Category Archives: Testimony & Briefings

Testimony of Diana Zuckerman at the Meeting of EPA’s National Environmental Justice Advisory Council on September 28, 2022

I’m Dr. Diana Zuckerman, president of the National Center for Health Research. We scrutinize the safety and effectiveness of medical and consumer products, and we don’t accept funding from companies that make those products.  Our largest program is focused on cancer prevention and treatment.  My expertise is based on post-doc training in epidemiology and public health, and my previous positions at HHS and as a faculty member and researcher at Harvard and Yale.

 Thank you all for the important work you’ve been doing and will be doing on this Advisory Council.  As a public health person, I’ve always been surprised at the lack of other public health advocates who are active on environmental issues and environmental justice issues, and I want to offer to be helpful in any way that would be useful to all of you.  We all know that lives are at stake.

I want to comment very briefly on the PFAS recommendations, since that’s an issue we’ve worked on for years.  Let me add that we are very concerned about all endocrine disrupting chemicals not just PFAS.

Everything I heard about PFAS this afternoon was inspiring and important.  I would just suggest that it’s a huge task, and I encourage you to start a little smaller in order to succeed in educating the public and especially environmental justice communities and at the same time focus on actions that are doable, that will inspire others, and that will make change happen.

Testimony of Dr. Diana Zuckerman About COPIKTRA FDA Advisory Committee Meeting on September 23, 2022

I’m Dr. Diana Zuckerman, president of the National Center for Health Research. We scrutinize the safety and effectiveness of medical products, and we don’t accept funding from companies that make those products. Our largest program is focused on cancer. My expertise is based on post-doc training in epidemiology and public health, and my previous positions at HHS and as a faculty member and researcher at Harvard and Yale.

In April this same Committee examined 6 randomized trials of Pi3K inhibitors used for hematologic malignancies and found that all reduced overall survival –despite potential benefit for PFS. FDA says that these consistent findings across multiple randomized trials within the same drug class is unprecedented in oncology.
That’s a shocking finding that we need to take seriously. And that’s the context for today’s meeting.

The sponsor did a 5-year randomized controlled post-market study – 3 years longer than the data that resulted in initial approval. They found the median OS was 11 months shorter than the comparison drug. In fact, 50% of the patients died during those 5 years, compared to 44% taking the other treatment – a treatment that is no longer considered effective and so is rarely used.

Then they analyzed patients with 2 or more prior therapies, since that was the indication. Those Copiktra patients lived about 3 months shorter – not as bad as the larger sample, but still worrisome. Especially since 56% died during the 5 years of the study, compared to 49% assigned to the other treatment.

Adverse events caused the deaths of 15% of the Copiktra patients compared to only 3% of the other treatment group. And the percentage of Grade 3 or greater AEs was 91%, and 78% had Serious AEs–about twice as high as the comparison group. This has clear implications for quality of life, in addition to the patients not living as long.

The FDA did the right thing by requesting this post-market study. And the sponsor did the right thing by completing the study. Now is the time to listen to the results. We urge this Advisory Committee and the FDA to make it clear that approvals will be rescinded when evidence indicates that promising short-term results are reversed based on longer term data from post-market studies.

Patients and oncologists want as many treatment options as possible, but we do patients no favors by maintaining approval for a drug that does more harm than good. As was true yesterday for other cancer treatments, the preponderance of evidence is clear today.

As a cancer survivor myself, I understand the need for treatment options. I thank this committee and the FDA for its objective, scientific analysis of the data presented yesterday and today. I hope it will help everyone understand that an individual patient may seem to do well on a specific treatment, but that treatment may not be the REASON the patient did well. There are other individual differences that cause some patients to do better than others, and to live longer than others. As FDA stated, these diseases are often indolent. That’s why large, long-term randomized controlled trials are so important – to help us understand which treatments are better for which patients.

There are so many problems with the data, including the very substantial changes in treatment standards that have occurred since this study was designed, the low number of US patients, and the dearth of nonwhite patients – all these support rescinding approval for this indication.

It takes years for FDA to rescind approval unless the sponsor does the right thing by voluntarily doing so. But your vote today will be very influential.

I hope that the sponsor will conduct new research to determine if a subgroup of patients can benefit from this drug under current treatment standards, and if a lower dose is safer as well as effective, and if so FDA should of course consider approval for a different indication. But that isn’t where we are today.

Testimony of Dr. Diana Zuckerman About PEPAXTO FDA Advisory Committee Meeting on September 22, 2022

I’m Dr. Diana Zuckerman, president of the National Center for Health Research. We scrutinize the safety and effectiveness of medical products, and we don’t accept funding from companies that make those products.  Our largest program is focused on cancer.  My expertise is based on post-doc training in epidemiology and public health, and previous positions at HHS and faculty member and researcher at Yale and Harvard.

All of us want more treatment options for refractory cancers, but we want patients to be able to have confidence that FDA approval means a product is proven safe and effective.  The OCEAN study of 495 multiple myeloma patients has important information that was not available when the drug received accelerated approval. Even if some patients taking Pepaxto do well, it is only with a randomized controlled trial that we can determine if Pepaxto is helpful or if the patients would do better without it.

Our Center’s analyses support the FDA findings that the data do not confirm the indication.  In the randomized trial comparing Pepaxto to another treatment option, median survival was 5.3 months shorter, and the death rate was slightly higher. 

The Sponsor says some patients do better but we agree with FDA that “Results from subgroup analyses cannot be used to conclude benefit in a subset of patients, when the overall patient population has shown a detrimental treatment effect.”

We also agree with the FDA that PFS is not improved and that “An anti-cancer therapy that prolongs PFS is not considered safe and effective if the therapy results in a detrimental effect on OS”

Public trust in the FDA has been weakened in recent years.  FDA standards matter to all of us.  Would you want your loved one to take Pepaxto rather than a superior treatment option?  Not all oncologists will be as knowledgeable about the data as those serving on this panel.

It concerns us that the sponsor continues to ignore FDA concerns, rely on shortcuts instead of better research, and that the company withdrew the drug in October but then rescinded the withdrawal.  Was this just a delaying tactic?  We agree with the FDA that the sponsor did not provide new data, and with Dr. Pazdur that FDA approval relies on solid information about appropriate dosage, which is lacking here.

Maybe Pepaxto would benefit some types of patients and better research is needed to prove that.  As FDA states, the preponderance of evidence from the prespecified analysis and in all other subgroups suggests an increased risk of death in patients and a potential for harm.”

We were pleased that the Committee voted 14-2 that the evidence does not support that the benefits outweigh the risks.

Diana Zuckerman Statement on the Role of FDA in Health Inequities Meeting of the National Academy of Medicine

July 26, 2022

Thank you for the opportunity to speak today on how current FDA policies contribute to health inequities.

The National Center for Health Research is a nonprofit think tank founded in 1999 that conducts research and scrutinizes research conducted by others to evaluate medical products, procedures, and policies. We do not accept funding from companies whose products we evaluate.

There are many reasons for health inequities in the U.S., but today I will focus on one that usually gets no attention: Federal laws regarding diversity in clinical trials.

The U.S. Department of Health and Human Services requires research studies to include people representing diverse racial and ethnic backgrounds. This is not always enforced, but the requirement is in the law and NIH, CDC, SAMHSA and other agencies make an effort to abide by this law.

The one exception among federal public health agencies is the FDA, which encourages but does not require diversity in clinical trials. They justify this because the agency doesn’t pay for the studies – the companies that make the products pay for the studies. However, taxpayers do pay for FDA staff that regulate these products, and taxpayers also pay for the products themselves.

Our NCHR Study of Racial Diversity

To see the impact of the lack of a requirement for FDA, we examined 22 of the highest risk medical devices reviewed by the FDA Advisory Panels for 4 recent years. We found:

  • The number of nonwhite patients in key trials ranged from 4 (3%) to 6,788 (17%).
  • Of 19 treatment devices, only 7 had analyses for racial groups for effectiveness and only 3 for safety.
  • 69% to 99% of the patients in the studies were White. The number of nonwhites was as low as 4; 1 for Hispanics.
  • There were too few patients in most racial or ethnic groups to draw meaningful conclusions.
  • Even when subgroup analyses were conducted, their conclusions were often discredited by the FDA, blamed on chance differences due to small sample size. If there was a lack of diversity or even when racial or ethnic differences were significant, that information was were often not included on the label, which is the main source of information for physicians and patients.

    Recent Examples from the FDA

    When the FDA reviewed the data on Aduhelm for Alzheimer’s Disease, they focused on 2 studies comparing placebo to high and low dosage:

    Study 301: 8 Black patients (half of 1%) and 37 Hispanic patients (2%)
    Study 302: 11 Black patients (less than 1%) and 67 Hispanic patients (4%)

    When the FDA reviewed data on the Reducer circulatory system device for angina, they found that there were no Black or Hispanic patients, and more than 80% of the patients were White or male, or both. And yet, most patients with angina are not White males.

    Why is Diversity Important in Clinical Trials?

    Response to treatment can vary due to genetics, health habits, metabolism, body part size/shape and other factors. If you exclude certain groups, you don’t know what works best for them. Keep in mind that you need enough patients to study safety and effectiveness for patients in each group.

    Example – Lutonix drug-coated balloon catheter to open blocked arteries

    You can see on this graph that the device seemed effective compared to the control group when men and women were combined. However, you can also see that the device was only effective for men, not for women. In fact, women did better with placebo. This is an example of how evaluating safety and effectiveness for a specific demographic group can provide information that is completely different from an analysis of a diverse group as a whole.

    Shortcomings of Very Small Samples

    When the racial or ethnic group is very small, the results may not be generalizable to the larger population that those patients represent. A few outliers can have an outsized effect on the outcomes – resulting in significant differences where they do not exist. Or, real differences may be apparent but not be statistically significant because the sample lacks statistical power.

    If an analysis is conducted on a small number of patients of a particular ethnic group, any differences could easily be due to chance. For example, the graphic below shows that the new drug seems to be more effective than an older drug (40% effective compared to 30% effective) , but that difference is not statistically significant. However, if the same difference was based on a much larger sample, it would be statistically significant.

    In conclusion, when the FDA approves a medical product that has not been evaluated on a relatively large number of patients in a specific racial or ethnic group, it is not possible to conclude whether the product is safe or effective for members of that group. If the FDA does not require adequate diversity in clinical trials used as the basis for FDA approval, then the agency should only approve those products for the types of individuals studied. That precision in approval decisions would create the incentive needed for companies to improve diversity in their trials and conduct appropriate subgroup analyses.

    Reference
    1. Fox-Rawlings SR, Gottschalk LB, Doamekpor LA & Zuckerman DM. (2018) Diversity in Medical Device Clinical Trials: Do We Know What Works for Which Patients? Milbank Quarterly, Vol 96 (3) 499-529.

    Dr. Diana Zuckerman Statement to CDC Advisory Committee On Breast Cancer in Young Women

    August 23, 2022

    I’m pleased to have the opportunity to provide this statement on behalf of the National Center for Health Research. We are a nonprofit research center, and our largest program is focused on cancer prevention and treatment. I previously worked at the White House office of Science and Technology Policy, the U.S. Department of Health and Human Services, the U.S. House and Senate, Harvard, and Yale. I am also a breast cancer survivor.

    Today I want to mention an issue that hasn’t been talked about: fear. Research shows that many young women are disproportionately afraid of breast cancer and that young breast cancer survivors are more afraid of recurrence than older survivors. I encourage you to think of what we can do together to help reduce that fear so that young women don’t let their fear overwhelm them as they become aware of and educated about their risks as well as their prevention and treatment options.

    Despite their fear, few women of any age know that diet and exercise help prevent breast cancer. You’ve heard today that alcohol increases the risk of breast cancer, but did you know that drinking more than 3 alcoholic beverages per week can raise the risk of breast cancer? We all know young women who drink much more than that. We should also educate young women about the link between cancer and ultra-processed foods – I’m not just talking about the usual culprits, I’m talking about sauces and many other prepared foods that we assume are healthy when we buy them at the supermarket. In addition, being overweight or obese also increases the risk of breast cancer and of recurrence, because fat cells make more estrogen. We should be educating young women about these strategies for reducing their risks, since these are changes they can control.

    Research shows that more women undergo mastectomies and bilateral mastectomies in the U.S. than most comparable countries. And yet, research shows that early-stage breast cancer patients who undergo lumpectomy (BCT) and radiation live longer with better quality of life than early-stage mastectomy patients, and a study of more than 23,000 young women with early-stage breast cancer found that the 10-year survival rate was at least as good for BCT plus radiation as for mastectomy. Research is needed to see how outcomes vary among women with specific demographic traits and risk factors, but the research available thus far is reassuring. On a personal note, as a professional in the field, I was shocked when my breast surgeon repeatedly urged me to consider a bilateral mastectomy for Stage 1 breast cancer. I had heard from many other women who had similar experiences. I am sure women who aren’t experts in the field, and especially young women, are being influenced by that kind of pressure.

    In addition to all the other important issues raised by this committee today, I want to add that we should make sure that young women understand the difference between lifetime risk of breast cancer and their annual risk of developing breast cancer. And the difference between DCIS and invasive breast cancer. Educating young women can help reduce their fear and help enable them to take the time they need to advocate for themselves based on the information needed to make the treatment decisions that are best for them.

    One last suggestion: We’ve heard many great ideas today about the information that primary care physicians, OB/GYNs, and the public need to know about young women and breast cancer, as well as prevention and treatment strategies. Wouldn’t it be great if CDC put together an education campaign on some of these key issues, to be shown on TV so it reaches a large audience?

    Who Should You Believe? A critique of the Aesthetic Society’s view of Breast Implant Illness

    By Diana Zuckerman, PhD.


    An article entitled “A Practical Guide to Managing Patients With Systemic Symptoms and Breast Implants” was published in the  Aesthetic Surgery Journal, (Volume 42, Issue 4, April 2022, Pages 397–407). This is a journal of the Aesthetic Society, which is the second largest association of plastic surgeons.  The authors are Patricia McGuire, MD, Daniel J Clauw, MD, Jason Hammer, MD, Melinda Haws, MD, and William P Adams, Jr, MD

    There are many outrageous articles denying the existence of breast implant illness, but this may be the worst since it was published after major studies documented that breast implant illness exists.  The authors are prominent plastic surgeons who are members of the Aesthetic Society and/or the American Society of Plastic Surgeons (ASPS), which are the two major associations for plastic surgeons.  All but one of the authors have financial ties to companies that make breast implants.

    The theme of the article is clearly stated in the summary: “Numerous studies have explored the possibility of an association between breast implants and systemic symptoms potentially linked to exposure to silicone. Some studies show no direct association whereas others provide insufficient scientific evidence to prove or disprove an association. Nonetheless, some patients with breast implants remain concerned about the possible role of their implants in systemic symptoms they may be experiencing. This paper provides a practical approach for plastic surgeons in managing patients with breast implants who present with systemic symptoms, including recommendations for patient counseling, clinical and laboratory assessment of symptoms, and/or referral. Integral components of patient counseling include listening attentively, providing unbiased information, and discussing the risks and benefits of options for evaluation and treatment.”

    In reality, there are numerous studies in major medical journals that show a “direct association” between breast implant illness and diagnosed diseases with similar symptoms.  But the plastic surgeons who wrote the article are saying there is no evidence.  They are also saying that since patients mistakenly think BII is real, surgeons should assure them that although BII it is not proven, research is underway to study the issue.  That gaslighting is intended to show the patients that their surgeon is open-minded.

    You might ask what is the evidence that the authors use to conclude that BII is not real?  To me as a researcher, this is the most mind-boggling part.  In addition to misquoting a 22-year old report from the Institute of Medicine – a report that is extremely outdated — and including a few individual case studies that just happen to all illustrate the authors’ view that breast implant illness isn’t real — the authors made several major errors:

    #1.  They state that “In 2019, an FDA advisory panel on breast implant safety determined that there is currently insufficient evidence of a causal relationship between breast implants and the diagnosis of rheumatologic disease or [connective tissue disease].” They footnote this statement with a document that was written by the FDA before the FDA advisory panel met in 2019 and which did not draw any such conclusions.

    #2. They state that “a number of epidemiological studies taken together are felt by many experts in the field to represent convincing evidence that there is no link between SBIs and auto-immune diseases.” The authors support that statement by listing 9 articles that they do not discuss. Almost all of the articles were funded by implant manufacturers and/or plastic surgeons, and 3 were published more than 20 years ago, based on poorly designed studies. One study was described as a study of 55,000 women, but in reality a large percentage of the patients dropped out before the study was completed.  Most outrageous of all, the last 2 studies listed actually concluded the opposite to what the plastic surgeons claimed:  The Israeli study and the Baylor study that both concluded that several autoimmune diseases with symptoms similar to BII are significantly increased after women get breast  implants.

    #3.  They mistakenly conclude that since women with saline breast implants also report BII symptoms, the symptoms are not related to the silicone shell.  This is a ridiculous statement since all breast implants have silicone shells.

    #4.  In contrast to their uncritical acceptance of poorly designed and biased studies funded by implant manufacturers and surgeons with financial ties to those implant makers, when the authors briefly mention studies showing that women with BII symptoms that improve after their implants are removed, they speculate (without evidence) that such improvement might be temporary.  It is notable that they didn’t even mention the 2021 study by Dr. Feng and her colleagues, which showed significant improvement in lung function after explant surgery.  That is no accident, since this Aesthetic Society article was published many months later.

    There are too many other careless errors in the article to list them all.  I can’t help but wonder if the authors read any of the studies they were supposedly quoting.  While urging plastic surgeons to pretend to be open-minded, the authors are anything but.  They repeatedly misrepresent research findings in order to support their biased view that the symptoms of breast implant illness are not caused by breast implants.

    In summary: This article makes it clear that the Aesthetic Society is encouraging their members to “gaslight” patients with BII, rather than help them get explanted.  Women who are seeking well-informed plastic surgeons should avoid the authors and think twice before believing anything they hear from plastic surgeons that belong to the Aesthetic Society, since the journal is published by that medical group.

    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.