Category Archives: Policy

Testimony of Dr. Diana Zuckerman About I-omburtamab FDA Advisory Committee Meeting

Policy, Testimony & Briefings

October 28, 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.  

My expertise is based on post-doc training in epidemiology and public health, my previous policy positions at Congressional Committees with oversight over FDA, my previous position at the US Department of Health and Human Services, and as a faculty member and researcher at Harvard and Yale. 

This is a terrible disease and the personal stories are very important.  What is the evidence that this treatment actually works?

The sponsor has provided data from 2 studies:

  1. A single center, single arm trial (Study 03-133) included 94 pediatric patients ages 0.9 to 13 years with CNS/LM relapsed neuroblastoma who received intracerebroventricular infusions.  Three doses were used: 25 mCi, 33.5 mCi, or 50 mCi, based on age. The Primary Endpoint was overall survival and the results showed 45% alive at 3 year.
  2. The second study is not completed yet.  The Interim report of this multi-center single arm study (Study 101) shows 20 patients with imaging evidence of CNS/LM disease.  The Sponsor reports 7 responders, but 3 of these are not confirmed.  That matters because transient responses are not necessarily meaningful, and therefore can’t be considered evidence.  The Primary Endpoint is 3-year overall survival, but those data are not yet available.

Safety

It is important to note that 19% of patients permanently discontinued using the drug due to an adverse reaction in Study 03-133 and 28% of patients in Study 101.  Most were due to myelosuppression.  However, 3% were due to chemical meningitis (3 cases in 03-133 and 1 case in Study 101), and there was one case of fatal intracranial hemorrhage

Shortcomings of the Studies

Only one study was completed and it wasn’t randomized or blinded or controlled.  The external control group was very small and they differed from the patients receiving the treatment, because the latter had more intensive prior treatment.  There were significant population differences as well as treatment differences between the treatment group and the external controls.  In addition, overall survival for this condition has improved since the control data sample was collected.

Therefore, we agree with FDA’s conclusion that differences in overall survival can’t be “reliably attributed” to the drug.  We also agree that “the application does not include reliable response rate data to provide supportive evidence.”

In Study 101, no patient demonstrated a response that can be unequivocally   attributed to the drug.  And there was no overall response rate calculated for Study 03-133  and only very limited overall response rate data in Study 101.

FDA has been the Gold Standard?  Do these data meet that standard?

The FDA Summary states: The comparator is too dissimilar to the treatment group.  There is no reliable information on tumor response rate.  Therefore, the submitted study cannot be considered an adequate and well-controlled trial necessary to establish effectiveness. That’s the standard that the law requires for FDA approval.

On the other hand, there is an unmet need. These children need treatment.  Should FDA be flexible even though the data are clearly inadequate?  Why isn’t this an accelerated approval application instead of a regular application? Are the data even good enough for accelerated approval?

Are FDA Decisions Perpetuating Poor Studies?

Why didn’t the sponsor conduct a randomized, double blind controlled trial?  This isn’t a rhetorical question.  What’s the incentive for any company to conduct a well-designed study if a poorly conducted study with questionable findings results in approval?  Those controversial decisions set a dangerous precedent.

Unfortunately, when FDA approves a drug based on inadequate data, all companies lose the incentive to conduct well-designed studies.  Not just the company whose product is approved, but all other companies as well.

Patients Deserve Better

We do patients and their families no favors by approving treatments that aren’t proven to work. 

FDA’s Expanded access program is the way to give patients access to experimental drugs, because it provides free treatments in a well monitored situation where the patients and families know that they are taking a risk using an experimental drug.  Why should patients pay to take an experimental drug, thinking it is proven safe because it is FDA approved?

I can’t believe I have to say this: Without an appropriate control group, it is not possible to provide evidence that patients and doctors need to make informed decisions.  Even a small study with a small well matched control group is better than nothing.

Unfortunately, the preponderance of evidence doesn’t support approval for this drug.

The Advisory Committee agreed with our assessment and voted 16-0 that the studies did not prove the drug improved overall survival. The FDA subsequently rejected the application.

NCHR Testimony at FDA Advisory Panel on Wound Dressings

Policy, Testimony & Briefings

October 26, 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. So I have no conflicts of interest. 

My expertise is based on post-doctoral training in epidemiology and public health, my previous policy positions at Congressional Committees with oversight over FDA, my previous position at the U.S. Department of Health and Human Services, and as a faculty member and researcher at Harvard and Yale. 

There are unique issues for the different types of wound dressings you are considering today, but they have some issues in common:

  1. They have been treated as 510k devices despite not being categorized as Class II or any other Class
  2. They have been used for years but FDA found very few studies pertaining to safety or effectiveness, and some were specific to particular types of surgery, such as diabetic foot ulcer care.  
  3. The information from FDA’s AEs reporting on the MDR system is  limited but the FDA has identified several potentially serious AEs, including toxicity, infections, and delays in wound healing.  These are important because they clearly can interfere with the success of surgery. 
  4. Most patients and surgeons assume that these products are proven safe and effective.  They would be surprised to know how little scientific evidence there is regarding safety and effectiveness.

You heard testimony from Madris Kinard from Device Events this morning, and saw her excellent analyses of adverse events based on information from the FDA database.  At our request, she also provided an analysis of wound dressings to our research center, based on the FDA total product life cycle database.  The results indicated thousands of reports of contamination and problems with non-sterile packaging of wound devices on the FDA.  Most were from the last 4 years. For the animal derived wound dressings, which are collagen dressings, there are 126 MDRs and 12 recalls.

FDA and other experts agree that MDRs are under-reported. It is a voluntary system, and as panel members mentioned this morning, it is difficult to distinguish between adverse events caused by the device vs. the procedure.  We all know that surgeons are very busy and do not strong incentives to report adverse events if the causes are unclear.  Keep in mind, for example, if a patient’s wound becomes infected, surgeons would not necessarily report it as an MDR for the wound dressing.

The FDA has delineated some very clear special controls for these devices if they are considered Class II and continue to be cleared through the 510k process.  These are good efforts that would improve upon the current regulatory policies for these devices.

But the special controls have 2 major shortcomings:

#1: They don’t include inspections, which could reduce harm caused by contamination and non-sterile packaging.

#2:  None of those controls will provide scientific data on the safety and effectiveness of any of these wound dressing products.   And that is the one crucial type of information that is missing. Insufficient information is currently available, especially regarding which specific products are safest and most effective for which indications.  The issue isn’t just different types of wound dressings, but the products made by different companies.  It is likely that some are better than others.  That is why I encourage you to urge the FDA to categorize wound dressings as Class III, so that we will finally have well designed clinical trials to determine safety and effectiveness. 

What about registries?  Registries can collect important information.  But as you consider all the medical devices being discussed today and tomorrow,  please remember that registries are controlled by medical societies and as such the data from them are not available to the public or the FDA, except for the information that those medical societies choose to make public.  So unfortunately, we can’t rely on registries to provide objective, comprehensive information about safety or effectiveness to the FDA or the public.

Comment of the National Center for Health Research Submitted to the EPA on the Designation of PFOA and PFOS as CERCLA Hazardous Substances, October 6, 2022

Legislation, Policy

October 6, 2022

The National Center for Health Research appreciates the opportunity to provide comments on the designation of PFOA and PFOS as CERCLA hazardous substances. We are a public health think tank that conducts research, scrutinizes research conducted by others, and determines how research findings can be used to improve health policies and explains what is known and not known about the risks and benefits of specific products, programs, and policies.

For several years, we have been actively engaged in the study of the impact of PFOA, PFOS, and other PFAS chemicals on human health. There is clear evidence that these chemicals can disrupt the endocrine system in humans even at low levels.  Exposure can exacerbate such common conditions as obesity, early puberty, attention disorders, and eventually cause cancer.  We are therefore writing in strong support of the designation of PFOA and PFOS as CERCLA hazardous substances. This is an important first step because it holds companies accountable for these toxic substances, which in turn will improve public health.

Unfortunately, detailed information is lacking on most of the thousands of compounds that comprise PFAS.  Since it is unlikely that EPA can compile comprehensive toxicity data on all members of this class of chemicals, EPA should make it an urgent priority to work with independent researchers and other federal agencies to develop a common definition of PFAS, and ensure that researchers and regulatory agencies assess and restrict these chemicals as a class. PFAS classes should be determined based on exposure data, chemicals that are located or utilized together, and other parameters such as structure. Known hazards in well-studied compounds should be assumed to extrapolate to similar compounds that lack good data, until research is conducted to fill those data gaps.

In conclusion, the National Center for Health Research agrees that the designation of PFOA and PFOS as CERCLA hazardous substances is consistent with the clear evidence that these chemicals disrupt the endocrine system, accumulate in the environment and in the human body, and can cause serious health problems for humans and other animals.  Since there are thousands of other chemicals with similar structures that are not yet regulated, despite the assumption that they can cause similar harm, we strongly urge the EPA to regulate PFAS as a class of chemicals for the protection of public health and our environment.

For additional information about our work in this area, contact info@center4research.org.

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

Testimony & Briefings, ,

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

General Treatment Issues, Testimony & Briefings

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

Other Cancers, Testimony & Briefings, Treatment & Management

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.

The FDA followed through and rescinded Pepaxto approval in December, 2022.

Joint Letter to Support FDA Proposed Rule Reducing Nicotine Levels in Cigarettes

Legislation, Policy, ,

September 12, 2022

Dr. Robert Califf
Commissioner
U.S. Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993

Re: Nicotine Standard

Dear Dr. Califf:

The undersigned public health, medical and professional organizations write in strong support of your recent announcement that FDA will issue a proposed rule to reduce the nicotine level in cigarettes to non-addictive or minimally addictive levels. Such a standard would generate massive public health benefits, preventing millions of young people from smoking and dramatically reducing the number of people who die from tobacco-caused diseases. We urge you to move forward with this proposal as quickly as possible.

Despite great progress in curbing smoking prevalence in recent years, tobacco use – primarily smoking – remains the leading cause of preventable death and disease in the United States, killing more than 480,000 Americans every year.1 Sixteen million Americans are currently living with a tobacco-caused disease.2 Over 30 million Americans currently smoke, and every day over 1,600 kids try their first cigarette.3 Approximately half of people who smoke will die prematurely as a result of their addiction, losing at least a decade of life on average compared to those who do not smoke.4

We applaud the Administration for taking action to reduce tobacco use as part of its Cancer Moonshot initiative.5 Cigarette smoking causes about 30 percent of all cancer deaths in the U.S.6 Reductions in tobacco use have already had an impact on cancer rates. According to CDC, 60 percent of the decrease in cancer death rates among men and 40 percent of the decrease among women from their peak in 1990 to 1991 until 2014 were due to declines in tobacco-related cancer deaths.7 More progress can be made and reducing nicotine levels will have a profound impact.

Nicotine is the primary addictive agent in cigarettes and other tobacco products. According to the U.S. Surgeon General, “the addiction caused by the nicotine in tobacco smoke is critical in the transition of smokers from experimentation to sustained smoking and, subsequently, in the maintenance of smoking for the majority of smokers who want to quit.”8 Thus, reducing the nicotine content in cigarettes to non-addictive or minimally addictive levels will prevent experimentation by the young from becoming a lifetime of addiction and tobacco-caused disease. It also will reduce the level of nicotine dependence in adults who smoke, making it easier for them to quit.

Current evidence establishes the potentially historic lifesaving impact of reducing nicotine content in cigarettes to non-addictive or minimally addictive levels. As you know, FDA estimated in 2018 that approximately 5 million additional adults who smoke could quit smoking within one year of implementation and, by the year 2100, more than 33 million people – mostly youth and young adults – would have avoided becoming regular smokers. Smoking rates could drop to as low as 1.4 percent, resulting in more than 8 million fewer tobacco-caused deaths through the end of the century.9 The dimensions of this public health benefit make timely implementation of this policy a moral imperative.

Reducing nicotine levels in cigarettes to achieve these enormous public health gains is technologically feasible. As FDA noted in its earlier Advance Notice of Proposed Rulemaking (ANPRM), there are a wide range of available technologies to reduce nicotine in cigarettes, including “through tobacco blending and cross-breeding plants, genetic engineering, and chemical extraction.”10 Indeed, the tobacco industry’s own documents show that the industry has a long history of manipulating nicotine levels in cigarettes to make them more addictive. As U.S. District Court Judge Gladys Kessler determined in her landmark opinion finding that the major cigarette companies had violated the federal anti-racketeering statute, “Defendants have designed their cigarettes to precisely control nicotine delivery levels and provide doses of nicotine sufficient to create and sustain addiction.”11 Surely the companies cannot now credibly maintain that they are unable to reduce nicotine levels to no longer sustain addiction. In addition, FDA has noted that recent scientific studies do not support concerns that nicotine reduction would cause people who smoke to compensate by increasing the number of cigarettes smoked or inhaling more deeply to increase nicotine intake. Studies of very low nicotine cigarettes have not found evidence of compensatory smoking but have found demonstrable reductions in cigarettes smoked per day and in exposure to harmful smoking constituents.12

To realize the full potential public health benefits of a nicotine product standard, FDA must extend that standard beyond cigarettes, to other combustible tobacco products. Exempting other combustible products would invite tobacco manufacturers to market existing, or develop new, non-cigarette substitutes, like the small, flavored cigars the industry introduced after flavored cigarettes (except menthol) were removed from the market. It also would make the exempted products a potential vehicle for youth initiation. Thus, we urge FDA to make any nicotine reduction product standard applicable to other combustible tobacco products.

Reducing nicotine in cigarettes and other combusted tobacco products will complement FDA’s proposed rules to prohibit menthol cigarettes and flavored cigars. By addressing flavors and nicotine levels, FDA will be able to target both what attracts youth to these products and what addicts them. FDA should continue its work to promptly finalize and implement the menthol cigarette and flavored cigar proposed rules. Moreover, FDA should continue to address high rates of e-cigarette use by youth by promptly completing statutorily required premarket reviews and removing from the market those products that are not “appropriate for the protection of the public health.”

Reducing the nicotine content in cigarettes and other combustible tobacco products will dramatically reduce addiction, disease, and premature death from tobacco. We applaud FDA for setting forth a bold plan to protect kids and public health and urge the agency to act quickly to complete the rulemaking process. Every day that passes means more kids moving from experimentation to addiction and more adults who want to quit, and try to quit, but remain addicted to a lethal product.

Respectfully submitted,

AASA, The School Superintendents Association
Academy of General Dentistry
Action on Smoking and Health
Allergy & Asthma Network
Alpha-1 Foundation
American Academy of Family Physicians
American Academy of Oral and Maxillofacial Pathology
American Association for Cancer Research
American Association for Dental, Oral, and Craniofacial Research
American Association for Respiratory Care
American Cancer Society Cancer Action Network
American College of Cardiology
American College of Physicians
American Dental Association
American Heart Association
American Public Health Association
American Society of Addiction Medicine
Americans for Nonsmokers’ Rights
Association for Clinical Oncology
Association for the Treatment of Tobacco Use & Dependence
Association of Black Cardiologists
Association of State and Territorial Health Officials
Asthma and Allergy Foundation of America
Campaign for Tobacco-Free Kids
Cancer Prevention and Treatment Fund
Catholic Health Association of the United States
Center For Black Equity
Children’s Health Fund
Commissioned Officers Association of the USPHS
Common Sense Media
Community Anti-Drug Coalitions of America (CADCA)
COPD Foundation
Counter Tools
Dana-Farber Cancer Institute
Emphysema Foundation of America
Family, Career and Community Leaders of America (FCCLA)
First Focus on Children
GLMA: Health Professionals Advancing
LGBTQ+ Equality
GO2 Foundation for Lung Cancer
HealthHIV
International Association for the Study of Lung Cancer
Kaiser Permanente
March of Dimes
National Alliance to Advance Adolescent Health
National Association of Hispanic Nurses
National Association of Pediatric Nurse Practitioners
National Association of School Nurses
National Association of Secondary School Principals
National Black Church Initiative
National Black Nurses Association
National Education Association
National Hispanic Medical Association
National LGBT Cancer Network
National Medical Association
National Native Network
National Network of Public Health Institutes
National Tongan American Society
North American Quitline Consortium
Oncology Nursing Society
Parents Against Vaping e-cigarettes (PAVe)
Preventing Tobacco Addiction
Foundation/Tobacco 21
Preventive Cardiovascular Nurses Association
Respiratory Health Association
SADD
Society for Cardiovascular Angiography & Interventions
The Center for Black Health and Equity
The Society for State Leaders of Health
and Physical Education
The Society of Thoracic Surgeons
Trust for America’s Health
Truth Initiative
US COPD Coalition

CC: Dr. Brian King, Director of the Center for Tobacco Products

1. HHS, The Health Consequences of Smoking – 50 Years of Progress: A Report of the Surgeon General, 2014 (2014 SG Report).
2. Id.
3. CDC, “Tobacco Product Use Among Adults—United States, 2020,” MMWR Morb Mortal Wkly Rep
2022;71:397–405, March 18, 2022, https://www.cdc.gov/mmwr/volumes/71/wr/mm7111a1.htms_cid=mm7111a1_w. Substance Abuse and Mental Health Services Administration (SAMHSA), HHS, Results from the 2019 National Survey on Drug Use and Health, NSDUH: Detailed Tables, Table 4.9A https://www.samhsa.gov/data/report/2019-nsduh-detailed-tables
4. 2014 SG Report
5. The White House, “President Biden Reignites Cancer Moonshot to End Cancer as We Know It,” Fact Sheet. February, 2, 2022, https://www.whitehouse.gov/briefing-room/statements-releases/2022/02/02/fact-sheet-president-
biden-reignites-cancer-moonshot-to-end-cancer-as-we-know-it/
6. American Cancer Society. Cancer Facts & Figures 2022. Atlanta: American Cancer Society, 2022.
https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2022.html
7. CDC, “Vital Signs: Disparities in Tobacco-Related Cancer Incidence and Mortality—United States, 2004-2013,” MMWR 65(44): 1212-1218, https://www.cdc.gov/mmwr/volumes/65/wr/pdfs/mm6544a3.pdf/.
8. 2014 SG Report.
9. Apelberg, BJ, et al., “Potential Public Health Effects of Reducing Nicotine Levels in Cigarettes in the United States,” New England Journal of Medicine, published online March 15, 2018. See also, “Tobacco Product Standard for Nicotine Level of Combusted Cigarettes,” Advance Notice of Proposed Rulemaking, 83 Fed. Reg. 11818, 11820 (March 16, 2018)(ANPRM)
10. ANPRM, at 11820.
11. U.S. v. Philip Morris, Inc., 449 F.Supp. 2d, 1, 309 (D.D.C. 2006), aff’d in relevant part. 566 F.3d 1095 (D.C. Cir.2009).
12. ANPRM, at 11820.

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

Policy, Testimony & Briefings, Uncategorized

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

    Testimony & Briefings

    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?

    Draft Senate Contact Letter for Patients Supporting User Fee legislation With Policy Riders

    Legislation, Policy

    [Date]

    Dear [Name of Senator],

    I am writing on behalf of myself as a cancer [patient/advocate] and constituent of the state of [add State] to convey my strong opposition to efforts to strip user fee legislation of important public health protections in favor of a “clean” user fee bill. I urge that as you work to reconcile these bills, you address urgent public health challenges by maintaining critical protections in the FDA Safety and Landmark Advancements Act (FDASLA), S. 4348.

    This legislation must include provisions that will help ensure the safety and efficacy of cancer drugs, as well as accuracy and reliability for cancer-related diagnostic tests. Accelerated approval reform is necessary to protect patients such as [myself/ my relative/other] from harmful and possibly ineffective treatments. Reform to diagnostic tests will provide the FDA with the authority and resources necessary to ensure that the highest-risk diagnostic tests are valid and reliable. Increasing numbers of patients make life-altering decisions based on diagnostic tests, which can be used to predict cancer or fetal abnormalities.

    We urge you not to forgo this key opportunity to advance long-awaited solutions for the American public. While some provisions could be strengthened still further from the Senate version, we express our continued support for the meaningful reforms contained in the bill, and hope that Congressional and committee leadership remain committed to negotiating these protections as you advance this important legislation.

    Thank you,

    [Name]

    [Affiliation if applicable]