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

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&

Harmed Patients Notified of/Included in a 'Groundbreaking Conference'?

June 13th, 2014 Conference

Evidence for New Medical Products:
Implications for Patients and Health Policy

Date: June 13th, 2014
Time: 8:30 a.m. – 6:00 p.m.
Location: American Association for the Advancement of Science, Washington, D.C.
Register here: http://www.aaas.org/oZT

This event is co-sponsored by the American Association for the Advancement of Science, Division of Pharmacoepidemiology and Pharmacoeconomics of Brigham and Women’s Hospital/Harvard Medical School, and National Center for Health Research.

Conference Focus

Better implementation of evidence-based medicine can improve the quality and cost-effectiveness of health care in the U.S. This can be challenging in evaluating newly approved drugs and medical devices. While current law requires that medical products be proven safe and effective, there is growing pressure to expedite access to promising therapies and to lessen the research and regulatory requirements for manufacturers. Unmet medical needs and patient demands call for a flexible approach to prescription drug and device regulation, but truncated premarket review may also lead to approval of products that are less effective than expected or have unanticipated safety problems. This groundbreaking conference will review the growing body of research on the medical and public health implications of medical product approval criteria, and examine these findings in the context of patient outcomes, costs, and health policy.

Confirmed Speakers Include (where are the harmed patient speakers?)

Jerry Avorn, MD, Professor, Harvard Medical School; Greg Curfman, MD, Executive Editor, New England Journal of Medicine; Congresswoman Rosa DeLauro; Aaron Kesselheim, MD, Harvard Medical School; Bernard Lo, MD, President, Greenwall Foundation; Rita Redberg, MD, Editor, JAMA Internal Medicine; Joseph Ross, MD, Yale Medical School; Patrick Ryan, PhD, Janssen Research and Development; Sebastian Schneeweiss, MD, Harvard Medical School; Lisa Schwartz, MD, Dartmouth; Joe Selby, MD, Executive Director, Patient Centered Outcomes Research Institute; Steven Woloshin, MD, Dartmouth; Robert Yarchoan, MD, National Cancer Institute; Diana Zuckerman, PhD, National Center for Health Research.

For more details on the program and registration, please go to http://www.aaas.org/oZT. There is no cost for attending the event, but space is limited and advance registration is required.