FDA OFfice Of Minority Health

Clinical Trials Lack Diversity & Microbiome = Cancer Disparity Outcomes

Under representation of minority populations in clinical trials is a real problem, and it results in significant cancer outcome disparities for under represented groups (discussed at the bottom of this post).  What this means is that the findings of clinical trials are limited and can not necessarily be generalized among those minorities under represented or omitted in the study population.  Such subgroups are missing information on how they would respond to the trial’s treatment.  “Potential racial, ethnic and other differences in response to drugs are important to FDA’s efforts to help ensure that the safety and effectiveness of drugs are studied in all people who will use the products once they are approved.” Christine Merenda, M.P.H., R.N. , Office of Minority Health (OMH) project manager.

Well, it is time to take the issue of clinical trial participant selection as impacting medicine one step further and realize other factors dramatically impact in real time, the affects of metabolism and load of therapy that is not being teased out of the clinical trials.  As this study, Pharmaco-metabonomic phenotyping and personalized drug treatment notes:

There is a clear case for drug treatments to be selected according to the characteristics of an individual patient, in order to improve efficacy and reduce the number and severity of adverse drug reactions1, 2.  However, such personalization of drug treatments requires the ability to predict how different individuals will respond to a particular drug/dose combination.  After initial optimism, there is increasing recognition of the limitations of the pharmacogenomic approach, which does not take account of important environmental influences on drug absorption, distribution, metabolism and excretion3, 4, 5.  

For instance, a major factor underlying inter-individual variation in drug effects is variation in metabolic phenotype, which is influenced not only by genotype but also by environmental factors such as nutritional status, the gut microbiota, age, disease and the co- or pre-administration of other drugs6, 7. Thus, although genetic variation is clearly important, it seems unlikely that personalized drug therapy will be enabled for a wide range of major diseases using genomic knowledge alone. Here we describe an alternative and conceptually new ‘pharmaco-metabonomic approach to personalizing drug treatment, which uses a combination of pre-dose metabolite profiling and chemometrics to model and predict the responses of individual subjects. We provide proof-of-principle for this new approach, which is sensitive to both genetic and environmental influences, with a study of paracetamol (acetaminophen) administered to rats. We show pre-dose prediction of an aspect of the urinary drug metabolite profile and an association between pre-dose urinary composition and the extent of liver damage sustained after paracetamol administration.

Even if you don’t totally get the above, recognize the two fold effect of deficiencies in clinical trial design; that due to diversity and that due to microbiome metabolic profiling.  

The FDA has been sanctioned with addressing the problems with disparity in clinical trials and as noted in this article, “Clinical Trials Shed Light on Minority Health”:

“There are many benefits to minority participation for researchers that extend, in a larger sense, to society. Minority participation helps researchers find better treatments and better ways to fight such diseases as cancer, diabetes, heart disease and HIV/AIDS. In addition, it uncovers differences by gender, race, and ethnicity that may be important for safe and effective use of therapies.”

“Getting more data on these differences is essential for FDA to truly know that a medical product will truly work and be safe for all patients, Bull says.”

“Members of minority groups may be more vulnerable to certain diseases. “We know, for example, that African-Americans and Hispanics have higher rates of diabetes, HIV/AIDS, obesity and cardiovascular disease,” says Bull. Native Americans and Asians have been shown to have higher rates of hepatitis, while Hispanics are disproportionately affected by diabetes.”

“But historically, both women and minorities have been under-represented in clinical trials. For example, according to a 2011 report from the conference “Dialogues on Diversifying Clinical Trials,” sponsored by FDA’s Office of Women’ s Health and the Society for Women’s Health Research and supported by OMH:

African Americans represent 12% of the U.S. population but only 5% of clinical trial participants;

Hispanics make up 16% of the population but only 1% of clinical trial participants; and

Men make up more than two-thirds of the participants in clinical tests of cardiovascular (heart and blood vessel) devices.”

Unfortunately, clinical trial design still needs to catch up and factor in the microbiome gut impact.  This review,  “Gut Pharmacomicrobiomics: the tip of an iceberg of complex interactions between drugs and gut-associated microbes” provides a glimpse into the known effects of the gut microbiota on xenobiotic metabolism, with emphasis on cases where microbiome variations lead to different therapeutic outcomes.  Included is impact of microbiome variations on drug response and toxicity, and the role of gut microbiota in the metabolism of conventional first line therapies and over-the-counter (OTC) drugs sometimes activating the drug whereas at other times, increasing toxicity or lowering the effect (see table below for acetaminophen, digoxin, sulindac, and several antibioitics and anti-fungals),  The authors also present several examples describing how the microbiome interacts with human metabolic enzymes in the liver and intestine, and they attempt to envisage a road-map for the future implications of the microbiome on therapeutics and personalized medicine (see below schematic).


The study,Diversity, stability and resilience of the human gut microbiota,” summarized how the microbiome community can change the metabolites (microbioata by-products) in such a manner so as to not have the same healthy benefits realized for soy foods:

“…differences in the microbiota and the microbiome may help explain interpersonal variations in gut metabolic processes, including metabolism of drugs and dietary substrates11,36. Because many of these metabolic pathways are outside the common functional core, they can underlie host-specific responses. For example, many health benefits of soy-rich diets, including positive outcomes for vasomotor symptoms, osteoporosis, prostate cancer, and cardiovascular disease, have been attributed to S-(-)equol produced from the soy isoflavone diadzein by bacterial rather than human enzymes37. Only 25–30% of the adult population of Western countries produce S-(-)equol when fed soy foods, compared to a 50–60% frequency in adults from Japan, Korea, or China38. Thus cancer-protective effects of soy described in Asian populations might not generalize to Westerners because of differences in key components of the microbiota.”

The Diversity, stability and resilience of the human gut microbiota,” study also summarized how the microbiota determines the toxicity for acetaminophen (Tylenol active ingredient):

“Similarly, gut microbiota indirectly determine whether acetaminophen will be metabolized to acetaminophen sulfate or acetaminophen glucuronide, potentially altering both efficacy and toxicity of this widely used analgesic36. Microbes mediate this metabolic phenotype by producing the compound p-cresol, which competes with acetaminophen for human enzymes catalyzing sulfonation36. Therefore, the results of drug trials conducted in one population (e.g. performed inexpensively in Africa or South Asia) may not generalize to a population that has a substantially different gut microbiota (e.g. Western populations). Understanding how the microbiota varies across the human population, and correlating this variability with specific microbial functions, is thus emerging as a component of personalized medicine.”

To appreciate the complex microbiome impact on drug metabolism, read the review, “Gut microbiome-host interactions in health and disease” which addressed the necessary metabolic pathways for the prescribed statin billion dollar global market):

“The effect of the gut microbiota on drug metabolism has been previously explored, and the metabolic pathway of several drugs, such as L-DOPA, sulfasalazine, digoxin and even glyceryl trinitrate, has been established in the gut [63]. However, metabonomic approaches are creating new insights into commonly prescribed drugs, such as simvastatin, that were not previously appreciated. This is the most commonly prescribed statin in a billion dollar global market. It serves as an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A, regulating hepatic cholesterol production. Simvastatin is degraded in the gut by hydrolytic cleavage of methylbutanoic acid from its backbone. Metabolism involves gut microbial processes of the demethylation of dimethylbutanoic acid, hydroxylation/dehydroxylation and β-oxidation, resulting in the production of 2-hydroxyisovaleric acid (3-methyl-2-hydroxybutanoic acid), 3-hydroxybutanoic acid and lactic acid (2-hydroxypropanoic acid), and finally re-cyclization of heptanoic acid to produce cyclohexanecarboxylic acid [64]. The implication is significant, as there may be much greater variability of statin drug metabolism between individuals than is currently appreciated, and this serves as an example for the need for better personalized approaches to drug development.”


Thus, clinical trial determined therapy that is based on under represented participant subgroups as well as no consideration of participant microbiome (diet variability arguably is the greatest influence of the gut microbiome although prior antibiotic use, and age are major players as well – see the post, “OPTIMAL MICROBIOME DIET FROM AMERICAN GUT DATA,”), seems to be significant considerations that are missing from clinical trial design.  These can dramatically have  deleterious impact as trial conclusions are generalized as suitable therapy for all patients.


One example of such is the disparity in breast cancer survival for US women of Hispanic origin who are  more likely to die from a breast cancer diagnosis even when their age, cancer stage, and tumor characteristics are similar.  This population is the largest growing minority group in the US, currently representing 17% of the US population and yet, they comprise only 5.6% of  National Cancer Institute treatment clinical trials  participants.

Two studies were presented at the November 9-12, 2014, 7th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved San Antonio, TX, that address the  disparity of Hispanic/Latino cancer outcome and clinician trial participation.

The study, “Culturally Sensitive, Computer-based Videos Increase Clinical Trial Awareness Among Latina Breast Cancer Patients,” presented by Patricia Chalela, DrPH, assistant professor of epidemiology and biostatistics at the Institute for Health Promotion Research, The University of Texas Health Science Center at San Antonio, reported that when Hispanic/Latino breast cancer patients are provided with information  beyond the usual which included a culturally sensitive, computer-based video on breast cancer clinical trials,  a tailored booklet on the topic, and receiving assistance from a patient navigator, there was an increase from 38 percent to 75 percent, in their taking steps towards participating in a clinical trial after receiving the information .  These additional steps increased  awareness of the clinical trial such as its purpose, enrollment requirements, and the risks, benefits, and potential as an appropriate treatment.  This seems an amazingly easy fix realizing that Latino women are incredibly underrepresented in National Cancer Institute treatment clinical trials where they represent only 5.6% of the participants  despite representing  17% of the US population.

Also presented this week was the study, “Family History of Breast or Ovarian Cancer is Linked to Triple-negative Breast Cancer in Women of Mexican Descent,” by Maria Elena Martinez, PhD, a professor at the University of California San Diego Moores Cancer Center in La Jolla.  Martinez reported that for 1,150 participants enrolled in their  Ella Binational Breast Cancer Study, when the participant reported having a first-degree relative with breast or ovarian cancer, they were almost twice as likely to have received a diagnosis of triple-negative breast cancer compared with another breast cancer subtype.  “Triple-negative breast cancer is one of the worst breast cancer subtypes in terms of outcomes,” said Maria Elena Martinez, PhD.   914 participants had information on breast tumor-subtype available.  This is one of the first studies to address the factors that might affect Hispanic/Latina women’s risk for breast cancer.  Other researchers have found a BRCA mutation to be higher among Hispanic/Latina compared to women of European descent and these studies are ongoing.

More information can be read at American Association for Cancer Research article, “Tackling Breast Cancer Health Disparities for Hispanics/Latinas.”

President Obama signed into law the 2012 Food and Drug Administration Safety and Innovation Act (FDASIA) in July 2012.  FDASIA was to  support efforts to enhance minority participation in clinical trials.  FDASIA required that FDA report to Congress by July 9, 2013 on the diversity of participants in clinical trials and the extent to which safety and effectiveness data based on such factors as sex, age, race and ethnicity are included in applications submitted to FDA.  FDA posted on August 22, 2014 the FDA Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data, which was mandated by Section 907 of the FDASIA, and opened a docket at Regulations.gov (Federal Register Number 2014-19881.  The FDA  docket solicited public comments on the action plan and was to plan additional opportunities for the members of the public to provide their input on various action items in the plan.”  The docket closed at 11:59 PM on October 21, 2014.  We will see what the final version of the FDA Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data looks like and time will tell how effective it will be.  There is an email address listed on the FDA FDASIA Section 907 webpage if you would like more information:  FDASIA907@fda.hhs.gov.

The overall five-year survival rate for female breast cancer patients in the United States is now 89 percent, compared with 63 percent in the early 1960s.  Lets achieve that across all minorities as well as figure out how to extend clinical trials to tease out microbiome impact on clinical therapy success.

In health through awareness,


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