FDA Ruffles Feathers by Delaying DMD Tx Review

WASHINGTON — Two drugs are competing for FDA approval as treatment for Duchenne muscular dystrophy (DMD), and the agency upset DMD advocates by delaying review of one of the drugs.

On Tuesday, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee discussed the safety and efficacy of BioMarin’s drisapersen (Kyndrisa), which is thought to slow the progression of DMD.

They had been set to discuss Sarepta’s eteplirsen this week, but that review was pushed to late January, and DMD advocates were frustrated by the agency’s decision.

In an Oct. 19 letter to Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research (CDER), they explained that the consequences of postponing eteplirsen’s review could affect providers’ prescribing habits and payer decisions.

“Families have been expressing concerns around potential approvals and the impact such decisions have on provider prescribing recommendation and the ability of providers to have adequate information on both compounds in order to recommend the most appropriate therapy for each patient,” they wrote. “These families also will need to navigate a complex payer environment and are concerned about being locked into an initial drug even if another therapy becomes available.”

The letter was signed by the Duchenne Alliance, Parent Project Muscular Dystrophy, The Race to Yes, and the “Be Reasonable” campaign from the Center for Duchenne Muscular Dystrophy at the University of California Los Angeles.

The representatives of the DMD community asked Woodcock to explain the reason for delaying the review and urged her to reconsider the change. A representative of Parent Project Muscular Dystrophy told MedPage Today that they had not received a response from Woodcock as of Tuesday.

DMD is a rare genetic disorder found only in boys, The disease causes severe deterioration of the muscles, leaving most boys too weak to walk in their teenage years. Most DMD patients live only until their mid-20s or early 30s. There is no cure for this disease.

The muscular degeneration seen in DMD is caused by an aberration in a gene that produces the protein dystrophin, without which muscles can’t function.

Both of the proposed drugs proposed are exon-skipping therapies that target the genetic aberration responsible for producing dystrophin. Drisapersen forces the mechanism that produces dystrophin to skip over the aberrant portion of the gene, exon 51, and then allows a “truncated” and “partially functional” form of dystrophin to be produced, according to FDA briefing documents.

While both drug targets the most common mutation in DMD, that mutation accounts for only 13 to 15% of DMD cases. The approval of either drisapersen or eteplirsen would be a boon for other exon-skipping therapies that have been modified to treat forms of DMD with different mutations.

Some patient advocates who support eteplirsen were said they were puzzled by the FDA’s decision to allow the drisapersen meeting to occur before eteplirsen’s review, especially when it appeared that BioMarin did not meet the agency’s request for confirmatory trials, according to The Street.

An FDA representative would not comment to MedPage Today on the completeness of BioMarin’s application. “Under the law, that is confidential information between the FDA and the company and we are not permitted to discuss specifics or release any non-public documents,” the spokesperson told MedPage Today.

In response to questions regarding why the eteplirsen review was delayed until January, the spokesperson told MedPage Today that advisory committee meeting dates are listed as “tentative” and aren’t considered final until posted in the Federal Register.

The spokesperson also wrote that the “FDA recognizes the unmet medical need in Duchenne muscular dystrophy (DMD), the devastating nature of the disease for patients and their families, and the urgency to make new treatments available.”

However, the FDA’s technical review of the research for drisapersen was not yielding positive results.

Drisapersen is administered to only a subset of patients with Duchenne muscular dystrophy, following a genetic test, and given via subcutaneous injection.

In briefing documents, technical reviewers described drisapersen’s safety profile as “concerning.” Regarding the effectiveness of the drug, they wrote “while there may be some evidence suggestive of efficacy of drisapersen, the evidence is inconsistent and in some cases contradictory.”

Terri Ellsworth of Pittsburgh whose son Billy, 14, has DMD, watched Tuesday’s proceedings and told MedPage Today, “it’s a very nervous time for our community.”

Billy has been taking eteplirsen since 2011, when he enrolled in a clinical trial. Eleven other boys received treatment in the same trial. Billy is still able to walk, feed himself, dress himself, activities unthinkable to many of his friends with DMD, she said.

Ellsworth commented that the review of drisapersin did not seem to be going well. Asked whether she was relieved that eteplirsen’s review had been delayed, she said, “I don’t know that I’m relieved. It’s just 2 more months of anxiety, but maybe this delay can be seen as a watch and learn experience.”

FDA Officials, Advisors Split Over New DMD Therapy

WASHINGTON — The FDA approved the first-ever drug for Duchenne muscular dystrophy (DMD), despite internal disagreements over the drug’s efficacy.

Eteplirsen (Exondys 51), a product of Sarepta Therapeutics of Cambridge, Mass., won approval from the agency — despite a split vote from its own advisory committee — to treat DMD patients who have a “confirmed mutation of the dystrophin gene amenable to exon 51 skipping” on Monday.

The FDA said it granted accelerated approval of the drug based on the surrogate endpoint of an increase in dystrophin production. However, its press statement failed to acknowledge the breadth of internal discord over this very point.

Following a conference call with investors Monday, Sarepta said that it anticipates charging $300,000 per patient per year for the new drug, according to Forbes.

‘The Principal Question’

The agency’s summary review chronicles a months-long dispute among senior staff and Janet Woodcock, MD, director of the Center for Drug Evaluation and Research (CDER) over what FDA Commissioner Robert Califf, MD, dubbed the “principal question — whether the quantity of dystrophin produced by eteplirsen is an effect that is reasonably likely to predict clinical benefit,” as required by FDA statute and regulation.

Woodcock said she believes that clinical benefit is predicted, but Ellis Unger, MD, office director of the CDER’s Office of New Drugs (OND) disagreed. Back in April, seven of 13 members of the Peripheral and Central Nervous System Drugs Advisory Committee also said they felt eteplirsen failed to meet the minimum standards for accelerated approval.

In a 27-page July appeal letter to the Office of Scientific Integrity, Unger noted that members of the review team for Division of Neurology Products unanimously concluded that the new drug application should receive a “complete response action” (i.e. a rejection) and that OND director John Jenkins, MD, also verbally supported that decision (Ronald Farkas, MD, PhD, a lead reviewer in the neurology products division who was highly critical of eteplirsen data has already left the agency, according to STAT).

In his appeal letter, Unger argued that the small increase in dystrophin shown in the trials was not “reasonably likely” to predict clinical benefit, and that the effect size of dystrophin levels was “inadequate on its face.”

He noted that methods for quantifying dystrophin in the field are not standardized. Nevertheless, it was not valid to compare an increase in”Becker-type dystrophin” with dystrophin levels cited in other mutation or patient populations measured at other laboratories. Becker muscular dystrophy is a milder form of muscular dystrophy in which a truncated version of dystrophin is produced by muscle cells.

That said, if such a comparison were possible, Unger continued, “the largest change reliably demonstrated in Study 301 [a study comparing pre and post-treatment values of dystrophin after 48 weeks] of 1.3% is an order of magnitude less that the minimum dystrophin levels cited to be important in affecting the course of patients with Becker muscular dystrophy (at least 10%).”

Califf Defers

After Unger’s appeal, Califf was called on by the Scientific Dispute Process Review board to either conduct his own scientific review of the data, or to direct a panel of experts to make a recommendation on the current data, and if it meets the standard for accelerated approval.

Califf chose to conduct his own review and ultimately deferred to Woodcock’s “judgment and authority.”

“Given that I do not have technical expertise beyond those already involved in this decision and the record contains adequate evidence to support her conclusion, I defer to the judgment of the Center Director to approve eteplirsen under accelerated approval,” he stated in a letter.

He also responded to a series of concerns over Woodcock’s actions, with regard to the drug:

  • Her “intense involvement”at the early stages of the review process for the drug
  • Her “extensive involvement” in planning and engaging in the April 25, 2016 advisory committee meeting
  • Her “initial decision” to approval eteplirsen on May 4, 2016, before the reviewers had even established a decision-making process
  • Her completion of a final decisional memorandum before Unger completed his own

At the core of such complaints was an underlying assumption of bias towards Sarepta, and the patient community, which Califf said he acknowledged.

“Overall, while I recognize the strain created by political and public pressures, given Dr. Woodcock’s well documented history of not bowing to such influences and a record in this case showing her close consideration of all relevant scientific evidence, I do not find that this deviated from her responsibility as Center Director, nor do I find that she succumbed to pressure from the patient community, the public, the press, or others.”

Califf defended Woodcock saying her “hands-on” management style has been a characteristic of her career thus far, and was not related to eteplirsen specifically. He said he acknowledged that her “general pattern of discourse and involvement” was not “typical,” but affirmed that he did not “find that her conduct was in conflict with the job requirements for Center Directors at the FDA.”

A Complex Process

MedPage Today spoke with two members of the advisory committee about the FDA’s final decision, which went against their recommendation.

The process of approving a drug is very complex, said Aaron Kesselheim, MD, JD, MPH, of Brigham and Women’s Hospital in Boston, and a temporary advisory committee member who voted against approving eteplirsen. “As an advisory committee member, you are only involved in one small slice of the decision-making process.”

Kesselheim said that he could not say whether the FDA’s ultimate decision was a surprise. He added that he knew that the agency received additional data on eteplirsen prior to its decision, but that he had not been able to review that data in depth.

“I’m hopeful that the effectiveness of the drug ends up being validated in additional trials,” he said, referring to the agency’s approval requirement of post-market research. “It’s a terrible disease, and the current treatment options, there aren’t a lot of them. So if this drug does turn out to work in helping extend people’s lives and making them better, that would be a great thing.”

Richard Kryscio, PhD, of the Sanders-Brown Center on Aging at the University of Kentucky in Lexington also voted against recommending the accelerated approval of eteplirsen. He called the data presented at the April review as only “borderline.”

However, he pointed out that “this is a rare disease, and the more we learn about the therapy that’s being suggested here, I think the better off we’ll be.” He noted that the FDA has asked Sarepta for additional data, including dose-response data, as a stipulation of approval.

Kryscio said he encourages parents in DMD activist groups to stay involved in the postmarketing research by getting patients to enroll in postapproval studies, “so we can get the kinds of data that we need.”

FDA Advisory Panel Splits on Second DMD Drug

To find out what has happened since this story was originally published on April 26, click here.

Weighing hard data against patient testimonials, an FDA advisory panel voted 7-6 that a new Duchenne muscular dystrophy (DMD) failed to meet the minimum standards for accelerated approval on Monday.

The Peripheral and Central Nervous System Drugs Advisory Committee’s vote signaled a lack of “substantial evidence from adequate and well-controlled studies” to trigger dystrophin production at a level considered “reasonably likely to predict clinical benefit.”

In other words, the chosen surrogate endpoint was inadequate to promote any claim that the drug would actually help DMD patients — at least in the majority’s view.

The panel also voted 7-3, with three abstentions, that a single historically-controlled study also did not offer substantial evidence of the drug’s efficacy.

In November, the same panel determined in more lopsided votes that the evidence in support of a similar agent, Biomarin’s drisapersen, was also weak.

Benjamin Dupree, a 23-year-old with DMD from Dallas, who was the panel’s patient representative, voted that the drug met the “substantial evidence” standard in both questions.

However, the Duchenne patient was deeply conflicted. “The study doesn’t provide what I think is adequate evidence to support all of this testimony that I’m seeing in here,” he said, referring to extensive public testimony, before breaking down in tears.

Eteplirsen (tentatively branded Exondys 51), a product of Cambridge, Mass.-based Sarepta Therapeutics, has been proposed for treating DMD in patients with a specific verified mutation of the dystrophin gene. The disease is thought to occur when a genetic mutation in exon 51 causes a shortage or lack of dystrophin protein. Eteplirsen is intended to prevent exon 51 from being translated, enabling muscle cells to produce a shortened but still functional form of dystrophin.

The panel’s first vote reflected the committee’s views regarding the drug’s suitability for approval under an accelerated approval pathway — using dystrophin levels as a surrogate endpoint. The second vote viewed potential approval based on clinical efficacy.

Chiadi Onyike, MD, associate professor of psychiatry and behavioral sciences at John Hopkins University School of Medicine in Baltimore, voted against approval in either an accelerated or conventional approach.

While eteplirsen may have caused the production of some dystrophin, “it’s very small … too small to go from dystrophin production to clinical effect,” he said.

Moreover, the question implies that dystrophin is responsible for clinical benefit, and “I’m not entirely sure that one should lock the clinical effect to the dystrophin production,” he said.

Onyike, echoing Dupree, said, “What I would consider meaningful evidence of testimony from the families is not properly measured in the study.”

William Dunn, MD, director of the FDA’s Office of Drug Evaluation I for the Division of Neurology Products, told the committee in opening remarks, “We come to you with sincere concerns, not because we take some perverse delight in keeping new medicines from those who urgently need them … but because it is our — we the FDA, and you, our advisory committee — collectively, it is our fundamental responsibility to ensure, as required by law, that the treatments we approve are effective.”

Dunn urged the panel to focus on “whether we can truly conclude that what these few eteplirsen patients are experiencing is clearly outside the natural variability of the disease.”

During an unusually long public comment period, many parents pleaded with the committee to speed the drug’s approval.

Mindy Leffler, from Seattle, described how her son regained the ability to pull himself into a car after taking eteplirsen. Leffler noted that “regaining definitively lost milestones” was not part of the natural progression for any Duchenne patient.

“Medical students are often told when they hear hoof-beats to think of horses not zebras,” she urged the panel, “Look to the obvious conclusion, rather than searching for the unlikely. It is now time to stop hunting zebras.”

When, at the end of a long day, Onyike called for an adequate controlled trial, as other panelists and FDA staff had before him, the audience erupted into jeers, shouting “biopsies hurt.”

One wheelchair-bound teen, cursing angrily, ran his vehicle through a couple rows of empty chairs before rolling out of the room.

For this application, Sarepta submitted two exploratory studies and a single clinical trial in two phases — a randomized placebo-controlled study and an open-label extension trial that used data from Italy and Belgium for comparison.

FDA’s technical experts noted shortcomings in the sponsor’s bioassay methods leading to possible “overestimation” of the percent of dystrophin-positive muscle fibers. The experts also pointed out the inability to distinguish drug-induced dystrophin from naturally-occurring dystrophin in immunofluorescence.

Sarepta’s re-analysis of the biopsied tissue by three independent experts found a mean percent of dystrophin positive fibers of 17% [± 10%] at 180 weeks, which was about one-quarter to one-third of Sarepta’s initial estimates at 48 weeks.

Similarly, using a Western blot assay, a fourth biopsy from patients at 180 weeks of treatment found dystrophin levels at 0.93% [± 0.84%] of normal muscle. The sub-1% increase was markedly different from the 10- to 20-fold increase with eteplirsen the sponsor initially reported at 12 weeks of treatment.

In the single clinical trial comparing three groups of four patients each at different doses — eteplirsen 30 mg/kg or 50 mg/kg versus placebo, the drug failed its prespecified endpoints.

But the technical experts were more concerned with the way endpoints were defined. For example two participants who completed the 10-meter walk-run (10MWR) also reported a score of zero on the 6-minute walk test (6MWT). This finding suggested possible subjectivity in decision-making regarding loss of ambulation.

The agency’s technical experts also considered whether less capable or less motivated patients might more frequently be relegated to natural history studies, and whether this could have confounded study results.

Lastly, the sponsor’s results showed no correlation between the amount of dystrophin patients had and their outcomes on the 6MWT.

Based on the clinical trial, the agency’s experts ultimately concluded, “[T]here does not appear to be any evidence of efficacy for eteplirsen.”

The FDA is not required to follow the advice of its advisory committees, but it often does.

Eteplirsen Approval Seen as Marking New Direction at FDA

On April 26, an FDA advisory committee voted 7-6 that the exon-skipping drug eteplirsen for Duchenne muscular dystrophy (DMD) failed to meet the standards needed for accelerated approval. It was widely assumed that the FDA would tell the drug’s developer, Sarepta Therapeutics, to try again with better data. That, of course, did not happen. In this follow-up, we report on how it eventually did turn out for the drug and for the DMD community.

To the surprise of many, the FDA approved eteplirsen in September with the trade name Exondys 51.

While patients and families applauded the decision, believing their efforts in collaborating with industry and the agency had paid off, critics in the medical and research community questioned whether the drug really worked, and whether the FDA had made the right call. Documents later revealed internal FDA friction, and even though the agency’s boss backed the approval, he also called for a key study supporting the drug to be retracted.

In addition, two recent events — passage of the 21st Century Cures Act, a major health bill meant to spur innovation and speed the delivery of new drugs, and the surprise election of Donald Trump as president — have sparked concerns that the FDA might inch closer to deregulation for the sake of innovation under the new administration.

Perhaps more than in previous White House transitions, confusion and uncertainty cloud the FDA’s future.

Yet while consumer groups express alarm, some clinicians and policy experts believe a dramatic reversal in the FDA’s core mission is unlikely. MedPage Today spoke with key stakeholders to gauge the importance of eteplirsen’s approval: what it means for patients and the future of the FDA’s review process.

Flash Point

In approving eteplirsen, the FDA had overruled its own advisory committee. The seven members voting against approval did not believe Sarepta had shown adequate evidence that eteplirsen triggered production of the protein dystrophin at a level that was “reasonably likely to predict clinical benefit.” (DMD is caused by a genetic deficiency in dystrophin.)

Moreover, several of the FDA’s senior staff members also saw evidence that patient benefit was inadequate, as documents detailing a months-long dispute between those staff members and Janet Woodcock, MD, director of the Center for Drug Evaluation and Research (CDER), showed. She overruled their conclusions and FDA Commissioner Robert Califf, MD, ultimately sided with Woodcock. Curiously, however, Califf also called for the retraction of a 2013 study that aimed to demonstrate that eteplirsen produces adequate levels of dystrophin, which he called “misleading.”

Insurers also appear to need more convincing that the drug is effective. The investment firm Jefferies found that three of five national payers and eight of 15 regional managed care organizations “denied or restricted coverage for the drug,” according to Gena Wang, PhD, CFA, an analyst for Jefferies. Wang told Endpoints News, a biopharma newsletter, the response was “in line with our expectation of pushback from private payers.”

Unlike private insurers, public payers such as Medicaid do not have the option to omit FDA approved drugs from their formularies.

The ripple effect of the eteplirsen decision could prove damaging to the healthcare system, Diana Zuckerman, PhD, president of the National Center for Health Research, told MedPage Today.“Many drug companies will be submitting applications that they wouldn’t have dreamed of submitting [before].”

Zuckerman said Woodcock’s decision stemmed from sympathy for the patients.

“She approved a drug not realizing that by approving the drug based on evidence that was so obviously inadequate many health insurance companies would just refuse to pay for it.”

Without insurance coverage, families have to pay $300,000 a year for the drug. “The company failed in its responsibility, the FDA failed in its responsibilities, and the patients are paying the price,” Zuckerman said.

If the agency continues to move in this direction, insurers will spend more money to perform their own analyses of product data. Money that could have been better spent on coverage, she added.

On the issue of coverage determinations, Annie Kennedy, senior vice president of legislation and public policy at the Parent Project Muscular Dystrophy (PPMD), said some insurers’ refusals stemmed from a misunderstanding about the burden of the disease. Only about 2,000 U.S. patients have the specific genetic mutation making them potentially eligible for treatment.

PPMD has also pressed insurers offering narrow coverage determinations, arguing that even non-ambulatory patients can benefit from the drug. Kennedy and others have been sharing additional pulmonary data demonstrating “stability” on functional tests in treated participants compared to “a steady decline observed in the DMD natural history,” according to Sarepta documents.


Kennedy anticipates that some insurers will revise their coverage determinations based on engagement with the community.

Looking Ahead

One of the FDA’s advisory committee members who voted against approving eteplirsen, Aaron Kesselheim, MD, JD, of Harvard Medical School/Brigham and Women’s Hospital in Boston, told MedPage Today that one of the challenges of that meeting was balancing the inconsistencies in the testimony he heard from patients and families with the data.

“How do we make sure that the patient voice is taken seriously, but at the same time also take the science seriously and come to an adequate final decision?” he said.

The newly passed “Cures Act” also has provisions that could affect the FDA’s review process. It allows the agency to use “real world evidence” in deciding whether to approve expanded indications for already marketed drugs.

If Cures is given “maximum flexibility” and FDA leadership has a deregulatory agenda, said Kesselheim,”I think the future will hold a lot more products like eteplirsen that are approved on the basis of a marginal effect on a surrogate measure that does not have a clear connection to clinical endpoints.”

“That’s going to put a lot of pressure on physicians trying to make the decisions whether or not to use the product [and] patients deciding whether or not to take the risk … in this context of insufficient information,” he added.

Trump’s election also brings the likelihood of new leadership at the FDA. Although he has made no announcement about replacing Califf as commissioner, most of his other appointees have been staunchly anti-regulation and many are coming from industry.

The possible change in agency leadership and the Cures Act together could allow the FDA to reconsider the balance between innovation and ensuring appropriate levels of safety and efficacy, said Caleb Alexander, MD, of the Johns Hopkins Bloomberg School of Public Health in a phone interview. Alexander chaired the FDA committee that voted on eteplirsen.

However, given the massive size of the FDA, whatever change does occur will be gradual, he said. “I’ll be surprised if it’s a total sea change.”

“While cases such as Addyi (flibanserin) and eteplirsen have been quite controversial, those represent a small fraction of the reviews that FDA has performed … I don’t think that those cases are reflective of wholesale change or any deliberate decisions … regarding a change in the evidentiary threshold for market access.”

As for the worry that the “Cures Act” could encourage the use of more real world evidence, Alexander saw no conflict between leveraging patient reported outcomes, for example, and high quality science.

He added, “There’s a reason the FDA has evolved toward the use of randomized controlled trials, and frankly I don’t see that reliance diminishing substantially anytime soon.”

Advocates Respond

In response to the backlash against the FDA’s decisions and scorching criticism of Sarepta’s own clinical trial, Kennedy explained that the community was “flying the plane as we were building it.” For example, meetings focused on developing guidance for a protocol regarding how best to measure dystrophin happened as Sarepta’s own research was already underway.

“I know there’s been a lot of blame cast at this cast of characters or that cast of characters and a 152-page document released about disagreements,” said Kennedy referencing the FDA’s summary review.

But, she noted, “What we think happened was exactly what accelerated approval was designed for … All of these policies and tools that so many people have pushed for, for so long … were applied by everyone collaboratively and now we’ll get to see how this plays out going forward.”

“Now the onus is on Sarepta to conduct further studies to show [clinically meaningful benefit], that continues to happen in the broader subset of the community. If we don’t, then the product will get pulled,” she said.

Still the Watchdog

The FDA, in an emailed statement, underscored that its commitment to holding drug manufacturers, including Sarepta, accountable for confirmatory studies to determine clinical benefit will continue.

“The required study is designed to assess whether eteplirsen improves motor function of DMD patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval,” wrote Sandy Walsh, a press officer for the FDA in an email.

As for the future direction of agency, Walsh noted, “In appropriate situations, the agency exercises flexibility when evaluating treatments for serious and life-threatening conditions. However, as each situation is unique, we cannot speculate on potential decisions on other product applications.”

House Subcommittee Presses Forward on 21st Century Cures

WASHINGTON — Roughly 95% of rare diseases have no FDA-approved treatment. Congress hopes that by equipping government agencies with better resources, it can accelerate innovation and bring cures to patients faster.

The latest draft of the 21st Century Cures bill would grant $10 billion in mandatory funding to the National Institutes of Health beginning in fiscal year 2016.

“The research committee is ecstatic to see this new provision in the bill, and we are deeply appreciative,” said Kathy Hudson, PhD, deputy director for Science, Outreach, and Policy at the NIH.

The House Energy and Commerce’s Subcommittee on Health invited top brass from the NIH and the FDA to offer their perspectives of the revised legislation at a hearing on Thursday.

Full committee chairman Fred Upton (R-Mich.) and ranking member of the Oversight and Investigations subcommittee Rep. Diana DeGette (D-Colo.) launched the 21’s Century Cure initiative a year ago.

Full committee ranking member Frank Pallone Jr. (D-N.J.), health subcommittee chairman Joe Pitts (R-Pa.), and health subcommittee ranking member Gene Green (D-Texas) joined with Upton and DeGette to release the bill’s second draft.

The five-member bipartisan team noted in a press release, “We’ve done things differently with 21st Century Cures, taking our time to listen and solicit feedback from every corner of the healthcare innovation infrastructure.” They pointed to the 24 roundtable discussions across the country, eight hearings, and several white papers that preceded the hearing.

Rep. Joseph Pitts, (R-Pa.), chairman of the Subcommittee on Health, said, “While increasing accountability, this legislation would invest in the basic research so critical to equipping our nation’s best and brightest with the tools they need to discover the underpinnings of disease.”

In addition to funding NIH, provisions of the bill also support efforts to:

  • Speed development for treatment of life-threatening illness
  • Repurpose drugs found ineffective for one condition and test them in another
  • Develop partnerships among patients, providers, and researchers
  • Promote an interoperable health system
  • Enhance telehealth practices
  • Advance the development of more targeted personalized treatments

Other provisions in the bill explored ways to bring patients’ perspectives into the research process.

Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, spoke of 20 “facilitated discussions” with patients around the burden of their disease and the effects of treatment. Research teams documented the conversations in a report called “The Voice of the Patient” and on occasion issued guidance based on patient feedback.

“What we learned is we need a much more structured and organized way to incorporate this input into drug development, and we think that what’s laid out in the discussion drafts will really help with that,” Woodcock said.

Other representatives spoke about the importance of having interoperability among electronic health records. Rep. Michael Burgess ( R-Texas) was frustrated that $28 billion had been sunk into trying to make electronic health records talk to each other, but “health data continues to be fragmented.”

Rep. Pitts added, “Imagine a world where your cellphone would not work with a land-line or if my cellphone did not connect with other networks. Ridiculous. Well, that’s the world of electronic health records.”

Hudson sympathized. In moving her mother from Texas to Minnesota she said, “I ended up carrying two boxes of paper medical records with me.”

She added,”I hope that doesn’t happen in the future, and I think we’re moving quickly to solve that problem.”

Hudson noted that interoperable systems are important in patient care but also “vital” for research, and especially important as the Precision Medicine initiative takes shape.

The Public Responds

Mary Woolley, president of Research!America, a nonprofit focused on public education, was pleased to see Upton and DeGette keep their promise to fund medical research.

“While it is important for the final language in the bill to allow for flexibility in the use of these funds in order to maximize their benefit, these additional dollars can empower NIH to sustain and embark on innovative studies that could reduce the prevalence and impact of costly and disabling conditions that continue to threaten individual and population health, our economic security, and global competitiveness,” said Woolley in a press release.

Vijay Das, policy advocate at Public Citizen’s Congress Watch, was less enthusiastic.

Das, in a press release, said that the new proposal is “riddled with dangerous provisions that would put patients at risk.”

“The 21st Century Cures initiative offers a horse trade: Increase funding for the world-renowned National Institutes of Health (NIH) in exchange for providing perks to the pharmaceutical and medical device industries to approve medications and devices faster based on weaker evidence,” Das said.

“Faster approval of new medicines will not spur innovation, but it will sacrifice safety. Passage of this legislation would put lives at risk.”

Woodcock told MedPage Today that while the new bill would speed development to biomarkers “[t]here’s no change to the time of our review process.”

“Most of the provisions here also are not for common diseases that have a lot of alternative therapies. They’re going to be for cancers or rare serious disease where the people have already said they’re willing to trade off some uncertainty to get access to treatment sooner.”

“I think it’s good of the patient groups to remind people that [safety is] an important side of the equation,” Woodcock added. “We don’t see anything in here that’s going to diminish that.”

Full Steam Ahead

Rep. DeGette said she found the level of consensus around the bill “striking and positive.”

She acknowledged that several members had commented on the new burdens the FDA would be tasked with as a result of provisions in the bill. Rep. Pallone counted more than 15 new guidance documents as well as separate approval processes for antibacterial and antifungal drugs for serious and life-threatening diseases.

Woodcock made clear that fulfilling these statutory requirements would create delays in reviewing applications, if the FDA was not given additional resources. “Currently, our drug review program is really going full speed. We’re making all our deadlines and we’d like to keep it that way.”

DeGette said, “We still need to find a way to fund the FDA for the things that we’re asking you to do and we know that. So, we’re going to do all of that.”

The next step is to have the bill scored and marked up, she said.

Senate Passes 21st Century Cures Act

WASHINGTON — The Senate passed the 21st Century Cures Act, sweeping legislation that aims to bring treatments more quickly from the lab bench to patients’ bedsides on Wednesday afternoon in a vote of 94-5.

“As a result of a lot of strong bipartisan work, we are sending a bill now to the president’s desk that will invest in tackling our hardest to treat diseases, put real dollars behind the fight against the opioid epidemic and make badly needed changes to mental health care in our country,” said Sen. Patty Murray (D- Wash.), Ranking Member of the Senate Health, Education, Labor and Pensions (HELP) Committee, just before the vote.

“I’ve heard often from those whose loved ones are suffering from Alzheimer’s, addiction, and other debilitating diseases,” wrote President Obama in a press release shortly after the vote, citing Vice President Joe Biden’s own tragic loss of his son Beau Biden.

“Their heartbreak is real, and so we have a responsibility to respond with real solutions,” Obama wrote, adding that he looked forward to signing Cures as soon as it reaches his desk.

The “Cures” bill authorizes a total of $6.3 billion for funding basic science, streamlining the FDA’s review process, and addressing the opioids epidemic. The bill also incorporates a handful of mental health reforms, aimed at improving care coordination, strengthening mental health parity laws, and promoting evidence-based treatments and therapies.

Murray thanked HELP Committee Chairman Lamar Alexander (R-Tenn.), who offered his own appreciation to his colleague and to those on both sides of the aisle.

Earlier this week Alexander called the bill’s provisions to invest in regenerative medicines “a game-changer” for stroke patients, those with heart disease or retinal disease and dubbed the entire package “another Christmas miracle” — referencing President Obama’s nickname for the 2015 rewrite of the “No Child Left Behind” education bill.

But not everyone was cheering: Public Citizen called the bill an early Christmas present for the pharmaceutical industry.

But the watchdog group didn’t sound only sour notes: in a prepared statement Michael Carome, MD, director of the group’s health research arm, claimed credit for helping to eliminate “provisions that would have 1) opened a gaping hole in the Physician Payments Sunshine Act for educational gifts made by industry to physicians; 2) increased medication prices and cost taxpayers an estimated $12 billion over 10 years; 3) encouraged hospitals to overuse the newest antibiotics, thereby contributing to the harmful spread of antibiotic resistance; and 4) allowed medical device manufacturers to make changes to high-risk medical devices without U.S. Food and Drug Administration oversight.”

Battling Opioids

Several Senators focused on the bill’s response to the opioids epidemic, emphasizing the current lack of resources and the slim capacity of many treatment facilities.

“When people with substance use disorder are turned away this means they remain on the streets, desperate, often committing crimes to support their addiction and at constant risk of a lethal overdose … Make no mistake this legislation will save lives,” said Sen. Jeanne Shaheen (D- N.H.) speaking from the floor on Tuesday.

Her colleague, Sen. Harry Reid (D- Nev.) said that the bill was “weak” in parts and “we could have done better,” but was also excited to see dollars for opioids.

“There should be far more, and it should be given a different way than we have it here, but it’s money,” he said. “And we have people … dying as a result of this scourge that’s sweeping America … So, that part of [the bill] is excellent.”

But the harshest critics of “Cures,”as the bill has been dubbed were unmoved by this sentiment.

Those opposing the bill included Sen. Bernie Sanders (I- Vt.), Sen. Jeff Merkley (D- Ore.), Sen. Ron Wyden (D- Ore.), Sen. Elizabeth Warren (D- Mass.), and Sen. Mike Lee (R- Utah)

The final breakdown for the bill is as follows:

  • $4.8 billion for the National Institutes of Health
  • $1 billion in state grants to help respond to the opioid crisis
  • $500 million in additional support for the FDA

Of the money allocated to the NIH over a 10-year period, the bill earmarks $1.8 billion for Vice President Joe Biden’s “Cancer Moonshot” project, — renamed “The Beau Biden Cancer Moonshot” — $1.6 billion for the BRAIN initiative, and $1.4 billion for President Obama’s Precision Medicine Initiative.

The Beau Biden Cancer Moonshot

The FDA’s funding would be geared towards bolstering research and staff, and like its sister agency, funds would be delivered over a decade, whereas the opioid grants will be administered over 2 years.

As Biden presided over a vote for cloture on Monday night, Congress offered an amendment to rename the Cancer Moonshot Initiative in memory of his son, Joseph “Beau” Biden III, who died from brain cancer in 2015.

“I think it fitting to dedicate this bill’s critical cancer initiatives in honor of someone who’d be so proud of the presiding officer [Biden] today: his son Beau,” said Senate Majority Leader Mitch McConnell (R-Kentucky).

That amendment passed without debate.

Winners and Losers

However, a second proposed amendment brought by Sen. Bernie Sanders (I -Vt.) did, receive pushback.

“I have been fighting the greed of the prescription drug industry for decades and as far as I can tell the pharmaceutical industry always wins. They win but the American people lose,” he said in a floor speech on Tuesday.

His legislation would allow Medicare to negotiate with drug companies and that would enable Americans to import their medications from other countries. Sanders stressed that both provisions had been endorsed by President-elect Trump during his campaign.

“Think about what you can do to pave the way for Mr. Trump coming in,” he said attempting to bait Senate Republicans who did not bite.

Full Speed Ahead

“One way to be sure and not get the work done we’re doing today is to add another topic,” said Sen. Roy Blunt (R- Missouri) who objected to Sanders’s amendment. “If everything’s a priority, nothing’s a priority.”

Sanders also criticized Cures for cutting $1 billion from Medicare and Medicaid programs and another $3.5 billion from the Affordable Care Act’s Prevention and Public Health Fund and for not giving enough funding to the NIH. Sanders said that if the bill passed it would still only grant the agency $7 billion less than it received in 2004, accounting for inflation.

The depletion of the ACA’s controversial fund also irritated the American Academy of Family Physicians, the group sent a letter to House leadership last week highlighting its disappointment, according to a press statement. The AAFP also noted that “the legislation stops well short of appropriately funding the important mental health and addiction provisions that are included.”

Mental Health

Echoing, Murray, Sen. John Cornyn (R-Texas) praised the bill’s mental health provisions noting that many families struggle to help their adult children who have mental health problems.

“Often there’s additional tools that need to be available to family members when they find that their loved one is getting sicker and sicker and not being compliant with their medication and potentially becoming a danger to themselves or to the community at large,” he said speaking from the Senate floor.

Cornyn noted that legislation will improve states and local government’s access to tools to help evaluate the healthcare needs of those in prison, so they can be helped. The bill also encourages the development of crisis intervention teams.

Though she voted for the bill, Sen. Debbie Stabenow (D- Mich.) urged Congress to “complete the job,” by delivering full-funding to community mental health centers.

The American Psychiatric Association applauded Cures saying it would improve the access and quality of care for people with serious mental illness, and those with substance use disorders.

“The bill will toughen enforcement of existing parity laws, helping to ensure that mental health care services are covered just like other health care services,” said Maria Oquendo, MD, PhD, president of the APA in a press release.

While Murray argued that another advantage of passing Cures now is to “lock-in” important investments ahead of the next administration, much of the actual funding in the bill will require Congress to appropriate or unlock dollars from various sources each year, such as sales from the federal Strategic Petroleum Reserve.

Approximately 420 organizations lobbied for the Cures bill, according to the The Center for Responsive Politics, including Blue Cross/Blue Shield, Roche, Amgen, and the Pharmaceutical Research & Manufacturers of America, the industry’s major trade association.

What Else is in the 21st Century Cures Act?

WASHINGTON — When most people think about the 21st Century Cures Act, they think about curing cancer and Alzheimer’s disease, and curbing the nation’s opioid epidemic. But the nearly 1,000-page healthcare spending bill, which President Obama signed in mid-December, also aims to reform the nation’s fragmented mental health system, improve access to electronic health data, and ensure that underrepresented individuals are included in important health research.

Mental Health

Approximately 13 million people in the U.S. have a serious mental illness or substance use disorder, according to the American Psychiatric Association (APA), which applauded the 21st Century Cures Act, calling its reforms to mental health a “huge step forward.”

The Cures Act included efforts to promote evidence-based treatments, strengthen mental health parity, and bolster the mental health workforce. The bill also established a grant program focused on early intervention for those showing warning signs of a potentially serious mental illness.

Earlier this year, Congress took aim at the Substance Abuse and Mental Health Services Administration (SAMHSA), saying that the agency had failed patients with serious mental health problems.

One almost immediate change the bill makes is to establish a new assistant secretary for Mental Health and Substance Abuse to oversee SAMHSA, explained Andrew Sperling, director of legislative advocacy for the National Alliance on Mental Illness.

Speaking in a phone interview with MedPage Today that included a public relations official, Sperling said he anticipates that Rep. Tom Price (R- Ga. ), the newly appointed Secretary of Health and Human Services, will have “a great deal of influence” in selecting that individual.

Better Integration, Better Care

The 21st Century Cures Act also designates a new Interdepartmental Serious Mental Illness Coordinating Committee, charged with summarizing advances in diagnosing and treating serious mental illness in a written report to congress. The committee — which includes members from SAMHSA, the Department of Defense, the Health Resources and Services Administration (HRSA), and other federal health agencies — will also be required to evaluate the impact of federal programs on important public health outcomes (i.e., rates of suicide, preventable emergency room visits, and homelessness).

Other key mental health-related provisions of the bill include the following:

  • Authorizing a grant program for assertive community treatment for adults with serious mental illness;
  • Authorizing a grant program to enable local governments to improve crisis intervention among emergency responders, clinicians, and law enforcement and funding to build registries of available inpatient psychiatric beds;
  • Establishing policies to create new residency programs to train future primary care doctors and psychiatrists about integrating mental and physical health;
  • Designating a nationwide hotline and online tool for improving access to mental health and substance use providers; and
  • Enhancing grant programs that offer behavioral health services for homeless and justice-involved individuals.

Also, the Cures Act, while not amending the Health Insurance Portability and Accountability Act (HIPAA), does outline the circumstances by which clinicians can share information with family members when a loved one is in crisis. “We hope this will ease the chilling environment around disclosure of information to family members,” by providing clinicians with greater clarity regarding when they can disclose, Sperling said.

With regard to mental health parity — equal access and coverage from insurers for mental health issues compared with physical concerns — most states have not been aggressively auditing insurers, an APA representative told MedPage Today.

However, the Cures Act calls for a standardized approach to auditing, and, on a federal level, requires the Department of Labor to periodically publish reports to showcase the volume of cases the agency has pursued.

Efforts to ensure more consistency and transparency could produce a “sentinel effect,” said the APA official. The more that insurers believe they risk being audited, the more likely they are to take internal compliance seriously.

Electronic Health Records

The Cures Act also strengthens efforts to improve and enforce health information interoperability.

Beginning in January 2018, vendors’ relative interoperability will be evaluated, and by 2019, those not in compliance will lose certification, explained Mandy Long, chair of the Electronic Health Records Association (EHRA) Clinician Experience Workgroup for the Healthcare Information and Management Systems Society (HIMSS), speaking in a phone interview with MedPage Today during which a public relations official was present.

“There are real teeth to [the language in the bill], and [the penalties] grow over the course of a couple of years,” said Long, who is also vice president of product management at Modernizing Medicine, an EHR and practice management software company in Boca Raton, Fla.

She noted that vendors who engage in data blocking can be fined up to $1 million per violation.

Long, whose daughter has Turner syndrome, also spoke as the parent of an ill child about the challenge of keeping specialists in different hospitals current with her daughter’s health status and tests. “We call it the ‘patient’s Bible’ — that binder that patients create for themselves, or their parents create [of various medical records] — we lug it from visit to visit or, God forbid, if we end up in an emergency situation; it’s awful and frequently out of date.”

Long said she believes the bill’s requirements to promote a scalable integration structure will have benefits for patients as well as industry.

The College of Healthcare Information Management Executives (CHIME) offers more specifics on the health IT provisions of the bill related to information blocking, interoperability standards, and hardship exemptions for decertified EHRs.

Superbugs, Vaccinations, and Equity in Research

Other elements of the bill include provisions to fight superbug infections, such as allowing the FDA to require manufacturers or reusable medical devices to share their cleaning instructions and verify that such methods work. The Cures Act also creates new requirements for the National Institutes of Health to encourage scientists studying similar topics to collaborate, with the goal of increasing the volume of data on underrepresented populations (i.e., women, children, and minorities).

Finally, the bill aims to raise maternal vaccination rates through efforts to prevent vaccine shortages and by incentivizing drugmakers to develop new vaccines for pregnant women. In addition, the act encourages pediatric drug development by allowing products given a “rare pediatric disease designation” from the FDA before 2020 the chance to be considered for a voucher until 2022.

Unpacking the 21st Century Cures Act

When the 21st Century Cures Act was signed by President Obama earlier this week, many praised the bill as a tribute to bipartisanship. The act passed with overwhelming support in the Senate, and was dedicated to Joe Biden’s son, Beau, who died last year from brain cancer.

Although the act earmarks funds for the Beau Biden Cancer Moonshot and BRAIN initiatives, the act is more than 1,000 pages long and includes provisions for a myriad of healthcare issues.

“The idea of the bill was to get new drugs to patients more quickly and new provisions have been added onto that bill partially because it’s the end of the year, other things didn’t get passed that needed to,” says Shannon Firth, Washington correspondent for MedPage Today. “But essentially what this bill does is it earmarks funding for congress to focus on things like brain research and cancer research, and also it helps revise some of the practices of the FDA.”

Much of the reporting on the Cures Act has been focused on the ways it impacts the FDA. “One of the problems that both the NIH and the FDA has is staffing,” explains Firth. Both agencies have issues keeping researchers from moving on to better paying jobs. Firth continues, “So this bill puts money toward the FDA in terms of keeping those talented researchers there.”

But the act will also have a significant impact on how the agency reviews and screens new drugs. “What the bill does is, it helps promote something called ‘patient focused drug development.’ And while some patient groups may say it’s a good thing, there are on the other side, consumer groups who are very concerned about some of the provisions in the bill. They’re concerned that it would weaken the FDA’s review process,” she explains.

While the act was passed with rare bipartisan support, it had some major detractors. Senator Elizabeth Warren (D-MA) and Senator Bernie Sanders (D-VT) were both vocal critics of the Cures Act, in part because they felt it gave a lot to pharmaceutical companies, without getting much in return.

“One of the things they were very focused on was controlling drug prices. Senator Sanders put out there an amendment, he wanted to allow Medicare to negotiate with drug companies to help lower the prices of drugs,” says Firth.

“He wanted to allow the importation of drugs from other countries and a lot of other countries, they spend a lot less on drugs than we do.”

She continues, “Those were two ways he thought that this bill could’ve been improved by allowing drug companies, who are getting a lot out of this bill, to actually also put something back in.”

The Cures Act also designates money to helping stem the opioid epidemic by making more beds available in treatment centers and encouraging medically proven methods to treat opioid addiction.

Some of these provisions fall under the umbrella of behavioral health, and will be impacted by mental health parity provisions bolstered by the Cures Act. The parity act will make it more difficult for insurers to deny coverage for drug addiction rehabilitation treatments, a significant barrier for many addicts.

The act also addresses mental health more directly. “What the bill does for mental health is it strengthens coordination, it elevates mental health to a position within the Health and Human Services, and it strengthens mental health parity,” Firth explains.

Listen to the full story here.