Penetrating the Universal Emerging Market: Answers to 10 Key Questions on Developing and Marketing Therapies for the Aging

Population

People try to put us down [Talkin' 'bout my generation] Just because we get around [Talkin' 'bout my generation] Things they do look awful c-c-cold [Talkin' 'bout my generation] Hope I die before I get old [Talkin' 'bout my generation] -Roger Daltrey, 1965 What the now 68 year old Roger Daltrey was likely unaware of is that 55 years later, we would be embarking upon the most pronounced growth of the older population ever experienced. Similar to many in his generation Mr. Daltrey would indeed be getting old before he died (fortunately). In 1965, when this iconic song was released, the global population of those aged 60 and over was 200+ million (approximately 6% of the worlds population); today it is around 760 million (~11%). The United Nations estimates that this number will grow to 1 billion in the year 2020.1 By the year 2050, it is expected that individuals 60 and older will comprise 21% of the earths citizens numbering 2 billion. Likely considered implausible in 1965, the fastest upsurge will be those 85 and older. While this is all said, among the life sciences industry geriatrics has often remained the proverbial elephant in the room. For the most part, it is not considered an exciting population and clinical trials are more difficult to design due to multiple comorbidities. Ironically, the life sciences industry possesses the dual responsibility for expanding the average lifespan as well as ensuring the future health and optimal function for those who reach older ages. A result of

innovation such as drug and device-delivered therapies to manage acute events and chronic conditions such as accidents, coronary artery disease, diabetes and even certain cancers and infectious diseases are no longer a death sentence. Nonetheless, the resulting longevity and accompanying frailty predisposes individuals to a whole host of other chronic ailments including Alzheimers disease, heart failure, and other forms of cancer and infections. Additionally, those with chronic diseases such as diabetes and hypertension are living longer with them. Taking therapy discovery to the next level requires a 360 degree perspective on what this population truly needs to ensure that older individuals have access to therapies which have safety and efficacy profiles specific to them and an adequately informed health care delivery system. It is well understood that addressing this demographic shift comes with significant challenges. However, it also affords an incredible opportunity for life science companies who can take on this challenge by specifically addressing this age group. Indeed there exists a huge potential to differentiate a companys products based on addressing this population with specific drugs, devices, and therapies. This is attune to the transformation of wheelchairs to scooters and the growth of 55+ and assisted living communities. This white paper will address the critical questions for the industry and suggest prospective approaches that the industry can leverage as progressive companies target the enormous global emerging market that is older adults. 1. Why Are We Living Longer And What Are the Consequences? The lengthened lifespan is the result of the coupling of two critical factors, a decrease in mortality from infectious diseases and breakthroughs in the treatment of chronic diseases such as heart disease

which have lengthened the average lifespan.2 In the early part of the 20th century, the introduction of anti-infective agents including antibiotics and sulfa drugs afforded life-saving therapy for individuals afflicted with most infectious conditions. Vaccines targeted to once epidemic diseases like smallpox, measles, scarlet fever, diphtheria, and polio virtually eliminated deaths from these conditions. In the case of chronic conditions, using the example of heart disease, improvements in risk factor management such as cholesterol lowering and primary percutaneous coronary intervention in the case of acute myocardial infarction have allowed patients to live significantly longer with heart disease than they might have even 50 years ago. Longevity opens up the risk for acquiring other diseases not common in younger individuals such as pneumonia, dementia and cancer.3 Aging also leads to certain disabilities such frailty in a number of individuals. In one Dutch study, approximately 10% of community-dwelling adults 65 and older were considered frail.4 Moreover the same chronic conditions that were managed well enough to get people to an old age still require careful control. Physiologic changes in aging (discussed in the following section) also may result in alteration in the response to the drugs used to treat them. 2. How is the Aging Population Different? Physiological changes occur with aging in all organ systems.5 For example, the cardiovascular system is affected by decreases in cardiac output, increase in blood pressure and arterial stiffening via arteriosclerosis. Individuals experience a decrease in lung vital capacity and slower expiratory flow rates coupled with impaired gas exchange. Progressive elevation of blood glucose occurs with age on a multifactorial basis Furthermore, aging impacts the pharmacokinetics and pharmacodynamics of many drugs by reducing hepatic metabolism (as low as 3050%) and renal function while increasing the volume

of distribution of lipid soluble drugs since lead body mass declines due to loss and atrophy of muscle cells. Consequently this extends a drugs elimination half-life. 3. Can Drugs Be Designed Specifically for Older People? Ideally, drugs destined for the geriatric population should be developed so that they ideally fit the needs of the aging body. They would produce effects at a pace which maintains physiological balance. This would be slow enough to reduce shock to the system yet as quickly as possible to relieve symptoms at minimal doses. While such products do not yet appear to be available, there is evidence of developments which if applied effectively could eventually accomplish this goal. For example, personalized medicine such as intelligent dosing uses computer models to address this challenge. The model takes into consideration a multitude of factors to determine the ideal medication dose for a given patient. In the area of drug delivery, innovations such as a multi-unit particulate system may allow drugs to be dosed in a highly precise and individualized manner by allowing a combination of different pellets within a capsule or tablet to take effect at different times and at varying strengths. More appropriate drug formulation is also being examined; possibly greater availability of liquid formulations, rapidly dissolving tablets, and even drug-impregnated film that may be placed on the tongue. Additionally, there has been interest among some researchers to address deficits in visual and tactile ability which result in difficulty of patients to differentiate one pill from the other. 4. What About Including the Very Old in Trials? While the number of older patients enrolled in clinical trials has somewhat increased over the first decade of the new millennium, clinical trial data in

the very old and oldest old, i.e. patients over 75 and older and 85, respectively, is nevertheless somewhat lacking. There is still not adequate data available so that providers can be confident that the medications they use in their geriatric patients are safe and effective in this population. For example, in a 2007 study sponsored by the Robert Wood Johnson Foundation which reviewed 109 clinical trials, it was revealed that a fifth of them excluded patients above a specified age, and that almost half of the remaining studies used criteria likely to exclude the elderly disproportionatelyfrailty or impaired cognition.6 In 1993, the FDA released guidelines focused on increasing the amount of geriatric information available in the label for drugs which will be predominantly used in this population. 7 By 1997, a Geriatric Use section was added to the label in order to report any pharmacokinetic or pharmacodynamic differences between the geriatric and overall populations.8 Recently there has been a greater push by regulatory agencies both in the US and Europe with the release of ICH guidelines titled, Guidance for Industry: E7 Studies in Support of Special Populations: Geriatrics driving toward the goal of ensuring that real world geriatric patients including oldest old, those with comorbidities, and receiving concomitant therapies are well-represented in clinical trials of new therapies or formulations.9 At current time, these remain only guidelines. The EU seems to be taking a more aggressive role as the EMA as part of the Agencys Road Map to 2015, has devised a Geriatric Medicines Strategy and has even put together a Geriatric Expert Group that is charged with providing scientific advice to CHMP and the EMA on issues related to the elderly.10

5. I Have Heard of a Pediatric Indication. Is there a Geriatric Indication? True, most companies are familiar with filing for pediatric indications. Since 1997, the opportunity to obtain pediatric exclusivity has allowed companies to further differentiate their products as well as gain an additional 6 months of protection against generic competition in the United States. Pediatric dosing makes excellent sense as drug metabolism in children differs from that of adults thus increasing the risk of adverse reactions and lack of efficacy. Such differences are even observed across the span of the pediatric age range. Without specific dosing in the label, clinicians are playing guessing games with their young patients. When you take a careful look at the pediatric situation with respect to the value of specific dosing, it is easy to see how this parallels the geriatric field. While many in the pediatric community warn that children should not be treated as little adults, it could be also cautioned that the elderly should not be considered as vigorous adults. Most clinicians feel that it is absurd to treat an 8 year old in exactly the same manner as someone who is 35; why should it not be just as illogical for a 75 year old to be treated the same as a 35 year old? By its nature, aging impacts the pharmacokinetics and pharmacodynamics of many drugs. Reduced hepatic metabolism (as low as 30-50%) secondary to changes in hepatic blood flow, liver mass and hepatic endothelium, reduction in renal function and increased volume of distribution of lipid soluble drugs all increase the elimination half-life of a drug. Altered sensitivity, common to several drug classes of drugs, results in accentuated effects in the elderly.11 Put together, this gives rise to an increase in adverse events in this population. Accordingly, the medical community is making due by practicing by the adage of start low, go slow and in general, cutting the dose of many common medications in the elderly.

Still, as these doses were not clinically studied, it is not clear if as adverse events are attenuated the drugs efficacy is being jeopardized. Why havent we heard more about geriatric exclusivity? Relative to the overall medication use in the U.S, the elderly are a sizable population. Although the 65 and older age group comprises only 13% of the population, they account for approximately 34% of prescription medication use. 12,13 Additionally, a recent survey conducted by the CDCs National Center for Health Statistics reported that almost 90% of individuals 60 and older had used at least one medication in the past month and 76% reported two or more.14 It would make logical sense that drugs used disproportionately by the elderly would already have geriatric-specific dosing in their labeling. This is not the case. Indeed, in a study performed by Steinmetz, et al, looking at the 50 oral drugs most commonly used by patients 65 and older in an in-patient setting, only 8 contained some form of altered dosing guidance in the label specific to geriatric patients.15 None included age-specific dosing. In researching circumstances in which geriatric exclusivity was granted, our search yielded only one. In 2005, the FDA approved geriatric dosing for Savient Pharmaceuticals Oxandrin (an anabolic steroid indicated for weight gain) and granted the product 3year marketing exclusivity.16 This is quite notable given the exclusivity for adding pediatric dosing is limited to 6 months. So goes the question of why companies are not pursuing geriatric dosing as a way to attenuate competitive threat, both branded and generic. Unmistakably, this pursuit does not make for a clean trial as the elderly are more likely than their younger counterparts to have more comorbidities and thus be on other multiple medications. This is most

likely why so few patients of 75 and older are included in clinical trials in general, even for drugs that are very appropriate to them. The opportunity for industry is substantial. In addition to the potential for an extra 3 years of exclusivity, providing specific dosing guidance for geriatric patients will likely result in providers using that particular drug over competitors or even generics. They may feel confident that they can circumvent adverse events while maintaining the optimal level of efficacy. We look forward to further discussion of geriatric exclusivity and why it is not being utilized by life science companies. 6. What Are Geriatric-Specific Endpoints? Most trials conventionally measure only endpoints which tend to signify the efficacy of the therapy as well as standard measures of safety and tolerability. As noted earlier, age-related physiologic changes may in fact alter an individuals response to a given therapy. Some of these may include those which impact cognition and function. Therefore, drugs being evaluated for a geriatric population would ideally include these endpoints which expand beyond efficacy and safety for example, if the drug results in delirium or incontinence. Review of the literature, commentary, etc. has revealed that there is still a call to action for such endpoints. To confirm this, using the website clinicaltrials.gov we performed a search of all interventional trials involving patients >66 years of age in which cognition was included as an outcome measure. Out of 209 trials, only five did not evaluating therapies for diseases involving the brain such as Alzheimers and Parkinsons disease. Although there is significant interest in including such endpoints for drugs used in older individuals, the level of importance has not been recognized by industry.

Efforts are being made by regulators to encourage the inclusion of such geriatric-specific endpoints. In the U.S. and in Europe, regulatory bodies have stated the goal of ensuring that drugs used primarily in the older population have been in clinical trials which adequately represent these patients. The E7 (referred to earlier) specifies that certain specific adverse events and age-related efficacy endpoints should be actively sought in the geriatric population, e.g., effects on cognitive function, balance and falls, urinary incontinence or retention, weight loss, and sarcopenia. 9 7. How Will Such Innovations Be Paid For? It is impossible to have a discussion about health care for the aging population without mentioning cost-containment policies. As we discuss the role of innovation in ensuring that quality and fulfillment of life are achieved while extending it, a key question is how this will all be paid. Moreover, are costcontainment policies with respect to newer more expensive therapies counterintuitive as they may result in higher costs down the road? In certain situations failure to use a certain medication may result in severe consequences for which the treatment may outweigh the cost of the actual medication. This involves a careful cost-benefit analysis to show that not using a certain medication will in fact raise the cost of treatment. In 2006, enacted as part of the Medicare Modernization Act of 2003, older individuals were now eligible for formal Medicare prescription plans (Medicare Part D) either through Medicare Prescription Drug Plans (PDP) or Advantage plans. At the same time these plans offer the geriatric population greater access to medications overall, they are still somewhat restrictive. Given the latest news regarding the elevated stroke risk in older women with atrial fibrillation (AF) regardless of anticoagulation status, we looked at the availability

within these plans, of newer agents approved for stroke prevention in AF, specifically Pradaxa and Xarelto. In clinical trials in which the median age was 71, Pradaxa demonstrated an advantage over warfarin while Xarelto was comparable. Both agents obviate the frequent monitoring and dietary restrictions required for warfarin therapy. We evaluated formularies for Medicare prescription drug benefits offered by two of the top health insurers in the U.S (one was a PDP and the other an Advantage plan) to determine coverage of these agents. The Advantage program did not cover either drug. Although the PDP offers both drugs, they are Tier 3 with an associated co-pay of $35-$45 and necessitate prior authorization. In comparison, warfarin is Tier 2 with the co-pay ranging from $8 to $12 co-pay with no prior authorization required. The issue of prior authorization for Medicare plans has been increasing. Based on results of the Avalere Health Analysis in 2011, the percent of drugs requiring prior authorization has increased from 12.4% in 2008 to 16.7% in 2011.17 8. Are There Other Means to Differentiate Current and Future Therapies for the Geriatric Market? Snowfish feels that highlighting the safety and necessity in this particular patient population can build meaningful differentiation. This involves a review of the drugs being used in older patients and how they are used. Based upon this assessment, if a particular product is not demonstrating benefit in this patient population or places them at an increased risk for an adverse drug reaction, a suitable alternative should be identified and developed. An example of this is the Beers Criteria. Dr. Mark Beers in collaboration with other experts released the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults, informally known

as Beer's Criteria. The criteria is a reference for healthcare professionals as it outlines drugs for which the risks outweigh the benefits in those 65 years and older. 18 With a handful of revisions since its inception, the Beers Criteria remains the foremost guide to drugs which either pose high risks of adverse effects or seem to have limited effectiveness in the geriatric population. Currently it categorizes drugs in the following ways: (1) potentially inappropriate for older people because they either pose high risks of adverse effects or appear to have limited effectiveness in older patients (2) potentially inappropriate for older people who have certain diseases or disorders because these drugs may exacerbate the specified health problems (3) used with caution in older adults. In the meantime, other tools have been developed including the Screening Tool of Older Persons (STOPP) criteria.19 Furthermore various mechanisms to reduce the prescribing of potentially inappropriate drugs (PIMs) in the elderly have been put in place at the regional and local levels. Regardless of available to tools and initiatives, considerable use of PIMs persists. A study from a group at Weill Cornell Medical College identified 38% of U.S-based older adult patients receiving home care were prescribed at least one PIM.20 A similar prevalence was found in Australia in which 40% of a sample of community-dwelling older adults was found to use at least one PIM.21 Lack of awareness among the general community of healthcare professionals may be one major reason for this relatively high rate of PIM use. A survey of eighty-nine physicians revealed that despite the fact that an estimated 25% of their practice consisted of patients > 65, many exhibited a poor knowledge of PIMs and were unaware of prescribing guidelines such as the Beers criteria.

9. Is There an Adequate Supply Geriatric Experts to Drive Innovation? A 1990 Institute of Medicine report titled Drug Development for the Geriatric Population commented that in the late 1980s there were few geriatric trained faculty in medical schools.22 They blamed those circumstances on the lack of drive to develop a geriatric research environment. As of 2012, there were 137 Liaison Committee on Medical Education (LCME)-accredited medical schools in the US. The encouraging news is that the vast majority of schools offer in some form, geriatric education or training. Still, the majority of the faculty who lead these programs do not have formal geriatric training; as of 2005, only 44% of directors of geriatric academic programs underwent either geriatric fellowship or earned a Certificate of Added Qualifications in geriatric medicine. Furthermore, of schools awarding a degree of doctor of medicine (MD), only seven reported having a full-fledged department. Instead, they tend to be divisions or sections of other departments such as internal medicine. As expressed in a 2009 article by Bernard, et al, a department provides for a seat at the table with respect to budgeting, strategic planning and allocation of resources within an academic institution.23 Such status may indeed enhance research program development. It should also be noted that as of this posting, unlike pediatrics, geriatrics is still considered a subspecialty. In contrast, in 16 countries within the EU, geriatrics is indeed a specialty.

10. Who Are the Current Life Science Players in the Aging Market? A handful of pharmaceutical companies have been beginning to take an interest in therapies for diseases of aging and those for frailty itself. In particular, Sanofi has instituted the Aging Therapeutic Strategic Unit. This department is charged with rethinking how treatments to the aging population should be developed and delivered. According to an article discussing the Unit, there is concentration in detecting, preventing and reversal of age-related dysfunctions, disorders, and diseases including Alzheimers, chronic pain, osteoarthritis, hearing disorders, sarcopenia/frailty. Pfizer put out a report titled Preventive Care and Healthy Aging which was commissioned through the Economist Business Intelligence Unit.3 This report highlighted the significance of healthy aging and the value of preventative care with respect to reducing the cost of care and profiled eight countries: Brazil, China, India, Japan, Russia, South Africa, the U.K. and the U.S. It not only summarized the significant challenges that must be overcome to implement this approach, but also underscored the benefits that governments (and citizens) can reap by implementing certain changes. In general, this report reinforced the notion that globally, we tend to take a very reactive approach to healthcare delivery which is counterintuitive to the care of older individuals.

Conclusion Well beyond what Roger Daltrey envisioned in the 1960s, his generation is spearheading the shift in the global population to where eventually, one-fifth will be aged 60 or older. It is medical innovation that has both allowed for this phenomenon and that will be necessary to maintain the health and well-being along with longevity. The issues described in this paper emphasize the need for creativity within the life science industry in order to take advantage of the various opportunities related to the aging population. For example, recognizing that patients will require continuation of therapy for chronic conditions for many years after the initial diagnosis, the industry can ensure that these treatments are as effective and safe for a patient at 70 as it was at 50 and leverage this as a competitive advantage.
1. World Population Ageing 2009. Available at: http://www.un.org/esa/population/publications/WPA2009/WPA2009_W orkingPaper.pdf. Accessed 1/3/12 Global Health and Population Aging. http://www.prb.org/pdf07/TodaysResearchAging4.pdf. Accessed 1/3/12. Preventive Care and Health Aging A Global Perspective. Economist Business Unit. Available at: http://digitalresearch.eiu.com/healthyageing/report. Accessed 1/3/12. Collard RM, Boter H, Schoevers RA, Oude Voshaar RC. Prevalence of frailty in community-dwelling older persons: a systematic review. J Am Geriatr Soc. 2012;60(8):1487-92. Boss GR. Age-Related Physiological Changes and Their Clinical Significance. West J Med .1981;135(6). Zulman DM, Sussman JB, Chen X, Cigolle CT, Blaum CS, Hayward RA. Examining the evidence: a systematic review of the inclusion and analysis of older adults in randomized controlled trials. J Gen Intern Med. 2011 Jul;26(7):783-90. US Food and Drug Administration Guideline for industry. Studies in support of special populations: geriatrics. 1994. Available at: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM 129519.pdf. Accessed 1/3/13. Federal Register (62 Federal Register 45313-45326). August 27, 1997. Guidance for Industry E7 Studies in Support of Special Populations: Geriatrics. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryIn formation/Guidances/UCM189544.pdf. Accessed 1/3/13. EMA Geriatric Medicines Strategy. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2011/ 02/WC500102291.pdf. Accessed 1/3/13. Crooks J, Stevenson IH. Drug response in the elderlysensitivity and pharmacokinetic considerations Age Ageing.1981;10(2):73-80. Ferrini A, Ferrini R. 2000. Health in the Later Years. 3rd edition. Boston, MA, McGraw Hill. 13. 14. Centers for Disease Control and Prevention and The Merck Company Foundation. The State of Health and Aging in America 2004. Gu Q, Dillon CF, Burt VL. Prescription Drug Use Continues to Increase: U.S. Prescription Drug Data for 2007-2008. Available at: http://www.cdc.gov/nchs/data/databriefs/db42.htm. Accessed 1/4/13. Steinmetz KL, Coley KC, Pollock BG. Assessment of geriatric information on the drug label for commonly prescribed drugs in older people. J Am Geriatr Soc. 2005;53(5):891-4. Savient Pharmaceuticals Files Citizens' Petition with the FDA for Oxandrin. Available at: http://investor.savient.com/releasedetail.cfm?releaseid=189758. Accessed 1/4/13. Initial Trend Analysis of 2011 Medicare Prescription Drug Plan Formularies. Available at: http://www.avalerehealth.net/news/archive/Avalere_Health_Analysis_of_2011_ Part_D_Formularies.pdf. Accessed 1/4/13. American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2012;60(4):616-31 Gallagher P, OMahony D. STOPP (Screening Tool of Older Persons potentially inappropriate Prescriptions): application to acutely ill elderly patients and comparison with Beers criteria. Age Ageing. 2008; 37(6): 673-679. Bao Y, Shao H, Bishop TF, Schackman BR, Bruce ML. Inappropriate medication in a national sample of US elderly patients receiving home health care. J Gen Intern Med. 2012 Mar;27(3):304-10. Beer C, Hyde Z, Almeida OP, Norman P, Hankey GJ, Yeap BB, Flicker L.. Quality use of medicines and health outcomes among a cohort of community dwelling older men: an observational study.Br J Clin Pharmacol. 2011 ;71(4):592-9. Report of a workshop - Drug Development for the Geriatric Population. 1990. Available at: http://books.google.com/books?id=HUErAAAAYAAJ&printsec=frontcover&sourc e=gbs_ge_summary_r&cad=0#v=onepage&q&f=false. Accessed 1/5/13. Bernard MA, Blanchette PL, Brummel-Smith K. Strength and influence of geriatrics departments in academic health centers. Acad Med. 2009;84:627-632.

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Melissa Hammond is Managing Director at Snowfish and an industry leader regarding the implications and opportunities of the growing geriatric population to the life sciences industry. Snowfish provides actionable insights for the life sciences industry and has worked with the leading companies for nearly a decade. To learn more about Snowfish, please go to www.snowfish.net or call +1-703-759-6100. 8