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Editorials

Pharmacovigilance in developing countries

BMJ 2007; 335 doi: https://doi.org/10.1136/bmj.39323.586123.BE (Published 06 September 2007) Cite this as: BMJ 2007;335:462

Who should best pharmacovigilate in developing countries?

Who should best pharmacovigilate in developing countries?

ANSWER: The following should all combine to do this together.

1. WHO: Remove the question mark from the title of this
communication and the World Health Organisation becomes the best ‘person’
to pharmacovigilate (if I may coin a useful word). The editorial of Munir
Pirmohamed and colleagues, 8 September, p 462 [1] raises some extremely
important points. I personalise WHO because it is often the brilliance and
integrity of one or two persons that drives good policy. Before the drug
Metrifonate was recommended for general usage to cure schistosomiasis,
when Dr Italo Barrai was head of Human Genetics at the WHO, and with the
advice of Dr A Davis, Malaria and Parasitology Division of the WHO, I was
invited at the Korle Bu Teaching Hospital, Ghana, by Dr David Scott, the
then WHO Schistosomiasis Project Director in Accra to find out how safe it
was to use the drug in a population where 1 in 3 was heterozygote for
abnormal haemoglobins resulting in about 3% of all children born
inheriting the gene from both parents causing disease [2,3,4]. Barrai also
knew that the high incidence in Ghana of G6PD Deficiency (including the no
-enzyme-at-all variety) [5, 6] plus the genes for beta-thalassaemia,
hereditary persistence of Fetal Haemoglobin (first described by Edington
and Lehmann [7, 8]), and the African type of alpha-Thalassaemia [9]
combine to produce the highest incidence in the world of hereditary
erythocytopathy [10]. Though the African type of African alpha
thalassaemia is quite innocuous, it reacts with G6PD deficiency to produce
serious haemoglobinuria under certain circumstances [11]. David Scott,
John Biles, and I had no difficulty identifying 1,011 Bilharzia ova
excreters on the borders of the Volta Lake at Anyabone, getting their
blood examined by Alex Bruce-Tagoe, George Yawson and Opare-Mante, and
separating the 26 with hereditary red cell disease required for the 3-
phase drug trial. Metrifonate proved curative, and as harmless to the 26
with hereditary erythrocytopathy (qualitative & quantitative) as to
the traits and non-traits [12]. One of our 3 main recommendations 33 years
ago was: “A Unit of Pharmacogenetics under WHO auspices might be desirable
to facilitate the assessment of new drugs in Africa where the incidence of
genetic red cell defects is so high” [page 64, Reference 12]. Has this
been done?

2. PHARMACEUTICAL COMPANIES: Much criticised though these have
been, they need commendation for inviting notification of side effects of
their products.

3. NATIONAL VIGILANCE: The 2 Ghanaian co-authors Kwame Attuah and
Alex Dodoo [1] may have seen the whole page statement in the Ghanaian
Daily Graphic of Monday 15 May 2006 which reveals how complex national
pharmacovigilance can be. Ghana, for instance, has (i) a National Drug
Programme (ii) a Pharmacovigilance Unit of the University of Ghana Medical
School (iii) a National Malaria Control Programme (NMCP) and (iv) the
multi-divison Ministry of Health, all these 4 of which appear to defer to
(v) the Food and Drug Board which alone gives the ‘Go Ahead’ to any
manufacturer that wishes to market drugs in the country. Such a situation
does not produce effective national pharmacovigilance if any, or some, of
these 5 ‘authorities’ disagree about something. Foreign investigators have
been known to state in their publications or broadcasts abroad that they
had obtained permission from one of these ‘authorities’, and this enabled
them to carry on whatever they wished in the country while the others that
assumed they also had pharmacovigilant authority, and who could have
monitored adverse reactions, knew nothing of what was happening.

4. FREE NATIONAL PRESS: In a dictatorship, it is not possible to
print anything without seeking permission from “the authorities”. Now the
Ghanaian media can describe in minute detail what has happened to those
taking particular drugs or who have been vaccinated recently, or not so
recently.

5. MEDICAL AND NURSING PERSONNEL. Sometimes these are the first to
raise the alarm, as my account in the Ghanaian Times, mentioned later,
reveals.

6. THE CONSUMER: Least to be ignored in the realm of
pharmacovigilance are patients and their relatives. In bold letters
“Furore over Artesunate-Amodiaquine” is the headline of the Daily Graphic
article mentioned above [13]. Remarkable side effects in young people,
most of them neurological, led to countrywide protests and anger that led
the Minister of Health, the Director-General of Ghana Health Services, and
the Director of Public Health of the Ghana Health Service come out to
explain the “new policy” that 15 African countries including Ghana had
agreed to adopt – the policy of changing their “first line anti-malaria
drug to Artesunate-Amodiaquine combination” [13].

The question that needs answering is this: What happens when the
public have pronounced a big ‘No Confidence’ verdict on a health “policy
change” that leads to morbidity? Does the Ministry of Health persist with
it nevertheless? This was not in the editorial remit of the authors’
important article [1], nor does the fact that national and international
corruption can cause worse havoc than poor pharmacovigilance. I finished
my series of seven weekly articles on Malaria in the Ghanaian Times [14]
with the following true story:

I have time for just another reason why drugs given in Ghana may not
work: CORRUPTION! This word has been used so frequently, that it has lost
its meaning and needs to be illustrated with a true story. Listen very
carefully. I was doing a ward round on Medical Floor Two at Korle Bu, with
Sister Devina Haizel, Staff Nurses Rose Yeboah and Edith Hadjor, medical
students, physiotherapists, and others. The diagnosis on the young lady in
the side room was such as urgently required an antibiotic, which was
prescribed. On my next ward round a few days’ later we were all surprised
to find the lady more ill than ever. I turned round and said: “Sister, has
this lady been given the Ampicillin 6-hourly as prescribed?” Oh yes, she
replied.

“Sister”, I said, “sometimes patients with a high temperature are
delirious, and throw pills away. Are you sure she is taking Ampicillin
regularly?” Oh yes. “I stood here until she swallowed the capsules, and I
made sure the night nurse did the same”. Well, either my diagnosis was
wrong, and the pills could not help her, or my diagnosis was right, and
the pills were wrong. “Sister Haizel, please bring me the Ampicillin that
she is taking for inspection”. She duly did. “Hmm, I see. These capsules
are rather different from the Penbritin I am used to. Excuse me one
moment”.

I left the ward round and asked the Telephone exchange at Korle Bu
Hospital to get me my friend Dr James Binka at the Government Chemical
Laboratories just beyond Tetteh-Quarshie round about. “James”, I said,
“This is Felix. How soon can you examine the contents of an Ampicillin
capsule for me?” Well, immediately. And James Binka offered to drive to
Korle Bu to collect about 5 capsules labelled 250 milligrams of
Ampicillin. In less than 24 hours, James was on the phone to me: “Felix”
he said, “I can’t talk on the phone, but I shall be with you soon”. He
must have flown, because we had not finished the ward round when he
appeared on Floor Two, panting. “Felix, this is serious! There is hardly
10 milligrams of actual Ampicillin here in a capsule labelled 250
milligrams. Some capsules have kokonte, and others a mixture of kokonte
and chalk!” Quick, we have to save this young girl, I said. I cannot now
remember which other Antibiotics we pumped into her, but she lived. We
began a quiet piece of research, and I identified a triumvirate of three
“sons of Belial” (the biblical term for rogues): An Italian that flew
empty capsules into Ghana from Milan, a Lebanese that provided a sprinkle
of Ampicillin powder with a large proportion of cassava powder (kokonte)
and chalk, and a Ghanaian who provided premises for the factory. They
supplied the Ministry of Health with Ampicillin! I got the names of all
three sons of Belial.

Not long after this, I made a trip to the Accountant’s office at the
Ministry of Health for some money to buy tyres for one of the vans of the
then Ghana Institute of Clinical Genetics, now Sickle Cell Centre. While
waiting my turn to see someone acting for the Accountant, who was away,
someone shouted out the name of the white man in front of the queue. I
recognised the name at once as that of one of the sons of Belial.
Instinctively, I jumped forward and shouted loudly, pointing my finger at
his forehead: “SO IT’S YOU!” Quite taken aback, that he should be thus
accosted, he turned to the friend who had called his name, and asked him:
“Who is that?” When he learnt that I was Dr Konotey-Ahulu from Korle Bu,
he must have realised that I was on his tail.

You will not believe what happened next. He sprang up. Gave me a
broad smile. Took me by the elbow, and gently steered me out of earshot of
the crowd, and asked me in a most charming voice: “Doctor. Have you built
a house?” He did not wait for any response, but went on: “I shall build
you two houses if you like!” Speechless, and flabbergasted, I pushed his
hands off my elbow, and made straight to the office of the Commissioner of
Health. I had no appointment, but he was glad to see me. This good
Commissioner (far better than most) listened to me in complete silence.
When I finished, he merely stood up, put his hands in his pocket, took out
a bunch of keys, walked to a large safe, opened it, and flung the heavy
door wide open.

On the top shelf of the safe were hundreds, nay thousands of the
kokonte Ampicillin capsules (half red, half black). I tried to shut my
mouth but couldn’t. Eventually, I stammered: “So-so-so you knew about
this?” As if afraid that he would be over-heard by someone, the
Commissioner merely nodded ‘Yes’ without saying it aloud. Then he added a
sentence, which is inappropriate for me to reproduce here for legal
reasons. I left his office depressed, and sweating. Within weeks, the dear
Commissioner was given another portfolio and moved on. Within another few
weeks, history intervened. Do you now have a little understanding of how
Corruption affects peoples’ health?

Readers of this article who feel the above exposure is something
rare, should turn to the front page of the Ghanaian Times years later
[Editor, please publish it again some time]: Friday 16th March 1984:
“POWDERED MAIZE IN AMPICILLIN CAPSULE Five Arrested in Kumasi and Accra.”
I wonder what happened to them. Were they given ‘Hard Labour’ as would
have been the case in the colonial days? Yesterday, it was Ampicillin.
Tomorrow, what stops it being anti-malarial drugs (single or combination)?
In an article by David Yeboah-Tetteh two weeks ago, entitled: Health
Sector Among Most Corrupt Institutions he said a Ghana Integrity
Initiative (GII) report has identified the country’s health sector “as one
of the most corrupt institutions”. And, as my true story above has shown,
Ghanaians can embrace international sons of Belial as well. The main
Editorial in this week’s Lancet in London (11-17 Feb 2006, page 447 [15])
is “Corruption in health care costs lives”. The Editorial goes on to
state: “The spectrum of corruption ranges from physicians with conflicts
of interest advocating a particular treatment for wrong reasons, to
aggressive marketing strategy by pharmaceutical companies..” This can
affect malaria control as well. ….[14]

Lack of expertise regarding pharmacovigilance was not Ghana’s
problem. Dr James Binka proved that in less than 24 hours, probably better
and quicker than any foreign expert was capable of. Had they heard of
kokonte? What we lacked in Ghana was not expertise (we competed with the
best in the world in their universities and showed our mettle) – what we
lacked was something that the developed world has in abundance and which
we need to emulate: PROBITY & DISCIPLINE! When we read that the
daughter of the British Monarch was fined for overspeeding after pleading
guilty, and members of the House of Lords can be jailed for perjury, and
multimillionaire business men in the UK are put in prison for fraud, and
the Head of State of the USA resigns for telling Watergate lies, we become
speechless. Pharmacovilgilance? We had better advocate this ethical
dimension to embrace pharmmacovigilance the developing world.

But a more serious aspect of Third World Health than
pharmacovigilance is the way we tend to focus on symptoms rather than the
disease that produces the symptoms. Without a doubt malaria, like AIDS, is
the very battle ground in the Third World today. There is plenty of money
in it, just like in HIV/AIDS. If one does not agree with how international
donors are handling things one just keeps quiet because “it is they who
bring the money …What can we do?” [16] How many body guards, I asked
recently, would be required to protect the one who criticised some of the
present global protocols for malaria control? [17]. Even governments are
threatened to be removed if they do not obey orders from abroad regarding
how they should behave towards “something called official policy”. On
Monday 8th July 2002, those in the UK heard Radio 4 announce on ‘The World
At One’ from the Barcelona AIDS Conference, a senior UN Official’s “threat
that any country’s leader should be ‘kicked out’ for failing to obey
official policy on AIDS” [18]. Out of order! Why should a UN Official
threaten to remove a head of state for not following prescribed “official
policy?” What if the people, elected democratically, have found the
“official health policy” not right for them? Do foreigners know what is
better for our health?

ANSWER: There are two camps (a) Those like Dr Jeffrey Sachs, Chairman
of the WHO Commission on Macroeconomics and Health, who had this
worthwhile goal: “The time has come to resurrect a worldwide effort to
control malaria, following decades of neglect during which the disease has
resurged in many parts of sub-Saharan Africa and other endemic regions”
[19] and (b) Those like Professor C J Peters, formerly Chief of the
Special Pathogens Branch of the US Centres of Diseases Control and
Prevention in Atlanta, Georgia, also with a worthwhile goal: “Population
growth continually challenges our ability to deal with emerging infectious
diseases. We must make intelligent choices so that we have the least
possible impact on our natural environment” [20] No guesses as to which of
the two worthwhile goals I, a Ghanaian African, prefer, which led me once
to comment that rolling back malaria effectively will save up to 3 million
children from death annually, and I posed the question: “But would
averting a malaria disaster not upset the population control lobby?” [21]

Intelligent Africans stand amazed at the frenetic emphasis on malaria
therapeutics, with hardly any mention of the Public Health measures that
were such a success in the good old Colonial Days [22, 23, 24], and which,
even now has kept other tropical countries like Singapore and Trinidad
virtually malaria free. We Africans dearly miss Dr Gro Harlem Brundtland
[25] who possessed that rare quality of character that made her capable of
resolving the problem of apparent contradictions of two worthwhile goals
(Sachs vs Peters). That rare quality is that of Ethics. We need good
people in high places to help the African. We need to get back to Public
Health in both the AIDS pandemic [26, 27, 28] and malaria control [21, 22,
23, 24]. Successful therapeutics with pharmacovigilance only medicates
symptoms; not a bad thing in itself. What we really need, however, are
friends that will tackle Africa’s basic problems and assist us to shift
our paradigms [29, 30, 31].

“I am praying hard” I said not very long ago [30] “for a 21st Century
William (or Williama) Wilberforce who will be bold enough to help save the
African from this predicament. My William Wilberforces would need the
staunch support of the three British Editors who had the integrity to
publish statements that called a spade a spade: Lancet (‘The Biological
Bomb [32]…public health in reverse [32]…HIV is a disease of mass
destruction’ [33]), Nature (‘Artificial HIV?’ [34]), BMJ (‘Issues of race
hinder public health’ [35] and ‘they even publicly rejoiced over the
possible elimination of black people by the disease, as one Member of
Parliament did in 1992” [36]).

I know my prayer will be answered.

Dr Felix I D Konotey-Ahulu MD FRCP DTMH Kwegyir Aggrey Distinguished
Professor of Human Genetics, University of Cape Coast, Ghana and
Consultant Physician/Genetic Counsellor Haemglobinopathies, 10 Harley
Street, London W1N 1AA. [felix@konotey-ahulu.com]

Conflict of Interest: None Declared

1 Pirmohamed M, Atuah KN, Dodoo ANO, Winstanley P.
Pharmacovigilance in developing countries. BMJ 2007; 335: 462

2 Konotey-Ahulu FID, Ringlehann B. Sickle cell anaemia, sickle
cell haemoglobin C disease, sickle cell beta thalassaemia, and
asymptomatic haemoglobin C beta thalassaemia in one Ghanaian family. BMJ
1969; 46: 607-612.

3 Konotey-Ahulu FID. The sickle cell diseases: clinical
manifestations including the sickle cell crisis. Arch Intern Med 1974.
133: 611-619.

4 Konotey-Ahulu FID. The spectrum of phenotypic expression of
clinical haemoglobinopathy in West Africa. New Istanbul Contribution to
Clinical Science 1978; 12: 246-257.

5 Owusu SK. Absence of glucose-6 phosphate dehydrogenase in red
cells of an African. BMJ 1972; 4: 25-26.

6 Owusu SK, Opare-Mante A. Electrophoretic characterisation of
glucose-6 phosphate dehydrogenase in Ghana. Lancet 1972; 2: 44.

7 Edington GM, Lehmann H. Expression of the sickle cell gene in
Africa. BMJ 1955a: 1: 1308-1311.

8 Edington GM, Lehmann H. Expression of the sickle cell gene in
Africa. BMJ 1955b; 2: 1328.

9 Van Enk, Lang A, White JM, Lehmann H. Benign obstetric history
in women with sickle cell anaemia associated with alpha thalassaemia. BMJ
1972; 4; 524-526.

10 Ringelhann B, Konotey-Ahulu FID. Hemoglobinopaties and
thalassaemias in Mediterranean areas and in West Africa: historical and
other perspectives 1910 to 1997. Atti dell’Accademia delle Scienze di
Ferrara 1998; 74: 267-307 (A Century Review).

11 Konotey-Ahulu FID. Alpha-Thalassaemia nomenclature and abnormal
haemoglobins. Lancet 1984; 1: 1024-1025, May 5.

12 Bruce-Tagoe AA, Yawson G, Opare-Mante A, Scott, D, Biles J,
Konotey-Ahulu FID. Accepatability of Metrifonate in patients with
hereditary erythrocytopathy (clinical haemoglobinopathy with or without
G6PD Deficiency or thalassaemia) during treatment of Schistosomiasis
Haematobium. Preliminary Report on pahse II of the WHO Metrifonate
Acceptance Trial in Ghana between 23rd April 1974 and 14 October 1974: In
First Annual Report by FID Konotey-Ahulu, Director, Ghana Institute of
Clinical Genetics, Korle Bu, Accra, Ministry of Health & Managing
Trustees of VALCO Fund, pages 49-66.

13 Amofah G. Furore over Artesunate-Amodiaquine. Daily Graphic
Accra 2006, Monday May 15, p 23.

14 Konotey-Ahulu FID. Epidemiology of malaria (5): The Why?
Question. Ghanaian Times Saturday February 18 2006, page 6.

15 Lancet Editorial. Corruption in health costs lives. Lancet
2006, February 11-17, page 447.

16 Konotey-Ahulu FID. Black people’s red faces and AIDS
prevention. Lancet 29 April Vol 355: 1559.

17 Konotey-Ahulu FID. Four bodyguards and the perils of unmasking
scientific truths. BMJ 2007; 335: 210-211, July 28.

18 Konotey-Ahulu FID. AIDS in Africa. Lancet 2002; 360: 1424,
November 2.

19 Sachs JD. A new global effort to control malaria. Science 2002;
298: 112-124.

20 Peters CJ. Hurrying towards disaster? Perspectives in Health
2002. Special Centennial Edition of PAHO, Washington DC, pp 14-20.

21 Konotey-Ahulu FID. Averting a malarial disaster. Lancet 1999;
354: 258, July 17.

22 Konotey-Ahulu FID. Fever and WHO recommendation. Lancet 1997;
1549, November 22.

23 Konotey-Ahulu FID. Public health in less developed countries.
Lancet 2000; 356: 1769-1770, November 2000.

24 Konotey-Ahuku FID. A non-sense mutation and protection from
severe malaria. Lancet 2001; 358: 927-928, September 15.

25 Brundtland Gro Harlem. World summit on sustainable development –
Importance of health in economic development makes it a priority. (Guest
Editorial) BMJ 2002; 325: 399-400.

26 Konotey-Ahulu FID. Clinical epidemiology, not seroepidemiology
is the answer to Africa’s AIDS problem. BMJ 1987; 294: 1593-1594, June 20.

27 Konotey-Ahulu FID. An African on AIDS in Africa (Guest
Editorial) The AIDS Letter – Royal Society of Medicine 1989, No 11,
Feb/March, pages 1-3.

28 Konotey-Ahulu FID. African AIDS through African eyes. (Guest
Editorial) AIDS Analysis Africa 1991; No 1, March/April, page 11.

29 Konotey-Ahulu FID. Probing anecdotes in traditional African
therapeutics. African Journal of Health Sciences 1994; 1: 53-56.

30 Konotey-Ahulu FID. Wake up call and need for paradigm shift:
One African’s response to AIDS in South Africa. 2 April 2003
http://bmjjournals.com/cgi/eletters/326/7387/495#30917 Rapid response to
AIDS in South Africa by Didier Fassin and Helen Schneider BMJ 2003; 325:
495-497 (See Reference 34)

31 Konotey-Ahulu FID. Controlling the three “P”s in Africa. Lancet
2005; 366: 634, August 20.

32 Lancet Annotations. The Biological Bomb. Lancet 1968; 1, 465,
March 20.

33 Schlagenhauf P, Ashraf Haroon. HIV/AIDS lowers UN’s global
population estimates (Authors quote Joseph Chamie, Director of UNDP as
saying “HIV/AIDS is a disease of mass destruction”. Lancet 2003; 361: 841
(November 8).

34 Seale J. “Artificial HIV?” Nature 1988; 335: 391.

35 British Medical Journal. Understanding AIDS in South Africa:
Issues of race hinder public health. BMJ 2003; 326: Front Cover, March 1.

36 Fassin D, Schneider H. The politics of AIDS in South Africa:
beyond the controversies. BMJ 2003; 326: 495-497.

Competing interests:
None declared

Competing interests: No competing interests

14 September 2007
Felix ID Konotey-Ahulu
Kwegyir Aggrey Distinguished Professor of Human Genetics University of Cape Coast Ghana
Consultant Physician Genetic Counsellor Haemoglobinopathies 10 Harley Street London W1N 1AA