Overcoming Diversity Obstacles: A Clinical Imperative

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Kim Ribbink and Denise Myshko

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22 Aug u s t 20 03 PharmaVOICE HE HUMAN GENOME PROJECT, research into responses to medicine, even the results of several clinical trials indicate that race and ethnicity do have bearing on the safety and efficacy of pharmaceuti cals. Consequently, it is critical that pharmaceutical companies, CROs, and inves tigators ensure that a diverse selection of patients are represented in clinical trials. Both the Food and Drug Administration and the National Institutes of Health in the mid1980s began to look at policies for inclu sion of women, and then minorities, in clini caltrial research. In 1997, the Food and Drug Administration Modernization Act (FDAMA) directed the FDA to examine issues related to the inclusion of racial and ethnic groups in clinical trials of new drugs. Furthermore, in January 2003, the FDA published a draft guidance recommending categories for collecting effectiveness and safe ty data during clinical trials for ethnic and racial demographic groups. If adopted, this would create a standard for classifying the var ious races. FDA recommends that drug man ufacturers use the categories for race and eth nicity established by the Office of Management and Budget during clinicaltrial The issue of disparity among different groups in clinical trial recruitment is glaring. This is a marketplace where the challenge is how a company can best market its medications. Everybody needs medications,and surely companies want everybody to buy their products. Sarah Harrison Overcoming Diversity Obstacles: A CLINICAL IMPERATIVE Traditional means of recruiting and retaining patients may not be enough to OVERCOMEAFRICANAMERICANS’HISTORICAL RESISTANCE TO PARTICIPATING IN CLINICALTRIALS.Pharmaceutical company sponsors, contract research organizations, investigators, and investigator sites have to WORKWITHCOMMUNITY LEADERS TOACTIVELY ADDRESSTHE SPECIFIC CONCERNS OFTHEAFRICANAMERICAN POPULATION and overcome barriers to advance medical outcomes. BY KIM RIBBINK AND DENISE MYSHKO T 23 PharmaVOICE Augu s t 200 3 DIVERSITY in clinical trials data collection to ensure consistency in evalu ating potential differences in drug response among racial and ethnic groups. “All studies have to collect data on racial make up,” says William Sietsema, VP of clin ical development at Kendle International Inc. “Reviewers will ask whether the racial break out in the trials differs much from the racial representation across the United States. If reviewers have reason to feel any particular race is underrepresented substantially, the FDA has a right to ask the sponsor to go back and do those studies. This could significantly delay the approval of the drug. Or the FDA could tentatively approve the drug with restricted labeling that indicates there is insuf ficient information on a particular race.” According to Edward F. Ikeguchi, M.D., chief medical officer and cofounder of Medidata 1 2 3 4 5 6 7 8 9 10 Cardiovascular disease Cancer Stroke Unintentional injuries Diabetes Homicide HIV/AIDS Chronic lower respiratory disease Nephritis, nephrotic syndrome,and nephrosis Influenza and pneumonia Leading Causes of Death for African Americans in the United States in 2000 Source:National Center for Health Statistics, 2002,Hyattsville, Md. For more information, visit cdc.gov/nchs. Solutions Inc., it is the responsibility of the pharmaceutical industry to know about disease disparity and incidence in diverse populations. “The degree to which a company puts a concentrated effort into studying a population depends on the risk/benefit ratio,” he says. “A company, however, doesn’t want to wind up in a situation where at the end of the research process, it finds out that there is indeed a dis parity in results in the drug profile from one racial group to another.” “Sponsors serious about recruiting patients from minority populations need to make a commitment to supporting the resources nec essary to make the recruitment initiative suc cessful,” says Thomas Schnitzer, M.D., Ph.D., chairman of RRI. Dr. Schnitzer also is a pro fessor of medicine at Northwestern University Feinberg School of Medicine. “This is not a If regulatory officials have reason to feel that any particular race is underrepresented substantially in a clinical trial, the FDA has a right to ask the sponsor to go back and do those studies. That could delay the approval of a drug. William Sietsema DIVERSITY in clinical trials 24 Aug u s t 20 03 PharmaVOICE matter of simply doing more radio ads or direct mail; recruiting patients from diverse populations is much more difficult than tradi tional recruiting. To be successful, sponsors need to develop longterm relationships with the referring groups, whether these groups are clinics, practices, or organizations.” To achieve success, sponsors will have to overcome serious obstacles. Participation by African Americans in clinical studies typically is lower than by Caucasians. According to a FDA review of new molecular entities approved between 1995 and 1999, 83% of clinicaltrial volunteers were white, 12% were black, and 3% were Hispanic. More recently, there have been several reports that have examined participation by different racial groups in studies being conducted for specific diseases. For example, a study published in the May 2002 issue of the New England Journal of Medicine revealed that AfricanAmerican and Hispanic HIV patients are only about half as likely as nonHispanic whites to participate in clinical trials of new HIV drugs. Together, African Americans and Hispanics comprise roughly 48% of HIV patients. And while there have been studies that specifically address the AfricanAmerican population — the most notable being the Jackson Heart Study, which is a singlesite prospective epidemiologic investigation of cardiovascular disease (CVD) among African Americans from the Jackson, Miss., metropolitan area — for the most part, African Americans remain underrepresented in clinical trials. Despite FDA and NIH initiatives, little has been done to enforce enrollment of diverse populations. ONEOFTHEMAJORBARRIERS FOR RECRUITING AND RETAINING AFRICAN AMERICANS IS ACCESSTO MEDICAL CARE. IN UNDERSERVED COMMUNITIES PATIENTS DON’T HAVE AS GREAT ANACCESSTO PHYSICIANS. Deborah Kniuksta TORECRUITAFRICANAMERICAN PATIENTS FORCLINICALTRIALS,WE NEEDTOGOBEYOND SIMPLY DOING MORERADIOADSORDIRECTMAIL.TO BE SUCCESSFUL, INVESTIGATOR SITES NEEDTODEVELOP LONGTERM RELATIONSHIPSWITH REFERRAL GROUPS,WHETHERTHESEARE CLINICS,PHYSICIAN PRACTICES,OR COMMUNITYBASEDORGANIZATIONS. Dr.Thomas Schnitzer PHARMACOMPANIESTEND TODO “ONESIZEFITSALL” CLINICALTRIALS,BUT NOW THERE IS GENETIC EVIDENCE THAT AFRICAN AMERICANS RESPONDDIFFERENTLYTO CERTAINTYPES OFCLINICAL PREPARATIONS. Dr. Michael Lenoir RECRUITMENT ADSHAVETO BE CULTURALLY APPROPRIATE. THE BEAUTY OFTHEMEDIANOW IS THATWECAN SEGMENTTO SPECIFICALLY REACHTHE AFRICANAMERICAN POPULATION,ORTHE KOREAN POPULATION,ORTHE CHINESE POPULATION. Liz Moench TWOKEYCOMPONENTSOF HEALTHCAREAREEDUCATIONAND ACCESS. IF INDIVIDUALS CAN’TGETTO THEDOCTOR,THEYDON’THAVETHE SAMEACCESSTOHEALTHCARE. I WOULD LIKETOSEEABROADER INTEGRATEDDEFINITIONOF HEALTHCARE,LOOKINGATHOWWE MANAGEHEALTHCAREASASOCIETY. Stedman Stevens 25 PharmaVOICE Augu s t 200 3 “The FDA isn’t enforcing any of the guidelines that it has been passing since the early 1990s,” says Brian Stone, M.D., chief medical officer of The Black Health Network. “When a company knows that nothing puni tive is going to happen, there really is no incentive for it to adhere to the guidelines especially if it requires additional effort.” AHISTORICAL BIAS There are vast historical and currentday reasons that African Americans resist partici pating in clinical trials. In the most welldoc umented case, the Tuskegee syphilis study, 400 illiterate or lowliteracy AfricanAmeri can male subjects in Alabama were systemati cally denied treatment by an agency of the U.S. government for more than 30 years. “When I was growing up in Alabama, I heard stories about experimentation on slaves, about bodies being removed from black grave yards for medical schools, the U.S. Health Department syphilis experiment, experimen tation on prisoners, the Willowbrook Hepati tis Experiment (in which uninfected mentally ill children were given viral hepatitis to study the course of the disease), and as recently as the 1970s, experimentation on MexicanAmeri can women who were given birthcontrol pills without their consent,” Dr. Stone says. The medical community must not only overcome past inequities and injustices but address current barriers that limit participation in clinical trials by diverse populations. A 2002 report, Unequal Treatment: Con fronting Racial and Ethnic Disparities in Health Care, conducted by the Board of Health Sciences Policy (HSP), Division of Health Sciences Poli cy (HSP), and Institute of Medicine (IOM) notes that minorities tend to receive lowerquality healthcare than whites do, even when insurance status, income, age, and severity of conditions are comparable. The sources of these disparities, according to the report, are complex and rooted in historical and contemporary inequities and involve many participants at several levels, including health systems, their administrative and bureaucratic processes, utilization man agers, healthcare professionals, and patients. The study committee focused part of its analysis on the clinical encounter itself and found evidence that stereotyping, biases, and uncertainty on the part of healthcare providers can all con tribute to unequal treatment. According to the report, the conditions in which many clinical encounters take place — characterized by hightime pressure, cognitive complexity, and pressures for cost containment — may enhance the likelihood that these pro cesses will result in care poorly matched to minority patients’ needs. Minorities may expe rience a range of other barriers to accessing care, even when insured at the same level as whites, including barriers of language, geogra phy, and cultural familiarity. Further, financial and institutional arrangements of health sys tems, as well as the legal, regulatory, and poli cy environment in which they operate, may have disparate and negative effects on minori ties’ ability to attain quality care. “Unfortunately, historic stereotyping, racial discrimination, and lack of experience in the multicultural marketplace are significant fac tors that have contributed to the omission and exclusion of racially and ethnically diverse seg ments in clinical trials,” says Sheila Thorne, president of Multicultural Healthcare Market ing Group LLC. Several studies over the past five years have tried to assess the attitudes of African Ameri cans toward medical research. Most recently, a Harris Interactive survey in June 2003 found that 86% of whites were more likely to consid er research participation compared with 70% of African Americans. Another report, published in the Nov. 25, 2002, issue of the Archives of Internal Medicine, contained results from a tele phone survey of 527 African American and 382 white respondents. The study found that African Americans (41.7%) were less likely than white respondents (23.4%) to trust that their physicians would fully explain research participation; and 45.5% of African Americans believed that their physicians exposed them to unnecessary risks compared with 34.8% of white respondents. The Unequal Treatment study concluded that a comprehensive, multilevel strategy is needed to eliminate disparities. Broad sectors — including healthcare providers, their patients, payers, healthplan purchasers, and society at large — should be made aware of the healthcare gap between racial and ethnic groups in the United States. Health systems should base decisions about resource allocation on pub lished clinical guidelines, ensure that physician financial incentives do not disproportionately burden or restrict minority patients’ access to care, and take other steps to improve access, including the provision of interpretation ser vices where community need exists. It is a business imperative that the industry embrace these suggestions to address the short fall in patient recruitment among multicultural populations. Results from several clinical trials have pointed to differences in the way people of different ethnic and racial backgrounds respond to medicine, making it critical from a scientific point of view that people from both sexes and all ethnic and racial backgrounds are included in a trial protocol. Furthermore, different population groups often referred to as minorities — African Americans, Hispanics, Asian Americans, and Native Americans, among others — now com prise the majority population in several cities and even states. By 2050, African Americans, Hispanics, and Asian Americans will comprise 50% of the U.S. population, according the U.S. Census Bureau 2001 report. BEHINDTHE SCIENCE African Americans and other minorities appear to respond differently to pharmaceutical products and are disproportionately susceptible to certain diseases than other patient popula tions. For example, antihypertensive agents such as angiotensin converting enzyme (ACE) inhibitors and betablockers are somewhat less effective in African Americans than in whites. At the same time, cardiovascular disease was the leading cause of death for African Ameri cans in the United States in 2000. Genetics may well play a role in how various populations metabolize certain drugs. Researchers are looking at the cytochromes P450 and, in particular, the enzymes 2C19 and 2D6 to assess response differences. 2D6, for example, is not present in some patient’s livers. Some people have mutations in one or more of the nucleic acids in the DNA sequence of a par ticular enzyme. As a result, the enzyme may be absent or have low, or no, metabolizing activity for drugs that are usually metabolized by that enzyme. In the United States, whites are more likely than people of African or Asian heritage to have low levels of 2D6, which metabolizes antidepressants, antipsychotics, and beta block DIVERSITY in clinical trials Results from several clinical trials have pointed to differences in the way people of different ethnic and racial backgrounds respond to medicine, making it critical from a scientific point of view that people from both sexes and all ethnic and racial backgrounds are included in a trial protocol. 26 Aug u s t 20 03 PharmaVOICE DIVERSITY in clinical trials ers. Additionally, among some of the drugs in the psychotherapeutic class, slower enzyme metabolism has been observed in people of Asian descent. Other studies have shown that African Americans have a lower response rate to several classes of antihypertensive agents (beta blockers and ACE inhibitors). About 3% to 5% of Caucasians and 20% of Asians and African Americans are poor metabo lizers of 2C19, which controls the metabolic process for such products as diazepam (Valium), phenytoin (Dilantin), and omeprazole (Prilosec). There are many complex factors that account for these differences, including diet, culture, and genetics, says Kenneth M. Borow, M.D., presi dent and CEO of Covalent Group Inc. “For example, AfricanAmerican subjects are at a much higher risk than Caucasians for the development of adverse consequences of hypertension, congestive heart failure, stroke, and chronic renal disease,” he says. “Some of this difference in incidence may be related to genetic differences in bioavailability of nitric oxide, an important mediator of endothelial function. It is important to study these disease states in African Americans to understand the pathophysiology and optimal treatment in this patient population. Another example of ethnic differences complicating treatment options is the nearly twice higher incidence of significant ASTRAZENECA HAS IDENTIFIED POPULATIONS THAT TYPICALLY HAVE BEEN UNDERSERVED IN CLINICAL RESEARCH AND DESCRIBES ITS THREEPART STRATEGY TO ATTRACTRESEARCHERS INTERESTED INTHESEAREASAND THE SUBMISSION OF INVESTIGATOR SPONSORED TRIAL (IST) PROTOCOLS INTHE NEXTTWOTOTHREEYEARS. The first area the company addressed was to identify “who” the underserved populations are. In a recent AstraZeneca A2Z report, the company reviewed the disparity in health services for certain racial or ethnic minority groups.The report summarized the findings document ed by the Institute of Medicine and other prestigious organizations, which were published in the Journal of the AmericanMedicalAssociation. AstraZeneca’s IST team took a firm stand to alter its thinking in this area and to focus on the healthcare needs of these underserved populations. In the same report, AstraZeneca outlined the percentage distribu tion of clinicaltrial participants within the U.S. population (see chart below).The data reveal that a substantial portion of the population is underserved and the health of these demographic populations will impact medical services and costs of healthcare in the United States. The populations identified,especially the senior group,are complex patients, typically being treated for several diseases simultaneously. These patients are underrepresented in registration trials based on the study design and exclusion criteria.The purpose of the registration tri als is to demonstrate efficacy and safety of drugs while controlling for other factors that may influence the results. Once the product is available in the market, its use expands to these more complexpatients coming into the healthcare system to treat multiple disease complaints.Managedcare companies have reported that of all their plan enrollees, about 20% are using the majority of services. AstraZeneca also addressed “why” research involving these popula tions should increase. Although it has been stated in news and print for several years, the increase in the proportion of these subpopulations will have an impact on consumer markets as the “voice”and demandsof these individuals will reach the “ears” of businesses. In retail markets, the focus on customization of messages and varia tions in product lines has been a wellestablished strategy for doing busi ness.The prediction from business research companies such as Tower Per rin is that healthcare will shift responsibility of medical care on to the consumer through cafeteriatype (multichoice) coverage. Two additional factors are, or will, change how healthcare is delivered. The first is the Internet. As a vehicle of information, the Internet provides access to global health data down to individual country reports of health benefits (i.e., low incidence of heart disease in France and Italy, longevity of life in Russia and China). This information can be easily accessed by UnderRepresented Populations — Targets for Research FEMALES UNDER 18YEARS HISPANIC OR LATINO 65YEARS OLD BLACK OR ASIAN OFAGE ANDOLDER AFRICAN AMERICAN 50.9% 25.7% 12.5% 12.4% 12.3% 3.6% Face of America — PopulationTrends Population Total — 281,421,906 Average percent of underrepresented populations — 19.6% Source:AstraZeneca,Wilmington,Del.,Nexium IST Team, June 2003.For more information, visit astrazeneca.com 27 PharmaVOICE Augu s t 200 3 obesity in black females compared with white females. If a drug is highly lipophilic, it may have very different bioavailability in obese sub jects compared with leaner subjects. The result may be the need for higher dosing requirements in the more obese patient population. This would be most appropriately delineated by actually studying the patient population at risk. Another justification for including African Americans in clinical research trials is to assess if regional geographic differences in standardof care and or diet, for example salt intake, impact clinicaltrial results.” In a report published in the New England Journal of Medicine, The Importance of Race and Ethnic Background in Biomedical Research and Clinical Practice, the authors note that gathering data on racial classification for use in medicine and biomedical research has given rise to debate. Some have suggested that racial classification may not be useful for biomedical studies, since it reflects a “fairly small number of genes that describe appearance” and “there is no basis in the genetic code for race.” The report’s authors note that excessive focus on racial ethnic differences runs the risk of under DIVERSITY in clinical trials patients in the United States, which is shifting the focus of the patientphysician interaction to one of customization of care. The second factor is temporal.The impact of decisions by baby boomers has been often quoted as driving market trends due to this population’s substantial voice in the market. Currently, baby boomers are entering their 50s, and in the next two decades they will account for the largest group of seniors in our country’s history. Baby boomers are increasing the senior subpopulation of the demographic profile, as the current seniors are living longer due to advances in nutrition and medicine. Conse quently, there will be an increase in the number of complex patients, who have multiple, simul taneous diseases, who will need medical care. The third item addressed by AstraZeneca is “how”to revise an IST research strategy to focus on these underserved populations. The primary goal for the company is to increase awareness of AstraZeneca’s interests in having more research in these demographic areas through focused and frequent communi cation with its field scientists and its investigators. This communication strategy has been designed in phases. Phase I (JuneDecember 2002) was to inform and educate AstraZeneca field sci entists about its interest in these areas.The company attempted to target frequent IST investigators, as they already have successfully completed other studies through the system. Notably, Dr. Phil Katz and Dr. Nimish Vakil have ISTapproved target populations.AstraZeneca also was able to attract the attention of new IST investigators, namely Dr. Anthony DiMari no, Dr. Ken Vega, and Dr. Yvonne Romero who have active IST protocols and plan to submit additional protocols for review. Phase II of the communication strategy is to increase awareness of the company’s interests in these study populations.The IST team has complet edanewbrochurewith special focus on the underserved populations,and Renata Maslowski, Ph.D., MBA, director, medical affairs, Nexium/Entocort, Paul Hoyle, Ph.D., director, medical affairs, AstraZeneca, and Henry Leher, Ph.D., product development scientist, gas trointestinal disease, have been presenting IST topic suggestions at regional gastroin testinal/MIS meetings since July 2002. Secondly, Dr. Maslowski presented the trends in GI research and funding to an audi ence of fellows and young investigators at the 2002 GRG Methodologies in Outcomes Research Meeting, with a followup invita tion to the 2003 meeting. AstraZeneca now is moving into the next phase of its communication strategy, which includes increased contact with investiga tors who may not be aware of the compa ny’s interests. New IST brochures have been mailed to currently active IST investigators and handcarried by MIS/PDS field scientists to additional targets.Dr.Romero and Dr.Alin Botoman have suggested nomination of Dr. Maslowski to the ACG committee on Inter national and Minority Affairs to broaden the awareness. Thirdly, Sandra JoshuaGotlib, director, gastroenterologyhealth economics and outcomes research, has identified a need to address academic institutions that educate healthcare personnel from minority populations,and noted that how these populations are studied will be very important with regard to language and cultural variations in health/nutritional practices. Phase III also will include identification of other “centers of excel lence,” or institutions that are recognized by the community as serv ing the specific needs of the underrepresented populations. Finally,a shift to include more research on these target populations is expected to increase the geographic specialization of care. Using information from the U.S.Census Bureau andmigration patterns with in the United States,both readily available resources from the Internet, will help identify optimal targets for these study strategies. Source:AstraZeneca,Wilmington,Del.For more information,visit astrazeneca.com TIME: Two to three years to increase IST sub missions on these targets audiences (starting from 2002). QUANTITY: A target percentage for these studies to grow steadily from 8% to 20%; 20% indicates the average of the demographic composite listed for women, minorities, chil dren, and seniors, treating each subpopulation as independent. It is likely that some IST pro posals will have overlapping underserved pop ulations included (i.e., senior women). INTERNAL RESOURCES: To be most effective, this project would be developed by a small working group of four to six people.Like ly candidates for the group would be MIS/PDS field scientists whohave access to investigators who are early advocates of the concept,and IST members with special interest in the project. BUDGET: Larger strategic meetings cost about $160,000. Smaller regional focus groups cost about $40,000 to $60,000 each.The sugges tion is to hold at least one meeting per region in the next two to three years. AstraZeneca has determined that the following resources will be required to meet its strategies for serving underrepresented populations 28 Aug u s t 20 03 PharmaVOICE DIVERSITY in clinical trials valuing the great diversity that exists among persons within groups. The report states, how ever, that this risk needs to be weighed against the fact that in epidemiologic and clinical research, racial, and ethnic categories are useful for generating and exploring hypotheses about environmental and genetic risk factors, as well as interactions between risk factors, for impor tant medical outcomes. “Much of the new evidence that has result ed from the decoding of the human genetic map has shown that there are significant genetic polymorphisms between different eth nic groups, particularly blacks and Asians, as relates to drug metabolism, drug transport, and receptor expression,” Dr. Stone says. The NEJM report points out that discrepan cies in racial and ethnic responses to disease are not purely genetic, but also are associated with access to quality of healthcare and education. Cultural influences and traditions also must be taken into consideration when evaluating a drug’s safety and efficacy in diverse populations. “We can’t just evaluate the science of the drug without taking into account how different populations take medicine, and how factors such as diet, environment, and culture impact patients while they are on a medication,” says Lucille C. Norville Perez, M.D., past president of the National Medical Association (NMA). “There are many intangibles that physicians must consider in the treatment plan for their patients and being of the same `race’ doesn’t nec essarily assume sensitivity to all of the cultural nuances needed for the delivery of quality care.” Statistics reveal that African Americans are more susceptible to certain diseases than other patient populations, including cardiovascular disease, diabetes, HIV, asthma, cancer, hyper THERE IS A LONG HISTORY OFDISTRUST AMONGTHE AFRICANAMERICAN COMMUNITY REGARDING CLINICAL RESEARCH,MUCH OF IT COMINGOUTOF THEVERY REAL PROBLEMS ASSOCIATEDWITH THETUSKEGEE STUDY.ONLY A GENUINE AND SINCERE EFFORT INVOLVING EDUCATION AND COMMUNICATION WILL OVERCOME THIS CONCERN. Dr. Kenneth Borow WEDESIGNOUR STUDIESTO REPRESENT ABALANCED POPULATION ANDTOMIMICTHE `REALWORLD’ IN BOTHTHE DEMOGRAPHICSANDTHEDISEASE ETIOLOGY.THE SELECTION OF INVESTIGATORSTO PARTICIPATE IN OURTRIALS AND FINDTHESE PATIENTS IS DONEWITHTHE TREATMENT POPULATION GOAL IN MIND. Lynn Baer WHEN PHARMACEUTICAL COMPANIES ESTABLISH A PROCESS OF ENSURING INCLUSION OF RACIAL AND ETHNIC POPULATION SEGMENTS IN CLINICALTRIALS, FDAAPPROVALOF PRODUCTS WILL BE ENHANCED. Sheila Thorne EDUCATION INITIATIVES SHOULDHELPAFRICAN AMERICANS ANDOTHER MINORITIES UNDERSTANDTHE CRITICAL NEED FORTHEMTO PARTICIPATE INTRIALS ANDTHE HEALTHCARE CONSEQUENCES FORTHECOMMUNITYWHEN THEY DON’T. Jucinda FennHodson THE FDA ISN’T ENFORCING ANYOFTHE GUIDELINESTHAT IT HAS BEEN PASSING SINCETHE EARLY 1990S.WHEN A COMPANYKNOWSTHAT NOTHING PUNITIVE IS GOINGTOHAPPEN,THERE REALLY IS NO INCENTIVE FOR IT TOADHERETOTHE GUIDELINES ESPECIALLY IF IT REQUIRES ADDITIONAL EFFORT. Dr. Brian Stone 30 Aug u s t 20 03 PharmaVOICE DIVERSITY in clinical trials tension, and infant mortality. (See related box on page 23.) Lynn Baer, senior director and head of clini caltrial operations at Novo Nordisk Pharma ceuticals Inc., says, “Certainly diabetes, hyper tension, and coronary artery disease are among those therapeutic areas that seem to affect the AfricanAmerican population more acutely. Since diabetes touches all demographic groups, we seek a patient population in our trials that mimics the disease in the real world.” The challenge for pharmaceutical compa nies such as Novo Nordisk and their partners is filling trials to meet realworld scenarios. Diana L. Anderson, Ph.D., president and CEO of D. Anderson & Co., concurs that recruiting the appropriate mix of patients for clinical trials is a challenge. She cites her experience in relation to recruit ing patients for a diabetes trial. “The target pop ulation for a diabetes trial is white, Hispanic, and black males,” Dr. Anderson says. “Even though we have a fair number of people from minority populations respond to our initial patientrecruitment strategies, 80% of those who follow up to participate are white males.” IDENTIFYINGTHE BARRIERS According to the HSP and IOM report, the healthcare workforce and its ability to deliver quality care for racial and ethnic minorities can be improved substantially by increasing the proportion of underrepresented U.S. racial and ethnic minorities among health pro fessionals. In addition, both patients and providers can benefit from education. Patients can benefit from culturally appropriate educa tion programs to improve their knowledge of how to access care and their ability to partici pate in clinicaldecision making. Recruiting minorities, whether they are Hispanic, Asian, or African American, is diffi cult for many reasons, says Stedman Stevens, president and chief operating officer at Phar maceutical Research Plus Inc. “Proportionally there may be fewer African Americans signing up for clinical trials because of economic or logistic issues,” he says. “There are much larger components, including the fact that patients are simply not aware of a trial, not aware of the benefits, and haven’t been educat ed about trials.” This lack of awareness about clinical trials is a huge barrier to recruitment across all pop ulations, says Deborah Kniuksta, assistant director of patient recruitment at Kendle International Inc. “In the industry, we tend to think that every one is very aware of clinical trials,” she says. “Since we live and breathe clinical trials, we take them for granted. But the general population has a limited grasp of clinical trials and the drugapproval process. I think this is even more true in minority populations.” While the primary burden of education may lie with healthcare providers serving their com munities, some say this burden should be shouldered by the pharmaceutical industry as INCREASINGLY, PHARMACEUTICAL COMPANIES ARE REC OGNIZING THE NEED TO INCLUDE MULTICULTURAL GROUPS IN CLINICALTRIALS FROMTHE POINT OFVIEWOF SOCIAL RESPONSIBILITY, SCIENTIFIC SAFETY AND EFFICA CY,AND BUSINESS IMPERATIVES. Onepharmaceutical company,GlaxoSmithKline,has begun to tack le diversity in clinicaltrial recruitment through several initiatives. “We have an 8,000patient prostate cancer riskreduction trial that’s just started titled REDUCE,”says RonaldWalls,M.D.,medical director,clin ical development andmedical affairs for cardiovascular andurologic dis eases, at GlaxoSmithKline. “We’ve put together an AfricanAmerican recruitment and retention advi sory board with the purpose of specifically addressing any culturally and regionally sensitive issues, to help develop culturally sensitive recruit ment materials, to accrue as many AfricanAmeri can physicians as we can to participate in the clini cal trials,and to retain patients onceenrolled in the clinical trial.” Dr.Walls was the key member of that commit tee, which was chaired by Dr. Clarence Young, VP andglobal therapeutic area lead for antiinfectives at GlaxoSmithKline. The trial involves a Glaxo SmithKline product called dutasteride, which is approved under the brand name Avodart for the treatment of benign prostatic hyperplasia. Dr.Walls says the group has just started its recruitment process, but its goal is to enroll as many African Americans as are reflected in the general population.“We’ve pulled together the world experts on accru al and retention of African Americans in the clinicaltrial arena,”he says. “Together, we’ve constructed the framework for an effective strategy for AfricanAmerican patient and physician accrual and retention.” Dr. Walls says the team has a great interest to learn not only what measures and efforts have been successful, but also what have failed. Dr. Walls also emphasizes that there is a general lack of clinicaltrial information on the AfricanAmerican population. For this reason, it is critical to have AfricanAmerican patients partici pate in clinical trials. Recognizing the importance of AfricanAmeri can associations, GlaxoSmithKline has reached out to the National Medical Association (NMA) and other national and regional advocacy groups. A Plan of Action INTERMS OFRETAINING AFRICANAMERICAN PATIENTS IN CLINICALTRIALS, IT IS CRITICALTO FIRSTLY BUILDTHE RELATIONSHIPWITHTHESE PATIENTS AND SECONDLYTOKEEPTHESE PATIENTS INFORMED ASTOTHEDEVELOPMENT OFCLINICALTRIALS.THIS IS ESSENTIAL FOR RETENTION OF PATIENTS. Dr. Ronald Walls DIVERSITY in clinical trials well. Traditionally, pharmaceutical companies have not made a concerted effort to reach out to diverse populations. “I don’t believe that we have, as an industry, directed our CRO part ners to target populations of color as a strategic requirement,” says Sarah Harrison, VP of customer strategy integration at AstraZeneca. “This does not apply only to populations of color, but to women, regardless of race or ethnicity; looking at the statistics of clinicaltrial enrollees, women are not included to any great extent.” Michael Lenoir, M.D., principal investigator for the National Medi cal Association’s (NMA) clinicaltrials program, Project Impact, says pharmaceutical companies tend to do “onesizefitsall” clinical trials, but now there is genetic evidence that African Americans respond differently to certain types of clinical preparations. “Additionally, within the AfricanAmerican community there has not been much discussion about what a clinical trial is, what the advantages are, or what the disadvantages are,” Dr. Lenoir says. “So for the most part, African Americans don’t know anything about clinical trials, with the exception of the Tuskegee study.” OVERCOMINGTHEBARRIERS Industry leaders say one strategy to recruit and retain African Ameri cans in clinical trials is to focus on recruiting AfricanAmerican physicians to conduct the studies. In an analysis conducted by CenterWatch in February 2002, 3% to 4% of the total number of boardcertified minori ty physicians — about 1,500 physicians worldwide — participate in clin ical research. Recent data show the percentage of AfricanAmerican physi cians in the U.S. is 3.7%, about the same as 75 years ago. Recruiting minority physicians as principle investigators, however, requires that sponsors and CROs make special efforts to train these physicians for research participation. “It is our belief that to improve the number of African Americans engaged in clinical trials, it is important to first increase the number of AfricanAmerican investigators,” Dr. Lenoir says. To this end, Project Impact — Increase Minority Participation and Awareness of Clinical Trials — has been working to introduce the issue of clinical trials to the AfricanAmerican physician community through a series of nationwide seminars. “AfricanAmerican patients are more likely to engage in clinical trials if AfricanAmerican investigators are involved,” he says. The NMA then works to connect those investigators with the pharmaceutical industry. According to the 2002 report by HSP and IOM, crosscultural cur ricula should be integrated early into the training of future healthcare providers, and practical, casebased, rigorously evaluated training should persist through practitioner continuing medical education programs. “The industry should be involved in helping to train minority physi cians to meet the qualifications that we need,” Ms. Harrison says. “And, if we’re going to use a CRO to facilitate the recruitment, then wehave to pro vide our CRO partner with the necessary resources and incentives. We can take an active role in supporting and sponsoring medical schools that are traditionally minority based and help graduate physicians who are ready to do clinical trials the way we want them and need them to be done.” Dr. Perez stresses that it is critical to start training at the college level. “We need to start to bring the historically black colleges and universities into the mix in relation to research.” There are 119 historically black colleges and universities, four of par ticular note are, Howard School of Medicine, Meharry Medical College, KingDrew School of Medicine, and Morehouse School of Medicine. Physician education is one aspect of bridging the gap. According to Ronald Walls, M.D., medical director of clinical development and medi cal affairs for cardiovascular and urologic diseases at GlaxoSmithKline. The proper infrastructure within the physician office to participate in clinical trials is critical. It is equally important that pharmaceutical companies and CROs help physicians make sure that the proper support is in place by hav ing culturally sensitive materials available to help enroll patients and by 32 Aug u s t 20 03 PharmaVOICE DIVERSITY in clinical trials making sure that there is a suitably trained and dedicated study manager. To help ease the financial recruitment bur den on sites and investigators, some suggest that economic incentives should be considered for practices that improve providerpatient communication and trust, and reward appro priate screening, preventive, and evidence based clinical care for minority populations. “It is important to acknowledge that clin icalresearch sites may have to put more effort into the recruitment of AfricanAmer ican subjects compared with Caucasian sub jects,” Dr. Borow says. “This extra effort is often required to overcome potential distrust on the part of African Americans regarding clinical trials. These subjects in particular must feel that they are clinicaltrial partici pants with a welldefined and understood purpose rather than merely `test subjects’ or `guinea pigs.’ Open and honest communica tion between the physician and the subject is essential. Patient education and a true will ingness on the part of study site personnel to address subjects’ questions and anxieties is essential. The result may be the need for the sponsor to pay the study site an additional stipend reflecting the additional time required with the subject. This is not meant as an undue incentive to the study site to recruit subjects, but rather it is an acknowl edgement that there may be more time required by the site to explain the benefits and risks of the study to the subject, thereby helping to overcome the subject’s skepticism and fear of the clinicalresearch process.” Ms. Kniuksta agrees that there is a need for companies to overcome suspicions of the gov ernment and scientists that may be held by some communities. “Even more important is the cultural sensi tivity of the research staff in dealing with dif ferent ethnic groups,” she says. “Cultural sen sitivity is probably more important than the actual race or ethnicity of the investigator.” Ms. Baer says Novo Nordisk has found sev eral approaches to be effective in raising aware ness about clinical trials for its therapies among diverse populations. “These include patienteducation venues, advertising designed to raise awareness about clinical trials being conducted, and working with large clinics that serve various demograph ic groups,” she says. “In addition, Novo Nordisk GETTING TO MARKET AS FAST AS POSSIBLE, BEARING IN MINDSAFETY,EFFICACY,ANDREGULATORYGUIDELINES, IS THE GOALOFALL PHARMACEUTICAL COMPANIES. In January 2003, the Food and Drug Administration published a draft guidance recommending categories for collecting effectiveness and safety data during clinical trials for ethnic and racial demographic groups. If adopted, this would create a standard for classifying the vari ous races. FDA recommends that drug manufacturers use the cate gories for race and ethnicity established by the Office of Management and Budget (OMB) during clinicaltrial data collection to ensure consis tency in evaluating potential differences in drug response among racial and ethnic groups. The 2003 guidance, however, came too late to help BristolMyers Squibb.Last year, in a review of the company’s hypertension therapyVan lev (omapatrilat), the Office of Drug Safety (ODS) raised concerns about the therapy. In controlled hypertension trials sub mitted in the original NDA filed in 1999, eight patients were hospitalized for angioedema associ ated with omapatrilat. Of those patients, six were black and two were nonblack patients. In March 2000,FDA’s Division of CardioRenal DrugProducts informed BristolMyers Squibb that additional research was needed to assess this adverse event. The company initiated a larger study, the OCTAVE Trial, in which 25,000 hypertensive patients were randomized to either omapatrilat or enalapril. The company’s evaluation of angioede ma risk revealed a two to threefold increase in risk for black patients and for current smokers. A one to twofold increase in risk also was identified for female patients,patients with seasonal allergies, and former smokers. OnMay 8, 2002,BristolMyers Squibb submitted a proposal for riskman agement strategies to be implemented during marketed use of omapa trilat. The ODS,however,noted several shortcomings of the proposed post marketing surveillance plan, including doubts about whether severe angioedema associated with omapatrilat can be adequately managedby a program primarily focused on education. Last October, BristolMyers Squibb acknowledged receipt of a letter from the FDA specifying that additional actions must be taken before the agency would consider approval of Vanlev.The company reported it was evaluating its options. Some people say part of the problem may be a dearth of African American patients in initial studies industrywide. “Just as Vanlev was approaching FDA approval, researchers started to notice that adverse events were occurring in African Americans,” says Edward F. Ikeguchi, M.D., chief medical officer and cofounder of Medidata Solutions Inc.“That put a big monkey wrench in BristolMyers Squibb’s plans. The company had to go back and look at its recruitment of African Americans for the trial, which was dismal.” Diversity and the Bottom Line COMPANIES DON’TWANTTOWINDUP IN A SITUATIONWHERE ATTHE ENDOFTHE RESEARCH PROCESS, IT BECOMESCLEARTHAT THERE IS ADISPARITY INTERMS OFWHATTHE DRUG PROFILE IS FROMONERACIALGROUP TOANOTHER. Dr. Edward Ikeguchi 34 Aug u s t 20 03 PharmaVOICE DIVERSITY in clinical trials offers a patientassistance program to help people who do not have private health insur ance and who do not qualify for private, local, state, or federal prescription reimbursement.” Word of mouth is regarded by some experts as the best avenue for reaching out to members of the AfricanAmerican communi ty, by working through opinion leaders and peer counselors, and putting together a sup port network for patients. When speaking to members of a community, companies also need to provide patients with the shortterm benefits of joining a trial program, such as assuring them of the best medical care, not having to wait to see doctors, and having per sonal contact with healthcare professionals. “In addition, position those who enroll in trials as community heroes,” Ms. Thorne says. “Companies should develop publicrela tions initiatives to showcase clinicaltrial par ticipants so the community can associate a familiar face with the clinicaltrial process, which will enhance community receptivity.” According to Dr. Walls, one of the approaches that has proved most successful in terms of prostate cancer clinicaltrial recruit ment has been to use prostate cancer sur vivors in the recruitment material. Prostate cancer affects African Americans at twice the rate of that of white Americans, and African Americans have the highest incidence of prostate cancer in the world. (See related box on page 30.) Dr. Ikeguchi says there is a strong connec tion related to the level of trust between the physician and the patient and the physician’s ability to put forth a good argument that an AfricanAmerican patient should participate in the clinical trial. “This is part of the whole concept of cul tural affinity,” he says. “We are trying to get through to the pharmaceutical sponsors that it’s worth their while to focus on the training, the education, and the development of clini cal sites with AfricanAmerican physicians as investigators. We are pushing the fact that there are wellestablished relationships in communities between minority physicians and groups such as the NMA, the Black Health Network, and the Association of Black Cardiologists. These groups are cultur al intermediaries that already have a strong, longlasting bond with doctors.” Dr. Lenoir says the NMA tries to over come the AfricanAmerican community’s healthy paranoia with regard to clinical trials by educating prospective participants on what a clinical trial is, what the restrictions are, why to engage in it, why not to engage in it, and how to be involved in the clinical trial process. REACHINGOUT The location of the clinical trial also can have an economic and cultural bearing on the success in recruiting and retaining patients from diverse backgrounds. “Sponsors and CROs often don’t choose sites that are in the community being tar geted,” Ms. Thorne says. “Sites are usually geographically not in the communities of the target ethnic audience and therefore inconvenient and unfamiliar to target ethnic patients.” “The most effective way to target any sub population is to go where these patients live,” Mr. Stevens says. “We need to go to their churches, to the YMCA, to the local pharma cy. That’s what we do with our local outreach programs. We tie in wellness events at all those venues. We also will do interviews with community physicians on local radio and tie these into nearby community events. So even though we as an organization are remote, we’re tying into the local physician, into the local patient, and into the local community.” Another possible way that pharma compa nies might reach out to AfricanAmerican physicians is through pharmaceutical detail reps, Ms. Thorne says. “Reps know the key opinion leaders who are African American in those respective com munities,” she says. “Reps should seek out these leaders to learn what organizations they belong to, who their colleagues are who would be helpful, and whether they potentially could be investigators.” According to some statistics, 85% of peo ple in America are not even aware that clinical trials exist. Thus, part of local outreach pro grams must include basic education about clinical trials for physicians and patients. And these education efforts need to be specifically designed for specific patient com munities, says Liz Moench, president of MediciGroup Inc. “Within the AfricanAmerican population, for example, the education communications process must be a steady, understandable, and ongoing process and the process has to take into account specific cultural aspects,” she says. “The AfricanAmerican community, by and large, has a matriarchal structure; there may be a grandmother or siblings who will have a lot of involvement. Patients need mate rials that they can share with other family members. These family members will be in a position to ask questions and/or may even sec ond guess the process. Investigators, study coordinators, and sponsors have to work hard er at fostering relationships. Patients need to feel in control.” Education efforts also need to dispel some of the myths and misunderstandings about clinical trials, says Jucinda FennHodson, VP of multicultural marketing at Palio Commu nications. “Education efforts should address issues of the past, but also assure patients that trials are now heavily regulated,” she says. “Education initiatives should help African Americans and other minorities understand the critical need for them to participate in tri als and the healthcare consequences for the community when they don’t.” Recruitment is just one aspect, since there also are issues related to retention and adher ence to the protocol, including diet. Ms. Thorne says many African Americans, Asians, and Hispanics eat highly seasoned food that can impact the efficacy of the project. She says it would be important to include dieticians who can design menus so these patients can still maintain their dietary preferences from a cultural perspective without impacting the taking of the drug. In addition, according to Ms. Harrison, sponsors need to communicate to the targeted population that the patient’s needs — be that transportation, childcare, or other accommo dations — will be considered. “There are things that may need to be added to the patient component to incentivize more patients to participate,” she says. The fact is that for industry the primary goal has been to get drugs approved fast, bear ing in mind safety and efficacy. To do that, Ms. Harrison says the industry relies on CROs to get enrollees in a trial as quickly as possible. “CROs first go to all the experienced inves tigators who they know, and these mostly white investigators are going to put people into trials who come to their office all the time, and who are cooperative, and who they know will be able to get back into the clinic,” she says. “This is just an example of the way things are done. We must have a strategic objective to have populations of color fully represented in trials.” PharmaVoice welcomes comments about this article.Email us at feedback@pharmavoice.com. It is a business imperative that the industry address the shortfall in patient recruitment among multicultural populations. 35 PharmaVOICE Augu s t 200 3 DIVERSITY in clinical trials Experts on this topic DIANA L.ANDERSON,PH.D.President and CEO of D.Anderson &Co.,Dallas;D. Anderson combines clinicaltrial experience and site management services with media and communication expertise aimed at accelerating clinicaltrial outcomes. For more information,visit dandersoncom pany.com.Dr.Anderson also is chairman of the board of trustees of the Association of Clinical Research Professionals (ACRP), Alexandria,Va.;ACRP is an international membership organization that represents more than 17,000 clinical research professionals from diverse organizations. For more information,visit acrpnet.org. LYNN BAER.Senior director and head of clinicaltrial operations, Novo Nordisk Pharmaceuticals Inc., Princeton, N.J.; Novo Nordisk A/S is a world leader in diabetes care, with a broad diabetes product portfolio, including some of the most advanced products within the area of insulin delivery systems.For more information, visit novonordiskus.com. KENNETHM.BOROW,M.D.President and CEO,Covalent Group Inc.,Wayne,Pa.; Covalent is a clinical research organization that designs and manages complex clinical trials for the pharmaceutical,biotechnology, and medicaldevice industries.For more information,visit covalentgroup.com. JUCINDAFENNHODSON.VP of multicultural marketing,Palio Communications,Saratoga Springs,N.Y.; Palio is a fullspectrum,strategically driven advertising and communications company. For more information,visit paliocommunications.com. SARAHHARRISON. VP, customer strategy integration, AstraZeneca,Wilmington,Del.; AstraZeneca is an international research based pharmaceutical company engaged in the development,manufacture,and marketing of prescription pharmaceutical products.For more information, visit astrazenecaus.com. EDWARDF. IKEGUCHI,M.D.Chief medical WILLIAMSIETSEMA.VP of clinical development,Kendle International Inc., Cincinnati;Kendle is a global provider of clinical development, regulatory/validation consulting,and medical communications services to the pharmaceutical and biotechnology industries.For more information,visit kendle.com. STEDMAN STEVENS.President and chief operating officer, Pharmaceutical Research Plus Inc., Severna Park, Md.; PRP was founded in 1994 to introduce a new method to accelerate patient recruitment for pharmaceutical clinical trials. For more information, visit prpi.com. BRIAN STONE,M.D.Chief medical officer, The Black Health Network,NewYork;The Black Health Network provides valueadded clinicalresearch services to pharmaceutical and biotechnology companies seeking minority investigators, site initiation, and data collection on an electronic data capture platform, and in depth physiciandriven health content geared toward the AfricanAmerican community and a minority physician referral system for virtually every medical specialty. For more information, visit blackhealthnetwork.net. SHEILATHORNE.President,Multicultural Healthcare Marketing Group LLC,Teaneck, N.J.;Multicultural Healthcare Marketing Group employs seasoned, inlanguage, in culture professionals with an indepth understanding of the pharmaceutical and healthcare industry and extensive experience in multicultural marketing.For more information, call 9733318322. RONALDG.WALLS,M.D.Medical affairs director, clinical development and medical affairs, cardiovascular and urologic diseases, GlaxoSmithKline,Research Triangle Park, N.C.; GSK,with U.S. headquarters in Philadelphia, is one of the world’s leading researchbased pharmaceutical and healthcare companies. For more information, visit gsk.com. officer and cofounder,Medidata Solutions Inc., NewYork;Medidata streamlines how organizations collect, verify, and report clinical research data, reducing the cost and time required to complete research programs.For more information,visit medidatasolutions.com. DEBORAHKNIUKSTA. Assistant director of patient recruitment, Kendle International Inc., Cincinnati; Kendle is a global provider of clinical development, regulatory/validation consulting, and medical communications services to the pharmaceutical and biotechnology industries. For more information, visit kendle.com. MICHAEL LENOIR,M.D. Principal investigator for the National Medical Association’s clinical trial’s program,Project Impact,Washington, D.C.;The NMA promotes the collective interests of physicians and patients of African descent by serving as the collective voice of physicians of African descent and a leading force for parity in medicine,elimination of health disparities, and promotion of optimal health. For more information, visit nmanet.org. LIZ MOENCH.President,MediciGroup Inc., King of Prussia, Pa.; MediciGroup was founded in 1993 with the vision of building longterm client relationships by providing innovative directtopatient clinicaltrial recruitment and retention programs.For more information, visit medicigroup.com. LUCILLE C.NORVILLE PEREZ,M.D. Past president, National Medical Association, Washington,D.C.;The NMA promotes the collective interests of physicians and patients of African descent by serving as the collective voice of physicians of African descent and a leading force for parity in medicine,elimina tion of health disparities, and promotion of optimal health. For more information, visit nmanet.org. THOMAS SCHNITZER,M.D.,PH.D.Chairman of the board of RRI, Dallas; RRI provides comprehensive rheumatology services ranging from extensive site management and patient recruitment to marketing.For more information, visit rri.net.

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