Clinical trials. Which patients do we include?

We are moving towards a drug development approach patient focused. Can we offer new innovative therapies to severe patients and ethnic minorities?
Doctor Examining Child

Clinical studies are based on a sample population that must be able to represent as truthfully as possible the response of the population at large. The characteristics of a sample will never be perfectly identical to those of the population, so it is essential that the sample is carefully chosen and is actually representative of the population. It is known that different races and ethnic groups respond differently to certain drugs and develop diseases with variable frequencies. Asthma and cancer are two examples. So clinical trials have to include patients of all ethnic groups, proportionally to the frequency of the disease manifestation. Unfortunately, this still happens too few. In addition, the target population choose may influence the success completion of a study and so the fate of a molecule. Historically, novel agents have been introduced in patients with advance disease states; if trials were positive, approval was sought, while subsequent studies defined the role of the drug in less severe or earliest forms of the disease. Recently, this approach is changed.

Ethnic minorities

The NIH Revitalization Act in 1993 had established that the NIH-funded research should include ethnic minorities. Esteban G. Burchard, professor of therapeutic science and bioengineering at the University of San Francisco said that: «However, twenty-two years later, the proportion of racial/ethnic minorities participating in clinical trials is persistently low and still the exception, not the rule». Less than 2% of cancer clinical trials had as main focus the racial and ethnic minorities, as reported in a study conducted by researchers at Davis Comprehensive Cancer Center in California. The study analyzed 10,000 clinical trials sponsored by the National Cancer Institute in January 2013 and it revealed that less than 150 of these had as keywords “racial/ethnic minorities”. This does not mean that other studies may have considered the matter, but not as a main focus. «In other words – says the first author of the paper Moon S. Chen, associate director of the UC Davis Cancer Center – 98% were trials that focused on cancer type rather than trials in which the driving force was to assure appropriate and adequate representation of one or more minorities. The attention that has been placed over the years on gender differences must now be translated at this other field». The study also analyzed the proportion of minority pediatric patients enrolled in cancer clinical trials. In this case the children belonging to ethnic minorities are well represented in clinical trials with very encouraging data of nearly 60%. «The record participation of different population in these studies indicate that comparable records is achievable also in clinical trials for adults», said Chen.

Multiethnic studies and research

«Clinical trials conducted in different populations can help scientific research understand the biological basis of disease, and why a drug produce a higher response rate and higher toxicity in one group that in another» said Karen Kelly hematologist and Director associated with the UC Davis Cancer Center. An example is the treatment of lung cancer and the role of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. The molecular characterization of tumors from patients who receive treatment revealed that in tumors harboring EGFR mutations treatment with gefitinib is very effective and that the Asian population has a frequency of EGFR-mutant tumors much higher than other ethnic groups (in one of the various studies, the frequency in Japanese patients was 26% vs 1.6% in the US). These data suggest that ethnic and geographic differences play a role in cancer pathogenesis, emphasizing the importance of multiracial clinical trials. This observation led to the development of the IRESSA Pan-Asia Study trial, which demonstrated the benefit of gefitinib over that of standard doublet chemotherapy for patients with advanced lung cancers harboring EGFR mutation. Data from this study have revolutionized the disease management worldwide.

Moreover, the research area is strongly influenced by pharmacogenomics. One example concerns the pharmacogenetics of irinotecan, a drug for colon cancer, which showed also toxic effects. It has been shown that polymorphism in the promoter region of uridine diphosphate glucuronosyltransferase 1 family, polypeptide A128 (UGT1A1* 28) influence risk of developing grade 4 neutropenia after irinotecan therapy. The frequency of this mutation is higher in Caucasians (12%) compared to the Japanese (3%). Another fact to be considered is the frequency of diseases in different ethnic groups. It is estimated that the incidence of cancer will increase by 99% in the minority compared to 45% estimated for the population at large between 2010 and 2030. Information is less clear however when it comes from drugs because studies in this regard are still very scarce. According to Burchard: «Including diverse populations in biomedical and clinical research is a must, ethically and scientifically. The facilities that are dedicated to the research should be adapted for this purpose».

Barriers to overcome

«Many barriers keep studies that could characterize such disparities from being proposed, funded, carried out and published» said Burchard. First you need to create a network of doctors who have experience in managing and approaching different communities and coordinators who have knowledge of the languages. Also publishing results focused on ethnic differences is complicated. «Most of high impact journals require that an association is found in samples from two independent studies. This demand is straightforward in European populations, because many banked samples exist, but much harder to meet for other group», said Burchard, which goes further to suggest that instead: «Grant applications should be regarded more favorably. Proposal must be encouraged and investors should create partnerships with physicians and with representatives of minorities. Finally it should be encouraged the recruitment of doctors and researchers from ethnic minorities that may sensitize the whole sector on the topic».

Which patient should come first?

Defining the population to be studied is a key step, from which it can depend the successful completion of a study and so the fate of a molecule. Historically, new molecules were introduced in studies with patients with advanced disease stages and only subsequently it was defined the role of the drug in less severe disease forms or in important subgroups as well as chemoprevention. However, recent studies in cardiovascular medicine and oncology have questioned this approach: many new drugs now seek to establish the safety and efficacy in early disease settings. Changing the initial target population raises questions about what is the optimal protocol: in the shift to earlier stages of the disease better for patients? This recent trend has a biological rationale or comes from the desire of the sponsors to gain a greater market share? Should regulators require proof that a treatment works in advanced stages? Muthiah Vaduganathan of Harvard Medical School and Vinay Prasad of Johns Hopkins University tried to answer these questions through the columns of the prestigious journal JAMA. «In general, patients with advanced disease states have the higher risk of poor outcomes such as death or relapse, despite receiving available therapies», said Vaduganathan and Prasad. «In this high-risk population it is more likely to experience events of interest, diminishing the effects of competing risks». For example, in patients with NYHA class IV heart failure, cardiovascular factors are a leading cause of death, while other concurrent causes play a larger role in milder disease. Therefore, focusing on high-risk patients can increase the power of the study, allowing a faster ending of the protocols. «Reducing the time between the discovery of new drugs and their use in clinical practice is a clear advantage and a stated goal in drug development. Traditional programs follow a biologically consistent approach to validating drug targets. In heart failure, continue Vaduganathan and Prasad, increased neurohormonal activation in patients with NYHA class III and IV heart failure makes these patients an attractive target for the initial evaluation of new therapies».

Studies on large populations

What about the broad inclusion criteria? According Vaduganathan and Prasad: «Theoretically studies should acquire a wide range of profiles of patients. However, despite the best intentions, some groups may be underrepresented. “Sicker” patients may be more “challenging” to enroll, because they present more frequently concomitant diseases. It is not known if these complex patients with advanced illness would experience the same adverse effects as those with milder disease». In a study of neprilysin inhibitors in heart failure, low systolic blood pressure, which is typically more common symptoms in patients with NYHA class III and IV, was a major determinant of frequency of adverse events, including hypotension and renal insufficiency. Thus, even if these large studies support the safety of drugs in a general population of patients with heart failure, they fail to provide useful information on security in those most vulnerable. «From a pragmatic point of view, continue the authors, the programs of drug development conducted in large populations are less able to prioritize patients that should start treatment earlier. If provided regardless of risk, expensive new first-in-class molecule can overwhelm health budgets. In the current financial environment, emerging clinical trials should consider selecting the groups at higher risk to guide a cost-effective and practical approach to the use of medication».

Ultimately, new drugs that reach the market are to be tested in groups which reflect closely the population of the real world in general and important high-risk subgroups. The recent changes in the protocol of the FDA require developers to increase the inclusion in studies of patients with severe multiple co-morbidities. «If the current trend continues – say Vaduganathan and Prasad – measures must be taken to ensure that the studies provide information on safety and effectiveness in the sickest patients. In addition to a comprehensive analysis of power, recruitment targets should be established for important high risk subgroups. Similarly, before stopping a trial early secondary to the benefit of a drug, a sufficient number of patients with advanced disease should be exposed to the drug. Robust programs are required to provide adequate safety data to justify exposure of patients with early-stage disease to the study drug».


Chen MS Jr, Lara PN, Dang JH, Paterniti DA, Kelly K. Twenty years post-NIH Revitalization Act: enhancing minority participation in clinical trials (EMPACT): laying the groundwork for improving minority clinical trial accrual: renewing the case for enhancing minority participation in cancer clinical trials. Cancer. 1 April 2014; 120 Suppl 7: 1091-6.

Burchard EG. Medical research: Missing patients. Nature. 2014 Sep 18; 513 (7518): 301-2.

Vaduganathan M, Prasad V. Modern drug development: which patients Should come first? JAMA. 2014 Dec 24-31; 312 (24): 2619-20.



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