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J Gerontol A Biol Sci Med Sci. 2009 April; 64A(4): 487–491.
Published online 2009 March 6. doi:  10.1093/gerona/gln042
PMCID: PMC2657175

Indications, Labeling, and Outcomes Assessment for Drugs Aimed at Improving Functional Status in Older Persons: A Conversation Between Aging Researchers and FDA Regulators

Working Group on Functional Outcome Measures for Clinical Trials*

FUNCTIONAL and mobility limitations increase with advancing aging. Many older people have difficulty in simple activities such as walking or standing from a chair, and cannot tolerate even light physical activity. The etiology of these functional limitations is complex and often ascribed to conditions that escape the traditional definition of disease, which is at the core of clinical medicine. Although our society urgently needs new treatments that can reduce the burden of physical decline among older persons, guidelines on how these treatments should be developed and tested are currently lacking in part because a consensus has not yet been achieved regarding the identifiable target diseases. The demographic imperative and resulting burgeoning in population morbidity can no longer be ignored and requires a substantial adaptation of the system of drug development. In simple words, although functional and mobility limitations are increasingly prevalent in older people, only a handful of clinical trials are under way to treat these problems.

During the past decade, aging research and drug development have found exciting common ground as products with the potential to alter underlying processes related to aging are identified. Several of these novel products are nearly ready for clinical trials in older adults. Whether weakness and limited functional capacity in the geriatric population should be considered a potential indication for drug approval was recently discussed by a group of scientists representing academia, the National Institute on Aging, and the Food and Drug Administration (FDA) in two separate meetings. The first meeting led to the publication of a manuscript that highlighted issues related to appropriate outcome measures for clinical trials of drugs designed to treat specific problems of aging. The emphasis in that paper was on the selection and use of instruments to assess physical function (1).

One important reason for the limited number of clinical trials is the lack of any real consensus on what constitutes an indication for a pharmacological treatment for poor functional capacity. The current study reports on the findings and recommendations of the second meeting. The focus of this meeting was on learning how the FDA evaluates proposals for an indication (that may be specific to geriatrics) and on exploring how several geriatric conditions might conform to this process.

FDA GUIDELINES FOR AN INDICATION

The following examples illustrate how indications for a recognized disease or medical conditions have successfully been formulated for the FDA:

21 CFR 201.80(c)(1)(i)

The drug is indicated in the treatment, prevention, or diagnosis of a recognized disease or condition, eg, penicillin is indicated for the treatment of pneumonia due to susceptible pneumococci; and/or

21 CFR 201.80(c)(1)(ii)

The drug is indicated in the treatment, prevention, or diagnosis of an important manifestation of a disease or condition, eg, chlorothiazide is indicated for the treatment of edema in patients with congestive heart failure; and/or

21 CFR 201.80(c)(1)(iii)

The drug is indicated for the relief of symptoms associated with a disease or syndrome, eg, chlorpheniramine is indicated for the symptomatic relief of nasal congestion in patients with vasomotor rhinitis; and/or

21 CFR 201.80(c)(1)(iv)

The drug, if used for a particular indication only in conjunction with a primary mode of, eg, diet, surgery, or some other drug, is an adjunct to the mode of therapy.

The obvious challenge for many problems of aging is that they do not fit well into any of these categories. Almost all categories require that a disease, condition, or syndrome, hereafter referred to simply as condition, be “recognized” before an indication can be approved. According to the FDA, criteria to determine if a condition is recognized may come from professional organizations, from guidelines (like Diagnosis and Statistical Manual of Mental Disorders, 4th Edition [DSM–IV]), from Centers for Medicare & Medicaid Services (CMS) codes, Clinical Modification (ie, ICD-9 CM) diagnostic codes, or Current Procedural Terminology codes. There are strong expectations that the existence of the condition is supported by an extensive evidence base and a consensus of the clinical or scientific community, and that clear objective measures to document the presence of the condition are available and accessible to prescribers. To the extent that many problems of aging have not been formally recognized by any of these processes, the FDA has no clear guidance on how to determine if a proposed indication would be acceptable.

In the remainder of this article, we discuss the opportunities and challenges regarding four highly prevalent conditions in the geriatric population that could potentially fall into these categories of indications.

Involuntary Weight Loss, Malnutrition, and Anorexia

This may be the most clear potential indication for a common geriatric condition. Involuntary weight loss, poor appetite, and poor nutritional status have been linked to increased morbidity and mortality among older people and particularly among institutionalized elderly people (2,3). Involuntary weight loss and malnutrition are recognized as a treatable phenomenon by the CMS with a specific “trigger” for when an intervention is appropriate (4). A number of potentially correctable and treatable causes for this condition have been identified, such as swallowing problems, poor food quality, and use of drugs that suppress appetite. However, aging has been associated with a dysregulation in appetite and a number of elderly individuals suffering from involuntary weight loss may benefit from the use of an orexigenic agent (5). Unfortunately, at the present time, no orexigenic agent is approved by the FDA to treat involuntary weight loss that is secondary to anorexia associated with aging. Because poor appetite rather than food availability is the potential “condition” for an FDA-approved indication, providing nutritional supplements may be ineffective in the treatment of involuntary weight loss. The appetite stimulants that are currently available (although used “off label”) are either not very effective (5) or may stimulate appetite but not the accretion of lean body mass (6), which is the true desirable outcome, likely to have a positive effect on mobility, health, and quality of life.

In this case, there is a clear condition (anorexia leading to involuntary weight loss) that is associated with increased morbidity and mortality that is well recognized by national professional organizations (American Dietetic Association, Gerontological Society of America, and the American Medical Directors Association) with specific criteria for intervention. However, because there is no approved indication for anorexia of aging, new potential agents that may stimulate appetite in this population of older patients may, at the discretion of the FDA, also need to demonstrate efficacy beyond increased appetite, food intake, or body weight. This may include decreased mortality or improved functional capacity, or both, depending on the target population with this condition.

Frailty

Although there is broad consensus, even outside the geriatric community, that frailty is a true clinical entity, the precise definition of this complex geriatric condition remains elusive. The Fried definition (7) provides a much needed operationalized construct for frailty and has been an invaluable stimulus for research in this important area. This definition of frailty uses five criteria that include weight loss (or loss of muscle), slow walking speed, exhaustion (or fatigue), muscle weakness, and low level of physical activity. Some of the frailty criteria can be easily and objectively assessed by a health care professional, whereas others, such as exhaustion (or fatigue) and level of physical activity are more difficult to quantify. However well recognized the condition or syndrome of frailty may be, it is clear that the etiology and potential treatment is multifactorial and complex (8,9). Deficiencies in skeletal muscle, defined on the basis of quantity (sarcopenia), quality (force production or cross-sectional area), or strength, or all, are important and validated components of frailty (10). However, reduced food intake (11), inflammation, anemia (12), vitamin D deficiency (13), and hormonal status (14) have also been suggested to play an important role in the etiology of frailty.

Although it is generally hypothesized that frailty is a final pathway with multiple etiologies, evidence is emerging that dysfunction of one or more of the critical mechanisms that maintain biological homeostasis and allow adaptation to stress underlies frailty. Thus, it is conceivable that new pharmacological targets for the treatment of frailty will emerge sometime in the future. However, the FDA considers frailty a problematic indication for a number of reasons, including the lack of clear consensus among clinicians and investigators on the definition of frailty, uncertainty about whether it is a treatable condition, and the absence of clear treatment goals. Primary end points for any clinical trial must be considered to be components of the condition or disease; however, the current operational definition by Fried and associates include criteria that are difficult to measure or not well defined. For this reason, until the geriatric community provides a consensus on clearly defined and easily measured criteria, the condition of frailty will unlikely be considered for an indication by the FDA.

Sarcopenia

Sarcopenia has been defined as the age-related loss of skeletal muscle mass (15). Sarcopenia appears to be a universal phenomenon and has been linked to a number of conditions including weakness, mobility limitations (16), disability, low bone density (17,18), and increased mortality. Like osteopenia, which is strongly associated with bone fracture risk, sarcopenia was initially considered a putative risk factor of specific distal outcomes such as falls, disability, fatigue, and low levels of physical activity. However, the influence of muscle on many of these factors is complex. Although muscle mass is related to strength, it is by no means the only determinant of force production. Increased and decreased physical activity have powerful effects on strength and functional capacity in older people that are not explained by changes in muscle mass alone. In older people, increased body fatness has been more strongly linked to low functional capacity than muscle mass (19). Nonetheless, although several factors may have a role, muscle weakness (20) and sarcopenia remain as extremely important determinants of low functional capacity in older people (21).

As with many conditions associated with advancing age, sarcopenia results from a number of factors, each of which may affect the trajectory of loss of skeletal muscle mass. Low testosterone, estrogen, and growth hormone levels in elderly people have an effect on muscle mass. Protein intake (22), vitamin D status (23), physical activity (24), and inflammation (25) also have been demonstrated to influence muscle mass in elderly people.

A specific criterion to better define sarcopenia has been described (26) and used by a number of investigators examining prevalence and impact of sarcopenia. This criterion of a muscle mass that is 2 standard deviations lower than the average for a 30-year-old man or woman has high specificity and can be measured with some degree of precision in most clinical settings in the United States. Among men and women aged 65 years or older, the prevalence of sarcopenia according to this definition is high and shows a striking increase with advancing age (27). Using this criterion, Janssen and associates (28) estimated that sarcopenia resulted in an estimated direct health care cost in the United States in 2000 of $18.5 billion ($10.8 billion in men, $7.7 billion in women), which represented about 1.5% of total health care expenditures for that year. The widespread use of dual x-ray absorptiometry to measure bone density as a diagnostic criterion for risk of osteoporosis has provided an opportunity to use this instrument for the purpose of identifying individuals with sarcopenia. Because skeletal muscle mass is a prominent determinant of lower functional capacity, perhaps diagnostic criteria for sarcopenia will use the Baumgartner criterion coupled with an easy-to-measure functional tool associated with morbidity and mortality such as gait speed or chair stand time. Sarcopenia may be an indication that is particularly responsive to an anabolic stimulus. Bhasin and associates (29) have demonstrated that testosterone administration in men with low testosterone levels results in a significant increase in muscle size and a proportionate increase in strength in both young and elderly men.

Although condition, etiology, prevalence, and consequences of sarcopenia have been well described, there is little consensus on its prevention or treatment. Resistance exercise can stimulate large changes in muscle mass and strength in healthy (30) and frail older people (31); however, no consensus exists on pharmacological or nutritional treatment for this condition. The FDA may not consider sarcopenia itself as an indication at this time. First, its direct association with functional status and quality-of-life outcomes is complex and still being researched. Second, no professional organization has issued a position statement concerning sarcopenia as a treatable condition. Because of this apparent lack of interest, concern, or consensus from professional organizations dealing with geriatric syndromes or conditions, the FDA has little evidence that the medical or geriatric community has a cohesive view of sarcopenia as a treatable geriatric condition.

Mobility Limitation Secondary to Muscle Weakness

Limited mobility is perhaps the strongest predictor of morbidity and mortality in older persons and is one of the most important contributors to quality of life. Measurements of functional capacity have been used to examine this condition and a previous meeting with FDA (1) outlined the importance of these measures for the examination of indication for any drug that targets muscle mass, weakness, or low functional capacity. Mobility limitations and weakness are easy to measure in geriatric patients, and both clinicians and patients understand their importance. Mobility limitation could potentially be accepted by the FDA because it is widely recognized as an important geriatric condition; is measured with instruments that have good validity, reliability, and sensitivity to change; has been well documented as to its relation to multiple adverse outcomes in older persons; and has been studied as to how it relates to clinically meaningful change. As for other potential indications described, the etiology for limited mobility is generally considered multifactorial, including sarcopenia or increased body fatness or both, balance disorders, joint pain and arthritis, cognitive impairment, anemia, and poor vision. However, there is increasing evidence that these risk factors tend to be related and to occur jointly in the same individuals and that they are all related to a common pathophysiological mechanism. Again, signaling molecules that contribute to the stability of the homeostatic network are the most likely candidates and may soon become targets for the treatment of mobility problems in older persons.

CONCLUSIONS

The list of potential indications that might be considered by the FDA for geriatric patients is by no means exhaustive. If we rely on the official regulations aforementioned, none of these geriatric conditions can be considered as fully acceptable as an indication for drug approval. With this limitation, should the search for potential pharmacological treatments for age-related sarcopenia or anorexia be stopped? We believe that this would not be in the best interest of the aging population and that an effort should be made to reshape the mechanism of drug approval to the emerging concepts of geriatric conditions that seriously reduce quality of life in older persons. At the same time, geriatrics researchers must become fully aware of the evidence needed by the FDA to develop new approach to drug indications and begin to work with the FDA in moving toward these new indications.

Although mortality may be an important end point for a number of diseases and conditions, improved functional capacity and independence are considered by most geriatricians as preferred end points for their elderly patients. A number of potential treatments for weakness and low functional capacity in elderly people are currently in development. These new treatments must be coupled with indications that are specific to the mechanism of action and conditions that are also specific to geriatric patients. Clearly, the important and daunting task of evaluating effectiveness and safety for any new indication (and its treatment) fall on the FDA. However, there is also an important task that must be addressed by the community of clinicians and scientists that are involved in the treatment and investigation of factors associated with frailty and poor function: coming to a consensus of what constitutes an indication and the specific criteria for the identification of any treatable condition and developing appropriate outcome measures. One interesting possibility is to formulate “mosaic outcome measures” including both “functional measures” (the true end point for quality of life) and biomarkers (that allow measures of the effect of the intervention on specific biological mechanisms).

In the past, changes in the approach to diagnosis and treatment of traditional diseases has opened the door for new therapies for the treatment and prevention of osteopenia (bone density), heart disease (cholesterol lowering), type 2 diabetes (insulin-sensitizing agents), and many others. As new therapeutic targets are identified and new agents are developed that specifically address functional problems in older persons, new approaches to drug testing and approval will be needed. A close partnership between FDA and the “geriatric” community is essential for this transformation to take place.

APPENDIX

Shalender Bhasin, Boston University School of Medicine; Mark A. Espeland, Department of Biostatistical Sciences, Wake Forest University Health Sciences; William J. Evans, Donald W. Reynolds Institute on Aging, University of Arkansas for Medical Sciences; Luigi Ferrucci, Director, Baltimore Longitudinal Study of Aging, National Institute on Aging (NIA); Linda P. Fried, Cornell University; Thomas M. Gill, Yale University School of Medicine; Marco Pahor, University of Florida School of Medicine; and Stephanie Studenski, University of Pittsburgh School of Medicine

NIA—Laboratory of Epidemiology, Demography, and Biometry

Jack Guralnik

NIA—Geriatrics and Clinical Gerontology Program

Susan Nayfield Sergei Romashkin(NIA representatives participated in and contributed to this meeting. Their opinions expressed in this article do not necessarily represent the views of the NIA.)

FDA—Food and Drug AministrationRobert PerlsteinLaurie BurkeMary Parks (FDA representatives participated in and contributed to this meeting, but this article should not be construed as an FDA policy statement.)

References

1. Working Group on Functional Outcome Measures for Clinical Trials. Functional outcomes for clinical trials in frail older persons. Time to be moving. J Gerontol Med Sci. 2008;63A:160–165. [PMC free article] [PubMed]
2. Morley JE. Anorexia and weight loss in older persons. J Gerontol A Biol Sci Med Sci. 2003;58:131–137. [PubMed]
3. Thomas DR, Verdery RB, Gardner L, Kant A, Lindsay J. A prospective study of outcome from protein-energy malnutrition in nursing home residents. Jpen J Parenter Enteral Nutr. 1991;15:400–404. [PubMed]
4. Thomas DR, Ashmen W, Morley JE, Evans WJ. Nutritional management in long-term care: development of a clinical guideline. J Gerontol Med Sci. 2000;55A:M725–M734. [PubMed]
5. Morley JE. Orexigenic and anabolic agents. Clin Geriatr Med. 2002;18:853–866. [PubMed]
6. Evans WJ. Editorial: megestrol acetate use for weight gain should be carefully considered. J Clin Endocrinol Metab. 2007;92:420–421. [comment] [PubMed]
7. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56:M146–M156. [PubMed]
8. Fried LP, Ferrucci L, Darer J, Williamson JD, Anderson G. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J Gerontol A Biol Sci Med Sci. 2004;59:255–263. [PubMed]
9. Walston J. Frailty—the search for underlying causes. Sci Aging Knowledge Environ. 2004;2004:pe4. [PubMed]
10. Cesari M, Leeuwenburgh C, Lauretani F, et al. Frailty syndrome and skeletal muscle: results from the Invecchiare in Chianti study. Am J Clin Nutr. 2006;83:1142–1148. [PMC free article] [PubMed]
11. Bartali B, Frongillo EA, Bandinelli S, et al. Low nutrient intake is an essential component of frailty in older persons. J Gerontol A Biol Sci Med Sci. 2006;61:589–593. [PMC free article] [PubMed]
12. Leng S, Chaves P, Koenig K, Walston J. Serum interleukin-6 and hemoglobin as physiological correlates in the geriatric syndrome of frailty: a pilot study. J Am Geriatr Soc. 2002;50:1268–1271. [PubMed]
13. Montero-Odasso M, Duque G. Vitamin D in the aging musculoskeletal system: an authentic strength preserving hormone. Mol Aspects Med. 2005;26:203–219. [PubMed]
14. Morley JE, Kim MJ, Haren MT. Frailty and hormones. Rev Endocr Metab Disord. 2005;6:101–108. [PubMed]
15. Evans W. What is sarcopenia? J Gerontol. 1995;50A(special issue):5–8. [PubMed]
16. Janssen I, Heymsfield SB, Ross R. Low relative skeletal muscle mass (sarcopenia) in older persons is associated with functional impairment and physical disability. J Am Geriatr Soc. 2002;50:889–896. [PubMed]
17. Walsh MC, Hunter GR, Livingstone MB. Sarcopenia in premenopausal and postmenopausal women with osteopenia, osteoporosis and normal bone mineral density. Osteoporos Int. 2006;17:61–67. [PubMed]
18. Ferrucci L, Russo CR, Lauretani F, Bandinelli S, Guralnik JM. A role for sarcopenia in late-life osteoporosis. Aging Clin Exp Res. 2002;14:1–4. [PubMed]
19. Lebrun CE, van der Schouw YT, de Jong FH, Grobbee DE, Lamberts SW. Fat mass rather than muscle strength is the major determinant of physical function and disability in postmenopausal women younger than 75 years of age. Menopause. 2006;13:474–481. [PubMed]
20. Newman AB, Kupelian V, Visser M, et al. Strength, but not muscle mass, is associated with mortality in the health, aging and body composition study cohort. J Gerontol A Biol Sci Med Sci. 2006;61:72–77. [PubMed]
21. Sowers MR, Crutchfield M, Richards K, et al. Sarcopenia is related to physical functioning and leg strength in middle-aged women. J Gerontol A Biol Sci Med Sci. 2005;60:486–490. [PubMed]
22. Campbell WW, Trappe TA, Wolfe RR, Evans WJ. The recommended dietary allowance for protein may not be adequate for older people to maintain skeletal muscle. J Gerontol A Biol Sci Med Sci. 2001;56:M373–M380. [PubMed]
23. Visser M, Deeg DJ, Lips P. Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam. J Clin Endocrinol Metab. 2003;88:5766–5772. [PubMed]
24. Hughes VA, Frontera WR, Roubenoff R, Evans WJ, Singh MA. Longitudinal changes in body composition in older men and women: role of body weight change and physical activity. Am J Clin Nutr. 2002;76:473–481. [PubMed]
25. Schaap LA, Pluijm SM, Deeg DJ, Visser M. Inflammatory markers and loss of muscle mass (sarcopenia) and strength. Am J Med. 2006;119:526. e9–e17. [PubMed]
26. Baumgartner RN, Koehler KM, Gallagher D, et al. Epidemiology of sarcopenia among the elderly in New Mexico. Am J Epidemiol. 1998;147:755–763. [Published erratum appears in Am J Epidermiol. 1999 Jun 15:149(12):1161] [PubMed]
27. Iannuzzi-Sucich M, Prestwood KM, Kenny AM. Prevalence of sarcopenia and predictors of skeletal muscle mass in healthy, older men and women. J Gerontol A Biol Sci Med Sci. 2002;57:M772–M777. [PubMed]
28. Janssen I, Shepard DS, Katzmarzyk PT, Roubenoff R. The healthcare costs of sarcopenia in the United States. J Am Geriatr Soc. 2004;52:80–85. [PubMed]
29. Bhasin S, Woodhouse L, Casaburi R, et al. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab. 2005;90:678–688. [PubMed]
30. Frontera WR, Meredith CN, O’Reilly KP, Knuttgen HG, Evans WJ. Strength conditioning in older men: skeletal muscle hypertrophy and improved function. J Appl Physiol. 1988;64:1038–1044. [PubMed]
31. Fiatarone MA, O’Neill EF, Ryan ND, et al. Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med. 1994;330:1769–1775. [PubMed]

Articles from The Journals of Gerontology Series A: Biological Sciences and Medical Sciences are provided here courtesy of Oxford University Press