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What's wrong with the 21st Century Cures Act

December 20, 2016

Tags: randomized controlled trials (RCTS)

Norman Bauman provided helpful links and comments about the 21st Century Cures Act in the Association of Health Care Journalists' discussion group. I share them (and quote from the sources) here:
• The 21st Century Cures Act is a deal that will give a lot of money to the NIH, FDA, Cancer Moonshot,etc., but will also weaken the FDA's standards of evidence used to approve drugs, particularly randomized, controlled trials (RCTs).
The 21st Century Cures Act, health IT and data (Rebecca Vesely, Health Journalism, AHCJ blog, 12-9-16)

With media watchdogs on the sidelines, pharma-funded advocacy groups pushed Cures Act to the finish line (Trudy Lieberman, Health News Reviews, 12-6-16) ‘Progress’ touted by pharma is a huge step backward for patients. "If the committee’s masterful sales job for the Cures Act is a textbook example of what constitutes effective PR and advocacy in Washington these days for legislation that may not be in the best interests of the public, press coverage offers a textbook example of media abdication of their watchdog role. As HealthNewsReview.org pointed out repeatedly over the past year and half, mainstream journalists, with some exceptions (including Carolyn Johnson at the Post and Sheila Kaplan at STAT) did not look closely, ask hard questions, or explore the downsides until the last few weeks when the Cures Act was a done deal headed for victory."
Health News Review stories about the 21st Century Cures Act

The 21st Century Cures Act -- Will It Take Us Back in Time? (Jerry Avorn and Aaron S. Kesselheim, N Engl J Med 2015; 372:2473-2475)
6-25-15 DOI: 10.1056/NEJMp1506964
Writes Norman: A case in the latest NEJM illustrates what it will mean to have fewer randomized controlled trials (RCTs).
A woman had oligodendroglioma, Grade II with features of Grade III. This case shows you how the treatment of glioma has improved dramatically in the last 12 years, with new drugs, and molecular markers to identify genetic subtypes which can accurately predict the response of a particular tumor to a particular drug. However, the reason they can predict that response accurately is that there are phase 3 RCTs to demonstrate the predictive value of these markers -- in many cases. When there are no RCTs, doctors can't predict the response, and they are reduced to guessing.

In this case, the patient's tumor had a molecular subtype which was associated with a relatively benign course and long-term survival. However, the tumor was progressing slowly, and they were trying to decide whether or how aggressively to treat it. Radiation was effective, but the patient didn't want to risk cognitive decline. A phase 3 trial found that her molecular subtype was responsive to a particular chemotherapy regime -- with radiation. Small phase 2 trials suggested that another drug would be effective, but there were no phase 3 trials to help them make a confident decision.

Bottom line: This shows how doctors (and patients) weigh the evidence of phase 3 clinical trials, phase 2 clinical trials, effectiveness and safety, and interpolate gaps in the evidence. Molecular medicine and new drugs won't do much good if we don't have high-quality, phase 3 RCTs to validate them. With more RCTs, patients in a position like this will have an easier decision. But the 21st Century Cures Act will result in fewer RCTs.

This is important for medical journalists to understand because, according to citations that I've posted on the AHCJ listserv, many journal articles, abstracts, press releases and news stories don't distinguish between association and causation -- which means the difference between RCTs and associational studies. It's also important to understand that the "nontraditional study designs" of the 21st Century Cures Act may leave patients without the information they need to make decisions about new drugs.

Case 38-2016 — A 52-Year-Old Woman with Recurrent Oligodendroglioma (Case Records of the Massachusetts General Hospital) (Andrew S. Chi, Daniel P. Cahill, Mykol Larvie, and David N. Louis, N Engl J Med 2016; 375:2381-2389
12-15-16 DOI: 10.1056/NEJMcpc1610101)
... This case was presented at Neurology Grand Rounds. Although continued observation was discussed for this patient, adjuvant therapy was ultimately recommended because of the infiltration that occurred throughout the left hemisphere.

Current data from randomized trials suggest the use of radiation therapy for a progressive low-grade glioma. However, radiation therapy confers a risk of cognitive decline, which occurs in a proportion of long-term survivors.22,23 . An alternative therapeutic consideration is chemotherapy alone, which has not been definitively associated with cognitive decline.

Evidence from randomized, phase 3 trials suggests that the molecular genetic subtype of this patient's tumor may be particularly responsive to a regimen containing procarbazine, lomustine (CCNU), and vincristine (PCV), which has been shown to prolong survival among patients with WHO grade III anaplastic gliomas with codeletion of 1p and 19q and among a subset of patients with high-risk, low-grade gliomas. However, all patients in these phase 3 trials were receiving treatment for newly diagnosed diseases and were given radiation therapy in addition to PCV chemotherapy. A survival benefit for chemotherapy alone in progressive low-grade glioma has not been established prospectively.

To avoid the risk of permanent cognitive decline, chemotherapy alone was recommended for this patient. In recent years, temozolomide has been used for diffuse gliomas of all subtypes and grades because it is associated with a safer toxic-effects profile than is PCV chemotherapy. Small, uncontrolled, phase 2 trials have shown clinical and radiographic responses associated with the use of temozolomide in patients with progressive and high-risk, low-grade gliomas.27 However, we are unaware of any data from prospective, randomized trials showing the effects of temozolomide in patients with low-grade or anaplastic gliomas. Furthermore, we are unaware of any data comparing temozolomide with PCV chemotherapy. Because this patient was asymptomatic and her glioma had already been proved to be slow-growing, the risks of treatment weighed heavily in the decision regarding the specific chemotherapy regimen. Ultimately, temozolomide was recommended because of its relatively favorable toxic-effects profile, and the patient received 12 cycles without having a clinically significant
adverse event.

New Report Exposes “Patient Advocacy” Groups as a Big Pharma Scam (David Dayen, The Intercept, 12-1-16) "Patient advocacy" groups have a unique power on Capitol Hill. They claim to represent the true voice of constituents, untainted by special interest bias. Politicians and the Food and Drug Administration use their endorsements as reflective of genuine public support. But a new study shows that nearly all of these patient advocacy groups are captured by the drug industry....Drug companies don’t only fund patient advocacy groups, but doctors, medical journals, university research, hospitals, and politicians. In a separate report, POGO explains how the industry helps fund the FDA through “user fees,” which they say come with strings attached."

Would Washington’s FDA Fix Cure the Patients or the Drug Industry? (Alec MacGillis, Pro Publica, 11-3-16) A bill that would speed up approval for medications and medical devices shows how a major initiative can get traction even in the midst of Washington gridlock — but critics say all the lobbying is drowning out some warnings about patient safety.

This bill promises to speed up drug approvals so much that it’s making people uncomfortable (Carolyn Y. Johnson, Washington Post, 7-20-15)

Michael Milken, from junk bonds to legislative advocate (Sheila Kaplan, STAT, 9-14-15) 'Not everyone is pleased with Milken’s behind-the-scenes advocacy. While supporters say the Cures Act ... would make it cheaper and faster to get cutting-edge drugs and medical devices to patients, critics warn that it would create dangerous regulatory shortcuts. They fear that Milken is doing the bidding of the Pharmaceutical Research and Manufacturers of America, the drug industry’s main trade group. “This is a bill that has many provisions that are exactly what PhRMA wants and what the device companies want,” said Diana Zuckerman, president of the National Center for Health Research, a nonprofit think tank in Washington.'