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Rapid Responses: Rapid Responses published:
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Remember bogus drugs
- Timothy R. Wiggin (14 September 2007)
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Who should best pharmacovigilate in developing countries?
- Felix ID Konotey-Ahulu (14 September 2007)
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Role of price; pharmaceutical industry's responsibility
- Muhammad Naim Siddiqi (24 September 2007)
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Pharmacolvigilance in developing countries - what is happening in developed countries?
- Sris Allan (23 October 2007)
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Timothy R. Wiggin, General Practitioner Northampton, NN2 6LS. Former Medical Officer, Nkhotakota, Malawi. tim.wiggin@gp-k83003.nhs.uk
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Pirmohamed et al do well in highlighting the delay in matching drug safety monitoring with increasing pharmaceutical provision to resource poor countries. But when it comes to such monitoring, are the drugs real or fake? Bogus pharmaceuticals are the scourge of rural dispensaries, health centres and government and faith-based hospitals. If side-effects occur, are they due to an authentic drug or fake one? Uncertainty questions the value of reports received by monitoring centres and the efforts made in sending them. Dispensaries operating on tight budgets are unlikely to buy from more expensive, secure outlets, even if government run. Bad experiences with suppliers, hear-say around the country-of-origin of local pharmaceutical stock, together with mishandling rumours at local outlets, all combine to influence which drugs are purchased and from where. Audit trails by monitoring centres of the various supply lines for bogus drugs often go cold; and so the problem continues. Tackling this issue is a costly yet very necessary step towards making pharmacovigilance in developing countries a worthwhile goal. Competing interests: None declared |
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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
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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 |
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Muhammad Naim Siddiqi, Assistant Professor and Consultant psychiatrist Department of Psychiatry . Aga Khan University Karachi Pakistan
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In resource poor countries, price becomes one of the most important
factors that dictates the quality of medicines.This happens in two ways;
Competing interests: None declared |
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Sris Allan, Consultant GU / HIV Physician Coventry & Warwickshire Hospital. Stoney Stanton Road, Coventry. CV1 4FH
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Dear Editor, I read the editorial by Munir Primohamed at al on the topic of Pharmocovigilance in developing countries with interest and agree with the authors to a certain extent. However, I would like to emphasis that safety profiles of drugs are still not adequately studied in developed countries. As an example some HIV drugs are introduced to the market prematurely having had efficacy and safety testing performed in a small number of patients before short term serious and long term adverse events are being fully explored and understood. In effect all approved drugs should be actively and meticulously monitored in developed countries in order for precise safety profiles to be compiled thus avoiding adverse drug reactions. The present system of voluntary reporting of adverse event is neither adequate nor complete. The licensing authorities should and must demand from the pharmaceutical companies to continue with the Pharmocovigilance on a long term basis to ascertain a profile of adverse events on the marketed drugs. Until and unless this is made an active process we will not be able to find the denominator population for adverse event in the community. While we are setting up policies and structures to monitor the safety profiles in developing countries, we should have a successful active policy of Pharmocovigilance in developed countries to monitor the situation so that information can be effectively conversed globally. The developed nations should lead a collaborative system of active monitoring with an emphasis on the necessity of reporting all adverse drug reactions with a prompt and comprehensive approach. It is paramount that we, as medical practitioners and associated medical professionals acknowledge and appreciate our role in Pharmocovigilance and aid in making treatment for patients safer. Competing interests: Dr Allan has been sponsored by various pharmacuitcal companies to attend scientific conferences. |
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