In July, the US House of Representatives approved the 21st Century Cures Act, which heads to the Senate for a vote this fall. While no one can complain about the Act’s purported goal of “bring[ing] our health care innovation infrastructure into the 21st Century,” or increasing funding for the National Institutes of Health, the optimism surrounding the legislation obscures measures buried within that many agree will make newly approved drugs and medical devices less safe and effective, increase the cost of medical products, and discourage innovation in biomedical research.
Long-term value to the public’s health is being sacrificed to the short-term goals of faster Food and Drug Administration (FDA) approvals for drugs and medical devices. Many of the provisions appear to be favorable to the pharmaceutical, biotechnology, and medical device industries, while not providing benefits to patients. We address some of our concerns with the bill below.
FDA Is Not The Bottleneck
The idea that FDA regulatory processes are a bottleneck to new drug development and approvals is not supported by evidence.
An increasing number of people have voiced concern about the quality of biomedical research being produced, including about the lack of reproducibility in research, and the setting of research agendas by those with interests other than public health.
This year, the FDA has approved 89 percent of applications for new drug uses, according to Forbes. If this data is any indication, the agency is, in fact, just the opposite of a bottleneck. When observing just how infrequently the FDA has recently rejected drug applications, notes Forbes author Matthew Herper, “the FDA is basically providing a rubber stamp.”
Fast-Track And Other NIH, FDA Programs
Much of what the 21st Century Cures Act plans to accomplish, such as facilitating drug and device approvals and simplifying clinical trial requirements, has long been underway at the FDA. The agency currently provides five expedited development and approval mechanisms for drugs, for example the breakthrough therapy and fast-track designations.
From 2002-2013, 56 percent of new drugs approved used at least one of these accelerated approval pathways, according to a recent study. Additionally, the FDA approves most drugs faster than its European and Canadian counterparts, other researchers have found. Most new FDA drug reviews take from just six to 10 months. In more than two-thirds, pivotal studies last six months or less, including for diseases needing treatment for years.
Through efforts such as the FDA’s Critical Path Initiative, scientific discoveries in fields such as genomics, imaging, and informatics are increasingly applied toward testing the safety and effectiveness of potential new medical products. And through the Accelerating Medicines Partnership, FDA is partnering with the National Institutes of Health (NIH), 10 pharmaceutical companies, and several non-profit organizations to increase the number of diagnostic tests and treatments available and reduce the time and cost of developing them. These are just two examples of ongoing government-funded programs, spearheaded by scientists, already addressing ways to speed drug development and innovation.
In addition, for those patients requesting access to a drug that is not approved by the FDA and thus not on the market yet, the process for requesting access to the product through so-called “compassionate use” provisions is in the process of being streamlined. Soon it will take a physician only about 45 minutes to complete the paperwork for such a request, and the agency approves the vast majority of requests for expanded access.
Doomed To Repeat?
Back in the 1950s, data from anecdotal reports, case series, and findings that a drug killed germs in test tubes were used to justify the marketing of antibiotics. These insubstantial forms of evidence have circled back into proposals in the 21st Century Cures Act.
After passage of the 1962 Kefauver-Harris Amendment to the Federal Food, Drug, and Cosmetic Act, which required drug manufacturers to provide proof of the effectiveness and safety of their drugs before approval, the FDA removed drugs from the market that didn’t meet adequate efficacy criteria. The drug company Upjohn sued to defend their product Panalba, a combination of two antibiotics, which the FDA pulled from the market. But the US District Court upheld the new evidentiary standard of “adequate and well-controlled investigations.”
The impact of eroding drug approval standards on especially vulnerable patients has also been addressed by the courts in previous decades. In the 1960s and 70s, the chemical compound Laetrile was heavily marketed and sold to cancer patients, despite no evidence of benefit. The FDA later was sued in a case that went to the Supreme Court, which reaffirmed that patients with unmet medical needs are the most vulnerable to promises of false cures. Thurgood Marshall summed up the opinion:
The [Food, Drug, and Cosmetics] Act makes no express exception for drugs used by the terminally ill and no implied exemption is necessary to attain congressional objectives or to avert an unreasonable reading of the term ‘safe’ and ‘effective’ … Nothing in the legislative history suggests that Congress intended protection only for persons suffering from curable diseases (US vs. Rutherford 1979).
Accelerating Antibiotic Resistance
Perhaps most concerning about the law is an unnecessary new fast-track pathway for FDA approval of antibiotics based on non-clinical data as well as small, early-stage clinical trials (Section 2121). Antibiotics could be approved based on data showing the drugs kill germs in test tubes or animals, although time and time again, it’s been shown this doesn’t always translate to effectiveness in people.
One recent example is bedaquiline (Sirturo), a drug for multi-drug resistant tuberculosis. While the drug kills the bacteria in patients’ sputum, in a clinical trial that followed patients for months longer than the pivotal trials on which approval was based, more than five times as many patients died in the Sirturo-treated group (10 out of 79) than in the comparison group (2 out of 81).
Another antibiotic, tigecycline (Tygacil), looked promising across the board in test-tube, animal, and pharmacokinetic/pharmacodyamic modeling studies. It was approved on the basis of non-inferiority trials to an older, effective comparator antibiotic, as antibiotics often are. This meant that it was about as successful a drug as the comparator, although there was a chance it could be less so. As it happened, tigecycline indeed increased the risk of death compared to the already available antibiotics. But the FDA didn’t issue an initial warning about the drug until 2010, ten years after it had been approved. The FDA reiterated and intensified this alert in 2013 by issuing a black box warning.
These examples, among many, highlight the risk of weak evidence in the drug approval process.
Incredibly, Section 2123 of the Cures Act specifies that hospitals may be paid extra every time they use new antibiotics (which are predicted to cost thousands of dollars) as opposed to older, already available antibiotics. Such incentives will encourage the unnecessary use of newer antibiotics in hospitals, where antimicrobial resistance is a serious problem.
Easing Already Weak Standards For Medical Devices
As currently drafted, the 21st Century Cures Act significantly weakens Americans’ protections from poorly designed medical devices. Medical devices already undergo much less stringent testing and review than drugs, which can result in potential problems that go undetected until the devices are already in patient use. For instance, in recent years, concerns have surfaced about metal toxicity from “metal-on-metal” total hip replacements. These widely used implants resulted in metal ion leakage, causing both systemic metal toxicity and severe local tissue inflammation, bone loss, and joint destruction, often resulting in permanent disfigurement and disability.
Section 2221 of the draft legislation allows device companies to make changes to devices, just like the change from partially polyethylene to all-metal hip implants, without informing the FDA or proving that the new design is safe and effective.
Section 2222 of the Act would allow FDA to consider evidence from case studies or medical journal articles as part of the “valid scientific evidence” needed to approve new high-risk devices. Relying on data from published studies is problematic, however. Journal editors and peer reviewers are completely reliant on the accuracy and integrity of authors. They do not have access to raw data, nor do they inspect clinical trial sites for evidence of problems. A large number of published articles are later found to be inaccurate or misleading.
Prasad and coauthors describe a fascinating example of a widely used anesthesia device that was ultimately found to be ineffective once a well-designed trial was completed. In other cases, FDA has identified serious violations related to the conduct of clinical trials, but these violations are rarely in the peer-reviewed literature when the trial is published. A significant reason is that those involved in funding, running, and publishing studies often have vested interests.
The approval process for medical devices should be strengthened, not weakened as the Cures Act attempts to do.
Faster Approval Now, More Safety Problems Later
The 21st Century Cures Act encourages shortcuts to drug approval through expedited review and the use of surrogate outcome measures in clinical trials. Surrogate outcomes are a substitute for a clinical outcome measure and typically don’t take as long or cost as much to measure. However, time and time again, it has been shown that shortcuts such as these lead to the release of ineffective or unsafe drugs onto the market.
The most publicized example of a drug gone bad after approval by expedited review is the non-steroidal anti-inflammatory drug Vioxx (rofecoxib). Vioxx, which was approved based on a surrogate outcome, was withdrawn from the market after five years and four months, following 55,000 deaths and tens of thousands of heart attacks and strokes. Later it was found that the full number of heart attacks experienced in a large trial supporting approval of the drug had been withheld by its manufacturer, Merck. The New England Journal of Medicine, where the study was published, was slow to publish an expression of concern about the missing data.
Harvard physicians Jerry Avorn and Aaron Kesselheim point out safety and efficacy concerns about two other drugs approved using surrogate outcomes: bevacizumab (Avastin) and rosiglitizone (Avandia). The breast cancer drug Avastin was approved via an accelerated approval program in 2008 but by 2011 it was found to improve neither quality of life nor survival of patients and FDA withdrew its approval for breast cancer treatment. The diabetes medication Avandia was found to decrease a measure of blood sugar in patients with diabetes, but increased their risk of heart attacks. In other words for these drugs, the operation was a success, but the patient died.
It can take more than a decade after approval for important safety information to be discovered and displayed in the label, researchers have found. Half of new black box warnings appear after a drug has been on the market for 12 years, and half of the drugs that are eventually withdrawn from the market because their risks outweigh benefits had been on the market for five years or more before they were withdrawn.
21st Century Cures Will Lead To Less Innovation
A recent investigation of 54 new cancer drugs approved by the FDA over the past decade found that 74 percent had no proof that they extended life, and few had proof for improving quality of life. “A veneer of innovation” is how Peter F. Thall, of MD Anderson Cancer Center in Houston, described the reliance on surrogate endpoints such as tumor shrinkage, or biomarkers, for drug approvals.
With the costs of these drugs running upwards of $100,000 annually, these ineffective drugs are a drain on individual patients, families, and the health care system.
About 90 percent of new drugs approved in the United States and Europe do not have any clinical advantage over existing drugs, according to teams of physicians and pharmacists in several countries.
Encouraging the pursuit of marginal, often clinically insignificant outcomes does the exact opposite of encouraging innovation — it fosters development of the next me-too drug of marginal or ultimately insignificant effectiveness.
Finally . . . Follow The Money
Much is being made of the bipartisan support behind the bill. Little mention is made of the bipartisan millions spent by the pharmaceutical and related industries on campaign contributions. According to OpenSecrets.org, among all 435 representatives in the US House, the top recipient of funds from the pharmaceutical and health care product industries for 2013-2014 was none other than Fred Upton (R-MI), the primary sponsor of the 21st Century Cures Act. The congressional sponsors count hundreds of professional associations and disease advocacy groups as allies on the bill. One would be hard pressed though to find any that do not take considerable money from industry.
In sum, the 21st Century Cures Act, instead of strengthening our drug approval process to ensure the safety of Americans, unnecessarily weakens the FDA’s approval process, and will subject our citizens to the needless risk of dangerous and ineffective medical therapies.