The FDA's Medical Device Problem

The F.D.A.’s Medical Device Problem

By RITA F. REDBERG and SANKET S. DHRUVA              JULY 17, 2015

THE Food and Drug Administration has been regulating the approval of medical devices since 1976, but its regulatory oversight has not kept pace with the increasing complexity of this technology. Many high-risk medical devices today are approved on the basis of just one clinical trial (as opposed to new medications, which usually require two trials). And only a small minority of clinical studies of medical devices are randomized, controlled and blinded — the gold standard for reliable evidence (and the benchmark to which studies of drugs are held).

As a result, there have been many warnings about, and recalls and withdrawals of, medical devices that were found to be dangerous only after they were on the market. (In 2009, for example, the Sprint Fidelis defibrillator, which by that time had been implanted in hundreds of thousands of heart patients, was recalled because it frequently malfunctioned, harming many patients and leading to numerous deaths.) And because the F.D.A.’s oversight of medical devices once they are on the market is also weak, it is very likely that many malfunctions and other problems remain undetected.

Incredibly, legislation that the House of Representatives passed last week would severely weaken, not strengthen, the F.D.A.’s already ineffective regulatory scheme for medical devices. The device industry may stand to benefit from this legislation, but the health of the public does not.

The legislation, disingenuously titled the 21st Century Cures Act, would make it possible for companies that produce high-risk medical devices to submit evidence of safety and efficacy based on sources other than clinical trials, including case histories (i.e., the experiences of individual patients). In other words, anecdotal evidence, rather than the scientific studies, could be used to approve devices.

This act would also create a new, faster approval process for “breakthrough technologies” that are believed — but not necessarily proved — to offer significant advantages over existing alternatives. This would allow a device to be approved based on even lower standards of evidence than are currently used, on the theory that the need outweighs the risk. The legislation defines “breakthrough” loosely, creating a perverse incentive for manufacturers to use this term both to take advantage of the faster approval process and as a marketing gimmick.

In general, the proposed law is likely to shift the burden of evidence to clinical studies that are conducted only after the devices have been put on the market. Unfortunately, such studies are often delayed months to years after a device is approved. Many are never completed (and even when they are, their findings are often not publicly available). Although the proposed law alludes to “timely postmarket data collection,” that vague directive needs to be clearly defined — and more important, enforced — by the F.D.A. In fact, according to a 2014 journal article co-written by one of us, the F.D.A. has never issued a warning letter or penalty for a postmarket study delay.

Even if a postmarket clinical study deems a medical device dangerous, it still can be difficult to remove it from the marketplace. In 2005, for example, an intracranial stent called the Wingspan was approved on an expedited basis to prevent recurrent strokes. When a high-quality clinical trial was finally completed, in 2011, it found that patients who had the device implanted were more likely to have another stroke and to die than those just receiving medical management. Despite this evidence, the F.D.A. did not withdraw the device (though it did narrow its recommended uses). The Wingspan continues to be marketed and implanted today, putting patients at unnecessary risk.

Once a medical device is developed and approved, its manufacturer often makes small changes intended as enhancements (such as using a different size wire or new material). Currently, the F.D.A. is the arbiter responsible for ensuring that these changes result in a safe and effective device. But alarmingly, the 21st Century Cures Act would establish a third-party program of nongovernment authorities to assess whether a company is permitted to make such changes. The act would enable the device manufacturer itself to select — and pay — the third party from an approved list. This flagrant conflict of interest would make it impossible for physicians or patients to have trust in the safety or effectiveness of updated medical devices.

The 21st Century Cures Act would subject millions of Americans to unsafe or untested medical devices. We urge the Senate, as it takes up the bill, to avoid these dangerous provisions. Unlike medical drugs, which can readily be discontinued if problems are found, many medical devices are permanently implanted and cannot easily be removed if found to be defective. Stricter evidence standards and increased federal funding of the F.D.A. are needed to ensure that innovative medical devices lead to better health.

Rita F. Redberg is a cardiologist at the University of California, San Francisco, Medical Center. Sanket S. Dhruva, a cardiologist, is a clinical scholar at Yale University.

http://www.nytimes.com/2015/07/17/opinion/the-fdas-medical-device-problem.html?emc=edit_tnt_20150717&nlid=50639700&tntemail0=y&_r=0

U.S. Congress & FDA: Human Guinea Pigs-"So Be It"

This new bill would add $9 billion for medical research. Here are 5 reasons critics are terrified.

Updated by Julia Belluz on July 14, 2015, 1:10 p.m. ET @juliaoftoronto julia.belluz@voxmedia.com

Last week, the House passed a bill in a 344-77 vote, an overwhelming consensus at a time when relations in Congress are mostly fractured. The bipartisan effort, known as the 21st Century Cures Act, infuses medical research with $8.75 billion over five years and purports to overhaul drug development and innovation to get lifesaving cures to people who need them faster.

The Cures Act has a chance of actually passing the Senate and getting signed into law. But critics say the legislation is trouble. "What we have here is a Trojan horse," Jerry Avorn, a professor at Harvard Medical School, told the New York Times. "The elevator pitch is very appealing ... But it is a vehicle for some regulatory changes that are really very worrisome."

Hidden in the bill's 352 pages is language some observers think will erode the quality of evidence the FDA uses to evaluate new drugs and devices, making it easier for companies to bring substandard or ineffective medicines and devices to market. The bill would also turn back some recent efforts to make relationships between doctors and drug companies more transparent.

I asked some of the concerned researchers to go through the bill's provisions that they found most worrisome. Here are their top five:

The bill encourages the use of anecdotes as evidence that drugs work

There are a few provisions in this bill that change the standards for the quality of evidence the FDA uses in considering drugs for the market. The idea is that in some cases, waiting for big clinical trials on new drugs slows down the regulatory process and keeps potentially useful drugs away from patients. In other cases, it's difficult to find a sufficient number of patients suffering with rare diseases to run a big trial. The bill encourages the use of early and easier-to-gather data to speed the process up.

But as Rita Redberg, editor of the journal JAMA Internal Medicine, wrote in a recent comment, this could amount to a dangerous trade-off: "In our rush to find new effective treatments, we should not harm our patients with ineffective toxic ones."

Take Section 2062, which would make it possible for companies to seek approval for their products based on anecdotes from doctors who have used the drugs in their patients. Because anecdotes can be cherry-picked and unrepresentative, they don't give a good overview of the actual impact of a medication. That's why regulators today generally rely on randomized control trials — experiments that randomly assign patients to a drug or placebo. If a drug works or harms people, it's clear it's the medicine that made the difference.

"This replaces the gold standard of randomized control trials, and basically says this idea is old-fashioned and if we want to get drugs and devices to market more quickly, we have to use different standards," explained Diana Zuckerman, president of the National Center for Health Research (@NC4HR) dz@center4research.org. "But these different standards are the old standards we used to use 50 years ago when we had disastrous recalls of terribly dangerous drugs and devices." 

The bill would also make it easier to get drugs through based on studies that don't yet have data on what researchers call "hard endpoints" (longer-term measures of whether a drug reduces death and the risk of heart disease). Instead, drug companies can use data on "surrogate endpoints" (blood test results, such as cholesterol levels, which may or may not have an impact on the measures that matter to patients — like reducing the risk of death and disease). But many times, surrogate markers turn out to be misleading, and don't tell us much about whether a drug actually works.

The bill allows antibiotics onto the market that have never been tested in people

Right now, the world is facing a crisis in antibiotic-resistant infections — that is, more and more patients are showing up in hospitals with bacterial diseases that don't respond to any of the available antibiotics on the market.

To encourage the development of new antibiotics, Section 2121 would expand the regulatory pathways that drug companies can use for patients who have no other option and are suffering from life-threatening bacterial illnesses.

So antibiotics would be able to get onto the market for the "limited and specific population of patients" who aren't responding to other drugs after only testing them in a limited number of patients (instead of testing and approving the drugs for a broader population, which costs more money and takes more time). 

Drug companies would also be able to submit "preclinical data" as evidence of an antibiotic's efficacy. This could mean animal studies — instead of the human studies that are typically required to prove a drug works. Drugs with promising results in animals only very seldom work in patients. "Do we really want to approve new drugs based on rat studies?" asked Zuckerman.

The bill lowers the quality of evidence required to approve medical devices

Section 2222 of the bill would change the standards of evidence the FDA uses to scrutinize medical devices, like heart valves or surgical lasers. It would amend the Federal Food, Drug, and Cosmetic Act to basically say that device companies can pass off anecdotes as valid scientific evidence that a medical device works. Case histories (or doctors' write-ups about particular patients), under the new language, would become acceptable data.

"This could mean relying on one doctor, paid for by a drug company, who has done an experiment on three patients, all healthy young men," said Zuckerman. "Because the doctor says, 'This worked great on my patients,' it could be considered sufficient evidence to approve it for all men and women of all ages and all health problems." This is an issue because a few doctor observations about his or her patients may not at all represent the true effects of a device and the experience many other people will have.

An accompanying provision — Section 2221: Third Party Quality System Assessment — would allow device companies to make modifications to their products without resubmitting the new models for FDA approval.

Take the example of heart valves, a high-risk device that goes through the most rigorous device approval hurdles (called the Pre-Market Approval Process). Zuckerman explained that these devices usually need one clinical trial to prove that they're safe and effective. Under the current law, if a company has an approved heart valve that it wants to update, it needs to submit those changes to the FDA, which decides if new clinical trials are warranted. 

Under the 21st Century Cures bill, the company would be able to hire a third-party company to apply for a special status. "The device company would have to prove to that third-party that they have good quality control mechanisms in place, in general, that could be used for the heart valves in question and for other devices on a list the device company gives to the third party," said Zuckerman.

If the third party certifies the device company, she added, that company would not have to apply for changes they want to make to any devices on their certified list for the next two years. 

She called this "a bonanza" for large and wealthy device companies and worried that more unsafe or ineffective medical devices could make it onto the market.

Daniel Carpenter, a Harvard professor who wrote a history of the FDA, calls these sections of the bill "the 19th Century Frauds Act." He continued: "The clauses on using purely observational data for drug approval and what amounts to anecdotal evidence for devices are deeply anti-scientific and would undermine the credibility of the American market for drugs and medical devices ... This Act would seriously undermine that credibility, and by extension the market as a whole."

The bill makes the regulation of drug development tools a political process

Drug development tools are methods or materials that are used to aid in the development of drugs. If the provisions in Sections 2021/2022 that deal with these tools are enacted, they could turn a scientific process into a political one, explained Gregg Gonsalves, a researcher at Yale Law School:

What industry is asking for here are adjudications on the use of key drug development tools very early on, with the guidance of outside experts now taking the central role rather than that of scientists at FDA. These decisions [then become] political ones in tete-a-tetes between [the experts] and the Secretary of Health and Human Services, and commitments to an approval pathway using these drug development tools are agreed upon in an almost binding fashion and are difficult to step away from.

So these provisions essentially create a parallel process outside of the one that already exists at the FDA. Expert groups would be able to meet with the Secretary of Health and Human Services and agree on how a new drug will be developed with a new tool — before the drug has been tested on many people. 

For instance, consider the case of irregular heartbeats: a company could make the case that a drug can alter irregular heart beats using an EKG test as a proxy for the effectiveness of a new medicine. They could argue for approval of the drug based on changes in patients' heart beats, as measured by the tool (the EKG).

"All these drug development tools — surrogates for the 'real thing,' that is, extending life and health—are imperfect," Gonsalves warned. "Making decisions about how to use them early on in the drug development process in the absence of any real clinical experience with a new drug is unwise, to say the least."

Once the companies and the Secretary make an agreement, he added, it can be difficult for the Secretary to rescind her permission. "Companies would have the right to a meeting in which they could appeal the decision face-to-face with [the Secretary]," Gonsalves explained. "This group of advisers would be of outsiders, biomedical research consortia, and 'other individuals and entities with expert knowledge and insights that may assist the Secretary,' which to me means companies and corporate entities could be part of this process of adjudication."

The bill reverses part of the transparency push about pharmaceutical companies paying doctors

The Sunshine Act is part of the Affordable Care Act (a.k.a. Obamacare), passed by Congress in 2010. It requires all drug and device companies to report the payments they make to physicians every year. The idea is that shedding light on the money exchanging hands will shame doctors and drug companies into better behavior.

One way drug companies reach doctors is through medical education, such as running biased medical conferences and publishing supplements (like advertorials) in journals, which influence the types of drugs and devices doctors use. This is why education payments were reportable under the Sunshine Act.

The Cures Act would add an exemption for reporting medical education payments, Harvard's Aaron Kesselheim, who has studied the bill, explained. "This increases the amount of things that doctors can be paid for without reporting it to the physician payment Sunshine database," he said.

The bill does little to address the real problem with the lack of drug innovation

The whole premise of the bill is that a clunky regulatory process is delaying cures from getting to patients.

But these critics say it's not clear that this legislation can solve the biggest problem here — the lack of promising treatments in the pipeline. In other words, a faster approval process can't fix a dearth of innovation from labs themselves.

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

In a June 2015 New England Journal of Medicine article, Kesselheim and Harvard's Jerry Avorn argued that current FDA processes are actually quite efficient, with numerous pathways for drug companies to seek faster approvals. How speeding up the process even further will lead to more cures is unclear.

http://www.vox.com/2015/7/14/8961923/21st-century-cures-act

http://bit.ly/1e0rfoJ

J&J Tylenol product: 38 years of harm-for-profit?

How Much Acetaminophen a Day is Safe? Canada May Decide It’s Less

After an investigation by the Toronto Star, Canada’s top health agency considers whether to lower the maximum recommended daily dose of the active ingredient in Tylenol and other painkillers.

by T. Christian Miller and Jeff Gerth

ProPublica, July 15, 2015, 12:08 p.m.

Canada’s top health agency is considering lowering the maximum recommended daily dose of acetaminophen, the active ingredient in Tylenol and other pain relievers.

Citing the risk of liver damage from overdosing on the popular pain medication, Health Canada announced it will review changes to labels, the creation of an educational awareness campaign and possible revisions to dosage recommendations.

Acetaminophen is considered safe when taken at recommended doses. Tens of millions of people use it weekly with no ill effect. But in larger amounts, especially in combination with alcohol, the drug can damage or even destroy the liver. In severe cases, acetaminophen overdose can cause death.

“Our goal is that we will have fewer effects on liver, less hospitalization, less instances of unintentional overdose, and we have more people that are informing themselves about all the products that they use, not just acetaminophen,” Supriya Sharma, senior medical adviser for Health Canada’s Health Product and Food Branch, told the Toronto Star, in an interview.

The announcement comes after the Star published a lengthy investigation last year on the potential dangers of acetaminophen. The Star, which was assisted in its reporting by ProPublica, found that acetaminophen use in Canada had been responsible for hundreds of deaths, tens of thousands of hospitalizations and tens of millions of Canadian dollars in health-care system costs over the last decade.

An earlier ProPublica investigation done in collaboration with This American Life examined the toll of acetaminophen in the United States. The investigation found that 1,500 people in the U.S. had died and tens of thousands more had been hospitalized as a result of overdosing on acetaminophen over the past 10 years.

ProPublica and This American Life also found that the Food and Drug Administration had delayed implementing safety measures for decades. McNeil Consumer Healthcare, the Johnson and Johnson unit that makes Tylenol, had worked to repeatedly block tougher safety warnings on its billion-dollar product.

Both investigations found a common problem known as “double dipping.” Acetaminophen is present in hundreds of over-the-counter medicines. Thus, people may take several medicines containing acetaminophen — say Tylenol and Theraflu — and not realize that they have exceeded the maximum recommended daily dose of acetaminophen, which is four grams, or eight 500-mg pills.

Another problem with acetaminophen: While generally recognized as safe and effective, the drug has a narrow safety margin — the dosage that can help is relatively close to the dosage that can begin to affect liver function. Some studies have suggested that liver damage can result from taking a few additional pills over the recommended daily dose for several days.

Canada and the United States are among the few industrialized nations in the world to allow unlimited access to acetaminophen. Countries such as Britain, France and Germany restrict access to the amount of acetaminophen that can be purchased, as well as the amount of medicine in an individual pill.

In response to the ProPublica story, McNeil said the company has always put consumer health first and that Tylenol is safe as long as it is used as directed.

After a 2009 FDA hearing in which experts raised new concerns about acetaminophen safety, McNeil changed the label on its Tylenol product to recommend no more than 3 grams, or six extra-strength tablets, per day.

The company maintains that acetaminophen’s safety compares favorably with other over-the-counter pain medications. (The FDA recently announced additional warnings about the risk of heart attacks of taking non-steroidal anti-inflammatory drugs, or NSAIDs, found in popular brands such as Advil.)

“McNeil takes acetaminophen overdose very seriously, which is why we have taken significant steps over the years to mitigate the risk,” the company wrote in an emailed statement.

“We will continue to work hard to educate and warn consumers of the dangers of acetaminophen overdose, reminding them to read the labels on all medicines before taking them, to take medicines only as directed and to be aware that any medicine they take has risks.”

The FDA did not respond to a request for comment on Friday. The agency has previously acknowledged that its procedure for regulating over-the-counter drugs, known as the monograph process, is cumbersome and slow. More than 38 years have passed since the FDA first began hearings on acetaminophen, and the FDA has yet to issue final guidelines on the safe use of the drug.

Last year, the agency announced that it would begin to review the monograph process in order to improve it.

It has yet to take any action.

http://www.propublica.org/article/how-much-acetaminophen-a-day-is-safe-canada-may-decide-its-less?utm_source=et&utm_medium=email&utm_campaign=dailynewsletter&utm_content=&utm_name=

Bayer Essure 'birth control' device had a WARRANTY!

 

Conceptus(R) Introduces the Only Patient Reliance Warranty for Permanent Birth Control

Essurance Promise (TM) Program Confidently Demonstrates the Essure(R) Procedure's Unprecedented Performance

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May 02, 2011 09:00 ET | Source:  Conceptus, Inc.

MOUNTAIN VIEW, Calif., May 2, 2011 (GLOBE NEWSWIRE) -- Conceptus, Inc. (Nasdaq:CPTS), developer of the Essure^® procedure, the most effective permanent birth control method available, today introduced the Essurance Promise^™ Program, the industry's first-ever patient reliance warranty program, at the American College of Obstetricians and Gynecologists 59th Annual Clinical Meeting.

The Essurance Promise^™ Program is an exclusive "out-of-pocket" payment assistance program for the Essure Confirmation Test. After a patient has had the Essure procedure and both inserts are successfully placed, she returns for her Essure Confirmation Test three months later. If she is told by her physician that the Essure procedure requires more time to be effective or she cannot rely on Essure for permanent birth for any reason at that time, the Company will pay her uncovered costs for the Essure Confirmation Test, up to a maximum of $150 per test, and in accordance with certain conditions. 

Conceptus is uniquely able to offer such a warranty program because the Essure procedure's clinical and real-world commercial performance is unsurpassed among all other permanent birth control options, including tubal ligation, vasectomy and the only other competing hysteroscopic sterilization product. For nearly a decade of clinical trial follow-up, there have been zero reported pregnancies with the Essure inserts when properly placed. Results in the commercial setting over this same time period are equally compelling and continue to reflect the Essure procedure's superb clinical performance. 

No other method of permanent birth control works better than the Essure procedure and no company other than Conceptus backs up their procedure with a reliance warranty, which gives women full confidence in this birth control choice.

"The Essurance Promise^™ Program is an innovative solution demonstrating our conviction that patients can rely upon Essure for permanent birth control. The warranty supports both physicians and patients by giving them peace of mind when they choose the Essure procedure, while emphasizing the importance of the Essure Confirmation Test," said Mark Sieczkarek, president and chief executive officer of Conceptus. "This program further advances our leadership role in the hysteroscopic permanent birth control market that we pioneered more than a decade ago."

The Essure procedure is the market leader between two competing hysteroscopic sterilization procedures and has been trusted by more than half a million women since 2002.  Following the introduction of the competitor's product last year, the market may have experienced confusion and lack of clarity regarding the differences between the two products. The Essurance Promise Program underscores Essure's unparalleled performance, including the fact that the competitor product's failure rate is 10 times higher than Essure's failure rate, based on three-year clinical data. In addition, Essure clinical trial patients have experienced zero reported pregnancies, while the competitor's product has resulted in 12 pregnancies in patients followed for five years. The Essure procedure has a proven clinical and commercial track record, but the competitor's product has yet to establish and report its long-term clinical and real-world, commercial safety and effectiveness.

A key competitive advantage of the Essure insert is its stainless steel/Nitinol inner/outer coil design, which is radiopaque and allows for visual confirmation of each insert's proper placement both during the procedure and during the Essure Confirmation Test. The competitor's insert is neither visible during the procedure nor during the confirmation test.  

"The Essurance Promise Program is unprecedented for a permanent birth control procedure. Essure is backed by a growing body of scientific data validating the optimal design characteristics and clinical performance of Essure's Nitinol coil insert, both in the FDA trials and the clinical evidence reported in the literature over the past decade," said Barbara Levy, M.D., Medical Director for Conceptus.  "I highly recommend that OBGYNs talk to their patients about the Essure procedure and the Essurance Promise Program."

Additional information on the Essurance Promise^™ Program

Federal Law prohibits any company from offering this kind of program to Medicaid or Medicare patients and is also restricted where prohibited by law. Complete program details can be found on the Conceptus physician website www.essuremd.com.

About the Essure^® Procedure

The Essure procedure, FDA approved since 2002, is the first permanent birth control method that can be performed in the comfort of a physician's office in less than 10 minutes (average hysteroscopic time) without hormones, cutting, burning or the risks associated with general anesthesia or tubal ligation. Soft, flexible inserts are placed in a woman's fallopian tubes through the cervix without incisions. Over the next three months, the body forms a natural barrier around and through the inserts to prevent sperm from reaching the egg. Three months after the Essure procedure, a doctor is able to perform an Essure Confirmation Test to confirm that the inserts are properly placed and the fallopian tubes are fully blocked, giving the patient reliance on Essure for permanent birth control.

The Essure procedure is 99.95% effective based on one year of follow up with zero pregnancies reported in clinical trials, making it the most effective form of permanent birth control on the market. The procedure is covered by most insurance plans, and when it is performed in a doctor's office the cost to the patient may be as low as a simple co-pay. Essure has been proven and trusted by physicians since 2002, with more than 500,000 women worldwide having undergone the Essure procedure.

About Conceptus, Inc.

Conceptus, Inc. is a leader in the design, development, and marketing of innovative solutions in women's healthcare. The Company manufactures and markets the Essure procedure. The Essure procedure is available in the United States, Europe, Australia, New Zealand, Canada, Mexico, Central and South America and the Middle East. The Company also promotes the GYNECARE THERMACHOICE^® Uterine Balloon Therapy System by ETHICON^™ Women's Health & Urology, a division of Ethicon, Inc., in U.S. OB/GYN physician offices.

The Conceptus, Inc. logo is available at http://www.globenewswire.com/newsroom/prs/?pkgid=7961

Please visit www.essure.com for more information on the Essure procedure. Patients may call the Essure Information Center at 1-877-ESSURE-1 with questions or to find a physician in their area.

© 2011 Conceptus, Inc-- All rights reserved. Conceptus, Essure, Essurance Promise and Your Family is Complete. Your Choice is Clear are registered trademarks and service marks of Conceptus, Inc.                                                                                                                    

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Investor Relations and Public Relations Contact:
Cindy Klimstra
(650) 962-4032

- See more at: http://globenewswire.com/news-release/2011/05/02/445842/220416/en/Conceptus-R-Introduces-the-Only-Patient-Reliance-Warranty-for-Permanent-Birth-Control.html#sthash.GdM5APMu.dpuf

Harmed Patients are Legally Screwed: Watch This Video

Medical device warranty: an antidote to industry entitlements? Congress is selling out!

The 21st Century Cures Act — Will It Take Us Back in Time?

Jerry Avorn, M.D., and Aaron S. Kesselheim, M.D., J.D., M.P.H.

June 3, 2015   (FiDA highlight)

In May 2015, the 21st Century Cures Act was introduced in the U.S. House of Representatives, with the goal of promoting the development and speeding the approval of new drugs and devices.1 Championed by the pharmaceutical, biotechnology, and device industries, the bill was approved unanimously (51 to 0) in committee and continues to be debated. If enacted into law, some of its provisions could have a profound effect on what is known about the safety and efficacy of medical products, as well as which ones become available for use.

Some aspects of the bill could indeed enhance the development of and access to new drugs. The legislation calls for annual increases in the stagnating budget for the National Institutes of Health (NIH) amounting to about 3% per year for 3 years when adjusted for inflation. It would also provide an additional $2 billion per year for 5 years to create an “NIH Innovation Fund.” Together, this support would help counteract the effects of sequestration and budget cuts that have reduced the purchasing power of the NIH to its lowest level in years. Given the crucial role that NIH-funded research plays in generating the findings on which so many new drugs are based,2 this boost would be a welcome development. Another useful provision could make deidentified data from NIH-funded clinical trials more available to researchers.

Other proposed changes could lead to less salutary outcomes for patients and the health care system. An underlying premise of the bill is the need to accelerate approval for new products, but this process is already quite efficient. A third of new drugs are currently approved on the basis of a single pivotal trial; the median size for all pivotal trials is just 760 patients. More than two thirds of new drugs are approved on the basis of studies lasting 6 months or less3 — a potential problem for medications designed to be taken for a lifetime. Once the Food and Drug Administration (FDA) starts its review, it approves new medications about as quickly as any regulatory agency in the world, evaluating nearly all new drug applications within 6 to 10 months, an impressive turnaround for such complex assessments.

Nonetheless, as introduced, the 21st Century Cures Act instructs the FDA to consider nontraditional study designs and methods of data analysis to further speed approvals. Adaptive trial designs and the use of Bayesian methods hold promise in some kinds of evaluations, particularly in oncology. However, more problematic proposals include encouraging the use of “shorter or smaller clinical trials” for devices and the request that the FDA develop criteria for relying on “evidence from clinical experience,” including “observational studies, registries, and therapeutic use” instead of randomized, controlled trials for approving new uses for existing drugs. Although such data can provide important information about drug utilization and safety once a medication is in use, there is considerable evidence that these approaches are not as rigorous or valid as randomized trials in assessing efficacy.

The bill would also encourage the FDA to rely more on biomarkers and other surrogate measures rather than actual clinical end points in assessing the efficacy of both drugs and devices. The FDA already uses surrogate end points in about half of new drug approvals.3 Some biomarkers are accurate predictors of disease risk and can be useful measures of the efficacy of a new drug (such as low-density lipoprotein cholesterol for statins). But though a drug's effect on a biomarker can make approval quicker and less costly, especially if the comparator is placebo, it may not always predict the drug's capacity to improve patient outcomes. Bevacizumab (Avastin) delayed tumor progression in advanced breast cancer but was shown not to benefit patients. Similarly, rosiglitazone (Avandia) lowered glycated hemoglobin levels in patients with diabetes even as it increased their risk of myocardial infarction. In 2013, patients began to receive a new drug for tuberculosis approved on the basis of a randomized trial relying on a surrogate measure of bacterial counts in the sputum — even though patients given the drug in that trial had a death rate four times that in the comparison group, mostly from tuberculosis.4 These provisions in the legislation would not immediately change FDA approval standards, but they would give the agency greater discretion, backed by congressional support, to approve drugs on the basis of less rigorous data.

The proposed legislation would make immediate changes with respect to new antibiotics and antifungals by enabling their approval without conventional clinical trials, if needed to treat a “serious or life-threatening infection” in patients with an “unmet medical need.” In place of proof that the antimicrobial actually decreases morbidity or mortality, the FDA would be empowered to accept nontraditional efficacy measures drawn from small studies as well as “preclinical, pharmacologic, or pathophysiologic evidence; nonclinical susceptibility and pharmacokinetic data, data from phase 2 clinical trials; and such other confirmatory evidence as the secretary [of health and human services] determines appropriate to approve the drug.” Antimicrobials approved in this manner would carry disclaimers on their labeling, but there is no evidence that such a precaution would restrict prescribing to only the most appropriate patients. If passed in its current form, the bill would also provide hospitals with a financial bonus for administering costly new but unproven antibiotics, which could encourage their more widespread use. The bill gives the secretary of health and human services the authority to expand this nontraditional approval pathway to other drug categories as well, if “the public health would benefit from expansion.”

The 21st Century Cures Act goes still further in altering the requirements for approving medical devices — an area long criticized for lack of rigor as compared with drug evaluations,5 though regulatory oversight has improved in recent years. As proposed, the new law would redefine the evidence on which high-risk devices can be approved to include case studies, registries, and articles in the medical literature, rather than more rigorous clinical trials. Another section would allow device makers to pay a third-party organization to determine whether the manufacturer can be relied on to assess the safety and effectiveness of changes it makes to its devices, in place of submitting an application to the FDA. Thus certified by the external company, a device maker would be authorized to continue to assess its own products on an ongoing basis.

Informed consent by patients in drug trials has traditionally been sacrosanct, with exceptions made only when consent is impossible to obtain or contrary to a patient's best interests. But another clause in the proposed law adds a new kind of exception: studies in which “the proposed clinical testing poses no more than minimal risk” — a major departure from current human subject protections. It is not clear who gets to determine whether a given trial of a new drug poses “minimal risk.”

Embedded in the language of the 21st Century Cures Act are some good ideas that could streamline the development and evaluation of new drugs and devices; its call for increased NIH funding may prove to be its most useful component. But political forces have also introduced other provisions that could lead to the approval of drugs and devices that are less safe or effective than existing criteria would permit.

Over the past 80 years, this country's regulatory approach has embraced steadily improving criteria for accurately assessing therapeutic efficacy and risk. Patients and physicians would not benefit from legislation that instead of catapulting us into the future, could actually bring back some of the problems we thought we had left behind in the 20th century.

http://www.nejm.org/doi/full/10.1056/NEJMp1506964?query=TOC&

June 4-6 Cinderblocks as foundation for a healthcare revolution!

https://www.eventbrite.com/e/cinderblocks2-tickets-6811480321

Be there - Grantsville, MD!

Here is the agenda.