to 15%.

“The final rule will mitigate the harmful impacts of Obamacare and empower states to regulate their insurance market,” CMS said Monday in a press release on the regulations. “The rule will do this by advancing the Administration’s goals to increase state flexibility, improve affordability, strengthen program integrity, empower consumers, promote stability, and reduce unnecessary regulatory burdens imposed by the Patient Protection and Affordable Care Act.” The release also asserted that the ACA “has led to higher premiums and fewer choices” and that the ACA “has priced many consumers out of the insurance market.”

Premium Increases for Comprehensive Plans

“The plan to allow the sale of policies with skimpier essential health benefits will inevitably cause premiums for good health insurance policies (the kind currently available through the ACA) to increase,” Diana Zuckerman, PhD, president of the National Center for Health Research, an organization that conducts, analyzes, and explains health-related research, wrote in an email.

“If very healthy people can buy skimpy health insurance policies, then people who know that they have health problems will be the only ones buying the better policies — resulting in an increase in costs. In other words, people with pre-existing health conditions such as cancer, heart disease, diabetes, and rare diseases, will be paying much more than anyone else — an outcome that most Americans do not want. The bottom line is that the result of these regulations will be exactly the opposite of the stated goal: rather than making healthcare more affordable, this would make health care much less affordable for the people who need it most.” […]

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Patient Advocacy Groups Take In Millions From Drugmakers. Is There A Payback?

Emily Kopp, Sydney Lupkin, and Elizabeth Lucas, Kaiser Health News: April 6, 2018

Pharmaceutical companies gave at least $116 million to patient advocacy groups in a single year, reveals a new database logging 12,000 donations from large publicly traded drugmakers to such organizations.

Even as these patient groups grow in number and political influence, their funding and their relationships to drugmakers are little understood. Unlike payments to doctors and lobbying expenses, companies do not have to report payments to the groups.

The database, called “Pre$cription for Power,” shows that donations to patient advocacy groups tallied for 2015 — the most recent full year in which documents required by the Internal Revenue Service were available — dwarfed the total amount the companies spent on federal lobbying. The 14 companies that contributed $116 million to patient advocacy groups reported only about $63 million in lobbying activities that same year.

Though their primary missions are to focus attention on the needs of patients with a particular disease — such as arthritis, heart disease or various cancers — some groups effectively supplement the work lobbyists perform, providing patients to testify on Capitol Hill and organizing letter-writing and social media campaigns that are beneficial to pharmaceutical companies.

Six drugmakers, the data show, contributed a million dollars or more to individual groups that represent patients who rely on their drugs. The database identifies over 1,200 patient groups. Of those, 594 accepted money from the drugmakers in the database.

The financial ties are troubling if they cause even one patient group to act in a way that’s “not fully representing the interest of its constituents,” said Matthew McCoy, a medical ethics professor at the University of Pennsylvania who co-authored a 2017 study about patient advocacy groups’ influence and transparency.

Notably, such groups have been silent or slow to complain about high or escalating prices, a prime concern of patients.

“When so many patient organizations are being influenced in this way, it can shift our whole approach to health policy, taking away from the interests of patients and towards the interests of industry,” McCoy said. “That’s not just a problem for the patients and caregivers that particular patient organizations serve; that’s a problem for everyone.”

Bristol-Myers Squibb provides a stark example of how patient groups are valued. In 2015, it spent more than $20.5 million on patient groups, compared with $2.9 million on federal lobbying and less than $1 million on major trade associations, according to public records and company disclosures. The company said its decisions regarding lobbying and contributions to patient groups are “unrelated.”

“Bristol-Myers Squibb is focused on supporting a health care environment that rewards innovation and ensures access to medicines for patients,” said spokeswoman Laura Hortas. “The company supports patient organizations with this shared objective.”

The first-of-its-kind database, compiled by Kaiser Health News, tallies the money from Big Pharma to patient groups. KHN examined the 20 pharmaceutical firms included in the S&P 500, 14 of which were transparent — in varying degrees — about giving money to patient groups. Pre$cription for Power is based on information contained in charitable giving reports from company websites and federal 990 regulatory filings.

It spotlights donations pharma companies made to patient groups large and small. The recipients include well-known disease groups, like the American Diabetes Association, with revenues of hundreds of millions of dollars; high-profile foundations like Susan G. Komen, a patient group focused on breast cancer; and smaller, lesser-known groups, like the Caring Ambassadors Program, which focuses on lung cancer and hepatitis C.

The data show that 15 patient groups — with annual revenues as large as $3.6 million — relied on the pharmaceutical companies for at least 20 percent of their revenue, and some relied on them for more than half of their revenue. The database explores only a slice of the pharmaceutical industry’s giving overall and will be expanded with more companies and groups over time.

“It’s clear that more transparency in this space is vitally important,” said Sen. Claire McCaskill (D-Mo.), who has been investigating the links between patient advocates and opioid manufacturers and is considering legislation to track funding. “This database is one step forward in that effort, but we also need Congress to act.”

What Drives The Money Flow

The financial ties between drugmakers and the organizations that represent those who use or prescribe their blockbuster medicines have been of growing concern as drug prices escalate. The Senate investigated conflicts of interest in the run-up to the passage of the 2010 Physician Payments Sunshine Act — a law that required payments to physicians from makers of drugs and devices to be registered on a public website — but patient groups were not addressed in the bill.

Some of the patient groups with ties to trade groups echo industry talking points in media campaigns and letters to federal agencies, and do little else. And patients, supported by pharma, are dispatched to state capitals and Washington to support research funding. Some groups send patients updates on the newest drugs and industry products.

“It’s through groups like this that patients often learn about illnesses and treatments,” said Rick Claypool, a research director for Public Citizen, a consumer advocacy group that says it does not accept pharmaceutical funding.

For the patient group Caring Ambassadors Program, industry funds are needed to make up for a lack of public funding, said the group’s executive director, Lorren Sandt. According to IRS filings and published company reports, in 2015 the group received $413,000, the bulk of which came from one company, AbbVie, which makes a hepatitis C treatment and has been testing a new lung cancer drug, Rova-T, not yet approved. She said the money had no influence on the Caring Ambassadors Program’s priorities.

“There aren’t a lot of large pockets of funding outside of the pharmaceutical money,” Sandt said. “We take it where we can find it.”

Other patient groups such as The National Women’s Health Network, based in Washington, D.C., make sacrifices to avoid pharmaceutical funding. That includes operating with a small staff in a “modest” office building with few windows and outdated computers, according to executive director Cindy Pearson. “You can see the effect of our approach to funding as soon as you walk [in] the door.”

Pearson said it’s hard for patient groups not to be influenced by the funder, even if they proclaim independence. Patient groups “build relationships with their funders and feel in sync and have sympathy” for them. “It’s human nature. It’s not evil or weak, but it’s wrong.” […]

They Weren’t Always Backed By Pharma

Into the ’80s and early ’90s, patient lobbying was generally limited and self-funded with only one or two affluent patients from an organization traveling to Washington on a given day, said Diana Zuckerman, president of the nonprofit National Center for Health Research.

But the power of patient-lobbyists became apparent after a successful campaign by AIDS patients led to government action and a national push to find drugs to treat the then-terminal disease. Zuckerman said she will never forget when two women visited her office and asked how breast cancer patients could be as effective as the AIDS patients.

“At the time, there were no breast cancer patients advocating for money or anything else. It’s hard to believe,” she said. “I still remember that conversation, because it was really a turning point.”

Soon after, breast cancer patients started visiting the Hill more frequently. Patients with other diseases followed. Over time, patients’ voices became a potent force, often with industry support.

Even some wealthy, high-profile organizations take industry money: For example, $459,000 of Susan G. Komen’s $118 million in 2015 revenue came from drugmakers in the database, according to public disclosures. Asked about the pharma money, the foundation said it has institutional processes in place to ensure that “no corporate partner — pharma or otherwise — decides our mission priorities,” including a scientific advisory board — free of sponsor influence — that reviews its research program.

Today, patient advocacy groups flush with more industry dollars fly patients in for testimony and training about how to lobby for their drugs.

Some years ago, as the groups increased in number, Zuckerman said, she started getting email invitations from advocacy groups to attend so-called lobbying days explicitly sponsored by the pharmaceutical industry. The hosts often promised training and usually some kind of keynote speaker at a luncheon in Washington — plus a potential scholarship to cover travel. Now, lobbying days involving dozens of patients from a single group are part of the landscape.

Dan Boston, president of lobbying firm Health Policy Source, said, “It would be naive to think these people on a Tuesday afternoon just happen to turn up in XYZ places,” adding that the money isn’t necessarily a bad thing. Money tends to flow toward citizen groups that already have the same priorities as their funders, he said. […]

Read the original article here.

FDA Proposes Allowing Medical Device Makers to Summarize Malfunctions

Jim Spencer, Star Tribune: February 24, 2018

A Food and Drug Administration (FDA) proposal to let medical device makers summarize malfunctions of certain products instead of filing a report for each incident has kicked off a debate over the public’s ability to judge safety.

Regulators and device industry representatives say the proposal is an efficiency measure limited to malfunctions that do not threaten lives or health and only involves the least risky devices on the market. Summaries that bundle “like events” into summary reports as the FDA proposes let the government, businesses and the public pick up on trends sooner, they say.

“I think it will be very good and not just for our members,” said Shaye Mandle, CEO of Medical Alley, the trade group representing Minnesota’s massive medical technology sector. “I think everybody wins.”

Currently, device makers must file individual reports of device problems with detailed narratives. Depending on the severity of the malfunction, those reports are due within five days or 30 days of a company learning about them from any source.

The move to quarterly filings of single report summaries concerns some patient advocates and those seeking more detailed public disclosure of device problems. They base their worry on existing FDA summary reporting programs that they say keep too many details secret.

“FDA already has difficulty keeping up with device reports that would generate corrective action in a timely manner,” said Jack Mitchell, director of health policy at the National Center for Health Research. “When companies have submitted summary reports in the past, it has resulted in less transparency, with neither FDA nor the public able to have access to adequate information about patients who have been seriously harmed by medical devices. This proposal would further weaken the current post-market safety surveillance system for devices, which is already passive and inadequate.”

Star Tribune investigations into current FDA summary reporting practices found that the agency allowed Medtronic to summarize a study that revealed more than 1,000 malfunctions of its Infuse bone graft in three sentences within a single “marker report” more than five years after the law required the company to reveal those adverse events individually. The FDA also redacted the total number of injuries and complications as a “trade secret” until the newspaper appealed the decision.

Medtronic says that it should have filed the data sooner, but says it misplaced the study for several years and reported it as soon as it was found. The company says it then complied with all requests the FDA made for information about the study.

Medtronic declined to comment on the new FDA summary program, deferring to its national trade group, the Advanced Medical Technology Association (AdvaMed).

In addition to letting Medtronic summarize overdue malfunction reports, the Star Tribune investigation discovered that the FDA has allowed other companies to offer limited, consolidated and sometimes redacted data on thousands of late individual malfunction reports through an informal process called “retrospective summary reporting.”

An FDA spokeswoman did not respond to a question about redactions. She said she could not speculate on whether individual products such as Infuse would qualify for the new summary reporting program, which lets companies that make products with certain device codes file quarterly reports in a summary format. Nor would she say how or if malfunctions resulting from non-FDA-approved uses of devices would be cataloged. Off-label use can be an issue. For instance, research has estimated that Infuse is used off-label 85 percent of the time. […]

Read the original article here.