Bill aims to expand drug indications minus randomized trials

By Robert Lowes,  Medscape
May 08, 2015

Can government regulators speed up the introduction of new treatments in hospitals and physician offices without sacrificing safety and effectiveness? Or does the expression “speed kills” hold true?

That’s the debate surrounding a bill in the Republican-controlled House called 21st Century Cures, which aims to fast-track the development and approval of new drugs and devices. Ironically, the legislative process has been slow-going as lawmakers strike compromises to defuse controversy.

The latest draft of the bill, released last week, won kudos from Democrats and Republicans alike for significantly increasing the budget of the National Institutes of Health (NIH), which funds basic research leading to new treatments. However, some experts still worry that the measure, not yet officially introduced as legislation, lowers the scientific bar for these new treatments to come to market — good for manufacturers, but not so good for patients.

One provision, for example, requires the US Food and Drug Administration (FDA) to evaluate the use of evidence from “clinical experience” — and not just from randomized clinical trials — for assessing a drug’s effectiveness and safety in two regulatory scenarios. One is to “help support the approval” of a new indication for a drug already on the market. The other is helping to support or satisfy postapproval studies that the FDA requires when it has its doubts about a drug.

Evidence from clinical experience, as described by the bill, includes data from observational trials, clinical registries, insurance claims, ongoing safety surveillance, and “patient-centered outcomes research activities.”

Diana Zuckerman, PhD, president of the nonprofit National Center for Health Research (NCHR), a think-tank that focuses on women, children, and families, looks askance at substituting clinical experience for randomized clinical trials. She told Medscape Medical News that the bill “would promote the snake oils and elixirs of the early 20th century.

“I call it eminence-based medicine — if some hotshot doctor says it works,” Dr Zuckerman said.

The push to consider clinical experience for expanding a drug’s indications, she said, is based on the false assumption that once the FDA deems a drug safe for an initial indication, “it can be used for everything else.” That assumption forgets that the FDA weighs benefits versus risks. The agency, for example, might approve a very toxic drug for a certain lung cancer because nothing else would save a patient’s life. However, the FDA may find the drug’s toxicity unacceptable when it comes to treating early-stage breast cancer, a condition for which there are many alternative treatments, and a far higher survival rate.

“Safety is very, very relative,” said Dr Zuckerman.

21st Century Cures also has come in for harsh criticism from the consumer watchdog group Public Citizen, which said that faster product approval based on weaker evidence will sacrifice safety, and Modern Healthcare magazine, which called the measure the “21st Century Quackery Act.” Yet another critic is Margaret Hamburg, MD, who stepped down as FDA commissioner earlier this year. Addressing the National Press Club in March, Dr Hamburg warned against relaxing the agency’s standards. “Innovation doesn’t matter if the product doesn’t work,” said Dr Hamburg, an appointee of President Barack Obama.

However, Politico Pro quotes another former FDA commissioner as saying that, unlike Dr Hamburg, he views the measure as a “positive step.”

“I don’t share the concern that inherently this means you are going to have to lower standards of safety and efficacy,” said Andrew von Eschenbach, MD, Wednesday, at a media briefing on 21st Century Cures organized by the Alliance for Health Reform. Dr von Eschenbach headed the FDA from 2006 to 2009 under President George W. Bush.

“The FDA’s Not Going to Do Anything That’s Inappropriate”

In an interview with Medscape Medical News, a high-ranking FDA official said that the agency already has begun to approve drugs based on clinical evidence short of randomized trials, and that it is proceeding cautiously.

“The FDA’s not going to do anything that’s inappropriate,” said Janet Woodcock, MD, director of FDA’s Center for Drug Evaluation and Research (CDER).

The FDA has sometimes relied on single-arm trials and case series to establish efficacy for new drug approvals or expanded indications, said Dr Woodcock. This approach holds promise, she said, for approving new uses of targeted cancer drugs already on the market, especially for rare tumor types in patients who don’t have other good treatment options.

At the same time, the FDA recognizes the limits of clinical evidence, including “pure observational data” gleaned from its own nascent Sentinel System, which searches the electronic health records of some 178 million patients for adverse events.

“It isn’t reliable enough [yet],” said Dr Woodcock. “We don’t even make definitive safety findings from that. We use it to bolster our safety assessments.”

So the FDA is still learning how to harness such clinical evidence. The future, she said, will “bring clinical research much closer together with healthcare.”

Less Industry Friendly?

21st Century Cures has been in the making since May 2014, when the initiative was unveiled by Rep. Fred Upton (R-MI), chair of the House Energy and Commerce Committee, and committee member Rep. Diana DeGette (D-CO).

In January 2015, the committee released a first draft of the legislation, which was criticized as catering to industry. Some of the most controversial provisions would have extended market exclusivity for various categories of drugs. The NCHR’s Dr Zuckerman credits lawmakers with removing this language from the latest draft.

Also missing, said Dr Zuckerman, are “micromanaging” provisions on biomarkers, those organic fingerprints such as RNA, proteins, and metabolites that can predict a patient’s response to a drug — one of the keys to personalized medicine. Under the first draft, she said, drug makers could have essentially pressured the FDA to adopt biomarkers of their choosing to expedite clinical trials. The draft legislation released last week merely calls on the agency to develop guidelines for developing biomarkers, a gentler directive for an agency already incorporating these measures into its work.

CDER’s Dr Woodcock told the health subcommittee of the House Energy and Commerce Committee on April 30 that biomarkers must pass the evidence test before the FDA accepts them as proxies for health outcomes.

“You have to know those biomarkers are reliable before you risk them on human life,” said Dr Woodcock.

Bill Exempts Some CME Activities From Sunshine Reporting
The latest version of 21st Century Cures covers a waterfront of issues. Among other things, the measure would:

Require the FDA to establish a priority review program for “breakthrough” medical devices “for which no approved alternatives exist.”

Establish that the FDA can consider registry data, peer-reviewed studies, and data collected outside the United States in evaluating medical devices. Like the proposed acceptance of clinical evidence other than randomized clinical trials, this provision has been criticized as a license for weaker scientific evidence.

  • Require the Centers for Disease Control and Prevention to set up a surveillance system for neurological diseases.
  • Require the FDA to incorporate patient-experience data in its regulatory decisions, a path the FDA is already headed down. “Patients are experts in their disease,” Dr Woodcock told lawmakers last week.
  • Allow NIH to require any researchers it supports to share their data.
  • Create an information system for scientists to use and analyze data from NIH-funded trials.
  • Create a fast-track approval process in the FDA for antibiotics in short supply.
  • Encourage the application of Bayesian statistical modeling in drug makers’ clinical protocols and new drug applications.
  • Exempts some continuing medical education activities of physicians from the controversial Sunshine Act. Drug and device manufacturers wouldn’t have to report giving physicians a medical textbook, tuition to attend an educational event, or a fee to speak at such an event.
  • Allow drug makers to share economic data concerning their products with third-party payers and their formulary committees.

The measure seeks to make electronic health record systems interoperable so that physicians can easily share research and clinical data, but lawmakers have not yet come up with specifics. Details also are pending for a provision seeking to make telemedicine more available to physicians and patients, and to repurpose drugs for serious and life-threatening diseases.

The general thrust of all these measures is to accelerate the development, testing, and market debut of new medical treatments. Bill supporters view the FDA approval process as antiquated and too slow, but Dr Woodcock noted in her House subcommittee testimony last week that her agency has been quicker on its feet lately. Last year, she said, the FDA okayed the highest number of new drugs in almost 2 decades, and the most new drugs for “orphan” diseases since Congress passed the Orphan Drug Act in 1983.

She also suggested that the FDA’s depiction as a bottleneck for innovation is exaggerated. The agency, she said, consistently reviews new drugs faster than its counterparts around the world.

“We don’t take a long time to get things approved,” said Dr Woodcock. “They take a long time to get developed.”

Bigger Budget for NIH, but Not for FDA

Appropriations for NIH shrank for 3 consecutive years beginning in 2011, reflecting across-the-board federal budget cuts that grew out of Congressional gridlock. The latest version of 21st Century Cures would significantly boost NIH funding, making the measure more palatable to Congressional Democrats and delighting the healthcare industry.

“The increased funding for the NIH in the 21st Century Cures draft is an important acknowledgement of the need for robust research,” said Kim Williams, Sr, MD, president of the American College of Cardiology, in a news release.

The draft legislation would lift NIH’s budget line to $31.8 billion in fiscal 2016, up from $30.3 billion in 2015. Increases of $1.5 billion would follow in both 2017 and 2018. The measure would allocate an additional $2 billion a year over 5 years for an NIH Innovation Fund to support, among other things, emerging young scientists and research in precision medicine.

At last week’s hearing of the health subcommittee of the House Energy and Commerce Committees, several lawmakers noted that the measure did not give the FDA more money even though it gave the agency more work to do.

Dr Woodcock acknowledged that the FDA is already “very stretched” and that giving its staff additional responsibilities could slow down its drug review program, which “is going full speed.”

“We have a saying in medicine — first, do no harm,” she said. “In enacting new legislation, you don’t break what’s fixed.”

Jeffrey Shuren, MD, director of the FDA’s Center for Devices and Radiological Health, added that more duties for the same number of FDA employees worsens turnover, as does noncompetitive salaries. “Were essentially a training ground for industry,” said Dr Shuren.

The 21st Century Cures draft needs additional tinkering to address this money problem, Rep. DeGette told Dr Shuren and Dr Woodcock.

“We still need to find the funds for the FDA to do the things you have to do,” DeGette said.

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