Exhibit B: Post 17: 3rd February 2006

Links are given to online full text resources, all other materials can be obtained via the Fade Library, just mail your request to library.services@fade.nhs.uk

Latest Technology Assessments and Appraisals

The clinical effectiveness and cost-effectiveness of computed tomography screening for lung cancer: systematic reviews (Black) 106 pages, Volume 10, number 3

Computed tomography (CT) screening for lung cancer does not currently meet the accepted National Screening Committee criteria, with no randomised controlled trials and no evidence to support its clinical effectiveness or cost-effectiveness.

The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer’s disease (Loveman) 176 pages, Volume 10, number 1

To provide an update review of the best quality evidence for the clinical effectiveness and cost-effectiveness of donepezil, rivastigmine and galantamine for mild to moderately severe Alzheimer’s disease (AD) and of memantine for moderately severe to severe AD.

FOOD: a multicentre randomised trial evaluating feeding policies in patients admitted to hospital with a recent stroke (Dennis) 136 pages, Volume 10, number 2

Study findings did not support routine supplementation of hospital diet for unselected stroke patients who are predominantly well nourished on admission nor did they support a policy of early initiation of percutaneous endoscopic gastrostomy (PEG) feeding in dysphagic stroke patients.

Latest Guidelines

NICE (2006) High dose rate brachytherapy for localised prostate cancer - Interventional procedures consultation document. NICE: London.

Prostate cancer is one of the most common cancers in men. It tends to affect older men, with the risk rising with age. It is not a single disease entity but may be indicated form an incidental biopsy finding to presentation with metastatic prostate cancer, which may or may not cause any symptoms or shorten life. Symptoms when they occur include urinary outflow obstruction and features of metastases, such as bone pain. Prognosis with prostate cancer is variable and depends on the grade of the tumour and stage of the diagnosed cancer. Treatment options depend on the stage of the cancer. Brachytherapy is a form of radiotherapy in which delivery of radiation is targeted directly to the prostate gland through the implantation of small radioactive pellets. Brachytherapy may be used in combination with external beam radiation (EBRT) in high dose therapy.

The consultation period ends on 28/02/2006.

Scottish Intercollegiate Guidelines Network (2005) Management of transitional cell carcinoma of the bladder. Edinburgh: Sign.

Transitional cell carcinoma of the bladder is the fifth most common cancer in men and fifteenth in women in Scotland. Seventy five per cent of patients present with superficial tumours and in 10% this will progress to muscle invasive cancer. Invasive cancer is diagnosed in 25% of patients and has a five year survival of less than 50%. Superficial disease recurs in up to 80% of patients. The guidelines cover referral and all aspects of medical and surgical management of superficial and invasive disease. Specific aetiological factors related to lifestyle and occupation are covered and information for discussion with patients and carers is highlighted.

Latest Reports

Department of Health (2006) Our health, our care, our say: a new direction for community services. London: TSO.

The White Paper, Our health, our care, our say: a new direction for community services aims to provide people with more choice and say over the care they receive in the community, and much closer working and coordination between health and social care. New measures outlined in the White Paper include:

Links are given to online full text resources, all other materials can be obtained via the Fade Library, just mail your request to

Shifting expenditure from spending on hospitals to spending on care closer to home and on preventative services

New responsibilities placed on local councils and the NHS to work together to provide joined-up care plans for those who need them

Bringing some specialties out of the hospital nearer to people including dermatology, ENT, orthopaedics and gynaecology

Introducing a new generation of community hospitals that will provide diagnostics, minor surgery, outpatient facilities and access to social services in one location

Pilot a new NHS “Life Check” to assess people's lifestyle risks, the right steps to take, and provide referrals to specialists if needed

Give patients a guarantee of registration onto a GP practice list in their locality and simplifying the system for doing this

Introducing incentives to GP practices to offer opening times that respond to the needs of patients in their area

Increasing the quantity and quality of primary care in under served, deprived areas through nationally supported procurement of new capacity with contracts awarded by PCTs

Supporting people to self care by trebling the investment in the Expert Patient Programme

Developing an “information prescription” for people with long term health and social care needs and for their carers, investing in professional education and skills development

Providing a Personal Health and Social Care Plan as part of an integrated health and social care record

More support for carers including improved emergency respite arrangements and the establishment of a national helpline for carers

Extension of direct payments and piloting of Individual Budgets for social care

Our health, our care, our say: a new direction for community services: A brief guide

Our health, our care, our say: a new direction for community services: Easy Read Version

Change Agent Team (2006)Making Connections, the third and final Annual Report. London: DoH.

This report covers the third year of the health and social care Change Agent Team. It will be their last report as they become part of the new Care Services Improvement Partnership (CSIP). The report reviews the work of the Change Agent Team during 2004/05 and highlights the team's new work areas such as development of Older People's Mental Health Services, Community Hospitals, Telecare and Extra Care Housing

Matrix (2005) Improvement partnership for hospitals: evaluation report. Coventry: NHS Institute for Innovation and Improvement.

This document summarises the lessons learnt from the Improvement Partnership for Hospitals (IPH). It shows that IPH did have an impact, and that people were most likely to adopt clinical systems improvement ideas after training at local and national workshops.

Ofcom (2005) Ofcom own-initiative investigation into the price of making telephone calls to hospital patients:A case closure document issued by the Office of Communications. London: Ofcom.

Ofcom closed its investigation into the price of telephone calls to hospital patients with a recommendation that the Department of Health ('DoH') review all aspects of the installation and operation of bedside telephone and entertainment systems in hospitals

Evidence from Journals

Trials

Latest Questions to the Primary Care Question Answering Service

ASSESSMENT AND DIAGNOSIS

In an otherwise healthy young male who has recurrent haematuria after exercise (jogging for an hour a day) what investigations should be done?

A patient stopped depo 6 months ago and still has no periods, which she wants to initiate, and suggestions?

What is the relative risk for a 14 year old girl travelling on long haul flights of thrombosis if she is on the contraceptive pill?

Are there any significant medical conditions that cause night terrors in a 2 year old child? What advice can I give the mother?

Is there any information on the reliability and validity of wound assessment charts?

Are there any up to date guidelines dealing with burns and scalds?

Can an Indian female vegetarian be suffering fromVitamin D deficiency as a result of her diet?

How high can a testsosterone level be before PCOS is unlikely and more sinister causes should be looked for?

What is the Cockcroft Gault calculation and how is it used?

Is there any guidance on the safety of biopsy of possible squamous cell skin cancer in primary care?

CAUSES, RISKS AND PREVENTION

Is there any evidence that bladder irritants (caffeine, alcohol, nicotine) are directly irritant to the bladder wall or are they deemed irritant by virtue of their diuretic properties? Does avoiding them actually help bladder stability?

Are veterinary workers, and workers at risk of exposure to animal body fluids at risk specifically of hepatitis B? What immunisations should such groups be offered and why?

What harm can result from allowing seizure activity in temporal lobe epilepsy to continue?

When can you start a COC after stopping the most common anti epileptic drugs e.g. Carbamazepine or Lamotrigine?

Are Tampons sterile? Is 'Toxic Shock Syndrom' related to length of time a tampon is left in the vagina or is it completely unrelated and can individuals suffer from this immeditely after a tampon is inserted?

Do pregnant women have to avoid goats as well as sheep?

Parents of a teenager with mumps recently contacted me about having a mumps vaccine. Is there any guidance on vaccinating contacts with mumps cases?

Use of antidepressants in children with depression (ages 5-18)

How suitable are IUDs (non-hormonal) for patients with multiple sclerosis?

Is it safe for a patient with IUDs (non-hormonal) to have a MRI scan?

If someone suffered poliomyelitis as a child, would this render them immune, thus not requiring further immunisation.

Is there any evidence to support not adminstering antipyretics either post vaccination or in fever

CARDIOVASCULAR DISEASE

In the elderly, should statins be started at lower doses e.g. simvastatin 10 or 20mg and titrated upwards?

In patients on multiple lipid lowering agents including a statin a fibrate and ezetimibe is the risk of pancreatitis cumulative with added agents?

What are the side-effects of statins?

Should patients on oral steroids be screened for aortic aneurysm? Is there an association between oral steroids and large blood vessel abnormalities?

INFECTIOUS DISEASES

Is there evidence that melatonin treatment improves symptoms of fatigue in patients with chronic fatigue syndrome?

NEUROLOGICAL DISEASES

Is there any evidence for use of oxygen therapy in the treatment of migraine. If so how should the oxygen be used ?flow rate

HEALTH MANAGEMENT

Do you know what the criteria is for chronic renal disease in the new contract? Will it be based on GFR and if so what is the cut off value.

GASTROENTEROLOGY

1)How long should a patient with ulcerative colitis continue to take oral mesalazine/5' ASA be continued to prevent relapse? 2) How should an acute exacerbation while on oral 5'ASA treatment be managed?

Hitting the Headlines - Evidence Behind the Press Stories

Possible new bird flu vaccine

A new vaccine against bird flu has been developed, reported six newspapers (2nd Feb 2006)(1-6). The reports were based on laboratory studies where a new vaccine had provided protection in mice. Two newspaper articles omitted to mention that it may be several years before a vaccine is available for human use (1,2).

Hope that a new bird flu vaccine had been developed was reported in six newspapers (1-6). Four reported that unlike conventional vaccines, this one could be stockpiled (3-6).
The newspaper reports were based on a series of experimental studies which tested a vaccine genetically engineered from the common cold virus (7). The studies were carried out on mice and investigated the ability of the vaccine to protect the mice from three variations of the H5N1 type of avian influenza infection, isolated from people. The researchers also looked at the method of delivery of the vaccine and its ability to produce T cells which fight infections.
The researchers' findings appear to follow from the results of the experiments. However, as stated in four of the newspapers, further development work and eventually trials in human volunteers are required before such a vaccine is made generally available.

Evaluation of the evidence base for adenoviral-vector-based influenza vaccine against H5N1 strains in mice

Where does the evidence come from?

The research was conducted by Mary A Hoelscher and colleagues at the Influenza Branch, Division of Rickettsial and Viral Diseases, Centers for Disease Control and Prevention, Atlanta USA, and the Department of Veterinary Pathobiology, Purdue University, USA.

What were the authors' objectives?

To develop an influenza vaccine and to assess the immunogenicity and efficacy of the vaccine to confer protection in BALB/c mice.

What was the nature of the evidence?

The researchers developed a vaccine by genetically engineering a common cold virus to produce the protein haemugglutinin subtype 5(H5HA), a component of the H5N1 avian influenza virus. Controlled trials of the vaccine were then carried out on mice in a laboratory.

What interventions were examined in the research?

In a series of laboratory experiments, groups of mice were vaccinated with HAd-H5HA, HAd-deltaE1E3, or rH5HA either in the presence or absence of 1% alum adjuvant. The control groups of mice received phosphate-buffered saline. Two doses of vaccine were given four weeks apart. Four weeks later all the mice were infected with a lethal for mice dose of the H5N1 HK/483/97 virus. The mice were monitored for clinical signs and bodyweight changes for 14 days. Further similar experiments were conducted to test more recent strains of the H5N1 virus isolated from people (eg HK/213/03) and investigate the route of immunisation (intramuscular or intranasal). The researchers used a further trial to determine whether the vaccine induced functional CD 8 T cells in mice, as these cells have been shown to contribute to viral clearance.

What were the findings?

HAd-H5HA and rH5HA plus alum produced better protective effect than the interventions used in the other groups against HK/156/97 virus. However, HAd-H5HA was the most effective against the two other virus strains tested. Overall, intramuscular delivery of HAd-H5HA vaccine induced consistently higher responses than intranasal delivery. Mice that received the HAd-H5HA vaccine had a three to eight fold higher frequency of CD8 T cells compared to the other groups.

What were the authors' conclusions?

That BALB/c mice immunised with HAd-H5HA vaccine were effectively protected from H5N1 disease. The authors also said the findings highlight the potential of an Ad-vector-based delivery system which offers stockpiling options for the development of a pandemic influenza vaccine.

How reliable are the conclusions?

As the studies are laboratory studies no formal assessment of the reliability of the authors' conclusions has been made. However, they would appear to be reasonable, given that the authors word their discussion in terms of what the research could 'potentially' lead to. Clearly further development work and eventually trials in human volunteers are required before such a vaccine becomes widely available.

Systematic reviews

Information staff at CRD searched for systematic reviews relevant to this topic. Systematic reviews are valuable sources of evidence as they locate, appraise and synthesize all available evidence on a particular topic.

There were no related systematic reviews identified on the Cochrane Database of Systematic Reviews (CDSR) or on the Database of Abstracts of Reviews of Effects (DARE).

References and resources

1. GM vaccine raises hopes of beating bird flu. The Guardian, 2 February 2006, p7.

2. Common cold cure for bird flu. Daily Mirror, 2 February 2006, p11.

3. New bird flu vaccine may be key to preventing pandemic. The Times, 2 February 2006, p8.

4. Cold virus link for bird flu vaccine. The Daily Telegraph, 2 February 2006, p13.

5. Vaccine hope on bird flu. The Sun, 2 February 2006, p27.

6. Scientists create a new bird flu vaccine. Daily Mail, 2 February 2006, p35.

7. Hoelscher MA, Garg S, Bangari DS, Belser JA, Lu X, Stephenson I, et al. Development of adenoviral-vector-based pandemic influenza vaccine against antigenically distinct human H5N1 strains in mice. The Lancet, (Early Online Publication).

Consumer information

Health Protection Agency - Influenza

NHS Direct - Avian flu

Science and development network - Bird flu: the facts

Previous Hitting the Headlines summaries on this topic

Antiviral treatment for avian flu. Hitting the Headlines archive, 19 January 2006.

'New drug promises to hit flu where it hurts'. Hitting the Headlines archive, 23 January 2003.

Drug stops flu's spread through families. Hitting the Headlines archive, 14 February 2001.

Aricept for dementia

Aricept is effective for people with mild, moderate and severe dementia without increasing NHS costs reported the Daily Mail on 25th January 2006. The newspaper report did not make it clear that cost data from the review did not relate to the UK and comments about the effectiveness in mild dementia may be overstated.

The Daily Mail (1) reported that Aricept is effective for patients with mild, moderate and severe dementia, helping with memory loss and daily living. They reported that Aricept was not more expensive for the NHS compared to placebo or sham, stating that this contradicts the latest guidance from the National Institute for health and Clinical Excellence (NICE).
The newspaper article is based on a systematic review (2) of 23 trials that compared Aricept to placebo. The authors concluded people with mild, moderate and severe dementia due to Alzheimer's disease treated for periods of 12, 24 or 52 weeks with Aricept experienced benefits in cognitive function, activities of daily living and behaviour. They also stated that there is some evidence that Aricept is neither more nor less expensive compared to placebo.
The newspaper article did not make it clear that the information on costs of the drug reported in the review were not specifically related to the UK. Also, most of the studies in the review were only 12 to 24 weeks duration and not all - 'for at least a year' as stated in the paper. The review is of reasonable quality though should be interpreted with some caution. Appropriate processes were not used in the review to reduce error and bias and the review did not specifically investigate the relative effectiveness of the drug in patients with different disease severity.

Evaluation of the evidence base for Aricept for dementia due to Alzheimer's disease.

Where does the evidence come from?

This systematic review was conducted by Jacqueline Birks at the Division of Clinical Geratology at the University of Oxford and Dr Richard Harvey at the University of Melbourne. The study was also supported by Barwon Health, Australia.

What were the authors' objectives?

To assess whether Aricept (donepezil) improves the well-being of patients with dementia due to Alzheimer's disease.

What was the nature of the evidence?

The evidence comes from a Cochrane systematic review of 23 trials, involving 5,272 participants. The review included double-blind randomised controlled trials (RCTs) that compared Aricept to placebo treatment, in patients who had been diagnosed as having probable Alzheimer's disease using accepted criteria. The participants in the studies had mild, moderate and severe dementia, however it is unclear from the review the proportion of patients with each level of severity. The mean Mini Mental State Examination (MMSE) scores ranged from 11-24 in the included studies. The review investigated the effect of Aricept on cognitive function, activities of daily living, global clinical state and quality of life. Side effects and some additional outcomes were also reported.

What interventions were examined in the research?

The trials included in the review compared either 5 or 10mg of Aricept per day to placebo treatment. Treatment duration in the included studies ranged from 12 weeks to 60 weeks, however only three of the included studies were of one year or more.

What were the findings?

Only 14 of the 23 studies reported results in sufficient detail to be included in the analysis.

In general, the trials found that Aricept had a beneficial effect in comparison to placebo for all aspects of Alzheimer's disease. Aricept had a beneficial effect in comparison to placebo in terms of physician assessed global state and cognitive function. There was also evidence from three studies of a benefit in terms of activities of daily living, though no evidence of any benefit in relation to quality of life. Aricept was associated with significantly more adverse events than placebo, particularly so for 10 mg of Aricept per day.

Two studies included in the review reported data on the cost-effectiveness of Aricept compared to placebo in various countries; but not the UK. There were no significant differences between Aricept and placebo, except for the total carer costs which was in favour of placebo.

What were the authors' conclusions?

People with mild, moderate or severe dementia due to Alzheimer's disease treated for periods of 12, 24 or 52 weeks with Aricept experienced benefits in cognitive function, activities of daily living and behaviour. There is some evidence that Aricept is neither more nor less expensive compared to placebo when assessing total health care resource costs. The evidence suggests that the benefits of Aricept at 10 mg once a day are marginally greater than 5 mg per day, however given the better tolerability of Aricept at 5 mg a day, the lower dose may be the better option. The debate of the efficacy of Aricept continues as the treatment effects are small and not always apparent in clinical practice.

How reliable are the conclusions?

The author's conclusions follow from the findings of the review. However, the review has weaknesses which should be considered. Only one reviewer screened the studies for inclusion in the review and extracted data so there is a possibility that bias or error may have been introduced and some potentially relevant studies may have been missed. Additionally, only a small number of studies were available for most of the outcomes. It is unclear what proportion of participants had mild, moderate and severe dementia and the effects of Aricept with regards to these various levels of severity were not investigated. Also, data relating to the cost of Aricept were limited, not quality assessed, and did not relate to the UK.

Systematic reviews

There were no additional related systematic reviews identified on the Cochrane Database of Systematic Reviews (CDSR). Three systematic reviews were identified on the Database of Abstracts of Reviews of Effects (DARE)(3-5).

References and resources

1. Alzheimer's outcry: drug that NHS plans to ration 'can ease suffering'. Daily Mail, 25 January 2006, p18.

2. Birks JS, Harvey R. Donepezil for dementia due to Alzheimer's disease. The Cochrane Database of Systematic Reviews 2003, Issue 3. Art. No.: CD001190. DOI: 10.1002/14651858.CD001190

3. Dooley M, Lamb H M. Donepezil: a review of its use in Alzheimer's disease. Drugs and Aging 2000;16(3):199-226.[DARE Abstract]

4. Wolfson C, Oremus M, Shukla V, Momoli F, Demers L, Perrault A, Moride Y. Donepezil and rivastigmine in the treatment of Alzheimer's disease: a best-evidence synthesis of the published data on their efficacy and cost effectiveness. Clinical Therapeutics 2002;24(6):862-886.[DARE Abstract]

5. Wolfson C, Moride Y, Perrault A, Momoli F, Demers L, Oremus M. Drug treatments for Alzheimers's disease: 1. A comparative analysis of clinical trials. Ottawa, ON, Canada: Canadian Coordinating Office for Health Technology Assessment (CCOHTA) 2000:1-124.[DARE Abstract]

6. Loveman E, Green C, Kirby J, Takeda A, Picot J, Payne E, et al. The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer's disease. Health Technology Assessment 2006;10(1).

7. Clegg A, Bryant J, Nicholson T, McIntyre L, De Broe S, Gerard K, et al. Clinical and cost-effectiveness of donepezil, rivastigmine and galantamine for Alzheimer's disease: a rapid and systematic review.Health Technology Assessment 2001;5(1).