Category Archives: Testimony & Briefings

Public Comment PDUFA VII Commitment Letter (Docket #FDA-2021-N-0891) From the National Center for Health Research

October 28, 2021 


The National Center for Health Research (NCHR) appreciates the opportunity to provide public  comments on the PDUFA VII Commitment letter, and to express our substantial concerns with the overall process, some of the content of the letter, and performance goals that should have  been made in the letter, but were not. 

The Prescription Drug User Fee Authorization (PDUFA) negotiation between the Food and Drug  Administration (FDA) and pharmaceutical industry is unlike regulatory processes at other federal  agencies. The typical process is more transparent, and includes meaningful stakeholder  engagement and feedback from the public. The fact that the very industries being regulated by  the FDA meet behind closed doors with FDA staff to negotiate a Commitment Letter, with no  members of the public allowed to even be in the room, raises important questions about why  industry has more say in FDA policies and practices than other Stakeholders. 

The Commitment letter submitted for public comment is even more problematic than usual  because it includes numerous policy/regulatory changes that would normally be determined by  Congress, not by a negotiation between regulated industry and a federal agency. Policy/regulatory changes should be deleted from the Commitment Letter. 

The remainder of this comment will focus on performance goals. 

As a public health think tank, NCHR has supported user fees as a way to improve resources for  the FDA. However, we have repeatedly expressed concerns that the performance goals being  negotiated by the FDA and industry are focused largely on the speed of the review and approval  process, as well as industry’s access to FDA staff, with no explicit metrics to measure the safety and effectiveness of the drugs that are being reviewed and approved. We support performance  goals that enable companies to communicate with the FDA early in the drug approval  process. However, the emphasis on speed has resulted in too little attention to whether the drugs  have clinically meaningful benefits for different populations of patients that outweigh the risks to  those patients. 

One of our concerns pertaining to the performance goals is the lack of FDA oversight regarding  whether commitments to diversity that companies made to the FDA are met in the studies used  as the basis of approval or post-market studies. When there are too few older patients and racial minorities to conduct subgroup analyses, as is often the case, it has been impossible to draw  conclusions about the safety and efficacy of these drugs across the different patient populations. 

Another major issue missing from performance goals is that the emphasis on various expedited  review pathways has resulted in FDA making approval decisions based on only one pivotal  study, and often based on a surrogate endpoint or biomarker rather than a clinical outcome that is  meaningful to patients, such as overall survival. When post-market confirmatory trials are  required, they are not monitored closely by the FDA; as a result, years pass before the studies are either abandoned or completed, often with much smaller, less diverse study populations and  higher loss to follow-up than was “required.” For example, in 2021, we learned that  several cancer drugs had been found to be ineffective in confirmatory trials, many years after  they had been approved for several specific indications under an accelerated pathway. A study recently published in JAMA Internal Medicine reported that these ineffective indications cost  Medicare more than half a billion dollars.1 Another example of potential harms from a  questionable review is the recent FDA approval of Aduhelm for Alzheimer’s patients.2 This drug  was originally approved for all Alzheimer’s patients based on a questionable biomarker studied  only in patients with mild Alzheimer’s and the FDA allowed the company 9 years to complete a  confirmatory study. Fortunately, the agency responded to public outrage by changing the  approval to only mild Alzheimer’s, since those were the only patients that had been  studied. Unfortunately, the company still has 9 years to confirm that the drug is effective, and, in  the meantime, other pharmaceutical companies are racing to submit applications based on the  same flawed biomarkers. These are just two examples of why enforcement of timely and  comprehensive post-market surveillance requirements should be required as essential  performance goals. The current version of the Commitment Letter does not do so. 

User fees have been used previously to generously support the Sentinel program’s post-market  surveillance system; however, the impact of that system is not explained to the general  public. FDA should notify Congress and the public about how many drugs have been removed  from the market due to Sentinel data, the number and type of label revisions that resulted, and  how adverse events found through Sentinel did or did not differ for drugs approved under  various review pathways. The number of years that specific products were on the market before  Sentinel reported the need for label revisions or removal from the market should also be  calculated and widely reported as part of the performance goals. 

User fees should also be used to improve communication with patients and caretakers, including older adults, people with disabilities, people who are not fluent in English, and those  with limited literacy skills. Information provided by the FDA should include different formats  and videos and virtual meetings should have the option for closed-captioning and American Sign  Language translation. 

In conclusion, we believe that the Commitment Letter should delete policy/regulatory proposals  and do more to ensure the safety of patients and consumers and the scientific integrity of the  drug review process using the types of metrics we have suggested as part of the performance  goals. We appreciate the efforts of the agency to work toward those ends,  but when patients, consumers and other stakeholders are excluded from the PDUFA  negotiations, their priorities are excluded. We urge the Biden Administration to improve the  PDUFA VII Commitment Letter in the ways described in this comment. 

For more information, please contact Dr. Diana Zuckerman at dz@center4research.org. 

 1 Shahzad M, Naci H, Wagner AK. Estimated Medicare Spending on Cancer Drug Indications with a Confirmed  Lack of Clinical Benefit after US Food and Drug Administration Accelerated Approval. JAMA Intern  Med. Published online October 18, 2021. doi:10.1001/jamainternmed.2021.5989 

2 FDA Grants Accelerated Approval for Alzheimer’s Drug, June 07, 202. 1https://www.fda.gov/news-events/press announcements/fda-grants-accelerated-approval-alzheimers-drug

Statement by Dr. Diana Zuckerman on Sintilimab at FDA Advisory Committee on Oncologic Drugs

February 10, 2022


I’m Dr. Diana Zuckerman, president of the National Center for Health Research. Our center is a nonprofit think tank that scrutinizes the safety and effectiveness of medical products, and we don’t accept funding from companies that make those products.  My expertise is based on post-doc training in epidemiology and public health, and as a faculty member and researcher at Vassar, Yale, and Harvard.  I’ve also worked at HHS and the White House, and I’m on the Board of the nonprofit Alliance for a Stronger FDA, which educates Congress about the need to support the work of the FDA.

On a personal note, I am a cancer survivor, and so I understand the pressure to find new treatments. My goal today is to be as objective as I can in evaluating the evidence regarding Sintilimab.

There are many problems with the data supporting this application, but let’s start with the first mistake:

#1: The sponsor did not consult with the FDA regarding the trial’s design or conduct.  That is almost always a big mistake, and it definitely is in this case. The result is a very inadequate trial design, including a non-representative group of patients.

#2: Most important to me, the study relied on progression-free survival as the primary endpoint.  We agree with FDA scientists that other drugs in the same class have shown highly significant improvement in overall survival. What matters most to cancer patients is how long they will live and the quality of their remaining lives, not whether or not they die of the cancer they are being treated for. So what could possibly be the justification for approving a cancer drug that is not as good as those already available for the same indication?

#3: FDA is sometimes flexible about its usual requirements, especially when there is an unmet need.  We agree with the FDA scientists that this drug does not address an unmet need, since several treatments proven to improve overall survival are already available.  This drug review therefore “does not warrant regulatory flexibility.”

#4: As you know, the data are all based on patients in China.  For the FDA to consider foreign data as the sole basis for marketing approval, the data are supposed to be applicable to the U.S. population and to U.S. medical practice. We agree with the FDA that the data presented today are neither. The population studied is not at all representative of the U.S.’s diverse population.  Equally problematic, the study’s comparative control arm was based on chemotherapy alone, and that is not consistent with the U.S. standard of care. Therefore a different control group would be needed to determine the benefits and risks of Sintilimab.

FDA notes that the studies have NOT been performed by clinical investigators of recognized competence.  And that FDA has not had enough contact with the investigators to be confident of their competence.

#5: The sponsor has proposed an additional study, but their proposed study does not address the serious design issues that have been criticized today. We agree with the FDA reviewers that this additional study does “not address the concerns regarding endpoint selection.”

In conclusion, you’ve been asked to vote on whether additional clinical trials with data applicable to U.S. patients and U.S. standard of care are necessary before a final regulatory decision is made.  I am very concerned about the inadequate informed consent for patients in the study that was conducted.  I hope you will agree that yes, additional trials are needed and they need to address all the major shortcomings of the data submitted so far before the FDA decides whether to approve it.  Overall survival is the essential endpoint, at a level that is meaningful to patients. The patients studied must be representative of U.S. patients in terms of race, age, and other key variables, and the comparison group needs to have the kind of medical care that is the standard of care in the U.S.

FDA notes that they have more than 25 applications whose studies are at least predominantly based on clinical trial data from China. Each should be evaluated on its own merits, but the FDA’s decision regarding Sintilimab should not set a precedent for FDA approval decisions of medical products that are not appropriately studied to determine the risks and benefits of patients in the U.S.

Comments on CMS’s Proposed Decision Memo on Screening for Lung Cancer with Low Dose Computed Tomography (LDCT)

December 17, 2021


We agree that former smokers would benefit from a higher rate of low dose computed tomography (LDCT) lung cancer screening. However, we are concerned with several major aspects of the Proposed Decision Memo’s discussion of Counseling and Shared Decision-Making.

  1. We urge CMS to amend language in the final draft of the Decision Memo to more accurately reflect the science-based evidence. The proposed memo currently reads that “Professional societies and provider groups have noted that providers have gained considerable experience and expertise and believe flexibility will reduce burden.” However, there is no evidence that providers have become better at counseling and shared decision-making regarding LDCT; on the contrary, there is evidence that there is already too much flexibility in how these discussions are framed. For example, research has found that shared decision-making conversations regarding LDCT focus on the advantages and rarely discuss the potential harms.[1] Healthcare providers spent less than a minute explaining the procedure and there was no evidence that decision aids were used. Patients deserve to make informed choices, and this is not possible under the current norms, which are too flexible. Rather than increase flexibility, CMS should provide explicit guidance for shared decision-making discussions on LDCT, such as requiring a checklist of key benefits and risks for the procedure that patients must sign after having read and discussed each point with their healthcare provider. For example, a decision-making tool could include a checklist that explains each benefit and risk in non-technical language, where the patient must initial each section to indicate that they read it, and then the physician must sign it to indicate the conversation took place, in the presence of the patient. In addition, any decision-making tool should highlight beneficiary eligibility criteria to ensure that patients who do not meet these criteria are aware that they are more likely to be harmed by LDCT screening.

 

  1. We urge that CMS maintain the requirement that shared decision-making conversations include a patient’s healthcare provider. Although research indicates that the decision-making conversations with physicians and non-physician practitioners are often inadequate, we believe the solution is to improve training for those conversations, rather than allowing health educators and others who are not healthcare experts to provide counseling and shared decision-making without the inclusion of healthcare professionals. Shared decisions regarding medical options should be made between a patient and a healthcare provider with whom they have an established relationship, which is generally their primary care physician. That is important because if there are any abnormal findings from the LDCT, it is the healthcare provider that the patient will need to follow-up with, not an educator. Shared decision making also provides an important opportunity to discuss smoking cessation options, which primary care physicians are best equipped to do. In summary, when patients engage in shared decision-making with their healthcare provider, that aids in informed decision-making while also helping ensure continuity of care. While health educators and others who are specifically trained to discuss the risks and benefits of LDCT can be an important addition to those doctor-patient conversations, spending more time with patients than physicians do and ensuring that patients clearly understand their options, they should not replace doctor-patient shared decision-making.

 

  1. We also urge that CMS reconsider its proposal to remove the specifications for the components of the shared decision-making tools. The agency justifies this change by stating that “the tools and guidance has matured since the early inception of shared decision-making.” We are not aware of evidence that the tools and guidance have matured, and ask CMS to provide guidance regarding decision-making tools that are based on peer-reviewed research-based articles.

 

  1. CMS also proposes removing the LDCT lung cancer screening registry requirement. We disagree with that proposal, since the ongoing revisions to guidance regarding LDCT screening can best be evaluated using a required registry.

As a final point, we question the assumptions that patients’ current low level of screening is a function of lack of flexibility in shared decision-making and of the criteria for eligibility. We believe it more likely that the major causes are:

  • Former smokers are aware that their smoking put them at risk of lung cancer and they are reluctant to get tested to find out they could have a fatal disease that they were warned about for years.
  • Former smokers who have friends or relatives that died of lung cancer are especially afraid of a diagnosis because they have seen the ravages of lung cancer.
  • Discussions about LDCT that extol the benefits and ignore the risks (which research indicates are typical of these conversations) are likely to be perceived as a sales pitch by skeptical patients. A more balanced conversation about what the procedure is like, the potential risks of screening, and what research says about the benefits is likely to be more effective.

NCHR firmly believes that patients deserve to make informed choices and need access to counseling and evidence-based shared decision-making tools in order to do so. For the reasons outlined above, we urge CMS to reconsider the proposed changes, to better ensure that patients receive accurate, balanced, unbiased information on whether or not they would benefit from LDCT screening.

References

  1. Brenner, A. T., Malo, T. L., Margolis, M., Lafata, J. E., James, S., Vu, M. B., & Reuland, D. S. (2018). Evaluating shared decision making for lung cancer screening. JAMA internal medicine178(10), 1311-1316.

Testimony of Diana Zuckerman, PhD, President of the National Center for Health Research at the FDA PDUFA Meeting, September 28, 2021

I’m Dr. Diana Zuckerman, president of the National Center for Health Research, a patient-centered and consumer-oriented public health think tank.  Our Center is very involved in FDA issues pertaining to the safety and efficacy of medical products, and I appreciate the opportunity to share my views today. 

PDUFA performance measures have focused on speed, but in addition PDUFA performance measures should evaluate whether patients are protected from ineffective or unsafe products being approved!  As Commissioner, Peggy Hamburg said innovation needs to mean products are better, not just new.  The performance goals we’ve heard about today fall short, because they emphasize speed and ease of approval, not on the quality of the outcome of FDA reviews or of the outcome for the patients using these products.  

PDUFA have resulted in more and faster approvals, but not all those approvals have helped patients, and some have seriously harmed them.

Premarket performance should also include evaluations of the percentage of applications that were rejected or withdrawn because there was a lack of evidence proving safety or efficacy.  And the specific reasons why they were rejected or withdrawn.

When post-market surveillance works, it should sometimes result in FDA warnings, recalls, or withdrawals.  FDA should provide the percentage of these for 5 years post approval and the reasons for those actions.

Performance should also include the percentage of products approved based on at least two well-designed studies providing solid scientific evidence.  As someone trained in epidemiology, I love big data, but since most applications are for new products not yet on the market, clinical trials will still be the best data available.  We want to know how many approvals were based on at least two phase 3 randomized, controlled trials demonstrating robust evidence of safety and efficacy and favorable benefit-risk profiles.

Performance should also be based on the percentage of approved products for which FDA mandated post-marketing studies and the percentage where those obligations were fulfilled – started and ended on time, conducted as required, and whether they did or did not confirm safety and efficacy.  As you know, FDA recently had a meeting on widely used cancer drugs that were approved for certain indications through accelerated approval but failed to provide data confirming that they worked for those types of cancer.  And yet the indications remained approved for years after it was obvious they did not work.  Those delays are harmful to patients and should be considered a performance goal worthy of user fee support.  

A newly published study indicates that too often a rejected application is subsequently resubmitted and approved when FDA ignores their own criticisms of the original application, even when those criticisms remain valid.  The controversial approval of Aduhelm is just the most salient example of that.

 Specific Changes to Commitment Letter

I have a general concern about the Commitment letter, because it changes policies that should be publicly debated by Congress and should include input from patient, consumer and public health advocates as part of any negotiations. Policies should not be negotiated behind closed doors at meetings that exclude those important perspectives.  

I have time to recommend 5 specific changes to the Commitment letter:

  1.   I was glad to hear about FDA’s new efforts to include patient preferences and involvement. The Commitment letter should specify that these activities should always include harmed patients, not just patients recruited by industry, who are often patients desperate for treatment.  All patient perspectives are important, we all are concerned about patients who urgently need a treatment that works, but harmed patients have too often been excluded from FDA meetings and committees.
  2.   Voluntary REMS strategies are rarely proven to work. The REMS program needs a complete overhaul or REMS should be avoided. Instead, most safety concerns should be resolved before products are approved. A good example is the REMS for prescription opioids, which FDA learned was not working. Few doctors took the voluntary training, fewer finished the voluntary training, and even those who were trained did not learn all the important issues that were included.
  3.   The letter should implement the National Academies’ public health framework for regulatory oversight of opioids.
  4.   In-person manufacturing inspections remain the most effective way to determine problems. We all understand that remote inspections were needed during the pandemic, but the Commitment letter should specify that remote inspections should be the exception.
  5.   User fees should fund independent, objective studies to assess and quantify the harms that resulted or were avoided due to approval decisions.

And I will just add one other issue, since enhancements to the Sentinel program were discussed earlier in this meeting.  I have been a strong supporter of the Sentinel post-market surveillance program, but it has been in place for years and cost an enormous amount of money.  So, it was distressing to hear this morning that the FDA is still trying to figure out how to use those data so that they can provide usable information about safety and efficacy.

In conclusion, those of us who respect and admire the FDA know how important it is as a public health agency. We must make sure that industry user fees do not interfere with that essential mission. When performance goals and the Commitment letter are made behind closed doors, it is difficult for the public to have confidence that the FDA is a public health agency.

NCHR’s Statement to FDA Advisory Committee Meeting on Neurological Devices

June 3, 2021


I’m Dr. Diana Zuckerman, president of the National Center for Health Research.  Our center is a nonprofit think tank that scrutinizes the safety and effectiveness of medical products, and we don’t accept funding from companies that make those products.  Today I’m speaking from my perspective as a scientist trained in epidemiology and public health who left Harvard more than 30 years ago to come to Washington D.C. to work in the House of Representatives. I worked as a Congressional investigator for the Subcommittee that conducted oversight over all of HHS, and that’s when I first learned about the laws and regulations governing the FDA.  I was responsible for several oversight hearings that attracted enormous media attention, because we found that patients had been harmed when the FDA was not following the law pertaining to FDA regulation of medical devices.

The law states that devices must be reasonably safe and effective.  It’s not exactly clear what reasonably safe or reasonably effective means, and often the FDA states that if they have reason to believe that similar devices are reasonably safe and reasonably effective, that’s good enough.  The special controls for Class II devices that the FDA has suggested for devices you’re reviewing today and tomorrow provide some evidence that the devices will work as intended and will be reasonably safe, but the general controls for Class I devices do not.

Neurological devices are important, and some of these devices are somewhat complex.  Obviously something called a “barf band” is not a complicated device, and it is an example of an acupressure device that costs only about $10, but if the goal is to prevent nausea and vomiting, and the company wants to sell it in the U.S., shouldn’t it be proven to work, like any other neurological device?  And some of those devices cost $20 or $30 or even over $200.   Just because the risks are small should not make it OK for FDA to let companies sell devices that are not effective if used as directed.  The standards for medical devices should be higher than the “let the buyer beware” standards of dietary supplements – which are basically nonexistent standards.

I was reassured that there are randomized controlled trials on many of the devices you’ll be reviewing today and tomorrow, but there are many different companies making many different versions of these devices, so the fact that some are shown to work doesn’t mean that they all work!  For example, when  chemotherapy patients want to reduce nausea and vomiting, they want to know if one of these acupressure devices is more effective than others.  And even when some devices are shown to work in a randomized controlled trial, that definitely doesn’t tell us that a new, similar device made by these same companies or any other companies will be safe and will be effective.  

The FDA has a reputation as the gold standard for safe and effective medical products, but that standard has been tarnished when patients are shown to be harmed in recent documentaries and in TV programs on during prime time this week.

I respectfully urge you to urge the FDA to up their game, by regulating all these neurological devices as Class II, and requiring the kind of meaningful evidence for new devices that we would want for any device that we use as health professionals, as patients, or as consumers.

Thank you for the opportunity to speak today.  I appreciate your service on this panel and look forward to hearing your discussion of these devices.

NCHR Statement at FDA Advisory Committee Meeting on Keytruda and Tecentriq for Advanced Urothelial Carcinoma

April 28, 2021


I’m Dr. Diana Zuckerman, president of the National Center for Health Research. Our center is a nonprofit think tank that scrutinizes the safety and effectiveness of medical products, and we don’t accept funding from companies that make those products.  I am trained in statistics, clinical trial design, epidemiology, and public health and was a faculty member and researcher at Yale and Harvard and a Fellow in Bioethics at Penn.  I’ve also worked at HHS. 

The details differ but in both cases our statistical and research analyses support the FDA findings that the data do not confirm the indication.

That’s especially important because both Tecentriq and Keytruda cause substantial adverse events and an alternative treatment has shown clear benefit!

FDA grants accelerated approval with requirements for post-market RCTs to evaluate overall survival to ensure clinically meaningful benefit.  But the randomized clinical trials conducted did NOT show benefit. How could FDA continue to offer accelerated approval for any drugs in the future if post-market RCTs results are ignored?

Most of you are clinicians and you’re used to trying different types of treatment in hopes that something will work. But the rules for FDA approval are different.  Shouldn’t cancer patients be eligible for free treatments in clinical trials instead of paying for treatment that isn’t proven to work – and that has risks?

Can other studies be used to confirm the indication?  FDA explained the problems very clearly.

  • Not appropriate to use studies with data based on patients that aren’t for the same indication:

      #1) PD-L1 high and

      #2) not eligible for cisplatin or other options.

NCHR Statement Regarding Cancer Drugs that Failed to Confirm Efficacy after Accelerated Approval

April 29, 2021


I’m Dr. Diana Zuckerman, president of the National Center for Health Research.  Our center is a nonprofit think tank that scrutinizes the safety and effectiveness of medical products, and we don’t accept funding from companies that make those products.  Today I’m speaking from my perspective as a scientist who left Harvard more than 30 years ago to come to Washington D.C. to work in the House of Representatives. I worked as a Congressional investigator for the Subcommittee that conducted oversight over all of HHS, and that’s when I first learned about the laws and regulations governing the FDA.  I was responsible for several oversight hearings that attracted enormous media attention, because we found that patients had been harmed when the FDA was not following the law pertaining to FDA approval.

The law is very clear:  Drugs and biologics must be proven safe and effective, and that’s defined as having benefits that outweigh the risks for most patients.  FDA’s memoranda that were provided to this Committee for this meeting and for each of these indications over these last 3 days have made it clear that the data do not support that.  This Advisory Committee has looked at the data, seen reasons for optimism when looking at nonsignificant trends, and recommended that the FDA keep drugs on the market that don’t meet the standard specified by law.  That’s your right to do that, since you are advising the FDA based on your perspectives, experiences, and interpretations of the data.

I want to thank the FDA scientists who carefully analyzed the data and presented their findings.  You did a great job.  I’m here to urge the FDA to follow in your footsteps and follow the law and rescind approval for these indications until the companies complete randomized clinical trials that prove that the benefits outweigh the risks. I especially want to thank Dr. Pazdur for explaining how the FDA’s Expanded Access program can fill in the gaps for patients who need access to these drugs.  The companies agreed to complete confirmatory trials as part of the accelerated approval of their drugs, and I strongly urge the FDA to hold them to it.

All of these companies are leaders in their field and absolutely capable of conducting the research needed to prove whether or not their drugs have benefits that outweigh the risks for the exact specific indications they were previously approved for.  The companies also have the ability to make expanded access quick and easy.  Let’s face it, if they don’t have the expertise and resources to do the studies and help with expanded access, who does?  If the data don’t confirm the initial accelerated approval, the companies should work with the FDA to design trials to narrow the indication to figure out which are the patients most likely to be helped and which are the ones most likely to be harmed.

Written Statement Regarding Artificial Turf to Woodbridge Ordinance Committee

March 16, 2021


Dear Members of the Ordinance Committee:

I am writing to share scientific information about artificial turf and playground surfaces, which I am confident will help you determine the best decisions to make for the children and adults in your community.

As President of the National Center for Health Research, I am writing at the request of many of your constituents to share the information we have provided to Members of Congress, state and federal agencies, state and local legislators, parents, and others who want to ensure that our children are not exposed to dangerous chemicals or metals when they play on artificial turf or playgrounds. Our nonprofit think tank is located in Washington, D.C. Our scientists, physicians, and health experts conduct studies and scrutinize research. Our goal is to explain scientific and medical information that can be used to improve policies, programs, services, and products.

We commend you for considering the possible risks of replacing grass fields and natural playgrounds with artificial turf. In the last two years, we’ve learned new information about lead and PFAS in artificial turf, as well as the risks of some of the newer infill materials that turf companies are using to replace tire crumb. Tire crumb has well-known risks, containing chemicals that have the potential to increase obesity; contribute to early puberty; cause attention problems such as ADHD; exacerbate asthma; and eventually cause cancer. However, the plastic grass itself has dangerous levels of lead, PFAS, and other toxic chemicals as well.  PFAS are of particular concern because they enter the body and the environment as “forever chemicals,” which means that they are not metabolized and do not deteriorate, accumulating over the years. Replacing tire waste with silica, zeolite, and other materials also has substantial risks.

Federal agencies such as the EPA and the U.S. Consumer Product Safety Commission have been investigating the safety of these products. Despite claims to the contrary, none have concluded that artificial turf is safe. Although the Trump Administration’s EPA stated that there was no conclusive evidence that the levels of chemicals in artificial turf was harmful to children, they made it clear that their research was based on assumptions rather than scientific research on children.

Lead

As you probably know, the American Academy of Pediatrics states that no level of lead exposure should be considered safe for children, because lead can cause cognitive damage even at low levels. Some children are more vulnerable than others, and that can be difficult or even impossible to predict. Since lead has been found in tire crumb as well as in new synthetic rubber, it is not surprising that numerous artificial turf fields and playground surfaces made with either tire crumb or “virgin” rubber have been found to contain lead. However, the Centers for Disease Control and Prevention (CDC) also warns that the “plastic grass” made with nylon or some other materials also contains lead. Whether from infill, plastic grass, or rubber playground surfaces, the lead doesn’t just stay on the surface. With wear, the materials turn to dust containing lead and other chemicals that is invisible to the eye and is inhaled by children when they play.

Why are chemicals that are banned from children’s toys allowed in artificial turf and rubber playground surfaces?

Synthetic rubber and plastic are made with different types of endocrine (hormone) disrupting chemicals (also called EDCs). There is very good evidence regarding these chemicals in tire crumb, based on studies done at Yale and by the California Office of Environmental Health Hazard Assessment (OEHHA).1

A 2018 report by Yale scientists detected 92 chemicals in samples from 6 different artificial turf companies, including unused bags of tire crumb. Unfortunately, the health risks of most of these chemicals had never been studied. However, 20% of the chemicals that had been tested are classified as probable carcinogens and 40% are irritants that can cause asthma or other breathing problems, or can irritate skin or eyes.2

There are numerous studies indicating that endocrine-disrupting chemicals (also called hormone-disrupting chemicals) found in rubber and plastic cause serious health problems. Scientists at the National Institute of Environmental Health Sciences (which is part of NIH) have concluded that unlike most other chemicals, hormone-disrupting chemicals can be dangerous at very low levels, and the exposures can also be dangerous when they combine with other exposures in our environment.

That is why the Consumer Product Safety Commission has banned numerous endocrine-disrupting chemicals from toys and products used by children. The products involved, such as pacifiers and teething toys, are banned even though they would result in very short-term exposures compared to artificial turf or playground surfaces.

A report warning about possible harm to people who are exposed to rubber and other hormone disrupting chemicals at work explains that these chemicals “can mimic or block hormones and disrupt the body’s normal function, resulting in the potential for numerous health effects. Similar to hormones, endocrine-disrupting chemicals can function at very low doses in a tissue-specific manner and may exert non-traditional dose–response because of the complicated dynamics of hormone receptor occupancy and saturation.”3

Studies are beginning to demonstrate the contribution of skin exposure to the development of respiratory sensitization and altered pulmonary function. Not only does skin exposure have the potential to contribute to total body burden of a chemical, but also the skin is a highly biologically active organ capable of chemical metabolism and the initiation of a cascade of immunological events, potentially leading to adverse outcomes in other organ systems.

Scientific Evidence of Cancer and Other Systemic Harm

It is essential to distinguish between evidence of harm and evidence of safety. Companies that sell and install artificial turf often claim there is “no evidence children are harmed” or “no evidence that the fields cause cancer.” This is often misunderstood as meaning the products are safe or are proven to not cause harm. Neither is true.

It is true that there no clear evidence that an artificial turf field has caused specific children to develop cancer. However, the statement is misleading because it is virtually impossible to prove any chemical exposure causes one specific individual to develop cancer.

As an epidemiologist, I can also tell you that for decades there was no evidence that smoking or Agent Orange caused cancer. It took many years to develop that evidence, and the same will be true for artificial turf.

I have testified about the risks of these materials at the U.S. Consumer Product Safety Commission as well as state legislatures and city councils. I am sorry to say that I have repeatedly seen and heard scientists paid by the turf industry and other turf industry lobbyists say things that are absolutely false. They claim that these products are proven safe (not true) and that federal agencies have stated there are no health risks (also not true).

However, we know that the materials being used in artificial turf and rubber playground surfaces contain carcinogens, and when children are exposed to those carcinogens day after day, week after week, and year after year, they increase the chances of our children developing cancer, either in the next few years or later as adults. That should be adequate reason not to install them in your community. That’s why I have spoken out about the risks of artificial turf in my community and on a national level. The question must be asked: if they had all the facts, would Woodbridge or any other community choose to spend millions of dollars on fields that are less safe than well-designed natural grass fields?

Dangerously Hot and Hard Fields

I lived in Connecticut for several years while on the faculty at Yale and Vassar, and I know the climate well. When the weather is warm and/or sunny, it is usually quite pleasant to be outside – as long as you aren’t on artificial turf or an outdoor rubber surface. Even when the temperature above the grass is 80 degrees Fahrenheit, artificial turf can reach 150 degrees or higher. Obviously, a 90 degree day is likely to be even hotter than 150 degrees on turf. That can cause “heat poisoning” as well as burns.

Artificial turf fields get hard as well. Turf companies recommend annual tests at 10 locations on each turf field, using something called a Gmax score. A Gmax score over 200 is considered extremely dangerous, and it is considered by industry to pose a death risk. However, the synthetic turf industry and American Society for Testing and Materials (ASTM), suggest scores should be even lower — below 165 to ensure safety comparable to a grass field. Will Woodbridge pay to have these tests conducted annually on all your public artificial turf fields?

The hardness of natural grass fields is substantially influenced by rain and other weather; if the field gets hard, rain or watering will make it safe again. In contrast, once an artificial turf field has a Gmax score above 165, it needs to be replaced because while the scores can vary somewhat due to weather, the scores will inevitably get higher because the turf will get harder. Gmax testing involves testing 10 different areas of a playing fields, to make sure all are considered safe.  Some officials average those 10 scores to determine safety; however, experts explain that is not appropriate. If a child (or adult) falls, it can be at the hardest part of the field, which is why safety is supposed to be determined by the score of the hardest part of the field.

Environmental Issues

In addition to the health risks to school children and athletes, approximately three tons of infill materials migrate off of each synthetic turf field into the greater environment each year. About 2-5 metric tons of infill must be replaced every year for each field, meaning that tons of the infill have migrated off the field into grass, water, and our homes.4 The fields also continuously shed microplastics as the plastic blades break down.5,6 These materials may contain additives such as PAHs, flame retardants, and UV inhibitors, which can be toxic to marine and aquatic life. Microplastics are known to migrate into the oceans, the food chain, and drinking water, and they can absorb and concentrate other toxins from the environment.7,8,9

Synthetic surfaces also create heat islands.10,11 In contrast, organically managed natural grass saves energy by dissipating heat, cooling the air, and reducing energy to cool nearby buildings. Natural grass and soil protect groundwater quality; biodegrade polluting chemicals and bacteria; reduce surface water runoff; abate noise; and reduce glare.12

Envirofill and Alternative Infills

Envirofill artificial turf fields are advertised as “cooler” and “safer,” but our research indicates that these fields are still at least 30-50 degrees hotter than natural grass. Envirofill is composed of materials resembling plastic polymer pellets (similar in appearance to tic tacs) with silica inside. Silica is classified as a hazardous material according to OSHA regulations, and the American Academy of Pediatrics specifically recommends avoiding it on playgrounds. The manufacturers and vendors of these products claim that the silica stays inside the plastic coating. However, sunlight and the grinding force from playing on the field breaks down the plastic coating. For that reason, even the product warranty admits that only 70% of the silica will remain encapsulated. The other 30% can be very harmful as children are exposed to it in the air.

In addition, the Envirofill pellets have been coated with an antibacterial called triclosan. Triclosan is registered as a pesticide with the EPA, and the FDA has banned triclosan from soaps because manufacturers were not able to prove that it is safe for long-term use. Research shows a link to liver and inhalation toxicity and hormone disruption. The manufacturer of Envirofill says that the company no longer uses triclosan, but they provide no scientific evidence that the antibacterial they are now using is any safer than triclosan. Microscopic particles of this synthetic turf infill will be inhaled by children, and visible and invisible particles come off of the field, ending up in shoes, socks, pockets, and hair.

In response to the concerns of educated parents and government officials, other new materials are now being used instead of tire crumb and other very controversial materials. However, all the materials being used (such as volcanic ash, corn husks, and Corkonut) have raised concerns, and none are proven to be as safe or effective as well-designed grass fields.

Conclusions

There have never been any safety tests required prior to sale that prove that any artificial turf products are safe for children who play on them regularly. In many cases, the materials used are not publicly disclosed, making independent research difficult to conduct. None of these products are proven to be as safe as natural grass in well-constructed fields.

I have cited several relevant scientific articles on artificial turf in this letter, and there are numerous studies and growing evidence of the harm caused by these synthetic materials. I would be happy to provide additional information upon request (dz@center4research.org).

I am not paid to write this statement. I am one of the many parents and scientists who are very concerned about the impact of artificial fields on our children. Your decision about artificial turf and playground surfaces can save lives and improve the health of children in your community.  You owe it to your community to make sure that you know the risks of artificial turf and do all you can to protect your children from both the known risks and the suspected risks. Your decisions about artificial turf will be cited by other communities, making it even more important that your decision is based on scientific evidence, not on sales pitches by individuals with conflicts of interest.

Officials in communities all over the country have been misled by artificial turf salespeople. They were erroneously told that these products are safe. On the contrary, there is clear scientific evidence that these materials are harmful. The only question is how much exposure is likely to be harmful to which children? We should not be willing to take such a risk. Our children deserve better.

Sincerely,

Diana Zuckerman, Ph.D.

President

 

References

  1. State of California-Office of Environmental Health Hazard Assessment (OEHHA), Contractor’s Report to the Board. Evaluation of Health Effects of Recycled Waste Tires in Playground and Track Products. January 2007. http://www.calrecycle.ca.gov/publications/Documents/Tires%5C62206013.pdf
  2. Benoit G, Demars S. Evaluation of organic and inorganic compounds extractable by multiple methods from commercially available crumb rubber mulch. Water, Air, & Soil Pollution. 2018;229:64. https://doi.org/10.1007/s11270-018-3711-7
  3. Anderson SE and Meade BJ. Potential Health Effects Associated with Dermal Exposure to Occupational Chemicals. Environmental Health Insights. 2014; 8(Suppl 1):51–62. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270264/
  4. York T. Greener grass awaits: Environmental & fiscal responsibility team up in synthetic turf. Recreation Management. February 2012. http://recmanagement.com/feature_print.php?fid=201202fe02
  5. Magnusson K, Eliasson K, Fråne A, et al. Swedish sources and pathways for microplastics to the marine environment, a review of existing data. Stockholm: IVL- Swedish Environmental Research Institute. 2016. https://www.naturvardsverket.se/upload/miljoarbete-i-samhallet/miljoarbete-i-sverige/regeringsuppdrag/utslapp-mikroplaster-havet/RU-mikroplaster-english-5-april-2017.pdf
  6. Kole PJ, Löhr AJ, Van Belleghem FGAJ, Ragas AMJ. Wear and tear of tyres: A stealthy source of microplastics in the environment. International Journal of Environmental Research Public Health. 2017;14(10):pii: E1265. https://www.ncbi.nlm.nih.gov/pubmed/29053641/
  7. Kosuth M, Mason SA, Wattenberg EV. Anthropogenic contamination of tap water, beer, and sea salt. PLoS One. 2018,13(4): e0194970. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895013/
  8. Oehlmann J, Schulte-Oehlmann U, Kloas W et al.  A critical analysis of the biological impacts of plasticizers on wildlife. Philosophical Transactions of the Royal Society B. 2009;364:2047–2062. http://rstb.royalsocietypublishing.org/content/364/1526/2047
  9. Thompson RC, Moore CJ, vom Saal FS, Swan SH. Plastics, the environment and human health: Current consensus and future trends. Philosophical Transactions of the Royal Society B. 2009;364:2153–2166. https://royalsocietypublishing.org/doi/full/10.1098/rstb.2009.0053
  10. Thoms AW, Brosnana JT, Zidekb JM, Sorochana JC. Models for predicting surface temperatures on synthetic turf playing surfaces. Procedia Engineering. 2014;72:895-900. http://www.sciencedirect.com/science/article/pii/S1877705814006699
  11. Penn State’s Center for Sports Surface Research. Synthetic turf heat evaluation- progress report. 012. http://plantscience.psu.edu/research/centers/ssrc/documents/heat-progress-report.pdf
  12. Stier JC, Steinke K, Ervin EH, Higginson FR, McMaugh PE. Turfgrass benefits and issues. Turfgrass: Biology, Use, and Management, Agronomy Monograph 56. American Society of Agronomy, Crop Science Society of America, Soil Science Society of America. 2013;105–145. https://dl.sciencesocieties.org/publications/books/tocs/agronomymonogra/turfgrassbiolog

Statement on Keytruda for Early Stage Triple Negative Breast Cancer

February 9, 2021


The National Center for Health Research is a nonprofit think tank that scrutinizes the safety and effectiveness of medical products.  We don’t accept funding from companies that make those products, so we have no conflicts of interest.  We welcome the opportunity to provide our views on Merck’s application for approval of Keytruda for the indication of high-risk early stage triple negative breast cancer.

Triple negative breast cancer has a lower survival rate than other breast cancers.  However, chemotherapy clearly improves 5-year survival.  Patients need additional treatment options but the bottom line for patients is that FDA should not approve an indication that is not proven to have clinically meaningful benefits, especially when the treatment has clear risks.   

The first issue to address is whether there is evidence that immune checkpoint inhibitors (ICIs) are effective for TNBC.  We agree with FDA scientists that “there is still uncertainty regarding ICIs for TNBC” based on the results from several clinical trials.

  • KEYNOTE-119 failed to meet its primary OS endpoint. 
  • KEYNOTE-355 has not met its OS endpoint. 
  • IMpassion130: clinical benefits need to be confirmed
  • IMpassion131 interim OS results favored control group

The second major issue pertains to pCR data in the study.  The results indicate only 7.5% improvement in pCRs at IA3 (the most recent interim analysis), which the FDA scientists point out may not be clinically meaningful even if statistically significant.  We agree.  The problem is that it is impossible to determine how this slight improvement would affect overall survival, and even if it does, how much neoadjuvant and adjuvant use each contribute to any benefit. 

FDA scientists were clear to the sponsor that there were concerns with their study design and that the application for approval was premature since the study was not yet completed.  The agency made it clear that that the event free survival (EFS) study results were not statistically significant, not clinically meaningful, and did not show a “stable trend.” 

FDA reviewers are clear that data on overall survival “are too immature to provide a conclusive interpretation regarding the difference in OS between treatment arms.” 

What about safety?

At IA3 (the most recent interim analysis), there were 96 deaths, which FDA points out “accounts for only 32% of the events needed for the final analysis. Therefore, the OS estimate may be unreliable, and the treatment effect size reported is subject to uncertainty.”

It is notable that the study included patient-reported outcomes (PROs), but unfortunately, KEYNOTE-522 was not designed to compare differences in PROs (symptoms, side effects, health-related quality of life), nor were these patient-reported endpoints prospectively identified and statistically tested. 

PRO assessments should have been more frequent, both for neoadjuvant and adjuvant treatments

Since many high-risk, early-stage TNBC patients will be cured with standard therapy, the key issue is whether this drug has benefits that outweigh the risks.  The benefits are unclear.  Therefore, the evidence of the drug’s “added toxicity” is worrisome.  FDA scientists concluded that “Some of these toxicities may be irreversible or require lifelong medication in patients cured of their breast cancer.

Although the sponsor counted 2 deaths due to immune-mediated adverse events, the FDA counted 4.  Either way, these deaths must be considered worrisome given the lack of clear evidence of a meaningful benefit.  And, there are many other serious adverse events in addition to the small number of deaths.   All-grade and grade ≥3 immune-mediated AEs and infusion reactions occurred more frequently in Keytruda patients compared to placebo:    43% vs. 22% for all grade AEs, and 15% vs. 2% for high grade AEs.  In fact, 10% of Keytruda patients had immune-mediated AEs and infusion reactions leading to hospitalization compared to 1% of placebo.  These included the following relatively high number of adverse events:

  • Infusion reactions (18%), 
  • Hypothyroidism (15%), 
  • Severe skin reactions (6%)
  • Hyperthyroidism (5%), adrenal insufficiency (3%), pneumonitis (2%), and thyroiditis (2%).

It is important to note that these adverse events were not resolved at the last assessment in the study for 19% of Keytruda patients.   It is also important to note that 16% of the Keytruda patients initiated thyroid hormone replacement during the study.

In summary, we agree with FDA scientists that the deaths are “particularly concerning in this curative disease setting.”

  • “All grade and grade ≥3 immune-mediated AEs were increased in [Keytruda] patients.’
  • Some “may be severe or lifelong.” 
  • The adjuvant treatment has fewer adverse events but “has not demonstrated a significant effect on any efficacy endpoint, and may be adding risk without benefit.”

Based on our analysis, we agree with the overall conclusions made by FDA scientists: 

  1. Neoadjuvant Keytruda “confers only a small absolute improvement in pCR rate of questionable clinical meaningfulness.
  2. Event-free survival and overall survival are “immature and unreliable.”
  3.  “The design and results of KEYNOTE-522 do not currently support a role for adjuvant [Keytruda].”
  4. Supportive data of clinical benefit … are lacking.” 
  5. Adding Keytruda “is associated with increased toxicity … which may be severe, irreversible, and/or require life-long medication in potentially curable and otherwise healthy patients.” 

In conclusion, the FDA and the medical community do patients no favors to approve a treatment that is not proven to benefit them and at the same time is proven to cause harm for a substantial percentage of patients.  The studies should be continued to determine whether the benefit of adding Keytruda to other treatments outweigh the risks.

 

This written statement was submitted to the FDA on February 8, 2021 and an oral version with PowerPoint slides was presented at the FDA Advisory Committee meeting on February 9, 2021.

We are pleased that the FDA Advisory Committee agreed with our views and voted 10-0 on February 9 in favor of deferring an FDA regulatory decision until the study is completed.

NCHR Statement by Dr. Diana Zuckerman at FDA Covid Vaccine Advisory Committee

October 22, 2020


I’m Dr. Diana Zuckerman, president of the National Center for Health Research. Our center scrutinizes the safety and effectiveness of medical products, and we don’t accept funding from companies that make those products, although I’ve personally inherited stock in Johnson & Johnson. My expertise is based on post-doc training in epidemiology and as a faculty member and researcher at Vassar, Yale, at Harvard. I’ve also worked at HHS, the U.S. Congress and White House.

We’ve heard today that the agencies are doing many things right, but the vaccine trials have serious design flaws. The standards set in FDA guidances and the study protocols make it likely that vaccines that will be authorized or approved won’t achieve what the public and policy makers expect. Instead, these vaccines will only be proven to reduce the risk of mild infections but not proven to reduce the risk of hospitalization, ICU use, or deaths.

The major flaws are as follows:

  • The FDA’s proposed primary endpoint is defined as symptomatic Covid-19 that can include only 1 very mild symptom, such as a mild cough or sore throat – as long as the person has tested positive.
  • FDA’s requirement of at least 2 months median follow-up after vaccination or placebo is too short to study efficacy.  Even if a person is exposed during that time, we don’t know the correlates of protection and so we need a longer follow-up to know how long an effective vaccine remains effective.  We can’t rely on post-market studies for that information, because once a vaccine is on the market, many people in the placebo control group will switch to a vaccine.
  • We don’t know whether diversity of study participants will be achieved in terms of age, race, or co-morbidities, especially for people who are exposed to the virus.
  • The requirement of at least 5 serious Covid-19 cases in the placebo group is completely inadequate for 2 reasons:
    • Serious Covid-19 cases are too loosely defined, and could include a case of mild Covid-19 if the patient has a blood oxygen saturation under 93%. But thousands of otherwise healthy Americans have levels below that.
  • Even if the definition were more stringent, such as requiring hospitalization or death, and even if there were no such cases among the vaccinated patients, the absolute difference in disease between 0 and 5 serious cases would not be clinically meaningful to individuals and could easily have occurred by chance.

The American public has been told for months that life can go back to normal when we have a vaccine.  It isn’t FDA’s job to achieve that overly optimistic goal for any vaccine, but it is FDA’s job to make sure that a vaccine has meaningful benefits for the health and lives of most Americans, and especially those most at risk.