Elderly patients: an increasingly relevant patient population.

BY: Simonetta Alvino 9. October 2012 09:19

It is likely that the Europe Union (EU) will face major challenges in relation to population ageing brought about by low fertility levels, improved medical and social care leading to longer life expectancy, and the baby-boomers entering the age of retirement. The number of elderly people in the EU – defined as those aged 65 years or over – is expected to grow from around 84 million (or 17% of the total population) in 2008 to around 141 million (or 29.9% of the total population) by 2050. The growth of the population aged 80 or more will be even more pronounced as more people are expected to live longer. The proportion of people over 80 is projected to almost triple in the EU and will account for a double-digit share of the total population by 2050 with more than 50 million people (Eurostat yearbook 2008).

As the proportion of this vulnerable population in society rises, it becomes increasingly important to ensure that their special needs are taken into consideration when developing, approving. and using new medicines. In fact, there is a perceived need for more systematic acquisition and assessment of clinical-trial data relating to the benefits and risks of medicines intended for use in the elderly. The World Health Organization (WHO) (November 2004), in the study “Priority Medicines for Europe and the World” concluded “The elderly are still unjustifiably excluded from clinical trials. Laws and guidelines should be developed that include the participation of the elderly”.

In 2006, the Committee for Medical Products for Human Use (CHMP) evaluated the adequacy of guidance on the elderly medicinal products and identified areas of improvements regarding:

1. The number of elderly patients participating in the clinical development programs.
2. The minimum requirements for two different age classes: elderly and very elderly.
3. The adequate representation of the elderly in the efficacy and safety database for integrating and completing the pharmacokinetics (PK) requirements. Ensuring that medicines are labelled appropriately for the elderly is important and this means that they should be included in clinical studies where special ethical, safety, and efficacy issues may arise.

In early 2011, the European Medicine Agency (EMA) published a “Geriatric Medicines Strategy” and established a Geriatric Expert Group, which will establish numerous regulatory actions, spanning from scientific advice to European Public Assessment Report (EPAR) template changes as well as post-marketing pharmacovigilance.

In parallel with the launch of EU Commission Pilot Innovation Partnership on Active and Healthy Ageing and the revision of the Clinical Trials Directive, we might see an increased political debate on the needs to ensure adequate representation of older patients in clinical trials, which could potentially lead to legislative initiatives (e.g. paediatric legislation). Currently, the European Forum for Good Clinical Practice (EFGCP) Geriatric Working Party is finalizing a document (guidance) which provides recommendations primarily on ethical aspects, on clinical trials performed in older people who may belong to a vulnerable patient population.

The pharmaceutical industry need to clarify their thinking and willingness on the matter of clinical development for older adults to face and proactively shape the discussions ahead and address the needs of this growing population.

Rheumatoid Arthritis: New Definition of Remission

BY: Anna La Noce 21. September 2012 10:59

It is widely recognized and recommended that current treatment of rheumatoid arthritis should be targeted to disease remission or, if this is not achievable, to minimal disease activity. In agreement with such recommendation, evaluation of remission and low disease activity are always included among efficacy end points of confirmatory trials of novel anti-rheumatic agents. However, this raises the problem of using a shared definition of remission that is stringent but achievable and could be applied uniformly as an outcome measure in clinical trials.

Remission has been commonly defined as a DAS28 lower than 2.6. However, in theory, this goal can be achieved even if more than 10 joints are swollen. Apparently joint erosion can continue progressing even when the DAS28 remission definition is met. In the last few year, the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) have focused on a definition of remission that reflects a state of absence of disease activity. In 2011, The ACR/EULAR proposed two options for assessing remission in clinical trials, a Boolean or an index based definition (Felson et al, Arth Rheumatism 2011;63:573-86). The Boolean definition requires that all following criteria show a score £ 1: swollen and tender joints, serum C-reactive protein (CRP) (mg/dl), patient global assessment (0 to 10). The index based definition requires a Simplified Disease Activity Index (SDAI) score £ 3.3. The ACR/EULAR have requested that both definitions are tested in future clinical trials and validated in observational datasets. Interestingly, the ACR/EULAR recommendation has been included in the revised European Medicines Agency (EMA) guidance on clinical trials in rheumatoid arthritis (CPMP/EWP/556/95 rev. 2, draft 2011), where remission or low disease activity are indicated as potential primary study end points, with remission in particular representing an optimal primary end point for trials in early rheumatoid arthritis. The EMA guidance also makes reference to the definitions of remission proposed by the ACR/EULAR.

In agreement with the ACR recommendation, data from previous clinical trials have been re-evaluated to compare the remission outcome based on the different definitions. For example, results from the TAMARA phase IIIB study (tocilizumab in patients with active disease despite stable dose of conventional or biological disease-modifying anti-rheumatic drug (DMARD) were analyzed to assess remission according to the new ACR criteria and to compare the results with the original analysis of DAS28-erythrocyte sedimentation rate (ESR) remission (Ilking-Konert et al, Ann Rheum Dis 2011;70:1986-90). At week 24, while nearly 50% of patients (47.6%) had achieved a DAS28 < 2.6, only 20.3% had attained the Boolean defined remission and 25.2% the index based remission (SDAI £ 3.3). As expected, the more stringent criteria of Boolean remission led to a considerable reduction of remission rate, that was consistent with the SDAI and with the Clinical Disease Activity Index (CDAI) remission (24.1% with CDAI < 2.8). This result indicates that Boolean criteria represent a remission model closer to what is to be intended as remission in the clinical practice, as compared with DAS28. A similar comparison was conducted in patients with early rheumatoid arthritis, for whom remission should be the primary therapy goal. Again, Boolean remission was attained by less than half of the patients compared to those that achieved a DAS28-CRP < 2.6. The new remission criteria are also being evaluated in observational or cohort studies, like the BRASS (Prince et al, Arthr Res Ther 2012;14:R68), the ESPOIR (Zhang et al, Arthr Res Ther. 2012;14:R156), early rheumatoid arthritis cohort studies (Kuriya et al, J Rheumatol. 2012;39:1155-8; Vermeer et al, Rheumatol. 2012;51:1076-80) and others. Data so far tends to confirm that the new Boolean and the SDAI remission criteria are better predictors of stability of joint damage progression compared with DAS28. Due to ACR/EULAR Boolean stringent criteria, remission may not be an achievable goal for many patients, with a number of swollen and tender joints as well as patient global assessment £ 1 being the main limiting factors.

New criteria are being evaluated in recently initiated clinical trials, in addition to DAS28, SDAI or CDAI criteria. Results from these studies may provide useful information on the performance and feasibility of the new ACR definition of remission and, most important, on the possibility of using this definition as a primary end point in future clinical trials, particularly in very early or early rheumatoid arthritis.

In the future, imaging may be included among the criteria for remission. In fact there is evidence that synovitis can still be found in patients in clinical remission and may lead to adverse functional and clinical outcome. Many questions concerning use of imaging for evaluating remission are yet to be answered, for example: the type of imaging method, the joints to be evaluated, the acceptable level of inflammation, and the impact of imaging remission on patient’s outcome.

Hormone Replacement Therapy in Menopause: 10 Years Post Women’s Health Initiative

BY: Simonetta Alvino 6. September 2012 13:42

The past decade has seen marked fluctuations in opinions concerning the merits and risks of postmenopausal hormone replacement therapy (HRT). In July 2002, menopause management faced a major turning point when the first data from the Women’s Health Initiative (WHI) trial were released (JAMA 2002;288:321-333). This study was categorized as a primary prevention trial for coronary heart disease (CHD).

However, the mean age at recruitment was 63 years, when menopausal symptoms have usually finished and HRT is rarely started, but this important difference from common clinical practice was not acknowledged at that time. Instead, WHI investigators concluded that HRT was not cardioprotective and that its risk/benefit ratio did not favor the use of postmenopausal hormones for prevention of chronic diseases. As a result, there was dramatic change in prescription habits following recommendations to reserve HRT for symptomatic women and to limit its use to the ‘shortest duration needed’ and to ‘the lowest effective dosage’. The results of the WHI changed the perception of the risk/benefit of HRT.

During the ten years which followed the publication of the WHI results, additional outcomes from subsequent analysis and new studies have kept alive the scientific debate: the increased risk for breast/uterine cancer and cardio-vascular disease found in the WHI have been increasingly viewed with scepticism and the focus of the research is now on other unresolved issues:

Critical window for starting HRT and treatment duration
Based on more than 40 observational studies on HRT, the total relative risk for CHD was 40-50% lower among current or previous users of HRTcompared to those who never had used it (p < 0.001). The key differences between the design of the WHI and the following observational studies on HRT were the timing of the initiation and the duration of HRT therapy and time since menopause. HRT administered around menopause, when there are still vascular estrogen receptors responsive to exogenous HRT, appears to reduce progression of atherosclerotic plaque. However, if HRT is administered many years after menopause, it is not beneficial and may sometimes disrupt established plaque with adverse effects.

The optimal treatment’s duration
The latest data on HRT do not warrant the fear and ultra-conservative approach adopted in 2002. Longer-term therapy is appropriate for women with long-term symptoms who are aware of the potential risks for their regimen in their personal circumstances. Individualised regimens can reduce the incidence of adverse outcomes.

HRT can be offered to informed women for as long as they have debilitating symptoms but the data are not yet strong enough to advocate it for chronic disease prevention (except perhaps for osteoporosis prevention near menopause with the option of other effective fracture prevention treatments at a later age). However, some women have continuing symptoms even into their seventh decade and they should not be denied HRT if their therapy and risks are individualized, understood, and not exaggerated.

The best formulations for minimizing breast/uterine cancer risks
Although the risks of HRT have been inflated by the popular press, there are potential side effects and risks that must be individualized and reduced by tailoring the therapy. Emerging data suggests fewer side effects with:

  • lower HRT doses
  • minimal use of systemic progestogens
  • use of non-oral routes in some women and the use of HRT in symptomatic women from near menopause

HRT remains the most effective therapy for vasomotor symptoms and urogenital atrophy. By 2030, an estimated 47 million women will be undergoing menopause each year. Quality of life is an important end point in women’s health research. We should not forget that a woman’s prolonged life expectancy has resulted in an extended postmenopausal lifetime, which could be longer than the woman’s entire reproductive age.

References

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Nedrow A, Miller J, walker M, Nygren P, Huffman LH, Nelson HD. Complementary and alternative therapies for the management of menopausal symptoms. A systematic evidence review. Arch Intern Med 2006; 166: 1453–1465.

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Renoux C et al. Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study BMJ 2010;340:c2519

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Santen RJ et al. Executive Summary: Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement J Clin Endocrinol Metab, July 2010, 95(Suppl 1):S1–S66