Jack Mitchell, National Center for Health Research, July 12, 2017

Thank you for the opportunity to speak today.  I’m Jack Mitchell, Director of Health Policy at the National Center for Health Research (NCHR).  Our research center analyzes medical and scientific data to provide objective health information to patients, providers and policy makers.  We do not accept funding from pharmaceutical or medical device companies, and so I have no conflicts of interest to report.

I’m not a scientist or clinician, but I previously worked in a senior position in FDA’s Office of the Commissioner and we have a number of science and public health PhDs on our staff.  I’m presenting the organization’s views on behalf of the many patients and consumers whom we represent.

While we strongly support the need for more and better treatments for AML (Acute Myeloid Leukemia) patients, we are very concerned about the data used to support the application for GO.  Problems with the trial design raise questions about its validity.

First of all, the only pivotal trial was open label, which increases the risk for bias.  The purpose of blinding in a clinical trial is to control for the placebo effect, since the knowledge that one is taking the newest experimental drug tends to encourage patients and clinicians to have a greater belief in a perceived effectiveness.

Second, all lower grade safety events and some important severe safety events were collected retrospectively, which increases the risk for inaccuracies.  And, which as FDA presenters have noted, limits the analysis of the safety profile.

Third, the trial took place only in France.  This is of note because there are numerous examples of medical products that do not work as well in American patients as they do in patients in other countries.  French patients can have different health habits and health care.  These issues would raise concerns, even if the data supporting approval was strong, which we believe they are not.  Instead, it is not clear that the data support the efficacy or safety of GO.

As I noted previously, the application is based on a single pivotal trial along with a review of the literature.  The pivotal trial does not provide evidence for overall survival, and the previous clinical trial included in the literature review found an inconsistent effect of GO in overall survival.  It is important to remember that this drug was approved based on a single trial and later removed from the market, in part, because the post-market study did not demonstrate effectiveness.

The pivotal trial and literature review do demonstrate improvement in event-free survival.  The trial also shows an improvement in relapse-free survival.  However, the important metric is overall survival, which is not clearly demonstrated.  FDA reviewers and the sponsor’s scientists showed that event-free survival does not correlate well with overall survival.  This especially is a problem in an open label study where the placebo effect can’t be controlled.

Our research center recently published an article in an AMA journal revealing that many cancer drugs have been approved based on surrogate endpoints, such as event-free survival.  But later studies have found that those drugs did not improve overall survival or quality of life.  We found that patients and their insurers were spending $100,000 or more and suffering serious adverse events for treatments that often had no measurable benefit for their health or survival.

The change in dosing does appear to reduce adverse events compared to the earlier version of this medication.  Nevertheless, there were still serious adverse events that can result in death.  The drug was associated with increased bleeding events, including four fatal hemorrhages, and liver disorders, including three fatal cases of VOD (veno occlusive disease).  There were no fatal hemorrhage or VOD events that occurred without exposure to the drug.   However, we acknowledge the sponsor’s efforts to address the ongoing VOD issue and risk profile.

It’s noteworthy that these results were in a clinical trial where patients are carefully monitored.  Patients in the real world are typically monitored less carefully than patients in clinical trials.  As a result, it is possible that more patients could continue on a drug causing serious adverse events because they hope the drug will improve their condition, putting themselves at increased risk.  Well-intentioned doctors who are unaware of the history of the drug may also decide to increase the dose of patients who are not improving, putting patients at greater risk for adverse events without improving the chance for survival.

In summary, surrogate endpoints, such as event-free survival, often do not predict overall survival or other measures of improved health or quality of life.  Given the research design, only one pivotal study, the lack of U.S. patients, and a less than convincing literature review, the data do not support sufficient support for approval.  The studies, in our view, do not provide strong evidence that GO is effective and there are still continuing safety concerns.

We believe that the evidence does not indicate that the benefits outweigh the risks, which is the most single important consideration before you today.  Thank you for providing this opportunity to present our views.

Megan Polanin, National Center for Health Research: June 21, 2017

Thank you for the opportunity to speak today. My name is Dr. Megan Polanin. I am a Senior Fellow at the National Center for Health Research, and I previously trained at Johns Hopkins University School of Medicine. Our research center analyzes scientific and medical data and provides objective health information to patients, providers, and policymakers. We do not accept funding from pharmaceutical companies, and therefore I have no conflicts of interest.

We realize that the goal of all five of the drugs discussed during this meeting are for treating rare pediatric cancers and that these patients desperately need new treatments. In some recent approval decisions, the FDA has been criticized for approving treatments for rare diseases based on inadequate data and wishful thinking. As a result, most insurance companies were not willing to pay for those approved drugs. Instead of getting free drugs in clinical trials, those patients are left with no affordable options. So, it is essential that the studies conducted are designed to be able to prove whether or not any of these 5 drugs have benefits that outweigh the risks.

We strongly support FDA Advisory Committee meetings like this one to garner input from experts on how best to design and conduct clinical trials for pediatric patients. This committee has been and will continue to be thorough in asking specific questions of the drug sponsors on their trial design while also offering helpful critiques and suggestions when needed.

Despite the challenge of studying these drugs for extraordinarily rare populations of patients, it is critical to uphold the scientific integrity of the proposed trials. For example, when possible, researchers should use randomized or well-matched control group/comparison samples for new drugs because it is the most methodologically sound design in order to demonstrate whether a drug is safe and effective. When a proper control group is not available, researchers should observe a robust single agent response rate in order to support a drug’s efficacy.

By law, FDA decisions are NOT based on cost, but you know that the cost of these drugs can be a huge issue for children and their families. In the last year, two drugs used to manage — not to cure — rare diseases were priced at $300,000 and $750,000 per patient, per year. As I noted, insurance companies are making sure these drugs are proven to work before they are willing to pay for them. You can help the FDA make sure that the evidence is clear.

When analyzing the proposed clinical trials, we urge this committee to keep in mind the possible pitfalls associated with using biomarkers and surrogate endpoints in lieu of outcomes that are most meaningful for patients such as overall survival and quality of life. A study published in JAMA found that only 14% of cancer drugs approved using surrogate endpoints were later determined to improve patients’ overall survival. Our Center found that only one of these drugs was proven to improve quality of life, and yet all were still on the market — costing an average of almost $100,000 per year. Let’s make sure that cancer drugs for children are proven to provide meaningful improvement in patients’ health or quality of life, if not both.

Additionally, there are clearly subpopulations of patients who respond better to treatment than others. We encourage the sponsors to further characterize the positive responders in order to target the population of patients who are most likely to benefit and least likely to be harmed by adverse events from their treatment.

Drug efficacy is a complex issue for children with chronic and/or rare diseases like the cancers discussed here. We commend the FDA and this committee for providing an open discussion focused on the best ways to test these five new drugs in pediatric populations. This marks a positive effort to help ensure that drugs are safe and effective for everyone for whom they are prescribed, particularly when the cost of these drugs can be so high.

Thank you for the opportunity to express our views.

Megan Polanin, PhD, National Center for Health Research: June 15, 2017

Thank you to the FDA and the Safe Use Team for hosting this meeting and for the opportunity to share our perspective. I’m Dr. Megan Polanin, and I am a Senior Fellow at the National Center for Health Research.

Our focus is patient-centered comparative effectiveness research. With support from PCORI (the Patient-Centered Outcomes Research Institute), we’ve trained about 120 patient advocates to understand the value as well as the limitations of clinical trials.

Some of the patients we’ve trained are desperate for new cures, and others have been harmed by medical products and believe that the FDA needs to require better evidence of safety before approving new drugs or devices.

But the one thing they all agree on is that patients aren’t really getting informed consent about the drugs they are taking. Most doctors aren’t talking to most patients about potential side effects, or even about how good the evidence is that the treatment will work. Most patients blindly fill prescriptions because they assume that the drugs are proven safe and effective for patients just like them.

A big problem is that doctors rarely tell patients if their prescriptions are off-label. Most patients who are prescribed a drug off-label don’t realize that the drug they are prescribed has not been approved for the particular indication they need. Research shows that off-label uses are often ineffective and have more adverse side effects than on label use. Patients deserve to know if a doctor recommends a use that hasn’t been proven to have benefits that outweigh the risks.

Reducing the chances of adverse drug events requires a discussion between the doctor and patient about any evidence that the drug really will do more harm than good.  Unfortunately, doctors often have limited information – most of which they got from drug reps, not from the FDA. Drug labels have gotten so long that most doctors and patients don’t read them. I ask you: Why include the chemical composition of the drug on those labels? Why not focus on the risks and benefits in simple language instead?

And, as we all know, many doctors don’t have a lot of time to discuss these kinds of issues with their patients, and many doctors are not skilled in having these kinds of conversations.

In addition, FDA rarely provides information to patients or doctors about adverse events for specific major demographic groups, such as women, men, people of color, or for older patients. Having that information clearly on the label would help reduce adverse drug effects.

Doctors and patients should be clearly told when a drug is approved on the basis of biomarkers, and whether there are other drugs for the same indication that are proven to improve survival or clinically meaningful health measures, such as fewer heart attacks or better quality of life.

Bottom line: An important way for the FDA to help prevent adverse drug events is to make sure that patients know in advance what kind of choices they have for prescription drugs, and which ones are likely to be safer for them as women, people of color, patients over 65, and people with a particular illness. Patients deserve to know this information before filling their prescription.

Stephanie Fox-Rawlings, PhD, National Center for Health Research: May 24, 2017

Thank you for the opportunity to speak today. My name is Dr. Stephanie Fox-Rawlings. I am a Senior Fellow at the National Center for Health Research. Our research center analyzes scientific and medical data to provide objective health information to patients, providers and policy makers. We do not accept funding from drug or device companies so I have no conflicts of interest.

The pivotal study that is the basis of today’s review only demonstrated a small improvement in the primary efficacy endpoint. After 2 years, about 2.3% more patients were without invasive disease if they took the drug compared to placebo. This difference was statistically significant, likely because the large number of patients in the study. However, such a small difference could be specific to this particular sample of patients and trial and might not be generalizable for all women with early-stage breast cancer.  It is impossible to say, since after 2 years over 90% of patients were free of invasive disease whether they received the drug or placebo.

Patients followed for 5 years had a similar result – about 2.5% were more likely to be cancer-free, while almost 90% of patients taking placebo were also cancer-free.   There are no data yet on overall survival, so the results aren’t compelling.

This small difference should be considered in the context of adverse events that are typical of cancer drugs: diarrhea, nausea, vomiting, and fatigue were common. However, some were categorized as serious events. Adverse events were so unpleasant that they caused 28% of patients taking the drug to drop out of the study, compared to just 5% of patients taking placebo.

The sponsor also presented data from an ongoing, open-label, single armed study aimed to reduce adverse events due to diarrhea with prophylactic treatment. However, there were still a high occurrence of diarrhea, and the treatment for diarrhea caused a different set of adverse events.  

Patients should not be exposed to adverse events if the drug isn’t proven to provide a real improvement.   The 2.3% difference between 91.9% and 94.2% is not impressive.  And with only one pivotal study, there is no way to know if that result would be replicated in a second study.

A recent study published in JAMA Internal Medicine found that when FDA approved cancer drugs based on a surrogate endpoint, such as cancer-free survival, later studies have not found a benefit in overall survival.  And yet, these drugs cost an average of $100,000 – often more – and can harm quality of life.

We see that neratinib’s benefit compared to placebo is similar to that of a previously approved drug.  That does not mean that it should be approved. Patients do not benefit from more new drugs on the market unless the new drugs are more likely to have benefits that outweigh the risks.

The FDA should be sure that new treatments provide a real benefit to patients before they are approved.   We recommend that the FDA not approve neratinib for breast cancer unless a clear benefit can be replicated, or a benefit for overall survival is demonstrated.

The Cancer Prevention and Treatment Fund is the major program of the National Center for Health Research, and can be reached through Stephanie Fox-Rawlings at sfr@center4research.org.

Jack Mitchell, National Center for Health Research: May 9, 2017

Good afternoon.  I appreciate the opportunity to address this distinguished panel and our FDA participants.  I’m Jack Mitchell, director of government relations for the National Center for Health Research (NCHR).   We conduct research, use research data to inform public policy, and advocate for safe and effective medical products.  NCHR accepts no pharmaceutical or medical device industry money, and therefore I have no conflicts to report.

We strongly support FDA efforts to strengthen the role of patients and we urge the agency to define patients as those who use medical products, whether or not they are seriously ill.  The patient-focused meetings with FDA and other patient initiatives mentioned by Dr. Mullins in her presentation are welcome and necessary.  I’d like to speak to broadening those patient perspectives.

We know it is a challenge for FDA to attract patients who are truly independent, since so many patient organizations are funded by industry, and many patients are trained and recruited to participate in FDA meetings by industry.  Of course, all patients deserve to be heard, but  industry-supported perspectives should be augmented by independent patient voices.

For example, a recent study by Harvard researchers found that almost all patients who spoke at FDA public meetings had ties to companies that could benefit from their remarks.  Another study, of an FDA advisory committee meeting on a drug for Duchenne’s muscular dystrophy, reported that of the fifty-one public speakers, all but one had financial ties to the company that makes the drug.  That one public speaker was from our research center.

There are patient organizations that are not funded by industry and can offer a more independent voice.  We suggest that FDA needs to do more to reach out to them and include them.  For example, the USA Patient Network is a new national organization consisting of patients who have received training to help them understand clinical trial research design and analysis, so they can serve as confident, well-informed patient representatives on FDA and NIH advisory committees.

In addition, the Patient, Consumer and Public Health Coalition is an informal coalition of about two dozen non-profit patient, consumer, physician, and public health organizations.  They work together to prepare public comments for the FDA and other health agencies, and to educate Congress about important health policy issues.

Patients from these organizations have made presentations before FDA advisory panels and public forums.  They usually pay their own way to FDA meetings.  Not surprisingly, they are dramatically outnumbered by patients whose travel, meals and other expenses are reimbursed by industry.

We respectfully ask the Science Board to ensure that FDA enhances efforts aimed at including these independent patient voices, not only for new drug development, but also on the wide range of public health initiatives in which the agency is engaged.

Your focus today is on innovation initiatives mandated by the 21st Century Cures Act.  We are concerned that the new law does not guarantee sufficient resources to implement all its FDA-related provisions.  For instance, it encourages the FDA to rely more often on preliminary data such as biomarkers, and allow third party review to replace FDA’s premarket scrutiny.

The law has already resulted in the FDA deregulating more than one thousand moderate risk devices that will no longer be required to submit 510(k) applications.  To better ensure safety, FDA needs to expend more resources to improve post-market surveillance, especially of medical devices.

Unfortunately, neither 21st Century Cures nor the user fees that FDA has negotiated provides sufficient resources for effective post-market surveillance, particularly for medical devices.  Patients from the USA Network and other independent patient organizations have provided documented evidence to FDA of serious, irreversible harm caused by fast-tracked device approvals and inadequate post-market surveillance.  They tell us that FDA often is not sufficiently responsive to their requests to strengthen patient safeguards.

We respectfully urge the Board to carefully address these patient recruitment and safety issues as you advise FDA about implementing the 21st Century Cures Act.  Engagement perspectives should include patients who have been harmed by medical products that were not as safe as the research indicated, or had risks about which the patients were not adequately warned.  While FDA is appropriately and routinely hearing from patients desperate for new treatments, those are not the only patients who have important perspectives from which the agency can learn.  Thank you.