Quick viewing(Text Mode)

Access to Essential Drugs in Poor Countries a Lost Battle?

Access to Essential Drugs in Poor Countries a Lost Battle?

SPECIAL COMMUNICATION

Access to Essential Drugs in Poor Countries A Lost Battle?

Bernard Pe´coul, MD, MPH Drugs offer a simple, cost-effective solution to many health problems, pro- Pierre Chirac, PharmD vided they are available, affordable, and properly used. However, effective treatment is lacking in poor countries for many diseases, including African Patrice Trouiller, PharmD trypanosomiasis, Shigella dysentery, , tuberculosis, and bac- Jacques Pinel, PharmD terial meningitis. Treatment may be precluded because no effective drug ex- ists, it is too expensive, or it has been withdrawn from the market. More- HE EFFECTIVENESS OF DRUGS DE- over, research and development in tropical diseases have come to a near pends on a long chain of fac- standstill. This article focuses on the problems of access to quality drugs for tors: research and develop- the treatment of diseases that predominantly affect the developing world: ment (R&D) of an appropriate (1) poor-quality and counterfeit drugs; (2) lack of availability of essential pharmaceuticalT agent, production, qual- drugs due to fluctuating production or prohibitive cost; (3) need to develop ity control, distribution, inventory con- field-based drug research to determine optimum utilization and remotivate trol, reliable information for health care research and development for new drugs for the developing world; and (4) professionals and the general public, di- potential consequences of recent World Trade Organization agreements on agnosis, prescription, financial accessi- the availability of old and new drugs. These problems are not independent bility, drug dispensing, observance, and and unrelated but are a result of the fundamental nature of the pharmaceu- pharmacovigilance. At each level, those tical market and the way it is regulated. involved may have conflicting interests, JAMA. 1999;281:361-367 www.jama.com and poor populations are the first to suf- fer the effects of frail links in this long due to fluctuating production or prohibi- THE PROBLEMS chain. Today, entire populations lack ac- tive cost; (3) need to develop field-based Examples of problems related to devel- cess to essential quality drugs, and the drug research to determine optimum opment and access to drugs and the mag- situation appears to be deteriorating, fur- utilization and remotivate R&D pro- nitude of the public health problems con- ther marginalizing much of the world’s grams for new drugs for the developing cerned are given in TABLE 1. population. world; and (4) potential consequences of Essential drugs are the foundation for the recent World Trade Organization Counterfeit and nearly every public health program aimed (WTO) agreements on the availability of Substandard Products at reducing morbidity and mortality in old and new drugs. For all these issues, Drug products must be produced ac- the developing world, and pharmaceu- practical recommendations to improve cording to good manufacturing prac- tical expenditure can account for a high the situation are proposed. tices.1 Unfortunately, many developing proportion of the total health expendi- The lack of access to essential drugs countries do not have the technical, fi- ture of a country. Important health pro- or vaccines because of economic rea- nancial, or human resources required for grams that rely on essential drugs in- sons raises new human rights issues in the application of such standards, and clude child survival programs, antenatal a world that remains divided among some developed countries may be less care, treatment of enteric and respira- wealthy countries, developing coun- strict when the product being manufac- tory pathogens, and control of tubercu- tries, and the rest of the world. Yet, tured is destined for exportation. To- losis and . Other major public financial access to drugs does not nec- day, the quality of drugs and, therefore, health issues exist for which there is no essarily mean correct use. Continuous their effectiveness and safety are less and effective pharmaceutical treatment. training for health care professionals, This article focuses on 4 main issues dissemination of reliable pharmacologi- Author Affiliations: Fondation Me´ decins Sans Fron- associated with the inaccessibility of cal data, and improvement of the man- tie` res, Paris, France. drugs for populations in greatest need: agement of drugs are fundamental steps Corresponding Author and Reprints: Bernard Pe´ coul, MD, MPH, Me´ decins Sans Frontie` res, (1) poor-quality and counterfeit drugs; in improving the quality of care in the 8 rue St Sabin, 75011 Paris, France (e-mail: (2) lack of availability of essential drugs developing world. [email protected]).

JAMA, January 27, 1999—Vol 281, No. 4 361 ACCESS TO ESSENTIAL DRUGS IN POOR COUNTRIES

Table 1. 1996 Worldwide Accessibility to Drugs or Vaccines for 10 Diseases* Incidence (I) or Diseases† Deaths† Prevalence (P)† Drugs or Vaccines Type of Problem Acute lower respiratory tract 3.9 394 (I) Ceftriaxone sodium (for severe cases Available but limited use, prohibitive in hospital) price Anti-Haemophilus vaccine (Hib Available but limited use, prohibitive conjugates Haemophilus) price Antipneumococcal vaccine (group A Clinical development (phase 1 trial) streptococci) Tuberculosis 3.0 7.4 (I) Isoniazid, rifampicin, pyrazinamide, Poor compliance with therapy and ethambutol hydrochloride, outbreaks of drug-resistant strains streptomycin, thiacetazone (isoniazid, rifampicin) Sodium aminosalicylate, ethionamide, Production not secured, toxic effects of capreomycin sulfate drugs Rifapentine Available but limited use BCG vaccine Effectiveness disputed Diarrhea 2.5 4000 (I) Ciprofloxacin (shigellosis) Available but limited use, prohibitive price Antirotavirus vaccine Available but limited use, prohibitive price Anticholera vaccine (whole cell B) Available but limited use Anticholera vaccine (103Hgr) Available but limited use Antishigellosis vaccine Clinical development (phase 2, 3 trials) Malaria 2.0‡ 300-500 (I) Clinical development (phase 3 trial) derivatives Available but production not secured for substandard products Coartemether Clinical development (phase 2, 3 trials) - Available but limited use Antimalaria vaccine (preerythrocytic) Clinical development (phase 2, 3 trials) Antimalaria vaccine (asexual erythrocytic Clinical development (phase 2 trial) stage) Preventable diseases (pertussis, 1.7 82 (I) Pertussis whole cell, measles, diphtheria, Substitution of classic formulations by measles, diphtheria, polio, oral polio, and tetanus vaccines new formulations, prohibitive price tetanus) (eg, acellular pertussis) Human immunodeficiency virus 1.5 3.1 (I), 22.6 (P) Antiretroviral drugs Available but limited use, prohibitive price Anti-HIV vaccines Clinical development (phase 1, 2 trials) Hepatitis B 1.2 200 (P) Hepatitis B recombinant vaccine Available but limited use Human 0.15 0.2 (I), 0.3 (P) sodium Production not secured (no commercial interest) isethionate Production not secured (no commercial interest) Production not secured (no commercial interest) hydrochloride No longer produced (no commercial interest) Leishmaniasis 0.08 2 (I) antimoniate Production not secured (no commercial interest) lipid complex Limited use Aminosidine Old drug (production stopped) Meningitis 0.04 0.4 (I) Ceftriaxone sodium Available but limited use, prohibitive price Oily chloramphenicol Available but production not secured for substandard products Antipneumococcal vaccine Clinical development (phase 2, 3 trials) Anti-Haemophilus vaccine (Hib) Available but limited use, prohibitive price Meningococcal A-C conjugates vaccine Clinical development (phase 2 trial) *For these diseases, there were a total of 16.07 million deaths of 52 million worldwide. One third (17.3 million) were due to infectious diseases (Ͼ90% in developing countries). †Data, in millions, are from the World Health Organization, World Health Statistics Annual, 1996.17 ‡Data indicated in World Health Statistics Annual as 1.8/2.2.17

362 JAMA, January 27, 1999—Vol 281, No. 4 ACCESS TO ESSENTIAL DRUGS IN POOR COUNTRIES less certain, especially for the poorest Poor quality may be accidental, with somiasis shows resistance to melarso- populations, who are attracted by lower- no intention to deceive, but oversights prol, and such resistance is becoming priced drugs sold outside pharmacies. in manufacturing or neglected controls more frequent (20% in Omungo, Recent years have seen an increase in can have tragic consequences. Such was Uganda).9 This drug was sold at an ex- the prevalence of counterfeit and sub- the case in recent decades with acetami- tremely high price and is now no longer standard drugs on the market. Counter- nophen syrups that contained, by mis- manufactured. Only through a joint ef- feit drugs are those that mimic authen- take, a lethal ingredient.4,5 fort of the World Health Organization tic drugs; substandard drugs are those (WHO), nongovernmental organiza- produced with little or no attention to Fluctuating Production tions involved in fieldwork, coopera- good manufacturing practices. of Essential Drugs tive bodies, and pharmaceutical compa- For example, during the meningitis epi- Drugs necessary for the treatment of cer- nies could this drug become available and demic in Niger in 1995 (41 000 cases re- tain tropical diseases have begun to dis- affordable again. ported), Niger authorities organized an ex- appear from the market because they are tensive vaccination campaign. In March commercially unprofitable. Many of these Prohibitive Costs 1995, Niger received a donation of 88 000 drugs were discovered in the 1950s and The prohibitive cost of antiretroviral Pasteur Me´rieux and SmithKline Beecham 1960s or earlier and are seldom or never drugs for treatment of people with ac- vaccines from neighboring Nigeria. A used in wealthy countries. quired immunoeficiency syndrome is Me´decins Sans Frontie`res (MSF) team An example is seen in the effort to treat well known.10 There are many other ex- working with local health authorities no- epidemic bacterial meningitis, caused by amples of drugs that are simply not af- ticed that the vaccines from Nigeria had Neisseria meningitidis, which is rampant fordable, most of which have been re- an unusual appearance (eg, difficult re- in sub-Saharan Africa. Efficacy of treat- cently marketed and therefore are still constitution, black filaments in the solu- ment with chloramphenicol in oily sus- patent-protected. tion). Inquiries were made and Pasteur pension (1 intramuscular injection re- Shigella dysenteriae type 1 dysentery is Me´rieux laboratories confirmed that the peated after 48 hours) for bacterial extremely contagious and, without ef- batch numbers and expiration dates did meningitis is comparable with the tra- fective treatment, is lethal in 5% to 15% not correspond to their records. The drugs ditional treatment with ampicillin (in- of cases.11 Since 1979, this disease has supplied had been substituted with coun- travenous injections 4 times daily for 10 been the cause of large epidemics in Af- terfeit drugs. Tests carried out found no days).6 The lower cost of chlorampheni- rica (for example, in Malawi in 1992 and traces of active product, confirming they col in oily suspension—only one tenth 199312 and in Burundi in 199411,13,14). were false. Bottles and labels were cop- the cost of ampicillin—and its simple ad- Shigella dysenteriae type 1 bacteria quickly ied to perfection.2,3 Pasteur Me´rieux sub- ministration make it particularly suit- became resistant to traditional treat- sequently filed a counterfeit suit. Some of able to the precarious conditions in de- ments. The only effective antibiotic drugs the false vaccines (approximately 28 000) veloping countries.6 This is particularly today are fluoroquinolones (eg, cipro- were located by batch number and de- important during epidemics. In Nigeria floxacin and norfloxacin). However, treat- stroyed. According to estimates, approxi- in 1996, for example, more than 100 000 ment with these new drugs is 10 times mately 60 000 persons were inoculated cases of N meningitidis infections were re- more expensive than the traditional treat- with false vaccines of a total 5 million vac- ported.7 However, production and avail- ment using nalidixic acid (approxi- cinated during the campaign. Such a pro- ability of chloramphenicol in oily sus- mately $20 vs $2).15 A special agreement duction would have necessitated an in- pension are no longer guaranteed. was reached between Bayer Laboratories dustrial-scale manufacturing facility, and Roussel-Uclaf stopped its production in and MSF in 1997 to make available treat- it is probable that the 88 000 vaccines 1995 and transferred its technology to ments with ciprofloxacin for 50 000 identified as false did not account for the another laboratory, which began pro- people for a unit price of $2 per treat- entire fraudulent production. duction last year. In the meantime, tem- ment. This example shows that it is pos- Me´decins Sans Frontie`res teams have porary solutions have ensured that a cer- sible to find a short-term ad hoc solution encountered similar field examples that tain (but far from sufficient) amount of with the pharmaceutical industry, yet no lead to the following conclusions: orga- chloramphenicol is made available. midterm solution is anticipated. nized illegal circuits seem inclined to The circumstances described herein A recent study of bacterial meningitis manufacture copies with the appearance also apply to other serious illnesses, such causedbyStreptococcuspneumoniaeinchil- of known trademark drugs (counterfeit) as leishmaniasis and its treatment with dren aged 2 months to 3 years demon- than comparatively less-expensive ge- meglumine antimoniate and African try- strated that use of ceftriaxone sodium neric products, whereas nonorganized il- panosomiasis and melarsoprol (Table 1). could reduce mortality from 66% to 32% legal circuits (small production) increas- The trypanocidal activity of eflorni- compared with treatment with chloram- ingly manufacture drugs that are thine hydrochloride was discovered in phenicol in oily suspension.16 Both anti- substandard or inadequate, including ge- 1985.8 It is the only treatment proven ef- biotics have a sustained action and require neric drugs. fective in cases in which African trypano- very simple protocols (daily intramuscu-

JAMA, January 27, 1999—Vol 281, No. 4 363 ACCESS TO ESSENTIAL DRUGS IN POOR COUNTRIES lar injection for a short time) and there- into new forms of existing drugs (eg, sus- to complete.23 Moreover, a successful out- fore are equally easy to use in adverse con- tained action or rectal formulation) and come is not guaranteed (as was the case ditions. However, ceftriaxone treatment the development of simpler treatment with oltipraz, an antibilharzial agent is 10 times more expensive than chloram- guidelines (eg, “one-shot” or short treat- abandoned during clinical trials). phenicol treatment.16 Streptococcus pneu- ments). This type of research cannot be 2. A Shift to More Profitable Pro- moniae is also one of the main developed unless technical and finan- duction. To cope with large investments causes of severe acute respiratory tract cial resources are made available and, and reduce duplicate spending, pharma- infections—the primary cause of child more importantly, unless new efficacy ceutical companies started an unprec- mortality in Africa.17 Therefore, ceftriax- criteria are applied to the treatment be- edented cycle of industrial consolidation one is vital but financially inaccessible to ing studied. and mergers at the end of the 1980s (eg, those populations that need it most. Glaxo and Wellcome, Sandoz and Ciba- Prohibitive pricing also extends to pre- Insufficient R&D for New Drugs Geigy, Roche and Synthex). This consoli- vention when new vaccines are not avail- Increasing drug resistance, adverse dation focused on the most profitable seg- able for the population most at risk. For effects, and the lack of feasibility of cur- ments of the market (infectious diseases, example, hepatitis B virus and anti- rent protocols point to the need for cardiovascular conditions, cancer, derma- Haemophilus vaccines are not accessible greater R&D into new drugs for dis- tology, and neurology), leaving tropical because of their steep price. Vaccines for eases found in the developing world. medicine largely out of the equation. hepatitis B, a disease predominantly From 1910 to 1970, the pharmaceuti- 3. Competition and Counterfeit- found in eastern Asia and sub-Saharan cal industry’s contribution was crucial ing of Drugs. Some drugs patented in Africa,18 are approximately 10 times more to the fight against endemic tropical the developed world are being copied in expensive than other vaccines included diseases: trypanocides and antiamebic developing countries, where patent rights in the Expanded Programme on Immu- agents in the 1930s (Bayer, Rhoˆne- of pharmaceutical products are not pro- nization promoted by UNICEF.19 Poulenc), during World tected. Such production competes, some- War II (Specia, Winthrop), and in the times fiercely, with the innovating labo- Essential Drugs Not Adapted 1960s, the discovery of leading anthel- ratory. For example, Bayer Laboratories, to Field Conditions mintics (Janssen). Since then, pharma- the patent holder of praziquantel, was Tuberculosis caused the deaths of 3 mil- ceutical companies have adopted a outpriced by Shin Poong, a Korean labo- lion people in 1997, but the current treat- completely different strategy.21 ratory that had developed a less- ment regimen, known as directly observed Among the 1223 new chemical enti- expensive manufacturing process.24 In therapy—short course (DOTS), is imprac- ties commercialized from 1975 to 1997, addition to copies of drugs resulting from tical and compliance is poor: only 23% 379 (30.9%) are considered therapeu- a different notion of intellectual prop- of the world’s population has access to the tic innovations, but only 13 (1%) are spe- erty rights, there are cases of pure and WHO tuberculosis control strategy.20 cifically for tropical diseases (TABLE 2). simple piracy (appropriation of the name Research to simplify or shorten the DOTS Two of these 13 drugs are actually up- and appearance of a trademark drug) that regimen is needed to make the treatment dated versions of previous products (new are frequent in countries where infor- more widely available. Furthermore, the formulations of pentamidine and am- mal markets play a significant role.25 emergence of strains resistant to com- photericin B), 2 are the result of mili- 4. Cost of Adhering to Quality Stan- monly used antibiotics has potentially dev- tary research ( hydrochlo- dards. There has been a general trend astating worldwide consequences. Cur- ride and ), 5 come from toward heavier regulations with which rent second-line treatments are too veterinary research (, benz- companies must comply to obtain ap- expensive, too complex, and too long, nidazole, ivermectin, oxamniquine, and proval before marketing a drug prod- and therefore not realistic for field con- praziquantel), and only 4 (0.3%) may be uct, which raise the costs of clinical de- ditions. Priority should be given to sim- considered direct results of R&D activi- velopment. The necessity of minimizing pler treatment guidelines that combine ties of the pharmaceutical industry (ar- therapeutic risks leads to reinforcement several antibiotics, which may not achieve temether, atovaquone, eflornithine, and of various quality standards (good clini- the same level of efficacy of more com- ).22 cal, laboratory, and manufacturing plex protocols but are at least more prac- Thus, it appears that pharmaceutical practices).26 In practice, when clinical de- tical for the field. Today, those with mul- R&D is abandoning tropical diseases. velopment incidentally identifies a prom- tidrug-resistant tuberculosis in countries There are 4 main reasons for this shift: ising product (eg, eflornithine for Afri- with limited financial resources are not 1. Costs and Risks of R&D Rela- can trypanosomiasis) or a new indication receiving treatment, which from a medi- tive to the Low Purchasing Power of (eg, atovaquone for malaria, ivermectin cal and humanitarian perspective is com- Developing Countries. A typical R&D for onchocerciasis, and albendazole for pletely unacceptable. program (from initial results to registra- lymphatic filariasis) for the treatment of Access to drugs for poor populations tion) would cost approximately $160 tropical diseases, the manufacturer of- would be greatly improved by research million and take between 8 and 12 years ten decides not to market the drug,

364 JAMA, January 27, 1999—Vol 281, No. 4 ACCESS TO ESSENTIAL DRUGS IN POOR COUNTRIES knowing it would be too expensive. The ment ratifies the worldwide imple- developing countries, which would also company generally decides to either make mentation of a free-trade economy. Its explain their limited investments in the exceptional arrangements (eg, dona- enforcement with regard to the pharma- countries concerned.28 The moment the tions in the cases of albendazole, atova- ceutical sector raises certain concerns. enforcement of patent protection becomes quone, and ivermectin) or takes nega- Two types of provision seem particu- effective (in developing countries, no later tive action (eg, discontinued production larly important for pharmaceutical com- than January 1, 2006) tropical disease of eflornithine). panies in developing countries: that research should logically start again, which puts an end to protectionist mea- funded by Western companies or by sures and that which defines as manda- manufacturers in developing countries. GLOBALIZATION AND DRUGS: tory the protection of patents on drugs However, it is unlikely that Western QUESTIONS AND CONCERNS and their respective manufacturing pro- manufacturers will devote much of their A discussion of the current landscape in cesses, such as the Trade Related Aspects effort to nonsolvent populations, with or the area of drug availability would not of Intellectual Property Rights Agree- without patents. Manufacturing compa- be complete without a consideration of ment (TRIPS). This is important because nies in developing countries may actu- the increasing globalization of the phar- many developing countries do not fully ally be motivated to invest more in maceutical industry and the potential im- acknowledge patent protection rights for research for new drugs, but such invest- plications of recent and upcoming world pharmaceuticals. ments will essentially respond to the need trade agreements. to shift their innovation capacity away Newly Invigorated Research? from finding ways to copy the patented Drugs: Another Industrial Product? Directors of pharmaceutical companies in drugs of developed countries and to- The General Agreement on Tariffs and the developed world have stated repeat- ward discovering new drugs.29 All things Trade (GATT) was signed on April 15, edly that the reason for not conducting considered, tropical research may not 1994, and was replaced by the WTO research on tropical diseases is the lack have a more promising future, even if pat- agreement, signed in 1997.27 This agree- of protection for innovations in some ents are widely enforced.

Table 2. Tropical Disease Drug Development Output, 1975-1997* Year Marketed Indication Product or Approved Development Context Marketing Approval of New Chemical Entities for Treatment of Tropical Diseases Malaria IM 1997 Chinese academy discovery; public/private collaboration (WHO-TDR/Rhoˆ ne-Poulenc-Rorer); Rhoˆ ne-Poulenc-Rorer/ Kunmig (China) agreement Atovaquone/proguanil 1992/1997 Glaxo-Wellcome antimalarial research; initially orphan product designation and approval for Pneumocystis carinii pneumonia associated with human immunodeficiency virus Halofantrine hydrochloride 1992 US Department of Defense discovery (WRAIR); public/private collaboration (WHO/WRAIR/SmithKline Beecham); US orphan product designation and approval for acute malaria Mefloquine 1987 US Department of Defense discovery (WRAIR); public/private collaboration (WHO/WRAIR/Hoffman LaRoche); US orphan product designation and approval for acute malaria Human African Eflornithine hydrochloride 1990 Hoechst Marion Roussel; US orphan product designation and trypanosomiasis approval for human African trypanosomiasis (Trypanosoma brucei gambiense) Nifurtimox 1984 Veterinary R&D (Bayer) Schistosomiasis Oxamniquine 1981 Veterinary R&D (Pfizer) Praziquantel 1980 Veterinary R&D (Bayer); public/private collaboration (WHO/Bayer) Helminthic infections Albendazole 1987 Veterinary R&D (SmithKline Beecham) 1981 Veterinary originally (Roche) Onchocerciasis Ivermectin 1989 Veterinary R&D (Merck); public/private collaboration (WHO/Merck) New Indications for Chemical Entities Human African Pentamidine isetionate 1950/1984 Rhoˆ ne-Poulenc-Rorer; galenic reformulation (mesylate to trypanosomiasis isetionate); US orphan designation and new approval only for P carinii infection Leishmaniasis Amphotericin B lipid 1962/1996 NeXstar; galenic reformulation of amphotericin B in liposomes; complex US orphan designation and approval only for treatment of invasive fungal infections *WHO indicates World Health Organization; TDR, Tropical Disease Research; WRAIR, Walter-Reed Army Institute of Research; and R&D, research and development. Products are listed by international nonproprietary names.

JAMA, January 27, 1999—Vol 281, No. 4 365 ACCESS TO ESSENTIAL DRUGS IN POOR COUNTRIES

Increasingly Prohibitive Prices? (eg, UNICEF, World Bank, the Euro- dustry, several public and private initia- A study sponsored by US pharmaceuti- pean Union, and nongovernmental or- tives have attempted to introduce public cal companies shows that granting drug ganizations), that would oversee the health criteria in R&D strategies. The patents does not tend to increase the price implementation of adequate and effec- 1975 Special Programme for Research of drugs on the market.30 This study, tive control procedures. The practical and Training in Tropical Diseases (spon- however, does not examine the prices of knowledge acquired by international or- sored by the United Nations Develop- new innovative drugs and declares that, ganizations to ensure the quality of ge- ment Programme, World Bank, and logically, the price of these new drugs neric drugs must be shared with health WHO) has had outstanding results in should be higher. Naturally, when the authorities in developing countries. In- strategic research (eg, entomology and manufacturing company is assured that vitations to bid, required by big spon- pathogenesis) and has bolstered re- its product cannot be copied, it holds a sors such as the World Bank, European search potential (eg, epidemiology and stronger position to negotiate prices with Union, and the US Agency for Interna- training). However, strategies for prod- public health authorities. Moreover, the tional Development, must combine qual- uct R&D that were actually launched in liberalization of international pharma- ity criteria and lower costs. Further- 1994 have yet to produce any convinc- ceutical trade entails the development of more, procurement of drugs should be ing results.31 Nevertheless, this pro- parallel imports between countries where centralized at a national level to rein- gram has succeeded in raising aware- the same drug is sold at different prices. force the responsibility of governments ness and has promoted reflection on Pharmaceutical companies, which are to make procurement, quality control, potentially effective tools, even if most consequently less inclined to grant sig- stock management, and distribution of projects focus exclusively on malaria nificantly lower prices to less developed essential drugs a priority. (eg, Multilateral Initiative on Malaria). countries, may instead set unique world- The US Orphan Drug Act implemented wide prices or delay marketing their drugs Increased Availability in 1983 also has produced significant re- in developing countries.28 In either case, To provide better access to effective treat- sults for rare diseases (157 new drugs access to drugs is jeopardized. ments for people in greatest need, sev- were commercialized and 837 new in- eral initiatives must be launched now, dications were developed from 1983 to even if their results will not be realized 1997), but no real impact has been seen RECOMMENDATIONS immediately. In the short-term, practi- with respect to tropical diseases.32 We can WHO’s Revised Drug Strategy and the cal solutions involving the various part- therefore conclude that while such ini- essential drugs concept are still key strat- ners must be found to maintain the pro- tiatives may occasionally boost the de- egies to help improve access to essen- duction of essential drugs. By establishing velopment of new drugs (eg, deriva- tial drugs and worldwide health. The es- public health priorities, new high- tives of artemisinine and pyronaridin), sential drugs concept is evidence based, priced drugs must be made available to they are unable to significantly redirect is simple, promotes equity, and is rooted the poor through solutions similar to R&D toward tropical diseases. In the in firm public health principles. WHO’s those implemented for Expanded Pro- midterm, a legal and fiscal framework assistance to countries and advocacy gramme on Immunization vaccines, for must be developed to spur R&D on tropi- work to promote the essential drugs con- which the supply is guaranteed by cal diseases or related areas, similar to cept and support countries in the for- UNICEF. These drugs could be made those developed in the United States for mulation and implementation of na- available by creating centralized pur- orphan drugs used in rare diseases. tional drug policies has resulted in change chase funds whereby manufacturers for the better. This strategy is a proven would be guaranteed large sales vol- Humanizing the WTO Agreements success but it needs to be continued and umes (financed by existing public and On the whole, it is regretful that WTO strengthened, and new ways of imple- private funds). The funds would also set agreements contain no specific provi- mentation have to be explored, given the forth, by consensus, compliance with sions that would guarantee both fund- changing context. In this spirit, the fol- drug indications. Finally, operational re- ing for ambitious tropical pharmaceuti- lowing recommendations are made with search in the field must be promoted and cal research and realistic pricing of respect to the 4 main issues that have developed in close collaboration with potential drugs. However, some devel- been developed in this article. health care professionals in developing oped countries were able to protect vul- countries. Such research should pro- nerable economic and business sectors Procurement of Quality Drugs duce simple, efficient, and low-cost pro- (eg, textiles, agriculture, and culture). To improve the quality of existing drugs tocols without losing sight of the risk- One can understand why wealthy coun- and their procurement, it is important benefit factor for the poorest countries. tries demand that developing countries to develop a permanent “Observatory of comply with regulations on unfair com- Drug Quality,” established by WHO in Restart of R&D petition. It is obvious that to meet press- collaboration with organizations in- In an attempt to offset this costly struc- ing public health needs, we need new es- volved in the provision of essential drugs tural evolution in the pharmaceutical in- sential drugs. To develop them, we need

366 JAMA, January 27, 1999—Vol 281, No. 4 ACCESS TO ESSENTIAL DRUGS IN POOR COUNTRIES innovative research and industry. To fund poor countries. However, it would 12. Paquet C, Perea W, Grimont F, et al. Aetiology of haemorragic colitis epidemic in Africa. Lancet. 1993; new research, industry needs commer- serve no purpose to demand new pub- 342:175. cially viable results. It is therefore vi- lic health or human rights in a manner 13. Paquet C, Leborgne P, Sasse A, Varaine F. An out- break of Shigella dysenteriae type 1 dysentery in a refu- tally important that the pharmaceutical that would suggest that such rights will gee camp in Rwanda. Sante. 1995;5:181-184. industry collaborates with organiza- soon become a reality. The current situ- 14. Paquet C, Van Soest M. Mortality and malnutri- tions like WHO, UNICEF, and the World ation points to the opposite. For a great tion among Rwandan refugees in Zaı¨re. Lancet. 1994; 344:823-824. Bank to identify the challenges and get proportion of the world, health condi- 15. Essential Drugs Price List. Copenhagen, Den- a clearer view of what they can achieve tions are worsening, and without fun- mark: UNICEF Supply Division; 1995. 16. Varaine F, Keita M, Kaninda AV, et al. Long act- together in developing sustainable mar- damental change in the pharmaceutical ing chloramphenicol versus ceftriaxone for treat- kets for new tropical pharmaceuticals. market, perspectives for improvement ment of bacterial meningitis in children aged 2-35 months. Paper presented at: Eighth International Con- It must be remembered that those de- are not encouraging. gress on Infectious Diseases; May 15-18, 1998; Bos- veloping countries that are the main ton, Mass. sources of cheap copies of patented Acknowledgment: As a medical emergency organiza- 17. World Health Statistics Annual 1996. Geneva, 31 tion present in 80 countries through 400 medical as- Switzerland: World Health Organization; 1998. drugs are nevertheless relatively poor. sistance projects, MSF undertakes to speak about the 18. Tandon BN, Acharya A, Tandon A. Epidemiol- Enforcing the WTO regulations will re- living conditions of those who cannot speak for them- ogy of hepatitis B virus infection in India. Epidemiol selves and to defend their right to vital health care. This Infect. 1996;117:313-325. move a source of affordable copies of in- article is mainly based on the field experience of MSF 19. Kaddar M. La mutation du marche´ mondial des novative quality drugs on which the poor- and our local partners. vaccins. Rev Prescrire. 1995;157:844-847. est countries depend. Developing We wish to thank the many field volunteers who, 20. Crofton J, Chaulet P, Maher D. Principes pour la in one way or another, have participated in gather- prise en charge de la tuberculose a` bacilles re´sis- countries, particularly the less ad- ing the information contained in this article. Special tants. Geneva, Switzerland: World Health Organiza- vanced, should be encouraged to take ad- thanks to Nathan Ford for reviewing the manuscript. tion; 1997. WHO/TB/96.210 (rev 1). 21. Trouiller P. Recherche et de´ veloppement phar- vantage of the limited alternatives of- maceutiques en matie` re de maladies transmissibles dans la zone intertropicale. Sante. 1996;6:299-307. fered by the WTO agreements. REFERENCES 22. Trouiller P, Rey JL, Olliaro P. Analysis of drug de- Specifically, they should be able to ob- 1. World Health Organization. WHO Expert Com- velopment patterns of six tropical diseases between tain compulsory licenses whereby na- mittee on Specifications for Pharmaceutical Prepa- 1975 and 1997. Paper presented at: Eighth Interna- rations. Geneva, Switzerland: World Health Organi- tional Congress on Infectious Diseases; May 15-18, tional authorities allow local manufactur- zation; 1996. WHO Technical Report Series 863. 1998; Boston, Mass. ers to circumvent patent rights (with 2. Pinel J, Varaine F, Fermon F, Marchant G, Mari- 23. Grabowski H. The effect of pharmacoeconomics oux G. Des faux vaccins anti-meningocoque lors d’une on company research and development decisions. Phar- certain conditions and in return for the epidemie de meningite au Niger. Med Maladies In- macoeconomics. 1997;5:389-397. payment of royalties to the inventor, as fect. 1997;27:1-563. 24. International Strategies for Tropical Diseases Treat- stipulated in article 31 of the WTO agree- 3. World Health Organization. Fake drugs: a scourge ments: Experiences With Praziquantel. Boston, Mass: 33 on the system. WHO Drug Inf. 1995;9:127-129. Harvard School of Public Health; 1996. ments). Judiciously enforced, such an al- 4. O’Brien KL, Selanikio GD, Hecdivert C, et al. Epi- 25. World Health Organization. Counterfeit Drugs: ternative seems to be the only recourse to demic of pediatric deaths from acute renal failure Report of a WHO/IFPMA Workshop. Geneva, Swit- caused by diethylene glycol poisoning. JAMA. 1998; zerland: World Health Organization; 1992. WHO/ balance the interests of the developing 279:1175-1180. DMP/CFD/92. and developed world. 5. Shakoor O, Taylor RB, Behrens RH. Assessment of 26. World Health Organization. Recommendations from the incidence of substandard drugs in developing coun- the ICDRA reinforce the mission of regulatory authori- WHO is in a unique position to argue tries. Trop Med Int Health. 1997;2:839-845. ties. WHO Drug Information. 1996;4:182-185. the case for health at an international 6. Pe´ coul B, Varaine F, Keita M, et al. Long-acting chlor- 27. Correa C. The Uruguay Round and Drugs. Geneva, level. Health-related nongovernmental amphenicol versus intravenous ampicillin for treatment Switzerland: World Health Organization; 1997. of bacterial meningitis. Lancet. 1991;338:862-866. 28. Intellectual Property: Patents and Pharmaceuti- and consumer organizations certainly 7. World Health Organization. WHO response to men- cals. Geneva, Switzerland: International Federation of have a supportive role to play, but WHO ingitis epidemic in Africa, 1997. Bull Wkly Epidemiol Pharmaceutical Manufacturers Associations; 1997. Record. 1997;72:313-320. 29. Lanjouw JO. The Introduction of Pharmaceuti- is the only intergovernmental organiza- 8. Doua F, Boa FY, Schechter PJ, et al. Treatment of cal Product Patents in India: Heartless Exploitation of tion with a formal international man- human late-stage gambiense trypanosomiasis with ␣- the Poor and Suffering? Cambridge, Mass: National difluoromethylornithine (eflornithine). Am J Trop Med Bureau of Economic Research; 1998. date to protect and advance health in- Hyg. 1987;37:525-533. 30. Rozek RP, Berkowitz R. The Effects of Patent Pro- ternationally. While WHO’s authority in 9. Legros D, Enyaru JCK, Evans S, Maiso F. An out- tection on the Prices of Pharmaceutical Products. White break of relapses among patients treated for T. b. gam- Plains, NY: National Economic Research Associates; this area has suffered in the last de- biense trypanosomiasis in Arua, Northern Uganda. Pa- 1998. cades, part of WHO’s strategy should per presented at: 24th International Scientific Council 31. Tropical Disease Research. From Investigation to now be to clearly and unambiguously put for Trypanosomiasis Response and Control (ISC- Eradication: Tropical Diseases Research Twelfth Pro- TRC); September 1997; Maputo, Mozambique. gramme Report. Geneva, Switzerland: World Health health first and provide leadership in pro- 10. Coll-Seck A, Sylla A, Over M, et al. Implications Organization; 1995:9-36. moting access to essential drugs. of therapies for developing countries. Paper pre- 32. Olliaro P. Will the fight against tropical diseases sented at: XII International Conference on AIDS; June benefit from orphan drug status? Trop Med Int Health. 28–July 3, 1998; Geneva, Switzerland. 1997;2:113-115. CONCLUSIONS 11. Centers for Disease Control and Prevention. Mor- 33. Velasquez G, Boulet P. Globalization and Ac- tality From Dysentery in Africa: A Follow-up Study cess to Drugs: Implications of the WTO/TRIPS Agree- Access to essential drugs is a basic in Burundi. Atlanta, Ga: Centers for Disease Control ment. Geneva, Switzerland: World Health Organiza- human right often denied to people in and Prevention; 1993. CDC internal report. tion; 1998.

JAMA, January 27, 1999—Vol 281, No. 4 367

Top View