Category Archives: Policy

Public Comments at the FDA’s Safe Use Symposium: A Focus on Outpatient Preventable Adverse Drug Effects

Testimony & Briefings
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.

Comments to FDA About Neratinib to Prevent Breast Cancer Reccurance

Testimony & Briefings
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.

Remarks to the FDA Science Board on Patient Engagement

Testimony & Briefings
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.

NCHR Comment on the USPSTF’s Draft Recommendations for Prostate Cancer Screening

Policy
National Center for Health Research: May 8, 2017

 

National Center for Health Research’s Comments on
the U.S. Preventive Services Task Force’s Draft Recommendation Statement
on Prostate Cancer Screening

Thank you for the opportunity to express our views on the draft recommendations for prostate cancer screening.

The National Center for Health Research is a nonprofit think tank that conducts, analyzes, and scrutinizes research, policies, and programs on a range of issues related to health and safety. We do not accept funding from companies that make products that are the subject of our work.

We support the efforts of the U.S. Preventive Services Task Force (USPSTF) to re-evaluate its recommendations in light of new research regarding prostate cancer screening that provides new insights into its benefits and risks. The issue of screening for prostate cancer is complex, because the benefits and risks vary in unknown ways for individuals. For a subset of men, the benefits may outweigh the risks, but for others the situation is reversed. Therefore, a recommendation that, for men aged 55-69 years, the decision is best determined by a patient and their doctor with a rating of “C” may be warranted. However, we have strong concerns about the basis for this change in recommendations and its likely impact on screening. We agree with the USPSTF that the risks outweigh benefits for men who are 70 years old and older.

Changing the grade and recommendation for men aged 55-69 from a “D” to a “C” and from “risks outweigh benefits” to “talk with your doctor” may make patients and practitioners believe that the data supporting screening is now stronger than it was previous.  Unfortunately, most doctors have neither the time nor the communication skills to do convey the ambiguities of risks and benefits to their patients.  As a result, the proposed change would be likely to increase screening for most men.

When the USPSTF changes a recommendation, the scientific data should strongly support that change.  It should indicate a difference in overall survival, not just a change in deaths from the specific disease being screened.

The review lists the benefits of screening for men 55-69 years as preventing 1.3 death from prostate cancer and 3 cases of metastatic prostate cancer for every 1,000 men screened over a 13-year period. The data supporting the 2012 “D” recommendation predicted that screening would prevent 0.7 deaths per 1000 men screened and did not include information about metastatic cancer. This is a small increase, but more importantly, prostate cancer screening has not been shown to improve overall survival.  Experts agree that the vast majority of men with prostate cancer will die with prostate cancer, rather than die of prostate cancer.  Instead, the vast majority will die of another cause.  And yet, the complications of prostate cancer treatment often substantially harm quality of life. Out of these same 1,000 men, 273 would have a positive PSA test, and 35 would get a cancer diagnosis. If these 35 men were treated with radical prostatectomy, 24 would not benefit from treatment, 7 would have long-term erectile dysfunction, and 2 would have long-term problems with urinary incontinence requiring a diaper.

The data on quality of life are definitely confusing.  While the surgical patients have the worst adverse events – primarily erectile dysfunction and incontinence, they tend to score well on general quality of life.  In contrast, the radiation patients are less likely to have these adverse events, but more likely to score poorly on various quality of life measures. Hormone therapy tends to have negative impact on adverse reactions and on general quality of life.

It seems clear that the general quality of life measures that were used in these studies are not measuring quality of life related to the adverse events that are assumed to be most severe – erectile dysfunction and incontinence – but in the case of radiation and hormone treatment, are measuring some significant problems.  And, perhaps active surveillance is also taking a toll on quality of life, because the knowledge that a man has prostate cancer has a negative impact when he doesn’t treat it.

Looking dispassionately at these numbers, it seems clear that patients’ decisions regarding treatment for prostate cancer should be carefully discussed with one’s doctor.  But the question here is screening, not treatment.  The data clearly indicate that screening is having a negative impact, because once a man has a high PSA and is found to have prostate cancer, he seems likely to feel worse than he felt before screening whether he seeks treatment or active surveillance.  Given that there is no evidence that any of these treatments improve overall survival, how can one justify recommending prostate screening for men with no symptoms?  If the USPSTF believes that it is important to reduce overtreatment and unnecessary harm, data on overall survival is crucial to determine if screening should or should not be recommended.

Even when screening tests accurately detect cancer, they cannot accurately predict whether a tumor will become life threatening within the man’s lifetime. There is a high rate of overdiagnosis and subsequent overtreatment. Longer-term studies and studies designed to distinguish between higher and lower risk populations (for unproblematic vs. concerning cancers) may help address these issues in the future. However, these data will not help men and their doctors with the issue now. On the other hand, the use of active surveillance as opposed to other treatments could help reduce harms, but only if it is considered a real option by doctors and patients.

If men decide to undergo screening for prostate cancer, it is important that they are educated about the risks and benefits of specific screening tests. Prostate-specific antigen (PSA) tests have a high rate of false positives, between 20% and 50%. This leads to unnecessary stress and anxiety, as well as increased follow-up testing. The PSA test alone is insufficient for diagnosis because it also detects other changes in the prostate and even urinary tract infections, making follow-up tests are necessary. One of the most common follow-up test is a biopsy, which has its own risks, including injury requiring hospitalization.

Changing the grade and recommendation for men 55-69 years of age testing from a “D” to a “C” and from “risks outweigh benefits” to “talk with doctor” will likely increase the use of screening. If done properly, this may help a small number of men. However, if discussions between doctors and patients are not effective at sharing information to help patients weight the risks, benefits, and the patient’s personal values, then there will be an increase in overdiagnosis, overtreatment, and medical complications.

The Cancer Prevention and Treatment Fund is the major program of the National Center for Health Research. For questions or more information, please contact Stephanie Fox-Rawlings at sfr@center4research.org.

References:

Draft Recommendation Statement: Prostate Cancer: Screening. U.S. Preventive Services Task Force. April 2017.
https://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/prostate-cancer-screening1

Draft Evidence Review: Prostate Cancer: Screening. U.S. Preventive Services Task Force. April 2017.
https://www.uspreventiveservicestaskforce.org/Page/Document/draft-evidence-review/prostate-cancer-screening1

Final Recommendation Statement: Prostate Cancer: Screening. U.S. Preventive Services Task Force. May 2012.
https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/prostatecancerscreening

Lin K, Croswell JM, Koenig H, et al. Prostate-Specific Antigen-Based Screening for Prostate Cancer: An Evidence Update for the U.S. Preventive Services Task Force [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Oct. (Evidence Syntheses, No. 90.) https://www.ncbi.nlm.nih.gov/books/NBK82303/

 

NCHR Comment on the USPSTF’s Draft Recommendations for BRCA-Related Cancer: Risk Assessment, Genetic Counseling, and Genetic Testing

Policy, Testimony & Briefings
National Center for Health Research: April 12, 2017

Thank you for the opportunity to express our views on the draft research plan for Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-related cancer risk.[1]

The National Center for Health Research is a nonprofit research center staffed by scientists, medical professionals, and health experts who analyze and review research on a range of health issues.

Based on its previous review, the USPSTF recommended risk assessment, genetic testing, and counseling for women with a family history of clinically important mutations in BRCA1 or BRCA2 genes.[2] However, as noted in the recommendations, there were a limited number of good quality studies that looked at long-term risks and consequences of testing for BRCA1/2 gene mutations. Additionally, only poor evidence was available to determine the risks and benefits for women without a family history.

We appreciate and support the USPSTF’s efforts to review and update recommendations based on evolving research. The current draft research plan has the potential to identify relevant research for the review and subsequent recommendations. We want to emphasize some points that we consider particularly pertinent.

The evidence regarding the likelihood of developing cancer for women with BRCA1 or BRCA2 mutations continues to evolve.  Shortly after mutations were discovered to increase risk for cancer, women were told that their cumulative risk of developing breast cancer or ovarian cancer was close to 100% for BRCA1 mutations and only slightly lower for BRCA2 mutations. Those estimates have decreased substantially since then, and according to the most recent estimates, around 55% to 65% of women who inherit BRCA1 mutations and around 45% of women who inherit BRCA2 mutations will develop breast cancer by age 70.[3] In addition, 39% of women who inherit the BRCA1 mutation and 11% to 17% of women who inherit the BRCA2 mutation will develop ovarian cancer by age 70. Despite these statistics, women who have lower chances of developing BRCA-related cancer due to the type of mutation and/or their age, still tend to believe that their lives are in immediate danger, with prophylactic surgery being the only real option. To make meaningful recommendations concerning screening, testing, and counseling around BRCA-related cancers, it is important to determine which BRCA1/2 mutations are clinically relevant, how they affect the likelihood of developing BRCA-related cancer and by what age they are likely to develop cancer, preferably 50, 60 and 70.

If a woman is diagnosed with clinically significant BRCA1/2 mutations, the major options are prophylactic medications, bilateral mastectomy or oophorectomy, or active surveillance.  All come with serious health risks, which means that the potential harm from screening, testing, counseling, and interventions can be serious.  The risks range from false security (and less vigilance) to unnecessary anxiety due to false positives resulting from inaccurate testing or poor counseling.

Poor or limited counseling, confounded by the lack of accurate, up-to-date information about the risks of treatment and management options, also may harm women who choose prophylactic treatments or surgery. Prophylactic surgery causes hormonal changes and self-image issues.  For women choosing mastectomy with reconstruction with breast implants, for example, there are known and unknown risks, including the possible development of ALCL, a type of lymphoma.  ALCL was thought to be extremely rare, but research now indicates that it is less rare than expected and can be caused by breast implants.[4]

The benefits and harms of testing, detection, and early intervention can differ for women of different age groups, socioeconomic status, ethnic origin and insurance status, in addition to family history of BRCA1/2 mutations. The research review and subsequent recommendations will be more beneficial if they are based on diverse populations, with subgroup analyses whenever possible to enable the USPSTF to determine if there are some demographic groups for which recommendations should be different.

In conclusion, we support The USPSTF’s efforts to provide updated recommendations on risk assessment, genetic counseling, and genetic testing on BRCA-related cancer, based on quality, up-to-date scientific studies. We hope the review will quantify the benefits and harms of each step starting with screening, in order to help USPSTF to make meaningful recommendations for appropriate subpopulations of women.

The Cancer Prevention and Treatment Fund is the major program of the National Center for Health Research. For questions or more information, please contact Stephanie Fox-Rawlings at sfr@center4research.org.

References

  1. USPSTF Draft Research Plan Draft Research Plan for BRCA-Related Cancer: Risk Assessment, Genetic Counseling, and Genetic Testing, March 2017.
  2. USPSTF Final Recommendation Statement BRCA-Related Cancer: Risk Assessment, Genetic Counseling, and Genetic Testing, December 2013.
  3. “BRCA1 and BRCA2: Cancer Risk and Genetic Testing.” National Cancer Institute, National Institute of Health, April 2015
  4. Safety Alerts for Human Medical Products- Breast Implants: Update- Breast Implant Associated Anaplastic Large Cell Lymphoma (BIA-ALCL), March 2017

 

NCHR Comment on the USPSTF’s Draft Recommendations for Breast Cancer: Medications for Risk Reduction

Policy, Testimony & Briefings
National Center for Health Research: April 19, 2017

Thank you for the opportunity to express our views on the draft research plan for Breast Cancer: Medications for Risk Reductions. The National Center for Health Research is a nonprofit research center staffed by scientists, medical professionals, and health experts who analyze and review research on a range of health issues.

In their previous recommendation, USPSTF found that treatment with tamoxifen or raloxifene was beneficial for a subpopulation of women at increased risk. However, these treatments only slightly reduced the occurrence of invasive breast cancer in these women and came with serious risks.

We appreciate and support the USPSTF’s efforts to review and update recommendations based on evolving research. The current draft research plan should identify relevant research for the review and subsequent recommendations. We want to emphasize some points that we consider particularly pertinent.

When considering the harms and benefits of medications to reduce the risk for invasive breast cancer, it would be beneficial to also compare the effect size to other options, such as lifestyle changes. Behaviors such as maintaining a healthy diet, exercising, abstaining from smoking, and low levels of alcohol consumption have been shown to be protective against several types of cancer, including breast cancer. In other words, the risk of developing breast cancer may be reduced by changes in lifestyle that have many other advantages and no risks. That context is important for women as they consider drug therapy that may help prevent breast cancer but that also increases the risk of other types of cancer as well as very unpleasant side effects.

We greatly support the inclusion of key question 4 to look at the difference between population subgroups for outcome measures. Studies that target understudied populations and/ or that include subgroup analyses for racially and socioeconomically diverse populations will enable the reviewers to understand the prevalence of breast cancer risk across demographic groups but also enable them to evaluate the effectiveness and risks of drug therapy for these subpopulations. This will enable the USPSTF to determine if recommendations should be different for some demographic groups.

We also support the inclusion of quality of life as an outcome measurement, as this is an important dimension in assessing the harms and benefits of using drug therapy to reduce breast cancer risk. Quality of life outcomes are important for the decision to undergo treatment and to continue after adverse effects become apparent. Considering how drug therapies affect quality of life will provide doctors and patients with important information for making an informed decision about prophylactic medication.

It is important that the review evaluate the long-term health outcomes in terms of benefit and harms extending beyond when treatment stops. Several studies evaluated for the previous USPSTF review suggested that reduced breast cancer risk continued for at least 3 to 5 years and the risks of some harms returned to baseline after cessation of treatment. However, it was unclear how long the benefit might continue or to what extent any or all risks diminished.

These studies showed only a small benefit of treatment (5 to 9 fewer invasive cancers per 1000 people treated). This was not very different from the increased risk for harm (4 to 7 more thromboembolic events, 4 to 5 more cases of endometrial cancer, and up to 15 more cases of cataracts per 1000 people treated). If these numbers change over longer time frames, then it could shift the risk/benefit ratio. This is especially important because, as the previous recommendation noted, women are already cautious of treatment due to the small benefit and potentially serious harms. It is also important to determine which women will most likely benefit from treatment, to increase cases of reduced risk and limit the chance of harms.

Most important, the studies used for the previous USPSTF review were not sufficiently long-term to determine if there was an effect on mortality. Given the similar statistics for benefits and serious harms noted above, the impact on mortality could be a deciding factor for many women considering these drugs.

In conclusion, we support the USPSTF’s efforts to re-evaluate recommendations as the scientific evidence expands and improves. The proposed draft review should facilitate this process and includes questions and outcomes that we agree are important. In addition, we strongly urge the USPSTF to consider how the apparently modest benefits of medications compare to specific lifestyle changes for reducing breast cancer risk.

The Cancer Prevention and Treatment Fund is the major program of the National Center for Health Research. For questions or more information, please contact Stephanie Fox-Rawlings at sfr@center4research.org.

 

References:

USPSTF Final Recommendation Statement: Breast Cancer: Medications for Risk Reduction. U.S. Preventive Services Task Force. December 2016.

USPSTF Draft Research Plan: Breast Cancer: Medications for Risk Reduction. U.S. Preventive Services Task Force. April 2017.

Letter to Senators on the Innovation for Healthier Americans Bills

Legislation
Patient, Consumer and Public Health Coalition: November 8, 2016

The Honorable Lamar Alexander
United States Senate
Washington, DC 20510

Dear Senator Alexander:

The undersigned nonprofit organizations represent members of the Patient, Consumer and Public Health Coalition, which includes more than 6 million healthcare providers, public health experts, and consumer and patient advocates.  We respectfully urge you to not advance the Senate’s Innovation for Healthier Americans bills or the House’s 21st Century Cures Act during the lame duck session of Congress.  While the House version of the legislation provides additional funding for the National Institutes of Health (NIH), both the House and the Senate versions contain more controversial measures which would lower safety and approval standards for drugs and medical devices at the Food and Drug Administration (FDA).

A number of leading medical experts, including a former Commissioner of the FDA, Dr. David A. Kessler, believe that the bill “could lead to the approval of drugs and devices that are less safe or effective than existing criteria could permit”. We believe that the far-reaching measures described below will significantly impact public health and safety and should therefore not be rushed into law in the final brief weeks of this Congress.

For example, the PATH Act, in both the House and Senate versions, would allow antibiotics to be approved based on minimal evidence of safety and effectiveness through a “limited population” approval pathway.  Unfortunately,  these antibiotics could then be widely advertised in order to increase sales, even though they may be much less safe or effective than older, less expensive antibiotics.

The MEDTECH Act, also in both Senate and House (Section 2241)  versions, would prevent the FDA from collecting adverse events caused by flawed electronic medical records and decision support software.  A study by the National Center of Health Research found that these types of health IT devices can cause like-threatening problems when they miscalculate incorrect drug dosages for chemotherapy drugs and other treatments.

The Advancing Breakthrough Devices for Patients Act, versions of which are in both House and Senate bills, would encourage shorter and smaller clinical trials for medical devices. These smaller studies make it impossible to include sufficient numbers of women, men, seniors, and racial and ethnic minorities. Moreover, a recent study of high-risk medical devices found that the median number of participants is currently only 65 patients, which is already too small to adequately evaluate safety and effectiveness for both men and women, let alone for elderly men and women compared to young adults, or for people of color. The House bill is even worse; for example, Section 2221 would permit companies that manufacture life-saving devices such as heart valves and stents, to be modified without submitting the new devices for FDA approval, as is now required.

Alarmingly, the bill in its current form also allows anecdotal and easily manipulated sources of health data to be used to approve new drugs (Section 2121).   It effectively would eliminate clinical trial drug testing for new medical uses (called “indications’ in the bill).  This measure also would result in the widespread use of medications for uses that are not approved by FDA, causing inevitable patient harm.  (Section 2012: Facilitating responsible communication of scientific and medical development).

In addition to the extensive dilatory effects on FDA’s ability to protect the public health, the bill also extends exclusivity provisions for the pharmaceutical industry, discouraging the use of cheaper generic drugs, and having the practical effect of increasing or maintaining higher drug prices, at a time when the vast majority of Americans are frustrated with and angered by rapidly increasing drug prices.  For example, the Advancing Hope Act, passed by the Senate, would continue the existing pediatric priority review voucher program through 2022. A recent GAO review of the program concluded that the program has questionable benefit.  And, by allowing drug makers to buy a priority review, the bill undermines FDA’s ability to set its work priorities based on public health needs.

There also is serious concern concerning whether the additional $550 million dollars allocated to FDA by the House version of the bill would be sufficient to carry out the extensive mandates outlined by the legislation.  FDA already is severely under-funded and cannot absorb unfunded mandates without dire consequences to its regulatory effectiveness and ability to protect public health.

The House version of the bill also weakens reporting requirements for the bipartisan Physician Payments Sunshine Act (“Sunshine”), a medical payments disclosure measure which is being successfully administered by the Centers for Medicare and Medicaid (CMS).  The Sunshine Internet data base has provided the public with a useful and readily accessible transparency tool that can be used to discover which physicians and surgeons are accepting payments from the pharmaceutical and medical device industry, how much, and for what purpose.

Until the Sunshine data base was established a few years ago, doctors were accepting hundreds of millions of dollars annually in undisclosed payments from industry, much of which was intended to influence drug prescribing practices and the physicians’ brand choice of medical devices.  The Sunshine Act does not prohibit or discourage these payments, merely makes them part of the public record, and allows patients and consumers to decide whether such payments influence their own medical treatment and choice of physicians.

In addition to weakening safeguards for patients and increasing the availability of treatments that are not proven either safe or effective, neither the House nor Senate bills include provisions to lower drug prices.  A recent study by a researcher at the National Cancer Institute found that most cancer drugs approved during a recent 5-year period are not proven to improve the health of cancer patients.  The National Center for Health Research assessed the cost of those ineffective drugs and found that they cost the same or more as cancer drugs that are proven to work.  A recent letter to Congress by a coalition of more than a dozen labor and public interest groups asked the Congress to delay consideration of the Cures/Innovation bills until there are measures included to lower drug prices.  We agree, but we also point out that several provisions in these bills would have the opposite impact, since many new drugs would be sold without clear evidence of efficacy, and yet those new drugs will inevitably cost more than older, more effective and less expensive treatments.

Sincerely,

National Center for Health Research
American Medical Student Association
American Medical Women’s Association
Annie Appleseed Project
Breast Cancer Action
Breast Cancer Coalition
Center for Medical Consumers
Connecticut Center for Patient Safety
Institute for Safe Medication Practices
Jacobs Institute of Women’s Health
Mothers Against Medical Error
MRSA Survivors Network
National Physicians Alliance
National Women’s Health Network
Our Bodies Ourselves
Quinolone Vigilance Foundation
TMJ Association
Washington Advocates for Patient Safety
WomenHeart
Woody Matters

For more information, please contact Jack Mitchell at jm@center4research.org.

Patient, Consumer, and Public Health Coalition Senate Briefing: Innovation for Healthier Americans

Policy, Testimony & Briefings
March 4, 2016

Below are the materials from the Senate briefing we hosted with the Patient, Consumer, and Public Health Coalition titled “Innovation for Healthier Americans: The Impact of Proposed Health Bills on Patients & Consumers”.

Lab-Developed Tests (LDTs): A Critical Role for the FDA

Examples that illustrate the need for FDA regulation of LDTs

FDA and Medical Software

Lab-Developed Tests (LDTs): A Critical Role for the FDA

Laboratory developed tests (LDTs) serve an increasingly important role in health care today. Compared to just a few decades ago, the tests are more complex, and inaccurate results are much more likely to endanger patients. When the FDA was given the responsibility to regulate medical devices in 1976, LDTs were basic laboratory tests, such as a blood sugar test. For that reason, the FDA chose not to regulate most LDTs. But today’s diagnostic tests are more complicated and, for example, may be used to obtain a genetic analysis of a cancer cell to guide treatment decisions. FDA regulation of LDTs will ensure patients and physicians are relying on tests that are safe and effective.

CLIA Cannot Substitute for FDA Assurance of Safety and Effectiveness

The CMS CLIA program does not determine if a test is accurate (which is called clinical validity). It instead ensures quality control mechanisms are in place. In contrast, the FDA review process evaluates the clinical validity of a test before it is approved (premarket) and after it is on the market (post-market surveillance). Clinical validity is essential to understanding the risks and benefits of any test. For example, an ovarian cancer test with a high rate of false positives will result in women receiving unnecessary hysterectomies, whereas a high rate of false negatives will result in cancer going undetected.

Transparency Will Increase Physician and Patient Confidence in LDTs and Encourage Innovation

Faulty tests erode the confidence of physicians and patients, and put patients’ lives at risk. The American Society of Clinical Oncologists (ASCO) has expressed agreement with the FDA’s proposals to improve regulation of LDTs, stating that “a patient’s treatment options are increasingly driven by detection of molecular abnormalities in the tumor that drive treatment selection. ASCO believes that the tests used to detect those abnormalities must be of the highest quality and thoroughly validated before being offered to doctors and patients.” Requiring FDA review prior to allowing a test to be sold and giving FDA the authority to gather and publicly share information about adverse events will give patients and providers the information they need to make informed treatment decisions. Non-LDT in vitro diagnostics (IVDs) are already under FDA regulation. Using the same regulatory processes will ensure higher quality tests for patients. That will stimulate, not hamper, the kind of innovation that saves lives and improves the quality of patients’ lives.

FDA’s Plan Follows a Risk-Based, Phased-In Approach to Ensure Efficiency and Responsiveness

The FDA draft guidance on LDTs lays out a risk-based, phased-in approach that will proceed over several years. This approach allows ample time for laboratories to come into compliance and will also ensure that the highest-risk devices are regulated as quickly as possible. The guidance document also proposes a series of carve-outs, permitting manufacturers of LDTs for unmet needs or rare diseases to escape the most stringent pre-market review requirements. This type of regulatory framework will protect the public health while being flexible enough to encourage the development of new tests for serious conditions.

Conclusions

In response to the FDA’s proposed regulatory framework, NIH Director Dr. Francis Collins stated that “this is good news for all who are working to turn the dream of personalized medicine into a reality.”1 We agree. The FDA’s draft guidance displays the agency’s willingness to balance its goals regarding safety and efficacy with its concerns about innovation and patient access — and all parties should work together to move our regulatory framework for LDTs into the 21st century.

Examples that illustrate the need for FDA regulation of LDTs

OvaSure Ovarian Cancer Test

The OvaSure ovarian cancer test shows the importance of FDA oversight of LDTs in protecting patients’ lives.

  • In June 2008, the test was marketed to screen for early-stage ovarian cancer in high-risk women based on peer-reviewed published data showing it could detect ovarian cancer with a positive predictive value (PPV) of 99.3%.
  • It was later discovered that poor study design led to a falsely high predictive value. The actual PPV was only 6.5%, meaning that only 1 in 15 patients who tested positive actually had ovarian cancer.
  • OvaSure was pulled from the market by October 2008 after a warning letter from the FDA but not before many women underwent unnecessary hysterectomies because of a faulty test.

Oncotype DX HER2 Breast Cancer RT-PCR Test

FDA regulation will help ensure the validity of LDTs that detect genetic tumor markers and guide drug therapy decisions. These LDTs are critical to the success of the Precision Medicine Initiative. Patients and their providers must be able to trust them.

  • The Oncotype DX HER2 breast cancer RT-PCR test was intended to diagnose early stage HER2 receptor positive breast cancers so that the appropriate HER2 targeted drug could be used.
  • In 2011, a group of prominent pathologists from three independent laboratories found discrepancies between this HER2 RT-PCR and other tests that are FDA-approved. They discovered that the test has poor sensitivity, resulting in many false negatives and women not receiving life-saving treatment. Patients died as a result.

FDA and Medical Software

Jay G. Ronquillo, MD, MPH, MMSc, MEng

In a study of FDA reported recalls, completed in 2016, we found:

  • Over the last 5 years, more than 600 different software devices totaling over 1.4 million units were recalled for moderate or high risk patient safety issues.
  • Nearly 200,000 units were recalled for having the most serious (life-threatening) risk to patients. Although recalls are officially considered voluntary, few would take place without FDA regulatory authority.

If MEDTECH becomes law, the FDA would not be gathering adverse event reports and encouraging recalls of many stand-alone IT devices with life-threatening flaws. The results of this study show that software flaws affect millions of patients and removing medical software from FDA regulatory oversight would be dangerous. The Senate can do better.

Medical software represents an increasingly important aspect of medicine. The MEDTECH Act and related bills would remove some health IT entirely from FDA’s regulatory oversight (e.g. electronic health records, clinical decision support). For other types of software, the FDA would be limited in its ability to identify safety risks. Industry says that deregulation would foster the creation of innovative new medical devices. However, the data above indicate that medical software must remain regulated by the FDA in order to protect patients from harm.

Some examples of the devices that were recalled in recent years because of their potential to seriously harm or even kill patients due to software errors include:

  • Oncology electronic medical record systems: recalled because they calculated and recorded incorrect drug dosage treatment.
  • Clinical decision support systems used during surgery: recalled because they erroneously switched patient data and failed to warn physicians about dangerous drug reactions.

Software devices are re-used repeatedly for different patients. A conservative estimate is that millions of patients being treated by hundreds of physicians would have unknowingly been at risk for poor care, serious injury, and even death if the software had not been recalled.

Conclusion: If medical software is removed from FDA regulatory oversight, millions of patients would be at risk from defective software.

What would impact of 21st Century Cures Act be on cancer and your healthcare costs?

In the News, Legislation, New Cancer Research, Policy
 NOVEMBER 23, 2015

This summary of an analysis published online in the prestigious medical journal BMJ on November 23, 2015, shows that using preliminary research to approve new medical treatments has high costs for patients’ lives and healthcare dollars.  These three very promising medications did not work, and one of them caused skin cancer and also made Alzheimer’s symptoms worse.

21ST CENTURY CURES ACT AND SIMILAR POLICY EFFORTS: AT WHAT COST?

BMJ 2015; 351 doi: http://dx.doi.org/10.1136/bmj.h6122 (Published 23 November 2015) Cite as: BMJ 2015;351:h6122

By Diana M Zuckerman, Nicholas J Jury, and Christina E Silcox

A controversial proposed law in the United States, the 21st Century Cures Act, is described by supporters as an innovative attempt to jump start the process of finding new cures for the thousands of diseases that currently lack effective treatments. But would this bill promote new cures, or increase the availability of new medical products that do not necessarily work? Alzheimer’s disease is often cited as an example of a devastating disease with enormous costs and no cure in sight. We examine the potential harms and costs that would have been incurred by three Alzheimer’s drugs that were rejected under current Food and Drug Administration approval standards but could have been approved under the standards promoted by 21st Century Cures and similar legislation.

We selected for analysis all the Alzheimer’s drugs reviewed by the FDA within the past five years for which a determination was made, to determine the likely impact of the proposed changes on their approval.

All three drugs had impressive results in preliminary clinical trials.  Two of the drugs showed great improvement based on the well-established biomarker of beta amyloid plaques on the brain, and the third based on tests of memory and cognition.  When larger, better designed clinical trials were conducted, however, two of the Alzheimer’s drugs were found to be ineffective, and the third drug caused an increase in memory problems and an increase in skin cancer.

Cost estimates

More than five million patients in the US have Alzheimer’s disease, about 1.3 million of whom are being treated with an Alzheimer’s drug. To conservatively estimate market share, we looked at the cholesterol lowering drug atorvastatin (Lipitor), which garnered 18% of market share during its first year on the US market based on biomarker data. If one of these drugs had gained a similar market share it would translate to 234,000 patients a year taking a drug that put them at risk of a greater loss of cognitive skills than if they had taken a drug already on the market, or perhaps no treatment at all. If semagacestat was the drug approved, almost 19,000 more patients would have developed skin cancer, based on the phase III results.

Most current Alzheimer’s drugs are available as generics, which has reduced their price. Donepezil has most of the US market share. The brand name version (Aricept) costs about $7500 a year at Walgreens, the largest pharmacy chain in the US. The brand name versions of memantine, galantamine, rivastigmine, and memantine-donepezil each cost over $5000 a year at Walgreens.

New drugs are priced based on the current market price of competing drugs, not on research and development costs. A conservative estimate is that a promising new Alzheimer’s drug would be priced similarly to Aricept ($7,500 a year). This is 87% more than generic donepezil, almost doubling the cost for any patient who switched to the new drug.

Assuming 18% of the market share before postmarket studies  are completed, we estimate the cost of treating 234,000 patients at $1.76 billion a year, or $7 billion over four years until postmarket studies were completed.  Given the modest benefit of current Alzheimer’s drugs, and the impact of current direct-to-consumer advertising practices in the US, a promising new drug would be expected to garner higher prices and more prescriptions, so the cost could easily double.

Since the cognitive abilities of patients with Alzheimer’s disease tend to worsen over time regardless of treatment, it would be virtually impossible for physicians to realize that semagacestat was causing cognitive decline or that the other drugs were ineffective. Physicians would also have been unlikely to notice that semagacestat increased patients’ risk of skin cancer. It would not have been until post-market phase III studies of cognitive and health outcomes were completed years later that physicians and families would have realized that the drugs were ineffective and possibly harmful.

Under pressure from Congress and industry, FDA standards have loosened in recent years, and the agency often approves products based on biomarkers that have good but inconclusive evidence of clinical benefit. For example, cancer drugs are often approved based on tumor shrinkage or progression-free survival and studies conducted after the drugs are in widespread use have shown that many do not help patients live longer. Osteoporosis drugs have been approved based on bone mineral density or microscopic bone fractures, rather than hip fractures that harm health. The proposed law and several other Congressional proposals would weaken current FDA standards further. As our examples show, this could to lead to patients taking ineffective and potentially harmful drugs and waste billions of healthcare dollars.

Read the whole article here.

Testimony of Dr. Anna Mazzucco before the FDA on “Framework for Regulatory Oversight of Laboratory Developed Tests”

Policy, Testimony & Briefings
By Dr. Anna Mazzucco
January 8, 2015

Thank you for the opportunity to speak today at this very important meeting.  My name is Dr. Anna Mazzucco, and I am speaking on behalf of the National Center for Health Research.   I received my Ph.D. in cell biology from Harvard Medical School, and I conducted post-doctoral research here at NIH. Our nonprofit organization conducts research, scrutinizes data in the research literature, and then explains the evidence of risks and benefits to patients and providers.  [Our organization does not accept funding from companies that sell medical products, and therefore I have no conflicts of interest.]

I am speaking as a scientist who appreciates the power of data and who also wants patients and physicians to have the best information possible before they make potentially life and death decisions.  The FDA released new guidance on laboratory-developed tests because of evidence that patients are harmed by faulty tests.

We applaud the FDA for their plan to improve oversight of lab tests and the NIH for their commitment to medical care. We have a few key points:

  • Many of these tests are used to diagnose a disease or determine a course of treatment.  If the test doesn’t work correctly, the patient may be exposed to risks from a treatment they didn’t need, OR not receive treatment that would help them.
  • When the FDA started regulating devices almost 40 years ago, these tests were very different.  They are now widespread and are the basis of high-risk decisions.
  • Under CLIA, test makers do not have to demonstrate “clinical validity”.  At FDA, approval standards include safety and effectiveness.  FDA review will improve transparency and data quality.
  • Current policies do not require adverse event reporting or manufacturing safeguards.  FDA approval does.  Patients using high-risk diagnostics deserve those protections.

Our Center has frequently urged the FDA to improve their oversight of medical devices. Despite past criticisms, we believe it is essential that FDA have the authority to regulate laboratory-developed tests in order to stimulate even better science, and help ensure that patients receive the full benefit of our growing scientific knowledge.

To paraphrase Dr. Josh Sharfstein’s JAMA article:

Patients travel in ambulances that are regulated, to hospitals that are regulated, for care using medicines that are regulated, administered by nurses and physicians, who are regulated. That same patient’s life or death should NOT depend on whether an unregulated diagnostic test result is accurate.

Thank you for the opportunity to speak today.