Brooke Laboratory, Division of Infection,

Inflammation & Repair Southampton General Hospital,

Southampton

The need for trials reflecting the real world of clinical practice

Stephen T Holgate

sth@soton.ac.uk

biosphere

familycommunity

culture

the living person

The living person is a complex system – it functions as an integrated self correcting whole.

organs

cellsgenes

tissues

molecules

How representative are efficacy studies in a particular disease to the

wider population?

1. Disparity between HCP view of asthma control and that of patients.

2. Representativeness of patients in clinical trials.

3. Over interpretation of pooled data.

4. Special considerations of children.

5. Single versus multiple interacting interventions.

6. Importance of co-morbidities and patient-centred outcome measures.

7. Interactions with placebo and Health Care Provider.

How representative are efficacy studies in a particular disease to the

wider population?

1. Disparity between HCP view of asthma control and that of patients.

Despite ICS or ICS/LABA therapy, only 28% of patients are well controlled according to the Juniper Asthma

Control Questionnaire

51% uncontrolled (poor)

28% well controlled

21% not well controlled

Partridge MR et al Links Attitudes and actions of asthma patients on regular maintenance therapy: the INSPIRE study

BMC Pulm Med. 2006 Jun 13;6:13.

Asthma out of control? A structured review of recent patient surveys

Holgate ST BMC Pulm Med 2006 Nov 30th; 6 Suppl 1: S2

• Review of 24 local, national and international asthma surveys of patients, carers and health care provider (HCP).

• Patients tolerate poor symptom control, possess meagre knowledge of current drug usage and display poor adherence to therapy.

• Many patients had a low expectation of having an appropriate encounter with a HCP.

• Urgent need to improve patient understanding of asthma, improved communication with HCP & improved education on the importance of achieving optimal control.

The patient’s perspective: adherence or non-adherence to asthma control therapy

Ulrik CS et al J Asthma 2006; 43:701-4

• Both accidental and intentional non-adherence with controller therapy is common among adults and children with asthma.

• Reasons – fear over side effects, lack of belief that controller therapy is effective or an essential part of therapy, lack of perceived symptoms.

• Reasons accessible through education of patients and caregivers.

How representative are efficacy studies in a particular disease to the

wider population?

1. Disparity between HCP view of asthma control and that of patients.

2. Representativeness of patients in clinical trials.

Evidence-based recommendations or “Show me the patients selected and I will tell you the results”

Bjermer L Respir Med 2006; 100 suppl A: S17-21

• By knowing the profile and action of a drug it is possible to design inclusion criteria that predict the results from the start.

• To prove that addition of an inhaled long-acting 2-agonist (LABA) is better than increasing the anti-inflammatory treatment – select mild stable highly reversible patients.

• To prove anti-inflammatory treatment is beneficial chose patients known to be corticosteroid responsive and slightly under-treated.

• Applying common inclusion and exclusion criteria renders only a few % of patient population to be eligible.

External validity of RCTs in asthma: to whom do the results of trials apply?

Travers J et al Thorax 2007; 62: 219-23

• Postal survey to 3500 individuals, respiratory questionnaire & PFTs.

• Participants (179) with current asthma assessed against eligibility criteria of 17 major RCTs in GINA Asthma Guidelines.

• 4% of met eligibility criteria in the RCTs.

• Most of the participants with current asthma would not be eligible for these RCTs.

Smoking

• 20% of asthmatic patients are current smokers.

• Smokers have more severe asthma with greater reduction in lung function and more symptoms.

• Smokers are always excluded from clinical trials in asthma.

Smoking affects response to inhaled corticosteroids or LTRAs in asthma

(Lazarus SC et al Am J Respir Crit Care Med 2007; 175: 783-90)

• Cross-over RCT in mild asthma; 44 non-smokers (ns) & 39 light smokers (s) – Inhaled Beclometasone (BDP) or oral Montelukast

• BDP increased FEV1 only in ns, whereas montelukast increased lung function only in s.

• Greater improvement in s suggest cysteinyl LTs play a greater role in asthmatics who smoke.

• Clinical importance of excluding smokers from asthma trials.

How representative are efficacy studies in a particular disease to the

wider population?

1. Disparity between HCP view of asthma control and that of patients.

2. Representativeness of patients in clinical trials.

3. Over interpretation of pooled data.

The use (misuse) of meta-analyses and systematic reviews

• Meta-analyses are regarded as providing among the highest level of evidence.

• The outcomes of such analyses depends upon the nature of the trials incorporated.

Sodium cromoglicate

SCG available since 1970.

Retracted and to be replaced: sodium cromoglicate: an ineffective drug or meta-analysis misused

Stevens MT et al Pharm Stat 2007; March 15th [Epub ahead of print]

• In1999 systematic review of SCG in childhood asthma followed by a Cochrane Collaboration Review; SCG ineffective.

• BTS Guidelines & WHO Model List of Essential Drugs reflect these conclusions.

• But failed to take account of: 1) Changes in formulations. 2)Combined outcomes in very young

children and teenagers. 3) Information on all end points e.g. one

primary end point based on only 4 of 24 studies included in the review.

• Reanalysis taking these factors into account revealed that, rather than having no effect, SCG was both safe and effective in asthma control, particularly in older children.

How representative are efficacy studies in a particular disease to the

wider population?

1. Disparity between HCP view of asthma control and that of patients.

2. Representativeness of patients in clinical trials.

3. Over interpretation of pooled data.

4. Special considerations of children.

Long-acting 2-agonists and paediatric asthmaBisgaard H, Szefler S Lancet 2006;367: 286-8

• Because of efficacy in adults, long acting 2-agonists (LABAs) are being widely used to treat asthma in children.

• Long acting 2-agonists are substantially less efficacious in children, especially the very young.

• Some evidence that LABAs increase exacerbations of asthma in children.

• Increase concerns over side effects – asthma deaths and FDA “black box” warning.

• The trend to use LABAs or combination inhalers eg Seretide or Symbicort in children’s asthma should be questioned.

How representative are efficacy studies in a particular disease to the

wider population?

1. Disparity between HCP view of asthma control and that of patients.

2. Representativeness of patients in clinical trials.

3. Over interpretation of pooled data.

4. Special considerations of children.

5. Single versus multiple interacting interventions.

Primary prevention of allergic disease by allergen avoidance

Arshad H et al J Allergy Clin Immunol 2007; 119: 307-13.

• Single early life interventions in children born of allergic parents failed to prevent allergic disease and even increased allergen sensitisation.

• A multiple intervention - food avoidance by mother and child (milk, egg, peanut etc), dust mite reduction, breast feeding or extensively hydrolysed formula.

• 120 children assessed at 1,2,4 and 8 years: OR asthma 0.24, atopic dermatitis 0.23, rhinitis 0.42 and atopy 0.13.

• Multiple and complex interventions may produce different outcomes than single interventions.

How representative are efficacy studies in a particular disease to the

wider population?1. Disparity between HCP view of asthma control and that of

patients.2. Representativeness of patients in clinical trials.3. Over interpretation of pooled data.4. Special considerations of children.5. Single versus multiple interacting interventions.6. Importance of co-morbidities and patient-centred outcome

measures.

Aspiration of inflammatory secretions from the upper airway into the lower airway

Shift from nasal to mouth breathing

Nasobronchial reflex

Systemic mediation of nasal and lower-airway inflammation

Allergic rhinitis and asthma: interactive mechanisms in one airway

Asthma, rhinitis, sinusitis, food allergy,

eczema & conjunctivitis

occur together in up to 80% patients

– important consideration in patient’s QOL

Co-morbidity is neglected in organ-centred RCTs

How representative are efficacy studies in a particular disease to the

wider population?

1. Disparity between HCP view of asthma control and that of patients.

2. Representativeness of patients in clinical trials.

3. Over interpretation of pooled data.

4. Special considerations of children.

5. Single versus multiple interacting interventions.

6. Importance of co-morbidities and patient-centred outcome measures.

7. Interactions with placebo and Health Care Provider.

Components of the therapeutic response

• Targeted intervention eg surgery or drug : specific effect or efficacy• Incidental e.g. practitioner interactions, healthcare setting

: non-specific effect or placebo.

• Treatment response in the real world – effectiveness = efficacy + placebo.

• With different forms of therapy the relative contribution of specific & non-specific responses differ.

The significance of the placebo effects

• Is placebo (non-specific effect) more than no treatment?

• Can the nature of a placebo effect alter the response of a specific therapy?

• What are the important factors that contribute to the placebo effect?

• Are there lessons that can be learned from traditional and complementary medicine?

• “Science versus Art”

The placebo effect is an important component of therapy

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Symptoms

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Anti-IgE MoAbPlacebo

But what about this?

But what about this?

Efficacy

Subtract placebo effect to reveal specific

response of intervention – blockade of IgE

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pain

sco

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Placebo

Acupuncture

Trial of medical acupuncture in arthritis

Acupuncture versus Placebo, 12% difference, P = 0.01

Effectiveness = Efficacy + Placebo

Acupuncture

PlaceboNon-specific

Specific

Do the neural correlates of acupuncture and placebo effects differ?

Dhond RP et al Pain 2007; 128: 8-12

• Neuroimaging demonstrates that acupuncture recruits a distributed cortical and subcortical brain network.

• These studies show overlap and differences in the areas of the brain activated by placebo.

• Acupuncture also has long-lasting effects eg on neuropathic pain that is linked to altered opioidergic and monoaminergic transmission.

New insights into placebo analgesiaBenedetti F et al Curr Opin Anaesthesiol 2003; 16: 515-9

• When optimal methods are used striking placebo effects can occur.

• Neuropharmacological and brain imaging show that placebo analgesia is mediated by endogenous opioids.

• During placebo analgesia other systems such as the respiratory and cardiovascular centres alter.

• However hidden medical treatments are less effective than open ones.

• Understanding the placebo effect may lead to better clinical trial design and medical practise such as protocols aimed at reducing drug intake.

Sites of action of placebos

Adrenal

Heart

Two types of information process in the organism behind two types of ‘error’

A-B-C-D-E-FI I I I I I

G-H-I-J- K- L I I I I I I

M-N-O-P-Q-R I I I I I I

S-T-U-v-w-x

information error

Symptoms

‘imbalance’

network processing

disease

sequential processing

Placebo, complementary and lifestyle interventions operate

here

Conventional treatments operate here

Lifestyle

Environment

Stress

BeliefsA - B - C….

organic error

Michael Hyland’s Intelligent Body Concept

ConclusionThe complexity of the therapeutic

response necessitates greater focus on real world effectiveness studies of

single and combined interventions in a wide group of patients across a disease

spectrum as well as special groups such as children, older people and

different ethnic groups - to ensure that any new treatment that is introduced is

generalisable.