DIVERSITY IN MEDICATION USE AND OUTCOMES IN AGING POPULATIONS Release Date: May 7, 1999 PA NUMBER: PA-99-097 P.T. National Institute on Aging National Center for Complementary and Alternative Medicine Office of Research on Minority Health Office of Research on Women"s Health THIS PROGRAM ANNOUNCEMENT USES MODULAR GRANT PROCEDURES. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. (SEE APPLICATION PROCEDURES. ALSO SEE MODULAR GRANT APPLICATION AND AWARD NOTICE http://www.nih.gov/grants/guide/notice-files/not98-178.html PURPOSE The National Institute on Aging (NIA) in collaboration with the National Center for Complementary and Alternative Medicine, the Office of Research on Minority Health and the Office of Research on Women"s Health invites qualified researchers to submit applications to investigate issues relevant to medication use and outcomes among older people. This program announcement solicits both basic and applied research proposals to investigate the multiple factors that influence medication use by the elderly. Goals of this announcement are to 1) identify the epidemiological, psychosocial, health care and clinical factors associated with medication use by older people, including the use of unconventional medical products, 2) assess social, behavioral, psychological and cognitive factors that play a role in older people"s understanding of and adherence to medication regimens, 3) determine the role of medical and pharmaceutical professionals in facilitating or hindering proper use of prescribed and over-the-counter medications and unconventional medications including herbs and dietary supplements, 4) refine methodologies to link these factors to medical or psychosocial outcomes, 5) investigate interventions to improve medication adherence and 6) increase our understanding of biological factors which contribute to therapeutic outcomes in the use of medications by the elderly. This Program Announcement solicits research on people in a range of residential or treatment settings (e.g., home, community, hospital, nursing home), with interventions directed at older people themselves, their family caregivers, or health care professionals. There is primary interest in understanding the influence that racial/ethnic, SES and gender play on the use of and outcomes of different drug regimens or unconventional medical products, and the need to develop and evaluate culturally sensitive interventions. Similarly, there is interest in cross-cultural influences on medication behaviors and outcomes. While the main focus is on human populations, studies utilizing animal models of human aging and age-related diseases are also appropriate to this program announcement. HEALTHY PEOPLE 2000 Each NIH PA addresses one or more of 22 Health Promotion and Disease Prevention priority areas identified. These areas can be found via the WWW at http://odphp.osophs.dhhs.gov/pubs/hp2000/hppub97.htm ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and domestic for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of state and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT The mechanism of support will be the individual research project grant (R01). NIA is also soliciting applications on this topic that have the potential for commercial application (see SBIR and STIR solicitations, which are available on the World Wide Web at: http://www.nih.gov/grants/funding/sbir.htm). Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. RESEARCH OBJECTIVES A recent report (Lazarou, Pomeranz, & Corey, 1998) found the incidence of serious and fatal adverse drug reactions (any noxious, unintended, and undesired effect of a drug which has been properly prescribed and administered, as defined by the World Health Organization) to be extremely high among hospitalized patients. What is unknown is the extent of the broader problem of errors in drug administration, or nonadherence, among the older population. Failure to follow medication instructions or to take medications as prescribed, whether intentional or unintentional, is a significant problem in virtually all younger and older patient populations. However, adherence among older patients may be of greater concern due to their heightened susceptibility to adverse drug reactions, differential responsiveness to side effects, greater exposure to prescription and over-the- counter drugs, physical and cognitive limitations, or a combination of these and other risk factors (e.g., the higher prevalence of co-morbidities). Furthermore, adverse drug effects may manifest differently in older people compared to younger age groups. Because older people living in the community consume one-third of all prescriptions, with most taking at least one medication and typically as many as four, these problems represent a serious health concern for the elderly. There is a relative lack of valid and reliable data on medication use in older age, especially among racial/ethnic minorities. Estimates suggest that 90% of all outpatients make mistakes in taking prescribed medicines, and that failure to follow the proper regimen results in 30 50% failure rate in achieving clinical results (National Council on Patient Information and Education, 1995). Prescription drug-related illnesses cost over $1 billion a year, including costs associated with 1.5 million extra hospital days, and over 100,000 deaths annually from side effects of prescription medicine. Nonadherence is potentially more serious in older people and is associated with higher treatment costs. Among the elderly, there is increasing availability and use of dietary supplements, herbal products, vitamins, minerals and hormones taken for the prevention and treatment of disease and in an attempt to improve well being. The reasons, motivations, and patterns of this use are not well understood nor is the potential for adverse effects of such use along with conventional drugs. Failure of many patients to discuss this use with their physicians makes the situation more complex and risky (Eisenberg, 1993). The current focus on medication use and outcomes among the elderly is particularly timely, due to growing concerns about polypharmacy and associated drug side effects, chronic drug use among older people, heightened industry testing of medications for the elderly, women"s health and minority aging issues, and changes in the health care system. To get a clear picture it is important to examine health system and provider prescribing patterns as well as patient drug taking behaviors. It is becoming increasingly clear that medication adherence is a complex behavior and that effective interventions to improve adherence can be developed only when mechanisms underlying the behavior are better understood (Park & Jones, 1997). The behavioral and social sciences have contributed to knowledge in this area through research on comprehension of drug labeling and information, behavioral and social factors influencing compliance in older people, influence of changing health care system on drug management issues, and interventions to enhance adherence and appropriate prescription behaviors. Research has identified some effective strategies for improving adherence, including patient information strategies, patient-centered counseling, behavioral reinforcement and patient support strategies, strategies related to the regimen, strategies aimed at health professionals, and organizational-level strategies. Cultural and gender diversity among the elderly may be another barrier to medication adherence. Issues in dealing with special populations include provider misconceptions about cultural or gender beliefs or practices and the impact of these misconceptions on provider patterns, culturally-based beliefs about medications, illness, and aging among patients and their families, and language and other barriers to effective communication with health-care providers. Furthermore, there may be differences in the prevalence of conditions among minority populations, as well as variation in the pathophysiology of disease processes. Attention to issues of medication adherence unique to special and minority populations, along with current research on diseases and conditions that disproportionately affect minority elders, may further help to alleviate the disease burden faced by these populations (Institute of Medicine, 1997). The Food and Drug Administration Office of Women"s Health has initiated a targeted public information campaign to raise awareness about safe use of medicines and ways in which women as principle users of medications and family health counselors can use medicines more wisely (1999). Further research is needed to understand which elderly subgroups are at greater risk for various types of nonadherence, the specific barriers encountered by aging individuals, and ways to address these problems. Topics needing research attention include: the extent and costs of inappropriate drug use, the cognitive, behavioral, and social factors influencing medication use, strategies for reducing medication errors and increasing compliance, development of drugs for specific conditions (dementia, sleep, cancer) and drugs that reduce side effects that limit compliance, and minority/ethnic and gender considerations in pharmacokinetics and drug taking behaviors. Institute of Medicine. 1997. Pharmacokinetics and drug interactions in the elderly and special issues in elderly African-American populations. Workshop summary. Committee on Pharmacokinetics and Drug Interactions in the Elderly. National Academy Press, Washington, D.C. Lazarou, J., Pomeranz, B.H., & Corey, P.N. (1998). Incidence of adverse drug reactions in hospitalized patients: A meta-analysis of prospective studies. JAMA, 279(15), 1200-1205. National Council on Patient Information and Education. 1995. Prescription medicine compliance: A review of the baseline of knowledge. Washington, D.C. Eisenberg, D.M., Kessler, R.C., Foster, C., Norlock, F.E>, Calkins, D.R., and Delbanco, T.L. (1993) Unconventional medicine in the United States prevalence, costs, and patterns of use. N. Engl. J. Med., 328:246-252. Park, D.C. & Jones, T.R. 1997. Medication adherence and aging. Handbook of Human Factors and the Older Adult. Academic Press, pp. 257-2871. The following are offered as illustrations of appropriate topics for research. Applications need not, however, be limited to these specific issues. Medication use among older people. While there are some widely quoted statistics about drug prescribing and taking behaviors, more research is needed in pharmaco- epidemiology to provide better data on who is being prescribed and who is taking specific types of medications. Further research is needed to determine the magnitude of the problem of medication misuse and adverse side effects among older adults. Suggested topics for research: o Racial, cultural and gender differences in medication prescription and use patterns, adverse side effects, and consequences of noncompliance in old age o The magnitude of and costs due to inappropriate prescribing or medication misuse in the elderly, including additional physician, clinic, or emergency room visits, hospitalization, and care of uncontrolled chronic disease. o The extent of over-the-counter medication and alternative therapy use by the elderly, the impact of alternative medicine on the use of conventional medications, the level of awareness among alternative medicine users of possible adverse interactions between alternative and conventional medications, and differences by ethnicity, income and education. Individual, social and cultural factors that may predispose elderly to nonadherence. Studies are inconsistent in their findings regarding age as a risk factor for non-compliance (in many cases studies did not include large numbers of old people, and rarely are the oldest old included). Factors associated with age, rather than age per se, appear to explain the higher non-adherence rates sometimes found in older populations. Additional research is needed on the individual and contextual factors that may predispose people to nonadherence as they age. Possibilities include number of medications prescribed or taken over- the-counter, complexity of prescribing schedules, physical or cognitive limitations, lack of information regarding appropriate use, or failure to comprehend medication instructions. Additional research suggestions include: o Influence of minority or ethnic status, socioeconomic status, illiteracy, and education on medication prescribing practices and adherence behaviors among the elderly. o The impact of gender expectations, multiple family/work roles, and women"s health concerns on prescription patterns and compliance behaviors. o The role of caregivers in facilitating or hindering adherence to prescribed regimens. o The extent to which older peoples" noncompliance is related to erroneous health beliefs, denial of illness or disease, or erroneous expectations from treatment. o The extent to which age-related cognitive changes limit compliance to medication regimens. Health care factors. Some data suggest that as many as 20% of prescriptions remain unfilled by patients. These and other nonadherence issues may suggest a lack of communication between medical providers/health care systems and patients that may be exaggerated among racial/ethnic minorities, low income populations or older women. Areas to investigate include: o How the content and format of delivery of prescription information to older patients as well as mode of drug delivery (e.g., pill, patch, inhalants) may influence adherence. o How changes in the health care system, different health care settings, and multiple providers may increase or decrease the vulnerability of older people to medication errors. o The role of physicians and pharmacists in medication prescription and dispensing, including factors associated with initiating discussions about adverse drug reactions. o The role of aspects of the patient/health care provider relationship, including treatment satisfaction, inadequate communication, poor rapport, and physician failure to elicit patient feedback. o The economic aspects of medication behaviors, including both reimbursed and out-of-pocket costs, and implications for prescription and use patterns. Outcomes and Intervention Research. Multiple outcomes should be assessed to determine short- and long-term effects of medication nonadherence on the physical health and functioning of older people. Outcomes include recall and comprehension of medical information, compliance with medication regimen, functional and health status outcomes, as well as cost effectiveness. Intervention studies can be targeted to improving health behaviors as well as health status outcomes. Areas needing further study include: o Development of new tools or refinement of existing tools for examining the nature and extent of over-the-counter and prescription nonadherence. o Cost-effectiveness analyses on the outcomes of interventions to enhance adherence. o Intervention research on theory-based strategies for improving adherence with medication regimens. Research directed at patients, family members, or providers (or any combination of the above), is encouraged. o Techniques to improve physician prescribing behaviors and pharmaceutical practices, including improving skills in listening for and eliciting information about potential side effects with patients. o The design of medication instructions and other tools to facilitate understanding of and adherence to medication instructions. o Development of more reliable means of detecting noncompliance. o Interventions to reduce the number of drugs community-dwelling and nursing home residents consume o Strategies to eliminate inappropriate sharing of medications within family and friend networks. Biological issues affecting medication use in the elderly. One of the most crucial areas of needed research is the prevention of negative outcomes due to drug-related problems in the elderly. Causes of therapeutic failure can be attributed to a variety of biological and clinical mechanisms. Further research is needed to inform clinical decision-making in the use of medications in older persons. Animal studies directed at basic mechanisms of drug action and interactions among drugs can contribute to research in this area. Suggested topics for research on pharmacokinetics and drug interactions in aging populations include: o Age-related changes in cellular transport mechanisms and extrahepatic metabolism and transport including the activity of different enzyme isoforms. o Mechanisms that cause variable responses to medications in aging racial and ethnic populations (e.g., race, ethnicity or gender). o Age-related hormonal changes affecting drug metabolism or drug sensitivity. o In vitro models for multiple drug regimens and multiple drug interactions that may be predictive of and correlated with in vivo research. o Models for drug interaction related to altered reflex activity and changing homeostatic mechanisms. o Changes with age in the effects of medications on sensory and motor systems and the implications for drug use or misuse. o Investigation of sensory and motor systems side effects in limiting compliance to medications. o Effects of medications on neural transmission and signal transduction in sensory and motor systems of aging organisms. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://www.nih.gov/grants/guide/notice-files/not98-024.html NOTE FOR APPLICATIONS FOCUSED ON AGING RESEARCH Applications received in response to this program announcement are expected to focus on scientific issues related to aging and to aging-related aspects of disease. In describing the plan to recruit human subjects, investigators may cite a focus on aging or on aging-related aspects of disease as the justification for why children will be excluded. In this regard, applicants may use Justification 1, the research topic to be studied is irrelevant to children, from the policy announcement. APPLICATION PROCEDURES Beginning with the June 1, 1999 receipt date, modular application, review, and award procedures will apply to all competing individual research project grants (R01), small grants (R03), and exploratory/developmental grants (R21) whose total direct costs do not exceed $250,000 in any year. Instructions for preparing applications in the modular format may be found at: http://www.nih.gov/grants/guide/notice-files/not98-178.html Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research, or may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-710-0267, email: GrantsInfo@nih.gov. Applications are also available on the World Wide Web at http://www.nih.gov/grants/funding/phs398/phs398.html The program announcement title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit the signed, original, single-sided application, along with five exact, single-sided copies and five collated sets of appendix materials to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Review Criteria o Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? o Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? o Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? o Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? o Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? The initial review group will also examine: the appropriateness of proposed project budget and duration, the adequacy of plans to include both genders, children and minorities and their subgroups as appropriate for the scientific goals of the research, or the justification for their exclusion, plans for the recruitment and retention of subjects, the provisions for the protection of human and animal subjects, and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other approved applications. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review o Availability of funds o Program priority INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome (E-mail correspondence is preferred). Please note that this is an ongoing solicitation and that standard application deadlines apply. Further information about NIA priorities and procedures can be found on the NIA Home Page at: http://www.nih.gov/nia. Direct inquiries regarding specific programmatic issues to the staff of the appropriate Institute/Center: Marcia G. Ory, Ph.D., M.P.H. Behavioral and Social Research Program National Institute on Aging 7201 Wisconsin Avenue, Room 533 MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 402-4156 FAX: (301) 402-0051 Email: Marcia_Ory@nih.gov Judith Finkelstein, Ph.D. Neuroscience and Neuropsychology of Aging Program National Institute on Aging 7201 Wisconsin Avenue, Room 3C07, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: Judith_Finkelstein@nih.gov Stanley Slater, M.D. Geriatrics Program National Institute on Aging 7201 Wisconsin Avenue, Room 3E327, MSC 9205 Bethesda, MD 20892-9205 Telephone: 301-496-6761 FAX: 301-496-1494 Email: Stanley_Slater@nih.gov Frank Bellino, Ph.D. Endocrinology Program Administrator Biology of Aging Program National Institute on Aging 7201 Wisconsin Avenue, Room 2C231, MSC 9205 Bethesda, MD 20892-9205 Telephone: 301 496-6402 Fax: 301 402-0010 Email: Frank_Bellino@nih.gov Division of Extramural Research, Training and Review National Center for Complementary and Alternative Medicine 31 Center Drive, Room 5B-36 Bethesda, MD 20892-2182 Telephone: (301) 402-2466 FAX: (301) 402-4741 Direct inquiries regarding fiscal matters at NIA to: Mr. David Reiter Grants Management Office National Institute on Aging 7201 Wisconsin Avenue, Room 2N212, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: David_Reiter@nih.gov OTHER INTERESTS IN THIS RESEARCH AREA Although not a formal sponsor of this program announcement, the National Institute of Mental Health is interested in receiving applications on medication use in older people as it relates to mental disorders or associated disability. Studies are particularly encouraged in the area of adherence and compliance to medication regimens prescribed for the treatment of mental disorders. Proposals to investigate factors associated with medication use and its outcomes, to study influences on older persons" understanding of and adherence to psychotropic medication regimens, to assess the roles professionals play in medication use patterns, or to develop and refine new interventions or linking methodologies in this area will be assigned to the Division of Mental Disorders, Behavioral Research, and AIDS. For such studies, please contact Peter Muehrer, Ph.D., Health and Behavioral Sciences Research Branch, NIMH at (301) 443-4708, Email: pmuehrer@nih.gov. Proposals to investigate epidemiological patterns of psychopharmacological medication use in the elderly population or to test interventions designed to improve medication adherence will be assigned to the Division of Interventions and Services Research. For such studies, please contact George Niederehe, Ph.D., Adult and Geriatric Treatment and Preventive Intervention Research Branch, NIMH at (301)443-9123, Email: gniedere@mail.nih.gov. AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.866. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410), as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke- free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.


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