Experts Weigh In on 21st Century Cures Act

Kate M. O'Rourke


November 18, 2015

Editor's Note: On July 10, the House of Representatives passed the 21st Century Cures Act, which is currently making its way through the Senate. If the bill is signed into law, it would boost funding for the National Institutes of Health and US Food and Drug Administration (FDA) and speed up the development and approval of new drugs and medical devices, among other initiatives. If passed, the FDA would also evaluate the use of evidence from clinical experience in addition to that from clinical trials, to support approval of a new indication for an approved drug or satisfy postapproval studies that the FDA sometimes requires.

Recently, Medscape asked three healthcare experts to weigh in on several aspects of the Cures Act: Julie Vose, MD, MBA, president of the American Society of Clinical Oncology (ASCO); Steve D'Amato, BSPharm, BCOP, president of the Association of Community Cancer Centers; and Diana Zuckerman, PhD, president of the National Center for Health Research.

Medscape: According to the Cures Act, clinical experience could come from observational studies, clinical registries, ongoing safety surveillance, and patient-centered outcomes research activities. Do you think using this additional clinical experience data to support the approval of a new drug indication or to satisfy postapproval studies is a good idea?

Dr Vose: Unfortunately, the postmarketing information that is captured is very minimal and patient reporting is very sketchy. So, I think trying to capture that information in the real world is very important. ASCO is conducting the CancerLinQ project, through which we are trying to capture data in the real world, for patients not on clinical trials. I think this will probably be good for hypothesis-generation [in terms] of looking for new indications for current drugs or for potentially new options for patients.

I think it is important to look at the data and put them in the context of the real world. Clinical trials, unfortunately, are very stringent, so we need to get additional information to see what really happens in the real world. Collecting all of the data is probably a way to improve safety.

[The Act] will help us alter the standard of evidence to help ensure that the FDA can maintain its focus on efficacy and safety of clinical trials, but it will give us additional information. As long as we collect information that is accurate and correct, I think it is a good use of resources.

Dr D'Amato: Overall, the idea is to make drug development and approval more efficient. It is important to constantly evaluate whether our regulatory regime is nimble enough to respond to technological advances. The proposals take steps to move beyond a rigid two placebo-controlled studies for approval to something that is more dynamic. New endpoints allow for a better focus on outcomes that are meaningful for patients, not just what is meaningful to the FDA.

Dr Zuckerman: I believe the Act will allow unsafe and ineffective drugs to market. Clinical experience should be used to supplement and help understand scientific data from clinical trials, not to replace such data. Clinical experience should be used to support or reject applications. Unfortunately, I've seen many examples at FDA meetings where companies use patient and doctor experiences to support their application for approval, and dismiss clinical experiences as meaningless anecdotes when they show terrible side effects.

The definition of "clinical experience" includes everything and the kitchen sink in the bill, and our suggestion that the definition be improved was ignored. I'm an epidemiologist by training. I am a strong supporter of analyzing big data from medical records, but those analyses need to be conducted in a careful and unbiased manner. That's very different from clinical experience defined as one doctor's experience with a few patients, for example, or one patient's experience with a drug.

Any scientist worth anything can tell you that the experience of a few doctors or patients does not predict the safety or effectiveness of a drug or device. And anyone who understands the FDA approval process—which unfortunately, many doctors and Hill staffers do not—realizes that even if a drug is already approved, it doesn't mean it's safe or effective for other uses. FDA approval is supposed to be based on whether the benefits outweigh the risks for a particular indication. To know whether that same drug has benefits that outweigh the risks for any other indication, or for the same use by other types of patients, requires scientific analysis.

On the other hand, a patient's experience can help us understand the benefits and risks of a drug. Patients and family members can help us understand the devastating impact of side effects, such as gastrointestinal perforations, for example, or how the benefits of a cancer drug enabled them to live at home instead of a hospital during their final weeks of life.

Medscape: In your view, is there a difference between lowering the threshold for approval of a drug to treat cancer vs, for example, diabetes?

Dr Vose: The threshold for approval needs to be put into context of the needs of the patient population. For serious and life-threatening diseases, such as cancer, we need to make sure that the medications get to the patients as soon as possible. There might be a difference in the threshold, depending on the disease. We have accelerated approval for life-threatening diseases.

Dr D'Amato: The methodologies used for drug approval in other disease states should incorporate similar mechanisms to ensure safety and efficacy.

Dr Zuckerman: The threshold should always be whether the benefits outweigh the risks for most patients who will take the drug compared with the alternatives. That is true whether the treatment is for cancer or for diabetes. But the standards are inevitably different for metastatic cancer that has few effective treatment options, compared with cancers for which effective treatments are available. For example, prostate cancer and breast cancer are very common cancers that can be deadly, but if caught early enough, patients can live long and healthy lives. Diabetes can also be deadly, but if treated appropriately, those patients can also live long and healthy lives.

So, the different threshold should not differentiate cancer vs diabetes, but rather differentiate between very aggressive or metastatic cancers that don't respond to existing treatments vs cancers for which safe and effective treatments already exist. Some patients are willing to take major risks with experimental drugs, even knowing they could die sooner, but most do not want treatments that will make them suffer more.

Medscape: The bill would require the FDA to make new tools and concepts, such as biomarker and surrogate endpoints, easier for drug makers to incorporate into their product development. Can you comment on this?

Dr Vose: I think the FDA in conjunction with the scientific community should have an expanded discussion about how to prove that some of these biomarkers are surrogate endpoints. The FDA is involved in putting on several workshops, and various societies are looking at some of these biomarkers. Unfortunately, if we just use survival as an endpoint, oftentimes the studies take too long to conduct or there are competing issues that interfere. So I do think we need to push the scientific community and the FDA on this to find better surrogate endpoints and biomarkers.

Dr D'Amato: The 21st Century Cures Act is responding to a revolution in drug development. The legislation could help the agency navigate the waters brought on by the evolution in study design. Of note, in many instances, the bill would provide the FDA with the discretion to consider alternative methods for demonstrating drug and device safety and efficacy, but not demand that they accept them.

Dr Zuckerman: Surrogate endpoints can help speed up the drug approval process. The problem is that surrogate endpoints are only surrogates for meaningful improvements in health. Many drugs that are effective in improving surrogate endpoints are not effective in improving patients' health.

A great example are two drugs for Alzheimer disease, developed a few years ago, that were thought to be a fantastic breakthrough because they seemed to dissolve beta-amyloid plaques in the brain—a well-established biomarker for Alzheimer disease. Early studies showed a strong impact on those plaques. Unfortunately, studies of memory and cognition found that the new drugs did not improve patient symptoms at all. In fact, the patients taking one of those drugs did worse than those taking placebo, and the drug also increased their risk for cancer.

Fortunately, the FDA did not approve those two drugs on the basis of biomarker data; they required the companies to prove that the drugs actually benefitted patients. When they couldn't prove that, the drugs were not approved.

The FDA is already spending considerable resources studying biomarkers. I think it would be great if Congress gave them more money to do that, but I don't think Congress should tell the scientists at the FDA how to do scientific studies of biomarkers or how to involve industry in the process.

Dr Vose disclosed honoraria from Sanofi; consulting or advisory role with Bioconnections; and research funding from Acerta, Bristol-Myers Squibb, Celgene, Genentech, GlaxoSmithKline, Incyte, Janssen Biotech, Kite Pharma, Pharmacyclics, and Spectrum Pharmaceuticals. Dr D'Amato has consulting or advisory agreements with Celgene, Amgen, Merck, Genentech, Lilly, Teva, and Takeda. Dr Zuckerman owns stock in J&J.


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