Tag Archives: clinical trials

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.

Congressman calls for FDA to continue vaccine trials

D’Andre Henderson, ABC News: December 29, 2020.


WASHINGTON, D.C. (WRIC) — Americans are hopeful that the COVID-19 vaccines will make 2021 a better year than 2020. However, there are concerns that Pfizer and Moderna will stop their clinical trials and immediately treat everyone in their placebo group.

Some scientists, doctors and now a Congressman argues that can be dangerous because they said there is still so much unknown about the vaccines.

Rep. Llyod Doggett of Texas wrote a letter to the Food and Drug Administration (FDA) urging for the clinical trials to continue.

“the continuation of clinical trials is critical to our understanding of the efficacy and length of immunity the vaccines offer,” Doggett wrote.

In the letter, Doggett said while the initial results received from Pfizer and Moderna are showing positive results, it’s not definitive given the limited data.

[…]

“Clinical trials have suffered from a lack of diverse participant enrollment and evaluation of subpopulations,” Doggett said. “Including individuals with comorbidities, children, pregnant and breastfeeding patients, long-term care residents and individuals with diverse racial and ethnic backgrounds.”

Diana Zuckerman, President of the National Center for Health Research, a non-partisan think tank in Washington D.C., agrees that the clinical trials should continue. She said healthcare workers who volunteered for the clinical trials should have immediate access to the vaccine if they want it.

“Like most public health experts, I’ve been very concerned that Pfizer and Moderna told the FDA that they want to stop their clinical trials of the COVID vaccine and instead immediately inoculate everyone in their placebo groups,” Zuckerman said. “While I understand the desire to reward the clinical trial volunteers for their service, it would be a huge loss of information from a public health point of view. Losing the placebo group means we’d have no way to scientifically determine which of the vaccines – if any — have 95% efficacy rates that last more than 2 or 3 months. Or how long the vaccine works on people over 75.”

Zuckerman added the people who volunteer for the clinical trials shouldn’t be vaccinated before those in priority groups such as teachers, essential workers, etc.

“Since many of the study volunteers are young and healthy, it also seems unfair for them to “cut in line” for a vaccine while healthcare workers and others at high risk are still waiting their turn,” she said.

[…]

Read the full article here

How the Coronavirus Pandemic May Affect Cancer Clinical Trials

Agata Boxe, Cancer Therapy Advisor: September 23, 2020


The health risks posed by SARS-CoV-2 to cancer patients have spurred changes in how cancer clinical trials are being conducted. Some of the alterations introduced by the National Cancer Institute (NCI) include using telemedicine visits, switching to electronic signatures for signing patient consent forms, shipping of oral medications to patients, and allowing researchers to skip collecting certain data. While the modifications may help to expand access to trials and lead to greater economic and geographic diversity of trial populations, they may also limit the amount of key information about the patient experience. Meanwhile, the pandemic itself may dissuade some groups of patients from enrolling in new trials altogether, thus negatively impacting the make-up of trial populations.

Like all other experts interviewed for this story, Hala Borno, MD, assistant clinical professor in the genitourinary oncology program at the University of California, San Francisco, was in favor of the changes that improved patient access to trials, such as the greater use of telemedicine. “In the context of a pandemic, there’s an opportunity to rethink the burdens that we place on patients and an opportunity to redesign the way in which we deliver cancer treatment in the context of the clinical trial,” Dr Borno said.

Dr Borno’s previous research showed that access to clinical trials was particularly challenging for disadvantaged social groups. Her 2018 study found that patients from lower‐income areas had to travel longer distances compared with patients from higher‐income areas to participate in cancer clinical trials. “What I observed is that patients coming from low-income neighborhoods are shouldering the largest burden of travel in order to participate in clinical research,” she said.

But the new measures may also lead to missing key information that is normally recorded during trials when they are conducted in person. Diana Zuckerman, PhD, president of the National Center for Health Research in Washington, D.C., noted potential complications with capturing the patient experience via videoconferencing compared to in-person visits. For example, it might be more difficult for researchers to notice potentially concerning symptoms that would otherwise be easy to see. “For example, if, as a doctor or researcher, I’m meeting with a patient in person, I might notice that they’re slumping in their chair or they look pale or they seem uncomfortable,” she said. “I might notice a lot of things about them that won’t necessarily be so obvious in a telehealth visit.”

Problems like bad lighting in a patient’s home may contribute to visibility issues. Children bursting into the room or a dog jumping on a patient’s lap may distract the patient from the purpose of the virtual visit. Finally, Dr Zuckerman wondered whether patients might not be as candid during online appointments as they would be during face-to-face visits about how they really feel while receiving treatment.

Jonathan Kimmelman, PhD, a professor and director of the biomedical ethics unit at McGill University in Montreal, said he wondered whether the decreased frequency of in-person interactions between patients and investigators might affect detection of adverse events.

[…]

Read the full article here

NCHR’s Public Comments on FDA’s Proposed Inclusion of Older Adults in Cancer Clinical Trials

May 4, 2020


National Center for Health Research’s Public Comments on FDA’s Proposed Inclusion of Older Adults in Cancer Clinical Trials Guidance for Industry

[FDA-2019-D-5572-0002]

We are writing to express our views on the FDA Draft Guidance on Older Adults in Cancer Clinical Trials. The National Center for Health Research (NCHR) is a nonprofit think tank that conducts, analyzes, and scrutinizes research, policies, and programs on a range of issues related to health and safety. We do not accept funding from companies that make products that are the subject of our work.

We have long urged the FDA to require older adults in clinical trials of drugs for the treatment of cancer and other diseases that are likely to be used by people over 65. When our Center’s president served on CMS’ Medicare Evidence Development & Coverage Advisory Committee (MEDCAC), she pointed out at every meeting that there were few if any patients over 65 who had been tested in clinical trials for the drugs and devices that were seeking to be covered by Medicare. As a result, it was impossible for the MEDCAC members to determine if the likely benefits outweighed the risks of any of those products, including cancer diagnostic tests and treatments.

We strongly support FDA’s efforts to improve the diversity of clinical trials and analyses of demographic subgroups, but have been disappointed that these efforts have not been enforced in a meaningful way. Subgroup analyses of safety and efficacy are essential for new drugs and devices so that patients and clinicians can make informed treatment decisions. New medical products should only be approved for populations for which there has been sufficient testing to determine that the benefits outweigh the risks. This is of particular importance for older adults in cancer trials. Moreover, if the FDA refused to approve cancer drugs for patients over 65 or over 70 when those age groups were not adequately studied, it would provide a substantial incentive for sponsors to be more vigilant about recruiting and studying patients in older age groups.

As stated in the guidance, it is not sufficient to only study the safety and efficacy of treatments among younger adults and assume that the results would be the same for older adults as well. We also strongly support the recommendation to evaluate smaller, discrete age groups (such as ages 65-74 and 75 and up), as well as the recommendation to collect additional safety measures for older adults, such as cognitive functioning. However, there are additional aspects of subgroup analysis that must be taken into consideration.

Subgroup analysis must determine the unique benefit to risk ratio for each subgroup, rather than determine whether the benefits of a treatment differ between younger and older patients. Older adults are more likely to have comorbidities that can affect how drugs are absorbed, metabolized, or eliminated, which may impact the safety and efficacy of a particular treatment. Therefore, there must be an assessment of the unique risks and benefits for older adults. It is not important to know that a medical product is more or less safe or effective for older patients compared to younger patients; what matters to older patients is whether the benefits outweigh the risks for patients in their age group.

In addition, it is not necessary that the proportion of older patients studied is consistent with the proportion of older patients with the particular type of cancer. What matters is that there be sufficient numbers of older adults so that subgroup analyses can be conducted to assess the benefits and risks of treatment for patients in several older age groups. Subgroup analyses are not meaningful if the numbers of older patients in the trials are small.

Since older adults are likely to be more frail and to have other serious comorbidities, it is imperative to determine the adverse effects and the efficacy of new drugs for older adults prior to FDA approval. All too frequently, post-market research, even if required, is delayed, follow-up is inadequate, or for other reasons the results are not as informative as had been expected.

The National Center for Health Research can be reached at info@center4research.org or at (202) 223-4000.

 

Everything is designed for men, even drugs

Producers Kim Mas and Ranjani Chakraborty, Vox: January 16, 2020


This short video explains why designing medicine around the “average man” is so dangerous. Most things in society are built for, and designed around, a specific “reference man.” This “standard human” is usually a white male in his 30s who weighs around 155 pounds. When we design everything from cars, to air-conditioned offices, to city streets, reference man is the default user. And when it comes to healthcare, that can mean deadly effects for women.  Watch the video above to find out how dosages are determined with “reference man” in mind. After dozens of women got into car accidents under the influence of sleeping pills they’d taken the night before, the FDA had to tell women to cut their dose in half; it turned out, women metabolize Ambien’s active ingredient twice as slowly as men. What was supposed to be a “gender-neutral” dose was anything but. Diana Zuckerman, president of the National Center for Health Research, explains why we need more inclusivity in clinical trials — for women, for people over 65, and for people of color.

https://www.youtube.com/watch?v=CVdn-2KE2bs

NCHR Comments on FDA’s Draft Guidance on Enhancing the Diversity of Clinical Trial Populations

National Center for Health Research; August 6, 2019


National Center for Health Research’s Public Comments on
Enhancing the Diversity of Clinical Trial Populations-Eligibility Criteria,
Enrollment Practices, and Trial Designs; Draft Guidance for Industry; Availability
[FDA-2019-D-1264]

Thank you for the opportunity to express our views on the critical issue of increasing diversity in clinical trials, and how FDA should be addressing this longstanding issue through guidance to its Centers and broadening clinical trial eligibility requirements.

The National Center for Health Research (NCHR) is a non-profit think tank that conducts, analyzes, and scrutinizes research, policies, and programs on a range of issues related to health and safety.  We do not accept funding from companies that make products that are the subject of our work, so we have no conflicts of interest.

For many years, NCHR has been strongly encouraging FDA to expand the diversity of clinical trials for drugs and medical devices to include more elderly patients, women, children, and individuals from a broad variety of racial and ethnic groups.  Too frequently, trials of drugs and devices which lead to FDA approval are still conducted mainly on white adults under the age of 65.  In some cases, treatments intended for men and women are primarily tested on one or the other, and not analyzed separately by sex.   In 2012, Congress passed a law urging the FDA to do a better job of expanding clinical trial participants to take into account the factors of age, race and ethnicity, and sexual differences.

There are reasons why a drug or device may be less safe or less effective for women, children, older patients, or certain ethnic or racial subgroups.  These differences in results for under-represented subgroups may not be minor or trivial.  According to a review of 167 new molecular entities approved by FDA between 2008 and 2013, approximately 20% had differences in exposure or response across racial or ethnic groups, or both.1

Lack of diversity in clinical trials has real world consequences on the knowledge about the effectiveness and safety of medical products.  Our research has identified several products that were less effective for certain subpopulations, which have important implications for clinicians and patients in choosing appropriate care.  In addition, the lack of age-related data has enormous consequences for Medicare, which is required to cover substantial costs for medical products that have not been studied on more than a few patients who were over 65.  Such lack of meaningful age-related testing results in the waste of many millions of taxpayer dollars on ineffective or even adverse medical outcomes.

In its proposed draft guidance, FDA has recognized the need to broaden eligibility criteria in order to increase diversity in enrollment.  However, there has not been sufficient incentive for drug and device sponsors to actively recruit more women, minority patients, children, and older patients.  In the past, FDA focused on the need for patient groups to encourage under-represented demographic groups to apply to clinical trials, rather than focusing on what companies should do to recruit under-represented patients to participate.  What is needed is an incentive for companies to ensure diversity, and the most effective incentive is if the FDA makes it clear that the agency will not approve medical products for all populations if the product was not tested for safety and efficacy on sufficient numbers of patients representing major demographic subgroups.

Certainly FDA’s draft guidance recommendation to make trial participation less burdensome for participants is a positive step, but that in itself will not result in the recruitment of a broader section of demographic subgroups who have been too often largely excluded in the past.  However, advising potential trial participants of possible reimbursement of travel and other trial expenses, as FDA’s draft guidance also recommended, may well help recruit older patients, parents of young children and caretakers of family members, and others who may otherwise lack the financial resources to enable them to participate in clinical trials.

We agree that measures to adopt enrollment and retention practices that enhance inclusiveness as outlined in the draft guidance should have a positive impact on the recruitment of broader demographic subgroups.  However, these should be “strongly encouraged” and not simply “considered.” The same is true for the recommendations for trial design and methodological approaches, which are also intended to broaden clinical trial participation.  The lack of meaningful incentives for sponsors to broaden clinical trial eligibility and recruitment has been a primary cause of why these various subgroups have remained under-represented for so long.

FDA issued a 1993 guidance for the inclusion of women trial participants in the clinical evaluation of drugs, and that situation has improved although more needs to be done in terms of using the data to restrict labeled indications when appropriate.  NCHR was critical of the 2014 FDA Action Plan for efforts to include more elderly patients in clinical trials as lacking in specificity.  This latest draft guidance is a chance for the agency to rectify these clearly identified and longstanding shortcomings.

The agency’s work with the Office of Minority Health, the HHS Office for Human Research Protections, and NIH, as well as the FDA Consumer page, indicates progress in improving enrollment diversity practices in clinical trials.  But our research indicates that much remains to be done.

We also point out that while this guidance pertains to CDER and CBER, diversity in clinical trials is also essential for medical devices, particularly implants.  Our research on devices approved through the PMA pathway following Advisory Committee consideration in 2014-2017 found numerous devices were tested primarily on white patients.2  For devices that included information about race, white participants made up 69%-99% of participants.  Most devices did not include information about the number of participants over the age of 65 years and many did not specify the range of ages of participants in trial(s).

In addition, of devices intended for both men and women, 45% (9/20) of devices were approved based on pivotal trials where less than 35% of participants were of the minority gender.  The implications of lack of diversity in clinical trials for high-risk medical devices are important.  For example, Lutonix, a drug-coated balloon catheter used to open a blocked artery, was found to be beneficial for men but not women; women’s outcomes were better with of the control balloon catheters.  A colorectal cancer test, Epi proColon, was, even though it was less accurate for patients older than 69 years of age than for patients less than 60 years old.  It was also found to be less accurate for black patients compared to white.

Thank you for the opportunity to comment on this important medical and patient issue.

National Center for Health Research can be reached at info@center4research.org or at (202) 223-4000.

References

  1. Ramamoorthy A, Pacnowski MA, Bull J, Zhang L. Racial/ethnic differences in drug disposition and response: Review of recently-approved drugs. Clinical Pharmacology & Therapeutics. 2015;97(3):263-273. https://www.ncbi.nlm.nih.gov/pubmed/25669658
  1. Fox-Rawlings SF, Gottschalk L, Doamekpor LA, Zuckerman D. Diversity in Medical Device Clinical Trials: Do We Know What Works for Which Patients? Milbank Quarterly.2018;96(3):499-529. https://onlinelibrary.wiley.com/doi/abs/10.1111/1468-0009.12344