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Drug evaluation in developing countries
71PS -April 1981
84
Vi®Wlp@it Drug evaluation in developing countries L. A. Salako Department of Pharmacology and Therapeutics. Unwersilyof Ibodan, Ibadan, Nigeria.
Introduction The objective of drug evaluation in developing countries is the same ~s that in developed countries - : h e prowsion of drugs with proven efficacy and safety. Evaluation begins with the testing of the drug for safety using experimental ~nimals and is complete'd with the total clinical experience with the drug. The investigations which make up clinical evaluation ~ake place in a number of phases which can be identified as: (I)lnitial studies in man (phase I and phase II trials), (2) Formal therapeutic trials (phase III and phase IV trials) and (3) Post marketing surveillance. For the ~tisfactory evaluation of drugs. certain principles have. over the years been formulated and il is in complyinR with them that problems arise, These problems ~ill be discussed as they are expel~Lenced in developing countries and with particular emphasis on clinical trials. Clinical evaluation in the context of developing countries. the term drug should apply not only to therapeutic substances but also to prophylactic substances including vaccines. Many of the so-called tropical diseases arc diseases of underdevclopment and their control rests as much with prophylactic vaccination as with drug treatment. The clinical evaluation of vaccines is therefore as important in developing countries as the evaluation of therapeutic substances. Drugs used in developing countries fall into t~o broad groups: (1) drugs used in disea:~es found mainly in developing countries, for example, helminthiasis, leishmaniasis, trypanosomiasis and other co~nmunicable tropical diseases and (2) dr~gs used for diseases of world-wide distribution. Thus cancer, cardiovascular diseases, mental disorders and metabolic diseases affect developing countries (as they do developed ~:ountries) and exert an enormous toll in terms of human suffering and costs to their economy. For both groups of drugs, the principle that drugs for use in El~,~*l~:tl%llt~h,Hotland
[tlolll¢.dlc'al P t ¢ ~ Itl~,l
Prereqais|te The first and most important prerequisite for a clinical trial is the availability of a preparation that has undergow: adequate preliminary tests in experimental animals and that has been approved for administration to human subjects by a reputable safety organization. Even after such a preparation has become available, there remain problems posed by peculiar circumstances prevailing in the tropics where most of the developing countries are situated. Special tests h~.vc to be carried out and data provided on the stability and storage characteristics under different conditions of temperature and humidity. It is often necessary to prepare special formulations for the developing countries and such special formulations have to be tested for bioavaillability and other pharmacokinetic properties to ensure that these properties have not been altered in the process of modif)ing the preparations to suit the special climatic conditions of some developing countries.
any given population should be assessed for effic,~cy and safety in the particular population applies. For the second group, since the drugs, which are usually produced in the more developed countries, would have been extensively ~ded in the country of origin and other developed countries for efficacy and safety, only limited clinical evaluation is required in developing countries. Such limited evaluation is necessary: (1) to answer the scientific question as to whether differences in race, geographical location, climate and nutrition have any effect on the already known responses to the drug and (2) to satisfy statutory requirements laid down by each country's Planning of the trial drug regulatory, agency, prior to the introOne of the most important responduction of a new drug for general use. sibilities in the planning stage is the clear With the first group of drugs, it is often definition of the objectives of the trial. The necessary to carry out detailed clinical staff structure and laboratc, D' support evaluation in developing countries, from would then be set at a level adequate to the initial studies in healthy volunteers to attain all objectives. For example, for the large-~ale controlled multi-centre or initial studies in man, a clinical laboratory field trials. Besides the problem of testing equipped to measure a wide range of new drugs in man, there is also a need to physiological and biochemical variables is re-evaluate many established or commonly es~ntial. Such laboratories are only found used remedies. Many of the presently well in a few teaching hospitals in developing established tropical disease drugs have countries and they are so often bogged never had adequate pharmacokinetic test- down with routine laboratory services that ing (enzyme induction, protein binding, they are reluctant to take on additional interaction with other drugs, etc.) and responsibilities essential for the initial judgements of their safety and efficacy rest administration of a drug to humans, as much on intuitive reasoning as on The successful conduct of a clinical trial acceptable scientific evidence, also requires the collaboration of statistiOnce of the major justifications for test- cians with extensive experience in the ing a new drug in man or for testing an old design and conduct of biomedical invesdrug for a new indication is the specific tigations. A team leader, who ideally medical need it is hoped the drug will meet. should he a clinician skilled in the design For most of the endemic tropical diseases, and practice of scientific clinical investigathe need for this study is easily justified. lion in man and in principles of cYinical However, for the more cosmopolitan dis- pharmacology, is equally essential. Such eases and the ~-called diseases of afflu- personnel are in short supply in many ence, it is difficult to justify the commit- developing countries. ment of what may turn out to be a sizeable fraction of the medical manpower Siting of the trial resources of a developing country to the Most clinical trials are conducted in hosexecution of a clinical trial of sufficient pital out-patient or in-patient departments. quality and size as to command inter- Very often the clinical trial team h~s to national acceptance. compete with other units in the health care
~5
I'IPS - A p r i l IqSI delivery system for hospital space and facilities for which, almost invariably, there i~, a greater d e m a n d than supply. Studies requiring the commitment of hospital beds or out-patient staffand facilities to any substantial extent fi~r several months are therefore difficult to sustain. Fiehl trials also have their own peculiar problems. If the goals of the W H O arc realised, there should be vaccines against malaria and possibly other tropical parasitic diseases available for large scale use before the end of this decade. The vaccines will have to be submitted to field trials before being released for general use, Ideally for such field studies an accurate census o f the population selected for the study should be available. Population mobility should be known and accurate records of births and deaths should bc available, There should be information on the identity and seasonal occurrence of all the communicable d i ~ a s e s endemic in the area as well as the transmission pattern of the infection under study. Access of the population to drugs other than those to be administered by the field team must be negligible. This information which is so essential is sadly lacking in many developing countries and this poses a problem to anyone embarking on the large-scale field trial of a vaccine in such couotries. Conduct of the trial Selection of patient~ entails accurate diagnosis and accurate assessment of the severity o f the disease under study. This is not often easy in developing countries due to interference with the course of the disease by previous treatment which cannot be evaluated. The widespread presence of coexisting diseases, e~pecially parasitic ones, also poses its o ~ n problems. Age specifications are difficult to achieve with precision because of the absence of reliable birth and death statistics. Some local customs or religious practices forbid free movement o f women in public places including hospitals. Matching of patients for severity o f illness, disease, age and sex, although desirable cannot therefore be rigidly pursued without seriously compromising the number of patients available for study. This, in particular, makes standardized multi-centre and multi-national studies difficult to conduct. The u. ¢ of other drugs concurrently with the drug under trial also poses its own problem. In many developing countries in Africa, the Indian subcontinent and South East Asia, the hospital is a place o f last resort, the patient having sought and received treatment from local traditional healers before coming to hospital. If such a
patient is included in a clinical trial, it ix difficult to restrain him from continuing aith any medication he may v.ell be receking from the traditional healer. Fortunately most of t h e ~ will be pharmacologically inert but some are active and may affect the response to the drug under ~lud~. Also, since drugs are generally available to the population in the black market and even in licensed pharmacies without prescription. patients may continue to take other potent drugs without reference to the clinical trial investigator. The rate of default amongst patients taking part in clinical trials in developing cot|ntries is undoubtedly higher than in developed countries. In a recent surge) of short term clinical trials reported in three journals in West and East Africa. the deflmlt rate was between 30 and 411%. The reasons for this high default rate include poor motivation, transl~rtation costs, unavailability of home help and unwillinghess to be away from work too frequentl 3 . The high rate of default has to be borne in mind ~ h e n deciding the numbers to be admitted to a trial so that the minimum number compatible ~ith statistical analysis of results will complete it. This prob!em also indicates a need to i n v o k e medical ,social workers in any major trial. The~ undertake regular visits to patients" homes and trace defaulters, if measurements to be made are not too specialized, the medical social worker ~ith a nursing background may take the measurements and superx ise drug administration. The home visits may also provide insight into habits of patients which are not elicited in hospital but ~,,hieh may contribute to non-compliance. Thus a patient who takes one meal a da~ ~ould not be included in a tri:d in which drugs would be administered three times :~ day after food. Irregularity in the suppl~ of drugs ma~ also constitute a major handicap, if. a~ ix usually the case. importati~n of drugs ix involved. There may be delay in the i~suing of import licence or in the clearing of ~he drugs from congested ports.
nor ,,~rite. Indeed. the ',igning ~,f docunwn!, ix ,,o widely regarded a,, an act of sel:incrimination that it,, ,,tt~ege,,t~on i,~ b~mn,.t to scare away nlan[~ of tho~' v, ho would otherwise ha~'e ~oluntecred. I-inally, many people in de~clt~ping countries belie~,e that the teaching hospitals ~here mo,,t of the clinical trials are conducted arc ccntrc, where patients are us~:d for experiments ~shich arc not nece,,saHly ill their best interest. An ins,m~tion t~. a patient to partieip:Jte in a trial in s~hich he may serxe a~ a placebo control ma~ thcrefl~re confirm hi~ worst fears and ,~eakcn his confidence in the doctor and the institution. Unlortunately, rather than gi~,e an outright refusal. man,, patient,, s~,illagree to participate only to cease attendance in hospital alt,,gethcL Prospects With the increa,,ing in|crest in drugs for tropical diseases ,,lk.arheaded b', the WHO. the need to c,,aluate drug,, in the endemic area., i,, being increa,,ingl} cmphasi,,cd. 1"o that end. for example. laborator), facilities to '~creen ne~ comi~unds for D~ssible tr~ panocidal action in vitro are being developed in Kcn3a and for antileishmanial action in expcnmcut:tl modeb, in Brazil. Pha,~, i and Pha,,e 11 clinical trials of ne~ antimalarial,, h,:'~,.' been initiated in Brazil and Thailand and more are planned for Zambia. For other tropical infection,, like filaria,,i,,, schi~,tosomiasis and Icpro..,.x. large ,~cale pha~-~: III and field trials are going on in (it~ana. Nigeria. India and ~,¢~,eralother de~ eloping countries. All clinical trial,, arc coordinated and ~tandardized u>ing ,,tandard protocols de~.elopcd b'~ the various Scientific ~,Vorking Group', of the '~, HO. ~,Vhcrc the trials in~ol~,e determimaion of the pharmacokinetie profile of the drug or the development of ri¢~ scn,,iti~ e method,, for estimating the drug in bitdogi,:al fluid~. assi~,tance ix gi~,en to ,,elected centre,, to develop stl2h capabilit.~ and t~ collaborate v, ith centrex in developed ctmntnes and the pharmaceutical indus| U ~ hilst ~,uch capabilit 3 is Ix'ing de~,elopcd, l~hc ",~,HO ha', also identified the establishment of ¢hnic:,l pharmacology centrcs for testing nc~ drugs Ethical issues ill endemic areas as a high p r l o r i t ~ a n d is encouraging the training of pcr~,onnel Experienced investigators kno~s ho~ difficult it is to explain the nature of an experi- in the .,,.-ience of clinical trials and the e~,tabment to otherwise educated and intellig,.nl li~ht'nent of nex~ chnical pharnlacolog.x cenlrer, in scxeral dcseloping countrie,,. but not medically or scientificall) qualified persons. They can therefore imagine hoa I t~H¢) Tcch R*7, ~,c~ 34l i l ' 4 ~ J ~.~,HO. ticnc~,~ 2 ~ H O 1-et'h. Rep .%.r 40311~¢~1~1.%~"HO. t ;t'nc~a much more difficult it is to explain the same 3 I~'HO l~ch Rep ",e" ~'1a311'4"5 .'~.|10 (;~nc~. thing to illiterate p e a n u t s in some remote village in Africa or Asia. Asking patients to L. A. .~,alako obalmed medical qaa,'ifi,'anorL~ at l otlindicate acceptance to participate in a trial ,bin ~ 'mver.~ltv ,rod a Ph.D. al .~helfie;,i ,~h' ha~ I~c,'n Cort~ultant irl ('/ina',d Pharmac,,h~g)' at the ~ rdL ersit~ by signing a statemcnl to that effect may be (.~,ll,~e ttt~$p~h~L lbadan ~ime I 0 " 0 ,rod ~'rot~'~,,r o f a good thing but is hardly worthwhile when Clina'al Ph,a'rr:~'ok~,~w there s~ce I~'3. He B a memdealing with patients who can neither read ber o f the Wt~.O advisory panel on drag evaluation.
84
Vi®Wlp@it Drug evaluation in developing countries L. A. Salako Department of Pharmacology and Therapeutics. Unwersilyof Ibodan, Ibadan, Nigeria.
Introduction The objective of drug evaluation in developing countries is the same ~s that in developed countries - : h e prowsion of drugs with proven efficacy and safety. Evaluation begins with the testing of the drug for safety using experimental ~nimals and is complete'd with the total clinical experience with the drug. The investigations which make up clinical evaluation ~ake place in a number of phases which can be identified as: (I)lnitial studies in man (phase I and phase II trials), (2) Formal therapeutic trials (phase III and phase IV trials) and (3) Post marketing surveillance. For the ~tisfactory evaluation of drugs. certain principles have. over the years been formulated and il is in complyinR with them that problems arise, These problems ~ill be discussed as they are expel~Lenced in developing countries and with particular emphasis on clinical trials. Clinical evaluation in the context of developing countries. the term drug should apply not only to therapeutic substances but also to prophylactic substances including vaccines. Many of the so-called tropical diseases arc diseases of underdevclopment and their control rests as much with prophylactic vaccination as with drug treatment. The clinical evaluation of vaccines is therefore as important in developing countries as the evaluation of therapeutic substances. Drugs used in developing countries fall into t~o broad groups: (1) drugs used in disea:~es found mainly in developing countries, for example, helminthiasis, leishmaniasis, trypanosomiasis and other co~nmunicable tropical diseases and (2) dr~gs used for diseases of world-wide distribution. Thus cancer, cardiovascular diseases, mental disorders and metabolic diseases affect developing countries (as they do developed ~:ountries) and exert an enormous toll in terms of human suffering and costs to their economy. For both groups of drugs, the principle that drugs for use in El~,~*l~:tl%llt~h,Hotland
[tlolll¢.dlc'al P t ¢ ~ Itl~,l
Prereqais|te The first and most important prerequisite for a clinical trial is the availability of a preparation that has undergow: adequate preliminary tests in experimental animals and that has been approved for administration to human subjects by a reputable safety organization. Even after such a preparation has become available, there remain problems posed by peculiar circumstances prevailing in the tropics where most of the developing countries are situated. Special tests h~.vc to be carried out and data provided on the stability and storage characteristics under different conditions of temperature and humidity. It is often necessary to prepare special formulations for the developing countries and such special formulations have to be tested for bioavaillability and other pharmacokinetic properties to ensure that these properties have not been altered in the process of modif)ing the preparations to suit the special climatic conditions of some developing countries.
any given population should be assessed for effic,~cy and safety in the particular population applies. For the second group, since the drugs, which are usually produced in the more developed countries, would have been extensively ~ded in the country of origin and other developed countries for efficacy and safety, only limited clinical evaluation is required in developing countries. Such limited evaluation is necessary: (1) to answer the scientific question as to whether differences in race, geographical location, climate and nutrition have any effect on the already known responses to the drug and (2) to satisfy statutory requirements laid down by each country's Planning of the trial drug regulatory, agency, prior to the introOne of the most important responduction of a new drug for general use. sibilities in the planning stage is the clear With the first group of drugs, it is often definition of the objectives of the trial. The necessary to carry out detailed clinical staff structure and laboratc, D' support evaluation in developing countries, from would then be set at a level adequate to the initial studies in healthy volunteers to attain all objectives. For example, for the large-~ale controlled multi-centre or initial studies in man, a clinical laboratory field trials. Besides the problem of testing equipped to measure a wide range of new drugs in man, there is also a need to physiological and biochemical variables is re-evaluate many established or commonly es~ntial. Such laboratories are only found used remedies. Many of the presently well in a few teaching hospitals in developing established tropical disease drugs have countries and they are so often bogged never had adequate pharmacokinetic test- down with routine laboratory services that ing (enzyme induction, protein binding, they are reluctant to take on additional interaction with other drugs, etc.) and responsibilities essential for the initial judgements of their safety and efficacy rest administration of a drug to humans, as much on intuitive reasoning as on The successful conduct of a clinical trial acceptable scientific evidence, also requires the collaboration of statistiOnce of the major justifications for test- cians with extensive experience in the ing a new drug in man or for testing an old design and conduct of biomedical invesdrug for a new indication is the specific tigations. A team leader, who ideally medical need it is hoped the drug will meet. should he a clinician skilled in the design For most of the endemic tropical diseases, and practice of scientific clinical investigathe need for this study is easily justified. lion in man and in principles of cYinical However, for the more cosmopolitan dis- pharmacology, is equally essential. Such eases and the ~-called diseases of afflu- personnel are in short supply in many ence, it is difficult to justify the commit- developing countries. ment of what may turn out to be a sizeable fraction of the medical manpower Siting of the trial resources of a developing country to the Most clinical trials are conducted in hosexecution of a clinical trial of sufficient pital out-patient or in-patient departments. quality and size as to command inter- Very often the clinical trial team h~s to national acceptance. compete with other units in the health care
~5
I'IPS - A p r i l IqSI delivery system for hospital space and facilities for which, almost invariably, there i~, a greater d e m a n d than supply. Studies requiring the commitment of hospital beds or out-patient staffand facilities to any substantial extent fi~r several months are therefore difficult to sustain. Fiehl trials also have their own peculiar problems. If the goals of the W H O arc realised, there should be vaccines against malaria and possibly other tropical parasitic diseases available for large scale use before the end of this decade. The vaccines will have to be submitted to field trials before being released for general use, Ideally for such field studies an accurate census o f the population selected for the study should be available. Population mobility should be known and accurate records of births and deaths should bc available, There should be information on the identity and seasonal occurrence of all the communicable d i ~ a s e s endemic in the area as well as the transmission pattern of the infection under study. Access of the population to drugs other than those to be administered by the field team must be negligible. This information which is so essential is sadly lacking in many developing countries and this poses a problem to anyone embarking on the large-scale field trial of a vaccine in such couotries. Conduct of the trial Selection of patient~ entails accurate diagnosis and accurate assessment of the severity o f the disease under study. This is not often easy in developing countries due to interference with the course of the disease by previous treatment which cannot be evaluated. The widespread presence of coexisting diseases, e~pecially parasitic ones, also poses its o ~ n problems. Age specifications are difficult to achieve with precision because of the absence of reliable birth and death statistics. Some local customs or religious practices forbid free movement o f women in public places including hospitals. Matching of patients for severity o f illness, disease, age and sex, although desirable cannot therefore be rigidly pursued without seriously compromising the number of patients available for study. This, in particular, makes standardized multi-centre and multi-national studies difficult to conduct. The u. ¢ of other drugs concurrently with the drug under trial also poses its own problem. In many developing countries in Africa, the Indian subcontinent and South East Asia, the hospital is a place o f last resort, the patient having sought and received treatment from local traditional healers before coming to hospital. If such a
patient is included in a clinical trial, it ix difficult to restrain him from continuing aith any medication he may v.ell be receking from the traditional healer. Fortunately most of t h e ~ will be pharmacologically inert but some are active and may affect the response to the drug under ~lud~. Also, since drugs are generally available to the population in the black market and even in licensed pharmacies without prescription. patients may continue to take other potent drugs without reference to the clinical trial investigator. The rate of default amongst patients taking part in clinical trials in developing cot|ntries is undoubtedly higher than in developed countries. In a recent surge) of short term clinical trials reported in three journals in West and East Africa. the deflmlt rate was between 30 and 411%. The reasons for this high default rate include poor motivation, transl~rtation costs, unavailability of home help and unwillinghess to be away from work too frequentl 3 . The high rate of default has to be borne in mind ~ h e n deciding the numbers to be admitted to a trial so that the minimum number compatible ~ith statistical analysis of results will complete it. This prob!em also indicates a need to i n v o k e medical ,social workers in any major trial. The~ undertake regular visits to patients" homes and trace defaulters, if measurements to be made are not too specialized, the medical social worker ~ith a nursing background may take the measurements and superx ise drug administration. The home visits may also provide insight into habits of patients which are not elicited in hospital but ~,,hieh may contribute to non-compliance. Thus a patient who takes one meal a da~ ~ould not be included in a tri:d in which drugs would be administered three times :~ day after food. Irregularity in the suppl~ of drugs ma~ also constitute a major handicap, if. a~ ix usually the case. importati~n of drugs ix involved. There may be delay in the i~suing of import licence or in the clearing of ~he drugs from congested ports.
nor ,,~rite. Indeed. the ',igning ~,f docunwn!, ix ,,o widely regarded a,, an act of sel:incrimination that it,, ,,tt~ege,,t~on i,~ b~mn,.t to scare away nlan[~ of tho~' v, ho would otherwise ha~'e ~oluntecred. I-inally, many people in de~clt~ping countries belie~,e that the teaching hospitals ~here mo,,t of the clinical trials are conducted arc ccntrc, where patients are us~:d for experiments ~shich arc not nece,,saHly ill their best interest. An ins,m~tion t~. a patient to partieip:Jte in a trial in s~hich he may serxe a~ a placebo control ma~ thcrefl~re confirm hi~ worst fears and ,~eakcn his confidence in the doctor and the institution. Unlortunately, rather than gi~,e an outright refusal. man,, patient,, s~,illagree to participate only to cease attendance in hospital alt,,gethcL Prospects With the increa,,ing in|crest in drugs for tropical diseases ,,lk.arheaded b', the WHO. the need to c,,aluate drug,, in the endemic area., i,, being increa,,ingl} cmphasi,,cd. 1"o that end. for example. laborator), facilities to '~creen ne~ comi~unds for D~ssible tr~ panocidal action in vitro are being developed in Kcn3a and for antileishmanial action in expcnmcut:tl modeb, in Brazil. Pha,~, i and Pha,,e 11 clinical trials of ne~ antimalarial,, h,:'~,.' been initiated in Brazil and Thailand and more are planned for Zambia. For other tropical infection,, like filaria,,i,,, schi~,tosomiasis and Icpro..,.x. large ,~cale pha~-~: III and field trials are going on in (it~ana. Nigeria. India and ~,¢~,eralother de~ eloping countries. All clinical trial,, arc coordinated and ~tandardized u>ing ,,tandard protocols de~.elopcd b'~ the various Scientific ~,Vorking Group', of the '~, HO. ~,Vhcrc the trials in~ol~,e determimaion of the pharmacokinetie profile of the drug or the development of ri¢~ scn,,iti~ e method,, for estimating the drug in bitdogi,:al fluid~. assi~,tance ix gi~,en to ,,elected centre,, to develop stl2h capabilit.~ and t~ collaborate v, ith centrex in developed ctmntnes and the pharmaceutical indus| U ~ hilst ~,uch capabilit 3 is Ix'ing de~,elopcd, l~hc ",~,HO ha', also identified the establishment of ¢hnic:,l pharmacology centrcs for testing nc~ drugs Ethical issues ill endemic areas as a high p r l o r i t ~ a n d is encouraging the training of pcr~,onnel Experienced investigators kno~s ho~ difficult it is to explain the nature of an experi- in the .,,.-ience of clinical trials and the e~,tabment to otherwise educated and intellig,.nl li~ht'nent of nex~ chnical pharnlacolog.x cenlrer, in scxeral dcseloping countrie,,. but not medically or scientificall) qualified persons. They can therefore imagine hoa I t~H¢) Tcch R*7, ~,c~ 34l i l ' 4 ~ J ~.~,HO. ticnc~,~ 2 ~ H O 1-et'h. Rep .%.r 40311~¢~1~1.%~"HO. t ;t'nc~a much more difficult it is to explain the same 3 I~'HO l~ch Rep ",e" ~'1a311'4"5 .'~.|10 (;~nc~. thing to illiterate p e a n u t s in some remote village in Africa or Asia. Asking patients to L. A. .~,alako obalmed medical qaa,'ifi,'anorL~ at l otlindicate acceptance to participate in a trial ,bin ~ 'mver.~ltv ,rod a Ph.D. al .~helfie;,i ,~h' ha~ I~c,'n Cort~ultant irl ('/ina',d Pharmac,,h~g)' at the ~ rdL ersit~ by signing a statemcnl to that effect may be (.~,ll,~e ttt~$p~h~L lbadan ~ime I 0 " 0 ,rod ~'rot~'~,,r o f a good thing but is hardly worthwhile when Clina'al Ph,a'rr:~'ok~,~w there s~ce I~'3. He B a memdealing with patients who can neither read ber o f the Wt~.O advisory panel on drag evaluation.