Karl Popper, Thomas Kuhn and the common sense of transfusion medicine

Albert FarrugiaRuth Sanger Oration

Adelaide 20 October 2009

Disclosures and Disclaimers

• Compensated services to the blood industry internationally

• None of the views expressed in this oration reflect those of my past or current affiliations

19 October 2009

Summary

• Some philosophy• Some epistemology• Some sociology• Some transfusion medicine• Some regulation• Acknowledgments• Final reflections

Scientific certainty

“It is certainly no small advantage that we enjoy living at the present day with the medical arts already brought to such a perfection.”

Galen106 A.D. – 211 A.D.

Scientific certainty• The fact of global warming is

"unequivocal." The certainty of the human

role is now somewhere over 90 percent.

Which is about as certain as scientists ever

get.

• I would like to say we're at a point where

global warming is impossible to deny. Let's

just say that global warming deniers are

now on a par with Holocaust deniers,

though one denies the past and the other

denies the present and future.

Ms Ellen Goodman

Two Titans

Five years after William Thomson Lord Kelvin made this statement in 1900, Albert Einstein published his papers on special relativity, the quantum theory of light and others

There is nothing new to be discovered in physics now. All that remains is more and more precise measurement

In so far as the statements of mathematics speak about reality, they are not certain, and in so far as they are certain, they do not speak about reality

Popper’s Falsifiability• Scientific theories make predictions

that can be proved wrong• At this point the scientific theory is

abandoned• Science makes testable predictions,

and then does the experiments• Most of science consists of trying to

prove itself wrong

“I generally have a lot of respect for common sense……..But it is not always reliable…..And in matters of scientific [] theory, it is extremely important to have a really critical attitude to it”

Falsificationism and progress of science• Science starts with problems.

• Falsifiable hypotheses are

proposed by scientists as solutions

to the problems.

• The conjectured hypotheses are

then criticized and tested.

– Some will be quickly eliminated.

– Others might prove more

successful.

• These must be subject to even

more stringent criticism and

testing.

• When a hypothesis is eventually

falsified, a new problem has emerged.

• This new problem calls for the invention

of new hypotheses, followed by

renewed criticism and testing.

• It can never be said of a theory that it is

true, however well it has withstood the

rigorous tests

• Hopefully it can be said that a current

theory is superior to its predecessors -

in the sense that it is able to withstand

tests that falsified those predecessors.

Benjamin Rush(Founding Father of USA, and famous physician)

• He believed the best treatment for Yellow Fever was vigorous bloodletting

• If patient got better it was because of treatment• If patient died then it was because the patient had been

too ill for any treatment to work.• This error in thinking illustrates one of the most

important principles in scientific thinking.• Rush violated the most important rule regarding the

construction and testing of theories in science: He made it impossible to falsify his theory.

Thomas Kuhn’s The Structureof Scientific Revolutions

• First published in 1962• Translated into 20

languages• Has sold over a million

copies• Has affected just about

every field and discipline• Remains a point of

controversy

Paradigms

.

• Framework that affects world view.

– Synonyms :Theory, Model,

Protocols, Patterns,

Methodologies, Routines,

Habit, Common Sense,

Customs, Rituals

• We may not even be aware of our

paradigms as we have always had

them, or we acquire them

gradually through our experience.

• Many times those around

us also share our

paradigms making us less

aware of them as we do

not encounter any

different paradigms

Kuhn’s viewsScience, like all other types of human activities, is a fundamentally social and community-based process

Science

• Science is based above all on

shared paradigms, not

methods or sets of facts

• Progress in science has been

discontinuous and

revolutionary, not incremental

and evolutionary – and

certainly not consensual

Scientific Revolutions

• Involve the replacement of one

paradigm by another

• Involve the rethinking of

everything that had been

“known” before

• Are driven by communities of

scientists who act to some degree

on “faith”

When a paradigm is good/bad?

•A paradigm is good when the problem to be solved is within the boundary that the paradigm is effective /efficient to solve.

•A paradigm is bad when it is no longer effective /efficient to solve your problem and yet, you are blinded by the paradigm without notice - Paradigm Paralysis.

•When:• the current paradigm failed to solve problem effectively or

efficiently.• you found a better way.

Then it’s time for a paradigm shift

Stages of Paradigm Shift• A paradigm shift is a REVOLUTIONARY way of thinking about an old

problem - a dramatic change in our perception.

An existing paradigm is in place

» Kuhn begins from the premise that a person or even an entire society

have one or more existing paradigms in place that are passed on from

generation to generation.

Investments made in existing paradigm

» By investments, Kuhn means many different things. For some people it

might mean their career or standing in their profession

Resistance to anomalies and preservation of existing paradigm

Adoption of new paradigm

Kuhn’s Basic Model

Gallileo Galillei Marie Curie Albert Einstein Neils Bohr Barry Marshall and Robin Warren

Paradigm Shifters

EDINBURGH 1983 CAPE TOWN 2006

MALTA 1981 PRAGUE 2006

EARLY MENTORS

The (current) paradigm of transfusion medicine (?)

• Blood component therapy

• Blood donation is safe and needs to be increased

• Voluntary non – remunerated donation

• National self sufficiency

• Sheltered from EBM, efficacy assumed historically

• Australia (and Germany, Yemen, Monaco, the Galapagos

Islands…) has the safest blood in the world

• Hospital practice unquestioned

The position of WHO “The Melbourne declaration”

• “evidence shows that regular voluntary, non-remunerated blood donors are the

cornerstone of safe and sustainable national supplies of blood and blood

products”

• “national blood services based on 100% voluntary non-remunerated blood

donations ...... will increase the safety of the blood supply by reducing the

transmission of transfusion-transmissible infections”

• “Urge all governments to appreciate and protect all voluntary non-remunerated

blood donors, develop a strategy for a stepwise progression from whole blood to

the preparation of labile components and ensure that all recovered plasma is

used for fractionation, thereby fully utilizing every donation”( http://www.who.int/entity/worldblooddonorday/MelbourneDeclaration2009.doc)

Blood Component Therapy

CT bad for kidneysMore ARDS with FWB

Whole Blood in the Management ofHypovolemia Due to Obstetric Hemorrhage

Alexander et al Obstet Gynecol 2009;113:1320–6)

Duration of red blood cell storage is associated with increased incidence of deep vein thrombosis and in-hospital mortality in patients with traumatic injuries Critical Care 2009, 13:R151 doi:10.1186/cc8050

P Spinella,C Carroll,I Staff, R Gross,J Mc Quay,L Keibel, C Wade, and J Holcomb

TRANSFUSION OF STORED LEUCODEPLETED RED BLOOD CELLS CAUSES CARDIAC, PULMONARY AND RENAL DYSFUNCTION AND INJURY.

• 20 pigs randomized to four units of 42 DO SAG-M RCCs or sham• RCCs similar to human at D42, s/n toxins, RBCchanges etc• Relative to sham group, Txd pigs showed:

– Acute Kidney Injury – 14% reduction in creatinine clearance, 46% reduction in free water clearance and 69% increase in urinary protein/creatinine ratio

• At autopsy – marked changes in renal tubular morphology with dilation and vacuolation

– Lung Injury – 10% reduction in lung compliance, 20% increase in inspiratory airway resistance

– Cardiac injury – nine fold increase in serum troponin– Endothelial injury – reduced excretion of urinary nitric oxide

BLOOD KILLS !Patel et al Bristol UK

2008 Report

Compared to the risks suggested by emerging evidence on stored red cells, these risks are insignificant

Safety of Blood Donation

Iron deficiency in Oz donors at start of fresh blood regulationDoherty et al ARCBS 2000

0

5

10

15

20

25

% Iron

deficient

Females Males

< 50> 50

[Iron deficiency defined as serum ferritin <12 µg/l]

Female Male

Age <50 >50 <50 >50 No. Dons 1 42.2 84.4 158.2 232.2 2 28.9 51.4 83.3 47.1 3 17.9 31.8 77.3 47.9 4 12.1 28.9 34.2 60.1

Australian Longitudinal Study on Women's HealthPatterson et al Quality of Life Research 9: 491±497, 2000.

• Associations between self-reported `low iron‘ and general health and well-being in women.

• Women who had `low iron' reported significantly lower mean scores, and greater prevalence of `constant tiredness' at baseline.

• Mean scores at follow-up were significantly lower for women who reported recent iron deficiency.

• The results suggested that iron deficiency is associated with decreased general health and well-being and increased fatigue.

% of Total Donor

Population Iron Deficient

ARCBS Hb threshold from 1/1/04

Males – 128g/L 6.2%

Females – 118g/L 22.0%

ARCBS Hb threshold from 1/1/05 (UK)

Males – 130g/L 6.0%

Females – 120g/L 20.6%

Council of Europe Hb threshold

Males – 135g/L 5.3%

Females – 125g/L 18.9%

COMMONWEALTH OF AUSTRALIA

THERAPEUTIC GOODS ACT 1989

SECTION 14 NOTICE

On 26 March 2002, ……… gave his consent for the Australian Red Cross Blood Service (ARCBS) for the collection of blood by the ARCBS to be exempt from the provision ……..[regarding pre-donation Hb]

The conditions for this consent under section 15(1) of the Act are that 1. …….. 2. This exemption is granted subject to:

(i) The ARCBS is to introduce the following haemoglobin cut-offs on 1 January 2004 Males 128 g/L Females 118 g/L

(ii) The ARCBS is to introduce the following haemoglobin cut-offs on

1 January 2005 Males 130 g/L Females 120 g/L

“Short-term iron replacement is effective and safe therapy for blood donors who are iron-deficient and is not harmful to those who have adequate iron…..iron should be recommended to all menstruating women to prevent harm”

TRANSFUSION 2006;46:1667-1681.

March 2009

BUT

• Gordeuk et al Trans

1990;30:239-245

• Randomised double blind trial of

low dose carbonyl iron in female

donors post donation

• Iron replaced 85% carbonyl

group vs 29% control (p<0.001)

• Deferral for low Hb 8% in

carbonyl group vs 36% control

• SO – what are we waiting for?

• (Is regulator cooperating?)

Safety and Ethics

Whole blood safety in LithuaniaVox Sanguinis (2008) 94 , 209–215

•In both first time and regular non-remunerated donors, anti-HCV and (1st time) HBsAg were much higher than in source (compensated) US donors

•No difference in risk ratio existed when comparing the regular donations who were remunerated and non-remunerated.

Germany University Hospital MarburgTransfus Med Hemother 2004;31:301–307

Look-back Procedures Because of Sero-converted Donors

RCBS Marburg p value*

Compensation No YesBlood units 86,331 179,426Total 16 2

<0.0001HIV 3 1 n.t.HBV 3 0 n.t.HCV 9 1 n.t.*Chi-square test.

Paid or unpaid?

Volunteerism? “What is true

volunteerism? ........ I was also struck, even recently, in 2003 by the photographs published in a newspaper: parades of medals - silver medals, star-studded and gilded silver medal – with perfectly identifiable persons. With this, maybe excessive visibility, aren’t there grounds to question the links between voluntarism and anonymity?”Professor Didier Sicard, President of the CCNE National Ethics Advisory Committee, Trans Clin Biol 2008

Donation in Italy• Offering a day off work increases

average donation rate by one/year• Donors cluster their donation days

around Friday – long w/e’s• Awards in the form of medals

increase donations• Public recognition of such award

increases them most of all“individuals are responsive to economic considerations in their blood donation decisions in a way that is largely consistent with standard economic intuition”

Lactera and Macis Bonn Institute of Labour 2008

Blood Donation is an Act of Benevolence Rather Than Altruism

• The sociology literature now abounds with studies showing that “altruistic” acts also benefit the givers

• This is also the case for “voluntary” blood donation - Fergusson et al University of Nottingham UK, Health Psychology 2008, Vol. 27, No. 3, 327–336

• Test two hypothesis for blood donation – Benevolence - both the donor and recipient benefit– Altruism - only the recipient gains

• Three United Kingdom–based studies » Committed blood donors were more willing to donate blood when exposed to a

benevolent message rather than an altruistic one. » Conclusions: The benevolence hypothesis is supported, suggesting that blood

donor motivation is partly selfish. » Blood donation campaigns should focus on benevolent rather than purely

altruistic messages.

Replacement Donors and WHO’s Blood Policy in South Saharan Africa

Policy

• Blood should only be sourced from voluntary non-remunerated donors

• Replacement donor system not mentioned in policies or recommendations

Claims

• <40%, 58% and 73% of blood in Africa in 2002, 2006 and 2007 was from voluntary donors – target by 2012 is 80%

• 12/46 countries have 100% VNRD (including Ghana and Malawi)

Reality

• Average annual blood collection rate is 5.14/103

• 77.9% VD, 21.9% family/ replacement donors, 0.2% paid donors

• 50% were from repeat voluntary donors.

• 17/41 countries had <50% VNRD

Blood as a Therapeutic Good

QUALITY…. EFFICACY….

…...AND COST

EFFECTIVENESS!!!SAFETY

Regulators’ brief

Getting therapeutic goods on the market.......and how blood is different

ASSUMEDPRECAUTIONISM GMP IGNORED(UNLESS

POLITICS SAYS OTHERWISE)

Blood components – Do they work?• RCCs

– “To increase oxygen delivery to the tissues”…but – Do tx red cells increase VO2 ?

• Yes, around the critical [Hb] ie about 50g/l, but• At 80 g/l, no obvious effect (Walsh et al 2004)

• Platelets• PLADO study – Low vs Medium vs High dose platelets• Same clinical outcome irrespective of dose

• FFP– Two higher quality trials - Both evaluated prophylaxis

– No benefit reported in either trial

The move to component therapy was driven by need for plasma derivatives for a few, not to improve care for the majority of recipients

What role can regulation have in a new blood safety paradigm?

• Regulation has contributed primarily to product quality through the

pharmaceutical model

• However, regulators also assess and approve efficacy and therapeutic claims

• With the increasing cost and complexity of the blood system, consideration

of such claims is becoming an urgent need

• Regulation also includes post-approval assessment and monitoring of

therapeutic goods on the market

• Increasingly, blood systems have implemented systems for such assessment

Proposed regulation of blood 2005- • Tiered system geared to risk• Risk seen as a function of

– Manufacturing complexity– Source– Historical use

• Established components exempt from efficacy assessment• THIS PRINCIPLE DEMANDS REVISION

“……the light of history will shine from their helmets……..”W.S.Churchill 1945

“Safe…never as safe……safer than its ever been….safest in the world”

Australia is, indeed, in a very envious position. We have one of the world’s safest and best managed blood supplies…….

Sen J McLucas, Minister for the TGA 2007-09

We are fortunate to live in a nation that has the safest blood supply in the world

Dr Janet HeinrichUS GAOCongressional testimony 1999

Blood Kills!Tell ‘em Mo

Arboviruses in OzARCBS 08 (Communicable Diseases Australia) Aust N Z Public Health. 2008; 32:354-60

Virus Number of notifications Notifications/105 popn.

2007 Last 5 year mean 2007 Last 5 year mean

Barmah Forest virus 1665 1366 8.1 6.7

Dengue Flavivirus 318 358 1.5 1.8

Unclassified Flavivirus 23 51 0.1 0.3

Japanese encephalitis 0 1 0 0

Kunjin 0 9 0 0

Murray Valley encephalitis

0 2 0 0

Ross River virus 4143 3513 19.7 17.3

The Dengue Story

• TGA concern early 2003 – request ARCBS to not use blood from Dengue areas

• ARCBS skepticism “…there is only minimal evidence for transfusion transmission, and

no other country in the world has introduced severe restrictions…..”

• Interaction led to policy – 14 April 2003– use plasma for fractionation, discard

transfusable components – during period of outbreak

TGA showed considerable courage – no other authority used this policy

There was nothing “consensual” about this – synthesis of two views, still strongly

held

TGA – Dengue is a blood risk

ARCBS – risk minimal and secondary to supply

maintenance

Blood in Hospitals

Moment of “Faine”Jon Faine Morning Program ABC Melbourne 27/8/07

………the Therapeutic Goods Administration is thinking only of blood and blood products, which they also licence, as a medicine and not as a gift from a donor………. Albert Farrugia, who's the - oh, a very senior person in the Office of Devices in the TGA. Well, my comment - my colleagues said that he was extremely upset at one of the presentations where they showed that one Melbourne hospital had been able to reduce the wastage of SFP - that's thawed but not transfused - down to about two per cent, which was really fantastic……..

49

-4

-2

0

2

4

6

8

10 Day 0Day 5Day 10

FFP

Fo

ld d

ecre

ase in

perm

eab

ility

ab

ove c

on

tro

l

The Protective Effects of FFP on the Endothelium after ShockHolcomb IABS Cambridge 209

Central hypothesis that FFP has the capacity to “normalize” injured endothelium by inhibiting and repairing the damage from a number of detrimental processes induced by Haemorrhagic Shock.

50

0

40

80

120M

AP

(m

mH

g)

B 10' 30' 1h 2h 3h 4h 5h 6h hours

FFP Day 5

FFP Day 0

*

*****

*

* *

p<0.05 end HS vs B*p<0.05 FFP Day 0; FFP Day 5 vs end HS

end of HS

FFP

Holcomb IABS Cambridge 209

Acknowledgments

Thanks to…….Innumerable colleagues from

the Transfusion Family

Manchester UK 1985

TWO RUTH SANGER RECIPIENTS !

http://en.wikipedia.org/wiki/File:Rowland_Hill_photo_cleaned.jpg

Take care of all your memories, said NickIf you cannot relive them,And remember, when you come to heal the sick, That you must first of all forgive them

Bob Dylan

Final Thoughts of a TransfusionistHistory and Beliefs

• Whole blood transfusion for haemorrhage saved lives

that would previously have been lost. Belief started there

• Blood became interdependent with the expanding

medical industry: businesses and empires were built.

• We market the “gift of life” to encourage donors and we

believe our own advertising

Final Thoughts of a transfusionistHistory and beliefs

• Having failed to appreciate pathogen related risks for a

long time, we now focus on marginal issues while major

problems are ignored.

• Component therapy has been preached to the world by

“experts” without regard to local needs

• We still damn whole blood without seeking evidence

about when it might be a good treatment

Consensual statements• People who fail to tackle climate change are acting

like an Austrian man who locked his daughter in a cellar for 24 years, an Anglican bishop has said.

• The Bishop of Stafford, Gordon Mursell, wrote in a parish letter that not confronting global warming meant people were "as guilty as" Josef Fritzl.

BBC 2008

British Foreign Secretary Compares Global Warming Theory Skeptics to Islamic Terrorists“...let us deny the terrorists the historical importance they claim to themselves………In practical terms that means avoiding the temptation to artifically polarise debate. …..I've seen it so often in the long-running debate on climate change: wheel out the resident sceptic, however unrepresentative or discredited, to generate tension and voice provocative views …. it is not the way to build a common consensus on the ground we share...”

Margaret Beckett

“New opinions are always suspected, and usually opposed, without any other reason but because they are not already common.”

“There must be more than one alternative policy ; they must come from more than a single source; and there must be sufficient dispersion of power in society so that competing sources of advice have a chance of being heard and acted upon”

The best option is the one which persuades and can be justifiedThe best process is the one which encourages argument

John LockeEnglish Philosopher(1632-1704)

Aaron Wildavsky American Political Scientist(1930-1993)

Toads

Towards a new paradigm…..and its already happening

• Whole blood needs to become a product again

• Supply to patients should not be impeded by non-clinical interests

• The blow torch of EBM needs to be applied to TM

• Plasma for fractionation should be collected for that purpose by the

fractionating agency

• Safety concerns need to focus on real issues

• Vein to Vein means oversight over the whole transfusion chain

“there is a crack, a crack in everything,that’s how the light gets in”

Leonard Cohen

“If it ain’t broke, break it”

Marvin Lee Aday(aka Meat Loaf)

BECAUSE

And, remember, in defiance of “common sense”………..