THE LANCET
`
`exhortation, short on cerebration, and shortest of all on
`consistency.
`
`Nicholas Coni
`Department of Medicine for the Elderly, Addenbrooke's Hospital.
`Cambridge CBZ 2QQ. UK
`
`Re-inventing WHO
`
`SIR—oFor those concerned about the future of WHO, your
`issue of Feb 4 contained good news. The hopeful message
`was not
`found in the entirely predictable response by
`Kickbusch (p 325), a member of Nakajima’s staff,
`to a
`previous Lancet editorial. Rather,
`in the news section,
`McGregor
`(p 312)
`reports that at
`the January WHO
`Executive Board meeting a decision was taken to develop
`and propose a new global health charter. This new charter,
`intended to be promulgated in late 1997, offers enormous
`promise, especially if several critical conditions are met.
`First, clarity and coherence in the analysis of global health
`problems, challenges, and possible solutions is essential.
`Although criticising the shortcomings of progress in realising
`the Alma—Ata Declaration (1976) is easy, a genuinely new
`and creative path forward will be more difficult to define.
`Global health is inextricably connected with global social,
`economic, and political realities. Since WHO was created,
`much has been learned about the biological and societal
`basis of health. A new vision can be built on the solid
`
`foundation of the preamble to the WHO constitution, with
`an updating to take account of such key elements as the
`insights for health arising from the modern human rights
`movement. A clear path forward must be both far—reaching
`and sufficiently concrete to mobilise the human and
`financial resources that protecting and promoting global
`health requires and merits. Then, as form follows function,
`organisational restructuring can ensue.
`Second,
`it
`is essential
`to recognise the strength and
`importance of the non-governmental organisations (NGOs)
`in health assessment, policy development, and assurance of
`services. Half a century ago, when WHO was created,
`NGOs were far fewer and less important; today, as shown by
`the Cairo conference on population, they are numerous and
`essential. Therefore, NGOs should not only be consulted,
`but
`also
`should
`become
`centrally
`involved
`in
`the
`development of a new health charter. Everyone knows that
`the United Nations (UN) and other official agencies can
`either give lip service to NGOs or take them seriously, and
`the difference will be critical and obvious.
`
`Third, the new global charter has to take account of the
`emerging realities
`in the UN’S involvement
`in health
`matters. Again, since WHO was created, and even more
`recently, many other parts of
`the UN system have
`(fortunately) interpreted their mandates to include health.
`For example, awareness of the importance of investment in
`people and on the linkage between health and development
`have led the World Bank and the UN Development Program
`to invest and focus increasingly on health, along with the
`more obvious UN participants such as UN Children’s Fund,
`UN Population Fund, UN Educational, Scientific and
`Cultural Organisation. Yet WHO’S entire budget is quite
`small compared with the resources of the World Bank or the
`UN Development Program. WHO needs to clarify its role
`within
`the UN system. How WHO organises
`these
`consultations and relations could determine the credibility of
`the new health charter.
`
`create unprecedented
`global public. New technologies
`communication opportunties, yet meaningful participation
`of an increasingly informed public is an as yet unrealised
`challenge for WHO in particular, and for the UN system
`more generally.
`
`J Mann
`Harvard School of PUbIIC Health, Frangons‘XaVier Bagnoud Center for Health and
`Human Rights. Cambridge. MA 02138, USA
`
`Ethics of n-of—1 trials
`
`SIR—We agree with Irwig et a1 (Feb 25, p 469) that medical
`research committee approval is unnecessary for n—of—l trials
`when the treatment and its indication for use are not new.
`
`We believe, however, that it is premature to call for n-of—l
`trials to be encouraged by health—care systems and for
`facilities to be made available to carry out n—of-l
`trials in
`daily clinical practice. Experience so far with n—of—l trials has
`been uncontrolled."3 Comparison of outcomes,
`including
`economic costs, between groups of patients randomised to
`receive treatment by n—of—l trials or by standard practice (an
`open, before-after test of therapy) is needed to show whether
`n—of-l trials are a cost-effective alternative to current clinical
`
`practice. In this respect, they are no different from other new
`interventions. Randomised controlled studies of n-of—l trials
`
`versus standard practice are feasible.4 Pending results of
`further such investigations, widespread use of n-of-l trials
`cannot be advocated.
`
`*Jeffrey L Mahon, Brian G Feagan, Andreas Laupacis
`Universrty Hospital, PO Box 5339, London, Ontario, Canada N6A 5A5
`
`1 Guyatt G, Keller IL, Jaeschke R, Rosenbloom D, Adachi ID,
`Newhouse MT. The n—of-l randomized controlled trial: clinical
`usefulness. Ann Intern Med 1990, 112: 293—99.
`2 Larson EB, Ellsworth A], Oas J. Randomized clinical trials in single
`patients during a 2—year period. jAMA 1993; 270: 2708—12.
`3 March L, Irwig L, Schwarz J, Simpson], Chock C, Brooks P. N of 1
`trials comparing a non—steroidal anti—inflammatory drug with
`paracetamol in osteoarthritis. BM} 1994, 309: 1041—45.
`4 Mahon JL, Laupacis A, Donner A, Wood T. A randomized trial of
`N of 1 trials versus conventional therapy. Clin Res 1993; 4: 180A.
`
`Response to a specific antioestrogen (ICI
`
`182780) in tamoxifen-resistant breast cancer
`
`SIR—Dowsett and colleagues (Feb 25, p 525) argue that the
`high response rate that we reported (Jan 7, p 29) to the
`specific antioestrogen ICI 182780 should be interpreted with
`care since patients were selected as likely to respond after
`failure of tamoxifen. In a similarly selected group of patients
`they report
`a high response rate to newer aromatase
`inhibitors. We have seen a response rate of 63% in similar
`patients (n=57) given the progestagen megestrol acetate.
`Thus, we agree that the patients are generally responsive.
`The selection was made because we were unsure of the
`
`potential activity of a specific antioestrogen after failure of a
`partial agonist antioestrogen. Our study showed a high
`response rate and a prolonged response duration. The
`median response duration on megestrol acetate was 14
`months, whereas in the small group of patients given ICI
`182780 the median duration of response has not yet been
`reached after 22 months. When used to treat human
`
`Finally, the preamble to the WHO constitution highlights
`the importance of “informed opinion and active cooperation
`on the part of the public”. The development of a new health
`charter is an historic opportunity to inform and educate the
`
`mammary tumours growing in nude mice, ICI 182780
`resulted in cessation of tumour growth for periods about
`twice
`as
`long as
`tamoxifen (Osborne CK, personal
`communication). Our data suggest that ICI 182780 might
`
`Vol345 ' April 15, 1995
`
`989
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`InnoPharma Exhibit 1045.0001
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`

`

`THE LANCET
`
`produce prolonged remissions in patients and may be better
`than standard endocrine therapies.
`Dowsett and co-workers point out that use of the no-
`change
`category of
`response to endocrine therapy is
`uncommon. We showed that if patients had no change of
`their
`tumour growth for at
`least 6 months their
`final
`duration of response and overall survival did not differ
`significantly from that
`in patients who had a partial
`remission.‘ Thus, we feel that it is important to recognise the
`no—change category of response since it is clinically relevant.
`In our study the longest responder to ICI 182780 has stable
`disease after 28 months of treatment.
`In practice,
`few
`clinicians change treatment when metastatic disease is
`classed as no change.
`Dowsett and colleagues suggest that treatment with ICI
`182780 is conceptually similar
`to that with aromatase
`inhibitors in that both treatments produce “pure deprivation
`of the oestrogenic signal”. In as much that, as we have
`argued,2 all endocrine therapies for breast cancer probably
`act directly or indirectly by reducing the oestrogenic signal in
`tumour cells, this comment could be correct. However, ICI
`182780 and aromatase inhibitors have different mechanisms
`
`of action. The ability of ICI 182780 to bind tightly to the
`oestrogen receptor (much more so than tamoxifen) and to
`downregulate
`the
`receptor might
`afford
`the
`specific
`antioestrogen a therapeutic advantage over other forms of
`endocrine therapy. Our results suggest that this hypothesis is
`worth pursuing.
`
`*Anthony Howell, John Robertson
`*CRC Department of Medical Oncology, University of Manchester,
`Christie Hospital NHS Trust, Manchester M20 4BX, UK; and Department of Surgery,
`City Hospital, Nottingham
`
`1 Howell A, MacIntosh J, Jones M, Redford J, Wagstaff J, Sellwood RA.
`The definition of the ‘No change’ category in patients treated with
`endocrine therapy and chemotherapy for advanced carcinoma of the
`breast. Eur] Cancer Clz'n Oncol 1988; 24: 1567—72.
`2 Howell A, DeFriend DJ, Anderson E. Mechanisms of response and
`resistance to endocrine therapy for breast cancer and the development
`of new treatments. Rev Endocr Rel Cancer 1993; 43: 1—17.
`
`Vitamin-D—receptor—gene polymorphism and
`bone loss
`
`SIR—Polymorphisms of the vitamin—D—receptor (VDR) gene
`have been linked with bone mineral density (BMD) in twin
`studies from both Australia‘ and the UK.2 Ferrari and
`
`colleagues (Feb 18, p 423) report in a study of 64 elderly
`women (and 8 men) that the annual rate of change in spinal
`BMD over
`18 months was
`small
`(+0-47%) and not
`significantly different from zero, but differed between VDR
`genotypes. They suggest that a similar genetic effect may
`also influence BMD changes in younger women. We have
`examined this potential relation in a larger group of healthy
`women soon after the menopause; these women should be
`experiencing greater rates of bone loss due to relative
`oestrogen deficiency.
`296 women within 5 years of the menopause were
`recruited from two population—based cohort volunteer
`groups. All were free of bone disorders and did not receive
`hormone replacement therapy or other medication known to
`affect bone throughout the study period 1988—93. BMD was
`measured at
`the lumbar spine and femoral neck by dual
`photon absorptiometry (Novo—BMC Lab 22a) at O, 12, 24,
`and 48 months
`in
`141 women and by dual—energy
`absorptiometry (Hologic QDR—IOOO) at 0, 12, 24, and 48
`months in 155 women. Coefficients of variation from repeat
`measurements on healthy volunteers were 08% at the spine
`
`990
`
`
`
`VDR genotype
`TT
`(0:71)
`
`Tt
`(n=96)
`
`tt
`(n=28)
`
`52-8 (3-7)
`
`52-5 (3-5)
`
`52-6 (3-3)
`
`50-5 (3-7)
`2 2 (1-3)
`
`50-2 (3-4)
`2-3 (1-4)
`
`50-4 (28)
`2-2 (1-4)
`
`161(0-06)
`660 (110)
`25-3 (42)
`
`1-61(0-18)
`67-0 (13-3)
`25-6 (4-1)
`
`1-62 (005)
`66-6 (14-1)
`25-3 (4-7)
`
`Mean (SD) age In years
`Menopause
`Mean (SD) age at onset in years
`Mean (SD) duration in years
`
`Mean (SD) anthropometry
`Height (m)
`Weight (kg)
`Body-mass index (kg/m2)
`
`Mean (SE) bone loss (% per year)
`~1-01(0-30)
`—1-09 (0-17)
`e131 (0-14)
`Lumbar spine
`
`Femoral neck —1-00(0-46) —0-48 {0-36) —1-00 (0-20)
`
`
`
`Table: Relation of vitamin D receptor genotypes, demographic
`variables, and bone loss in 195 women
`
`and 1-6% at the hip for both techniques. Rates of Change
`in BMD for each individual subject werercalculated by
`least-squares
`regression analysis. DNA was
`extracted
`from leucocytes, PCR used to amplify a 740 bp DNA
`sequence, and the Tag] restriction enzyme used to detect
`VDR alleles. The genotypes were coded as TT, Tt, and tt;
`the tt genotype is equivalent to the previously reported BB
`genotype.l
`Full results (three or more scans and VDR genotype) are
`available for 195 women. Genotype frequencies were as
`expected from other populations. There were no significant
`differences in anthropometric or menopausal characteristics
`between the genotype groups
`(table). There was no
`difference in the rate of change in BMD from hip or spine
`between the VDR genotypes (analysis of variance, p=0-55
`and p=0-37). For the total group the 95% CI for rate of
`change in BMD were —1-32 to ~~0-88% per year at the
`spine, and —l-08 to —0-45% per year at
`the hip. The
`proportion of women with spinal bone loss below the lower
`95% CI of ~1-32% per year (as used by Ferrari et al) was
`similar in the three groups: 35/71 (TT), 38/96 (Tt), and
`10/28 (tt). The same was true of losses at the femoral neck.
`By contrast with Ferrari and colleagues’ findings,
`in a
`larger
`and longer-duration study we have
`found no
`association between VDR genotype and bone loss from
`lumbar spine or femoral neck. We believe that the VDR
`gene acts predominantly to determine peak bone mass and
`that other genes are likely to be involved in the regulation of
`bone loss after the menopause.
`
`R W Keen, P J Major, J S Lanchbury, T D Spector*
`*Rheumatology Department, St Thomas' Hospital, London SE1 7EH, UK; and
`Molecular Immunogenetics Unit, UMDS, Guy's Hospital, London SE1
`
`1 Morrison NA, Qi JC, Tokita A, et al. Prediction of bone density from
`vitamin D receptor alleles. Nature 1994; 367: 284‘87.
`2 Spector TD, Keen RW, Arden NK, et al. Vitamin D receptor gene
`(VDR) alleles and bone density in postmenopausal women: a UK twin
`study. j'Bone Min Res 1994; 9: $143.
`
`SIR—Ferrari and his colleagues conclude that the variability
`in the response of bone mass to calcium intake and vitamin
`D supplementation may be predicted by analysis of VDR—
`gene polymorphisms. We
`investigated the
`effects
`of
`1 or(OH)D3 (05 pg per day) with or without calcium
`supplementation (as calcium lactate of 1-5 g per day) on
`lumbar—spine mineral density in 31 Japanese adults (4 men,
`27 postmenopausal women; mean age 68-3 [SE 14] years),
`in whom lumbar—spine mineral density (L2—4) was lower
`than in age and sex matched Japanese controls. BMD of
`L2~4 was measured with dual energy X—ray absorptiometry
`(DPX, Lunar Co)1 before and after (mean 80 [SE 0-7]
`
`
`Vol 345 - April 15, 1995
`
`lnnoPharma Exhibit 1045.0002
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