Definition of a Guinea Pig: Ask the FDA!

Barely Half of Postmarket Studies Completed After 5 Years

FDA fails to enforce requirements

• by Larry Husten, CardioBrief September 20, 2017 
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Pharmaceutical and device companies are often taking advantage of a lenient (or, some would say, negligent) FDA to shirk their obligation to perform timely post-approval studies, a new Perspective published in the New England Journal of Medicine shows.

The topic has gained increasing  visibility and importance as the FDA has granted approval to many new drugs and devices without all the evidence that might ideally be required.For safety as well as efficacy, the FDA has allowed much of the burden of proof to shift from pre-approval to the post-approval period.

But in an analysis of 614 post-approval requirements and commitments imposed by the FDA in 2009 and 2010 (the first full years after the FDA gained the power to require these studies), Steven Woloshin at Dartmouth Institute for Health Policy and Clinical Practice and colleagues showed that only 54% of these studies were completed after 5-6 years. They found that 20% of "required" studies had not been started and 25% were delayed or ongoing as of September 2015.

"It's not a secret that we need a better post-market system," said former FDA Commissioner Robert Califf, now at Duke University. "The good news is that technology is no longer the limiting factor -- it's all about culture, organization and priority setting by policy makers, clinicians and patients and their 'carers' (families and loved ones)."

The authors observed that in many cases there didn't appear to be any good reason for the delays. For instance, more than 5 years after approval of buprenorphine/naloxone film (Suboxone), no protocol had been submitted for assessing the risk of QT-interval prolongation, "even though the design of such studies is highly standardized and participants are observed for a limited period."

"The slow, irregular pace of post-approval studies contrasts starkly with the short, rigid deadlines and other shortcuts used to speed marketing approval," the authors wrote.

The FDA should "do more to ensure that sponsors meet post-approval deadlines," the authors urged. Although the FDA has the power to impose fines or other penalties on companies that fail to live up to their obligations, "to our knowledge, it has never imposed such fines." They also recommend that the FDA set shorter deadlines for post-approval studies.

"Woloshin and colleagues offer some useful insights into the FDA's use of post-approval studies to confirm and further evaluate drugs' safety and efficacy at the time of approval," said Joe Ross of Yale University. "While more than half were completed, many were not. This study is only made possible by the efforts at FDA to provide public transparency of the post-approval requirements, but more information could help the public and the profession understand why certain requirements were not fulfilled, whether these studies were intended to provide key clinical information to inform practice (as opposed to safety info that instead came from another clinical study), and even for those studies that were completed, whether the results were published and made available."

Sanjay Kaul of Cedars-Sinai Medical Center said that it is not unreasonable to shift "the regulatory burden from the pre-approval phase to a life cycle-based approach. However, the success of such an approach is predicated on a rigorous and timely post-approval phase. That 1 in 5 post approval studies had not even been started after 5 to 6 years calls into question the degree to which the changes in the FDA's regulatory authority in 2007 have resolved the challenge of reducing the number of unfulfilled post-approval requirements. This can hardly be reassuring given the 21st Century Cures Act which calls for faster marketing of drugs and devices at the cost of stringent evidentiary standards! Even though the FDA has congress-legislated authority to revoke approval of drugs and devices that failed to confirm clinical benefit on post approval studies, it rarely does so! It is difficult to put the genie back into the bottle."

The "bottom line," said Kaul, is that "marketing drugs and devices faster can only be justified if there are much better post-market data to reliably support efficacy and safety."

• https://www.medpagetoday.com/cardiology/cardiobrief/68035

Any COI? Dr. Robert Califf: FDA Commissioner and former Duke University researcher.

Document Claims Drug Makers Deceived a Top Medical Journal

By KATIE THOMAS MARCH 1, 2016

It is a startling accusation, buried in a footnote in a legal briefing filed recently in federal court: Did two major pharmaceutical companies, in an effort to protect their blockbuster drug, mislead editors at one of the world’s most prestigious medical journals?

Lawyers for patients suing Johnson & Johnson and Bayer over the safety of the anticlotting drug Xarelto say the answer is yes, claiming that a letter published in The New England Journal of Medicine and written primarily by researchers at Duke University left out critical laboratory data. They claim the companies were complicit by staying silent, helping deceive the editors while the companies were in the midst of providing the very same data to regulators in the United States and Europe.

Duke and Johnson & Johnson contend that they worked independently of each other. Bayer declined to comment. And top editors at The New England Journal of Medicine said they did not know that separate laboratory data existed until a reporter contacted them last week, but they dismissed its relevance and said they stood by the article’s analysis.

But the claim — that industry influence led to the concealing of data — carries echoes, some experts said, of an earlier era of drug marketing, when crucial clinical data went missing from journal articles, leading to high-profile corrections and a wave of ethics policies to limit the influence of drug companies on medical literature.

“It just feels like it’s a real ethical breach,” said Dr. Lisa Schwartz, a professor of medicine at Dartmouth, of the failure to include the lab data in the letter. “If you know the direct answer to this question, then how can you not provide it to be able to give insight?”

Xarelto, which is sold in the United States by Johnson & Johnson and overseas by Bayer, had nearly $2 billion in United States sales last year and is the best seller in a new category of drugs seeking to replace warfarin, an older blood thinner. The two companies hired the Duke Clinical Research Institute to run a three-year clinical trial involving more than 14,000 patients that led to Xarelto’s approval by regulators. But those results have come under scrutiny since September, when the companies notified regulators that a blood-testing device used in the study had malfunctioned.

The trial compared the number of strokes and bleeding events experienced by patients taking Xarelto with those of patients using warfarin. The concern is that the faulty results may have led doctors to give patients the wrong dose of warfarin, which could have favored Xarelto.

Last month the Duke researchers published an analysis in The New England Journal of Medicine and concluded that the problems with the device did not change the trial’s results.

But some in the medical community questioned their findings because their method required them to essentially guess which groups of patients were more likely to be affected by the malfunctioning device.

A better way to evaluate the device, other researchers said, would be to compare the device readings with test results that were done at a central laboratory. Investigators did that at two points in the trial, drawing blood from more than 5,000 of the patients who took warfarin and sending the samples for testing. The blood was taken 12 and 24 weeks after patients enrolled in the trial.

But the Duke researchers made no mention of the lab data in their letter. In an interview, journal editors said they did not know about the lab data until last Tuesday, when a reporter for The New York Times asked them about it.

“At the time we published the letter, we didn’t know that it existed,” said Dr. Jeffrey M. Drazen, editor in chief of The New England Journal of Medicine.

Dr. Drazen disputed the lawyers’ claim that the editors had been misled about the data, and said it was not relevant to the letter that was published.

Last week, lawyers in the case against Johnson & Johnson and Bayer filed a legal brief in federal court in New Orleans, asking a judge to unseal documents in the case, which involves more than 5,000 lawsuits filed by patients and their families who claim they were harmed by Xarelto. Of those, 500 involve patient deaths.

In a footnote, the lawyers said that during the process of vetting the Duke researchers’ letter, a peer reviewer asked about the existence of lab data that would allow a comparison with the device’s readings.

“Despite being provided this opportunity to respond to the peer reviewers,” the lawyers said, the “defendants remained silent on this point, thereby misleading the NEJM.”

Dr. Drazen confirmed that a peer reviewer, whose identities are kept confidential, had asked about such data, but said the editors had rephrased the question to ask whether such data was available throughout the course of the trial. Duke then answered no, he said.

The letter’s three authors, two from Duke and one affiliated with the University of Edinburgh in Scotland, declined to comment, as did a spokesman for Duke.

Dr. Drazen questioned the value of comparing lab results taken at only two points during the trial, noting that people’s blood-clotting levels can vary greatly over time. “There’s so much variation among people that it probably wouldn’t be clinically informative,” he said.

However, he said, the Duke researchers had since agreed to conduct an analysis of the lab data.

Dr. Drazen also said that the editors had not been in contact with either Johnson & Johnson or Bayer. A spokeswoman for Johnson & Johnson said the analysis by Duke was conducted independently of the company. Although a company employee serves on the trial’s executive committee, she said he recused himself “from the conduct of the reanalysis, the drafting of the research letter, and provided no feedback before it was submitted.” Bayer declined to comment.

In a previous statement, Duke said it had conducted its research separately from the two companies. But this fall, Bayer submitted an analysis to the European Medicines Agency that was nearly identical to the approach used by the Duke researchers, comparing the outcomes of patients who had specific medical conditions with outcomes of those who did not. And the legal document filed last week cites a document obtained from one of the companies that describes the peer-review process.

Some experts say this case is reminiscent of other instances in which drug companies concealed or altered drug-trial data in medical journals. In 2005, for example, The New England Journal of Medicine published a rare Expression of Concern after it learned that researchers had failed to include three heart attacks in a study of the painkiller Vioxx, made by Merck, which has since been withdrawn from the market. In that case, editors learned that data had been deleted from the trial manuscript two days before it was submitted to the journal.

Such controversies led to changes in the way that journal articles are published. Authors are now required to disclose their outside financial interests and the role that drug companies played in articles’ publication.

Several researchers said they were surprised that Duke and the editors at the journal did not see value in comparing the lab data, especially since Bayer and Johnson & Johnson have submitted such information to regulators in Europe and the United States.

“I think it’s always important to make sure that you have all the information to answer the scientific question before publication,” said Dr. Rita F. Redberg, a cardiologist who is also editor of the medical journal JAMA Internal Medicine.

Less than a week after the Duke letter was published, the European Medicines Agency released its own report, which contained analyses using the independent lab comparisons. The agency concluded the device most likely did not affect the trial’s outcome, but it did find that the device was highly inaccurate.

Dr. Steven Nissen, a cardiologist at the Cleveland Clinic, served on the Food and Drug Administration advisory panel that voted to approve Xarelto in 2011. He was one of two members who voted against the drug. He expressed doubt that any after-the-fact analysis would give doctors and patients answers. “Given the fact that the device was inaccurate, there is no way anybody can tell you what would have happened in the trial,” he said.

The Lancet and NEJM: Medical Industry Corruption More Dangerous Than All Wars

Shocking Report from Medical Insiders

Published On: Fri, Jun 19th, 2015

 By F William Engdahl

A shocking admission by the editor of the world’s most respected medical journal, The Lancet, has been virtually ignored by the mainstream media. Dr. Richard Horton, Editor-in-chief of the Lancet recently published a statement declaring that a shocking amount of published research is unreliable at best, if not completely false, as in, fraudulent.

Horton declared, “Much of the scientific literature, perhaps half, may simply be untrue. Afflicted by studies with small sample sizes, tiny effects, invalid exploratory analyses, and flagrant conflicts of interest, together with an obsession for pursuing fashionable trends of dubious importance, science has taken a turn towards darkness.”

To state the point in other words, Horton states bluntly that major pharmaceutical companies falsify or manipulate tests on the health, safety and effectiveness of their various drugs by taking samples too small to be statistically meaningful or hiring test labs or scientists where the lab or scientist has blatant conflicts of interest such as pleasing the drug company to get further grants. At least half of all such tests are worthless or worse he claims. As the drugs have a major effect on the health of millions of consumers, the manipulation amounts to criminal dereliction and malfeasance.

The drug industry-sponsored studies Horton refers to develop commercial drugs or vaccines to supposedly help people, used to train medical staff, to educate medical students and more.

Horton wrote his shocking comments after attending a symposium on the reproducibility and reliability of biomedical research at the Wellcome Trust in London. He noted the confidentiality or “Chatham House” rules where attendees are forbidden to name names: “’A lot of what is published is incorrect.’ I’m not allowed to say who made this remark because we were asked to observe Chatham House rules. We were also asked not to take photographs of slides.”

Other voices

Dr. Marcia Angell is a physician and was longtime Editor-in-Chief of the New England Medical Journal (NEMJ), considered to be another one of the most prestigious peer-reviewed medical journals in the world. Angell stated,

“It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor of the New England Journal of Medicine.”

Harvey Marcovitch, who has studied and written about the corruption of medical tests and publication in medical journals, writes, “studies showing positive outcomes for a drug or device under consideration are more likely to be published than ‘negative’ studies; editors are partly to blame for this but so are commercial sponsors, whose methodologically well-conducted studies with unfavorable results tended not to see the light of day…”

At the University of British Columbia’s Neural Dynamics Research Group in the Department of Ophthalmology and Visual Sciences, Dr Lucija Tomljenovic obtained documents that showed that, “vaccine manufacturers, pharmaceutical companies, and health authorities have known about multiple dangers associated with vaccines but chose to withhold them from the public. This is scientific fraud, and their complicity suggests that this practice continues to this day.”

Lancet’s Dr. Horton concludes, “Those who have the power to act seem to think somebody else should act first. And every positive action (eg, funding well-powered replications) has a counter-argument (science will become less creative). The good news is that science is beginning to take some of its worst failings very seriously. The bad news is that nobody is ready to take the first step to clean up the system.

Corruption of the medical industry worldwide is a huge issue, perhaps more dangerous than the threat of all wars combined. Do we have such hypnosis and blind faith in our doctors simply because of their white coats that we believe they are infallible? And, in turn, do they have such blind faith in the medical journals recommending a given new wonder medicine or vaccine that they rush to give the drugs or vaccines without considering these deeper issues?

F. William Engdahl is strategic risk consultant and lecturer, he holds a degree in politics from Princeton University and is a best-selling author on oil and geopolitics, exclusively for the online magazine “New Eastern Outlook”.
http://nsnbc.me/2015/06/19/shocking-report-from-medical-insiders/

FDA Could Be Sustainable AND PREVENT Harm

The FDA Could Earn Over $60 Million A Day From Enforcing The Law

Stuart Buck

October 14, 2015

Many clinical trials on medicines and devices are subject to a 2007 federal law that requires the results to be publicly disclosed on a federally sponsored website within a year after the clinical trial is over. The reason for this requirement is simple: to give doctors and patients full information so that they can make educated decisions about a given treatment. If disappointing clinical trial results remain hidden, while only the most positive results are published and presented in the media, doctors and patients can be wildly misled.

Unfortunately, investigators have found that over half the time, clinical trial sponsors fail to abide by the law, sometimes failing to disclose results even after five years have elapsed. Even more unfortunately, the Food and Drug Administration (FDA) has never once imposed the legally authorized $10,000-per-day fine for failure to disclose a clinical trial’s results.

Compliance With Reporting Requirements

The most recent investigation was published in the New England Journal of Medicine (NEJM) in March 2015. The authors identified 13,327 clinical trials that were registered on ClinicalTrials.gov, that were completed between 2008 and 2012, and that were subject to the 2007 federal law requiring full disclosure. A mere 13.4 percent of the clinical trials actually disclosed their results within the 12 months required by law, and even after up to four years had elapsed, only 50.5 percent had disclosed the results or asked for a delay (see Figure 2 in the NEJM article).

In a twist that ought to embarrass academics, industry-funded trials were more likely to disclose results than the National Institutes of Health (NIH)-funded trials, which were in turn more likely to disclose results than academic medical centers. The authors found 6,599 clinical trials that were overdue on reporting results.

Increasing Fda Enforcement

If the FDA imposed a $10,000 per day fine on each of these 6,599 outstanding trials, clinical trial sponsors would be responsible for $66 million in payments in the first day alone, adding up to over $24 billion per year.

Although the $24 billion figure shows the size and scope of the problem, the collective fines would never reach that amount because as soon as the FDA actually begins enforcing the law, the researchers who conducted these 6,599 trials would finally be incentivized to report the trials’ results.

Why doesn’t the FDA enforce the law? Some have argued that ClinicalTrials.gov is an antiquated and difficult-to-use website. True enough, but given that 38 percent of trials do disclose their results at some point, it is clearly not impossible to do so. This is not a reason to leave the federal law completely unenforced.

The NEJM article states that one reason for lack of enforcement is that a new rule on clinical trial report is still pending. But the 2007 law itself requires basic reporting of results; the only point of a new rule is to expand the requirements to include other items, such as protocols. The mere fact that a rule may be expanded in the future is no reason to leave the current requirements unenforced. Yet another possibility is that the FDA does not want to get bogged down in lawsuits from companies or universities that have a valid reason for delay. But this argument would suggest, at most, that the FDA ought to levy a fine only when truly merited, not that the FDA should never enforce the fine at all.

My proposal: as an experiment, the FDA should give the 30-day notice required by statute, and then set aside a single week in which it will levy the $10,000-per-day fine on all overdue trials. Assuming that there are around 6,600 overdue trials that don’t come into compliance within the 30-day grace period, the FDA would end up imposing over $460 million in fines within a week’s time. In so doing, it would make a strong statement that disobeying the law and hiding clinical trial results is no longer acceptable.

And within a week, compliance with the law would likely shoot up astronomically, and we would have more complete knowledge about how well or how poorly drugs actually work. In turn, we could all make better decisions about how to improve our nation’s health.

http://healthaffairs.org/blog/2015/10/14/the-fda-could-earn-over-60-million-a-day-from-enforcing-the-law/

FDA historically allows fraudulent ads of pharmaceuticals and medical devices targeted to women.

The Vernacular of Risk — Rethinking Direct-to-Consumer Advertising of Pharmaceuticals

Jeremy A. Greene, M.D., Ph.D., and Elizabeth S. Watkins, Ph.D.

August 19, 2015

Aside from New Zealand, the United States is the only country with a strong pharmaceutical regulatory infrastructure that allows direct-to-consumer advertising (DTCA) of prescription drugs in print, broadcast, and electronic media. U.S. consumers are accustomed to full-page ads in newspapers and magazines detailing a drug's benefits — followed by another page of fine print in which its contraindications, risks, and side effects are spelled out in minute detail and equally minute print.

That may soon change, however, as the Food and Drug Administration (FDA) moves to enact new regulations regarding risk communication in DTCA. Earlier this year, the FDA sought public comments on new guidance for pharmaceutical marketers on communicating risks to consumers in print advertisements. This proposal, which the FDA has kicked around in one form or another since 2004, responds to mounting research showing that reprinting highly technical package inserts in print ads does very little to communicate risks to consumers. The goal is to communicate those risks in a new vernacular.

Instead of reproducing the fine print meant for physicians and pharmacists, the FDA proposes that drug marketers use a new “consumer brief summary” focused “on the most important risk information . . . in a way most likely to be understood by consumers.” A summary written in everyday language might take the form of a Q&A list, for example, or a Drug Facts box like those on packaging for over-the-counter medicines. Drug marketers are being asked to use popular idiom to communicate with people with a wide range of literacy levels; to use larger fonts and more readable formats; and to use visual elements such as white space, logos, and color schemes to highlight the most relevant risks.1

Public comments on the proposal have focused on the challenges of implementation. How many risks are too many to print? How will a manufacturer — or the FDA — know when language is too simple, too technical, or pitched “just right” for average Americans? Missing from this conversation is a broader perspective on the vernacular of risk in pharmaceutical promotion — as something that is not a new DTCA-related duty for the FDA but fundamental to the origins of the category of prescription drugs and their regulation over the past half-century.

After passage of the 1938 Food, Drug, and Cosmetic Act, which established the distinction between prescription-only and over-the-counter drugs, consumers received most information about the latter through ads and most about the former from their physician or pharmacist. Indeed, the category of “prescription-only” medications enabled industry to avoid having to communicate risks directly to consumers in marketing materials. The 1938 law required drugs to carry labels providing “adequate directions for use” and “adequate warnings” to protect users from harm. Partly to sidestep this mandate, drug manufacturers restricted the sale and marketing of their products to doctors, who could comprehend highly technical presentations of indications, contraindications, toxicology, and adverse effects.2

This order of things was upset in the late 1960s, after highly publicized Senate hearings on the safety of oral contraceptives. Women's health activists demanded action after the revelation that knowledge of the health risks associated with the Pill — including potentially fatal pulmonary emboli — had often been kept from women or left for doctors to convey at their discretion. Beginning in 1970, the FDA required manufacturers to include information for patients in every package of birth-control pills. Unlike technical package inserts for pharmacists, this patient package insert (PPI) would outline the health risks of the Pill in clear, everyday prose.

The 1970 Patient Package Insert for Oral Contraceptives.

Yet as the FDA quickly discovered, there was no clear consensus on how best to provide risk information to patients. The first draft of the PPI became a flash point in debates over the relationships between the FDA, drug manufacturers, consumers, and physicians. Entitled “What You Should Know about Birth Control Pills,” the 600-word document described in lay language the health risks, side effects, and contraindications of oral contraceptives. Both the medical profession and the pharmaceutical industry vigorously opposed the proposed pamphlet, and the FDA's parent agency, the Department of Health, Education, and Welfare, advocated revising the wording to address legal issues. In response to pressure from professional, industrial, and government interests, the FDA developed a shorter, less detailed version. The revised text, 100 words long, listed just 5 symptoms of side effects, whereas the earlier draft had listed 25. Gone were statistics on increased risk for and mortality from thromboembolism; the edited version simply mentioned blood-clotting disorders as a possible complication.

During the commenting period on the PPI, the FDA received more than 800 responses, most of them complaining about inadequate disclosure of adverse effects. Yet the insert that finally went to press was even more anemic: it listed no symptoms at all, telling consumers to “notify your doctor if you notice any physical discomfort.” Four of the insert's seven sentences described the availability of an information booklet, which patients could request from physicians. This 800-word booklet, jointly written by the American Medical Association (AMA), the FDA, and the American College of Obstetricians and Gynecologists, provided more information, but very few women actually received it.

It wasn't until 1977, after the FDA mandated use of a PPI to communicate newly disclosed health risks associated with estrogen products, that consumers earned the right to routinely receive the same technical package information as physicians and pharmacists. Then, in 1979, the FDA proposed a lay-language PPI for all prescription drugs. But when physicians, pharmacists, and drug companies balked, the agency scaled back its ambitions to a 3-year pilot program for 10 types of drugs. Even this reduced mandate failed to take effect, after the Reagan administration — seeking deregulation, privatization, and smaller government — required federal agencies to review the necessity and cost-effectiveness of existing and proposed regulations. The FDA deferred implementation of the PPI program in 1981 and canceled it the next year, relying instead on a voluntary private-sector approach.

After the revocation, some written information about prescription drugs was produced by a patchwork of organizations, including the AMA, the U.S. Pharmacopeia, and the American Association of Retired Persons.3 When the FDA began in 1985 to allow drug companies to advertise in mass-market magazines and newspapers so long as they included a “fair balance of information,” as required for ads in medical journals, companies began developing their own “patient information sheets,” which often simply reprinted the text of the package insert written for physicians and pharmacists. This information provision had little to do with educating consumers and much to do with expanding marketing opportunities. The medical terminology, dense verbiage, and tiny fonts of these inserts have made them inscrutable to the average consumer and virtually useless as information sources.4

The FDA's Medication Guide program, proposed in 1995 and launched in 1999, aimed to mitigate this problem for some outpatient prescription products, with user-friendly information to be distributed at the point of sale. The most effective of these guides might serve as templates for risk communication in DTCA. Moreover, in 2015, companies could harness the power of communications technologies such as smartphone-scannable QR codes to link such information to print ads or online materials for interested consumers.

Yet the primary risk-communication challenges the FDA has faced are not technological but social. In the case of the Pill, the PPI's opponents were able to dilute and delay efforts to provide patients with clear, comprehensive risk information. The U.S. medical consumer's voice has grown stronger since the 1970s, and the FDA increasingly relies on social scientific research in its decisions. Nonetheless, the success or failure of the current proposal depends on the agency's ability to capture the interests of all stakeholders.

For all its capacity to encourage overdiagnosis and overmedication, DTCA's virtue is that it treats consumers as people who deserve to know something about the compounds they take into their bodies. After 30 years of DTCA, it's not clear that advertising is the best medium for communicating risk information,5 but marketers should at least be required to try to communicate risk information as effectively as they do their promotional messages.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on August 19, 2015, at NEJM.org.

SOURCE INFORMATION

From the Division of General Internal Medicine and the Department of the History of Medicine, Johns Hopkins University School of Medicine, Baltimore (J.A.G.); and the Department of Anthropology, History and Social Medicine, University of California, San Francisco, School of Medicine, San Francisco (E.S.W.).
http://www.nejm.org/doi/full/10.1056/NEJMp1507924#t=article

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&