Placebos and HIV Lessons Learned

Lessons learned” is a popular termin international circles.Typically

used to sum up the results ofa review of experiences, it has a reas-suring pedagogic tone. The “stu-dents” have done their home (orfield) work, and have acquired therelevant knowledge. Presumably anymistakes they might have made in thecourse of their studies will not be re-peated, because the “lessons” havebeen “learned.” The real world of in-ternational clinical trials differs signif-icantly from the tidy schoolroommetaphor. Nevertheless, it is still use-ful to ask: Are there lessons to belearned about future trials from thecontroversy over placebo-controlledtrials of zidovudine (AZT) to pre-vent mother-to-child HIV transmis-sion in developing countries? The an-swer is that there are some procedur-al cautions, but few unchallenged“lessons.”

The trials involved over 12,000women in seven countries and werefunded by the U.S. Centers for Dis-ease Control and Prevention and theNational Institutes of Health.UNAIDS and French agencies werealso involved in similar trials. Basedon preliminary results of the trials inThailand, which showed a reductionof 51 percent in transmission inmothers given a short course of AZTcompared to those who received a

placebo, similar trials underway inAfrica and the Dominican Republicwere suspended. Both enthusiasticproponents of the trials and their vo-ciferous opponents asserted that theirviews had been vindicated.1 The pro-ponents declared that such significantresults could only have been achievedwith placebo arms; the opponentssaw the results as evidence that place-bos were never needed in the firstplace. First Lesson Learned: Even un-ambiguous scientific results of con-troversial clinical trials do not neces-sarily result in ethical consensus.

In retrospect, it is not surprisingthat these trials became so controver-sial. They brought together two issuesthat have been the subject of ethicaldebate for years: the use of placebocontrols in clinical trials and the ethi-cal standards for conducting trials indeveloping countries. In addition, thistrial added the highly charged ele-ments of the rapid spread of HIV inthe developing world, the administra-tion of drugs to pregnant women, andthe transmission of a fatal disease tonewborns. Although the issues hadbeen discussed among the investiga-tors and sponsoring agencies and theirimmediate circles of advisers, therewas no broad discussion in ethicsforums or in other arenas where someof the complexities could have beenexplored without the distraction ofmedia-aimed charges and counter-charges. Second Lesson Learned: Anytrials with a combination of these ele-ments are likely to be controversial;

broad and open discussion shouldtake place before trials are imple-mented.

ACTG 076

The study on which all the devel-oping trials studies were based—

ACTG (AIDS Clinical Trial Group)076—was itself fraught with contro-versy. Conducted in the UnitedStates and France, it demonstratedthat AZT was effective in reducingthe rate of maternal-infant HIV trans-mission of HIV. The rate of transmis-sion in the treated group was 8 per-cent compared to 25 percent in theplacebo group. The difference be-tween the two groups was so substan-tial that the data safety and monitor-ing board felt it was unethical to con-tinue and stopped the trial early. Sub-sequent data have confirmed the ef-fectiveness of AZT in preventingperinatal transmission in women whowould not have been eligible for 076because of their lower CD4 countand more serious disease progression.From 1984 through 1992, the esti-mated number of children with peri-natally acquired HIV increased everyyear, then declined 42 percent duringthe period 1992 to 1996. Neverthe-less, the 076 regimen is not 100 per-cent effective.

The 076 trial—perhaps one of thefew trials that is known around theworld by its numerical designation—went through several significant revi-sions before it was implemented.Some of these controversies involvedthe selection of subjects (whetherminority women were being unfairlyburdened by being selected or unfair-ly denied access); consent (whetherfathers as well as women had to giveconsent); safety (the long-term effectof AZT on developing fetuses); andjustice (whether it was unethical toprovide AZT to women only duringpregnancy, and to follow the healthof babies but not their mothers). Al-though these controversies were notcentral to the debate about applyingthe results to developing countries,they form an important background.

H A S T I N G S C E N T E R R E P O R T 1November-December 1998

Carol Levine,

Placebos and HIV Lessons Learned

by C A R O L L E V I N E

The World of Research Subjects

Despite the unequivocal nature ofthe results, the 076 protocol is notnecessarily the best regimen to pre-vent HIV transmission. The studywas not designed to establish an opti-mal regimen to prevent transmission,or to determine which of the threetypes of administration (oral, intra-venous during delivery, and post-birth to the infant) contributed mostto prevention, or whether all threewere necessary.

Although the 076 protocol estab-lished short-term safety for the dosesof AZT used, it is not knownwhether there are long-term safetyrisks to the children born withoutHIV infection who would not havebeen infected in any case. Some evi-dence of cancer in AZT-treated micehas caused some concern but manyinvestigators believe this is not likelyto be a real risk at the 076 dosage.

On the basis of the 076 results,the regimen became the standard ofcare for treatment of pregnant wo-men in the United States and otherdeveloped countries. As triple thera-pies (two nucleoside analogs and oneprotease inhibitor) replaced mono-therapies as the standard of care forHIV-infected patients in the UnitedStates, the use of a single agent inpregnant women—a lower standardof care—was questioned. The effectof protease inhibitors on perinataltransmission has not been document-ed, although increasingly U.S. clini-cians are using these therapies inHIV-infected pregnant women andstill seeing declines in HIV-infectednewborns. Despite the proven bene-fits, the 076 regimen is not universal-ly used even in the United States.Some women are outside the healthcare system and fail to obtain optimalprenatal care; others are not coun-seled about their HIV risk and do notknow that they are HIV infected; stillothers refuse AZT or are not able toadhere to the 076 regimen.

While the standard of care is ei-ther not available to all HIV-infectedwomen in the United States or hasbeen altered for some women, devel-oping countries cannot afford to pro-

vide the 076 treatment regimen toeven the majority of HIV-infectedpregnant women. Neither do theyhave the medical infrastructure toprovide the complete regimen, espe-cially intravenous administration atdelivery. Many women do not receiveprenatal care early enough to institutethe complete regimen. There is an ur-gent need for an effective, shorter,practical regimen.

One of the questions left unan-swered by 076 was whether someAZT—even considerably less thanthat used in 076—will reduce therate of perinatal transmission. Un-published but widely available datafrom the 076 trial on women who re-ceived less than the full protocolshowed a decreased in HIV transmis-sion, albeit a smaller decrease than inthe full-protocol group. Supporters ofthe placebo-controlled trials questionthe validity of these data. One studyin North Carolina using a survey de-sign provided statistically valid datashowing a reduction in transmissionin infants who received any zidovu-dine.2 On the other hand, a smallprospective study from Uganda ofAZT administered late in pregnancydid not show any benefit. The Thairesults support the hypothesis that asmaller dose of AZT than the one in076 will reduce HIV transmissionsignificantly. A still debated questionis whether this should have or couldhave been known without the use ofthe placebo arm in trials. Third LessonLearned: 076 was the first step in aprocess, not the final answer.

Trial Methodology and theEthical Use of Placebos

In clinical research, prospective,randomized controlled trials con-

stitute the most reliable scientificmethodology for drawing conclu-sions about safety and efficacy. RCTsare the “gold standard.” But they areby no means the only acceptablemethodology, and often trade-offs aremade. Other methodologies are pos-sible in some cases (equivalency stud-ies, case-control studies, historical

controls), but these generally provideless conclusive data or answer morenarrowly constructed questions. Still,the most direct way to answer thequestion “Is an experimental regimenbetter than nothing?” is to conduct aplacebo-controlled trial.

There is likely to be ethical agree-ment on two main points:

First, some placebo-controlled tri-als are ethically justifiable. Some ex-amples: a trial in which there is noknown effective drug or vaccine forthe condition; a trial involving sub-jects for whom the approved treat-ment has proven ineffective or whocannot tolerate the treatment; or ashort-term trial in which the subjectsreceive the active agent should itprove effective.

Second, some placebo-controlledtrials are not ethically justifiable. Ifthere exists a proven regimen that canprevent death or serious side effects,and that treatment regimen is avail-able to prospective research subjectsoutside a clinical trial, it is unethicalto use placebo rather than the provenregimen in a clinical trial to test anew experimental regimen. An exam-ple might be a trial in which a widelyavailable drug known to be effectiveis withheld from a placebo group sothat the agent being tested will beshown to be clearly superior to aplacebo, rather than marginally moreeffective than or equally effective asthe drug already available.

Looking to published statementsand principles, one can find supportfor both proceeding with and notproceeding with placebo-controlledtrials of AZT to prevent HIV trans-mission. Statements by the WorldMedical Association’s Declaration ofHelsinki and the Nuremberg Codeappear to preclude proceeding withthe AZT placebo-controlled trials be-cause they place the interests of soci-ety over the interests of the subjectsor fail to provide the subjects with themost effective proven therapeuticmethod (Helsinki)3 or do not preventall avoidable suffering or injury(Nuremberg).4

2 H A S T I N G S C E N T E R R E P O R T November-December 1998

A group that specifically consid-ered the use of placebo controls inHIV studies concluded:

Placebo controls are especially dif-ficult to justify ethically when theendpoints of an RCT are death orserious disability . . . When theoutcome is death or serious dis-ability, by the time an RCT reach-es the organizational stage, prelim-inary evidence almost always sug-gests strongly that the new therapyis more effective than placebo . . .Although active [control arms]and historical controls are general-ly associated with reduced efficien-cy and validity, these are often ap-propriate trade-offs.5

Perhaps the most relevant publicstatement is the 1993 guidelines ofthe Council for International Orga-nizations of Medical Sciences(CIOMS) in collaboration with theWorld Health Organization (WHO).It stated:

[In a randomized clinical trial] thetherapies (or other interventions)to be compared must be regardedas equally advantageous to theprospective subjects: there shouldbe no scientific evidence to estab-lish the superiority of one over an-other. Moreover, no other inter-vention must be known to be su-perior to those being compared inthe clinical trial, unless eligibilityto participate is limited to personswho have been unsuccessfullytreated with the other superior in-tervention or to persons who areaware of the other interventionand its superiority and have cho-sen not to accept it.6

Placebo-controlled trials of perinataltransmission fail to comply withthese conditions.

On the other hand, other guide-lines and principles in the same doc-uments can be used in support of theplacebo-controlled trials. These stressthe importance of the problem to beaddressed (Helsinki) and the human-itarian objectives (Nuremberg). Again,the most relevant document is the

CIOMS-WHO guidelines, notablyguideline 8, entitled “Research In-volving Subjects in UnderdevelopedCommunities,” including developingcountries. The placebo-controlledtrials in developing countries meetimportant conditions addressed bythis guideline as Christine Grady andothers have noted.7 The trials addressthe health needs and priorities of thecommunities, and they have been re-viewed by local ethical review com-mittees. Consent of individual sub-jects was part of the process of re-cruitment. However, the reasons theresearch could not be carried out“reasonably well” in developed coun-tries are ethical, not scientific. Fur-ther, there is at least a question aboutthe quality of the informed consentobtained from the subjects; one re-port from Cote d’Ivoire casts doubton whether women were fully in-formed and given enough time—lessthan five minutes after being in-formed they were HIV-infected—tomake a voluntary decision. Theprospect of free medical care was themain reason women said they agreedto participate.8

Guideline 10 of the CIOMSguidelines is entitled “Equitable Dis-tribution of Burdens and Benefits.” Itrequires that individuals or commu-nities to be invited to be subjects ofresearch should be selected in such away that the burdens and benefits ofthe research will be equitably distrib-uted. Placebo-controlled trials in de-veloping countries fulfill this require-ment since the burden of HIV infec-tion and perinatal transmission fallsinequitably on the population inthese countries, and the benefits to begained by rapid completion of studiesof an affordable, effective regimen areconsiderable and will also accrue tothese same developing countries.

Fourth Lesson Learned: Ethical de-clarations, guidelines, and principlesprovide a framework for analysis butdo not always give consistent answersto issues raised by specific cases. TheCIOMS-WHO guidelines should berevised for internal consistency in

light of the issues raised by the AZTplacebo-controlled trials.

Arguments in Favor of the Trials

Good arguments, albeit of differ-ent kinds, can be offered to sup-

port or oppose the trials. The conclu-sion one reaches depends more on thevalue one places on certain types ofarguments rather than on the strengthsof the arguments themselves.

A utilitarian calculation concludesthat the most efficient study is themost ethically sound. In this view, aclinical trial in developing countrieswith one arm using an affordable,practical, experimental regimen andthe other arm using placebo could becompleted more quickly and wouldinvolve fewer subjects than any otherresearch design. The sooner a trial iscompleted, the faster the new, afford-able regimen (if proven effective) canbe made available to pregnant wo-men in the developing country. Thelives of more infants will be saved byearly, widespread introduction of thenew, affordable regimen than wouldbe saved in any other study design.Therefore, it is ethical to conduct aplacebo-controlled trial since theoverall number of infant deaths pre-vented will be greater than in any ofthe alternatives.

A second calculus involves whatgovernments and health ministrieswill do. In this view, it is useless andunethical to design a study using aregimen that will never be introducedinto the country in which the study isconducted. The 076 regimen willnever be affordable or practical in de-veloping countries. A clinical trial inwhich this regimen was comparedwith the lower-dose experimentalregimen would be likely to show thatthe 076 regimen is more effective inpreventing transmission, so the ex-perimental regimen would have beenviewed as “inferior.”

On the other hand, the low-dose,experimental regimen is likely to bemore effective than placebo, so theexperimental regimen will be judged


to be “better than nothing.” Healthministries will not recommend theintroduction of a treatment regimenthat has been deemed “inferior” toother known treatments; but theywill recommend the introduction ofa treatment regimen that has beenshown to be better than nothing. Indeveloping countries at present, preg-nant women receive no treatment, somany more deaths will be preventedonce the new experimental regimen(if effective) is introduced. Therefore,this argument concludes, it is ethicalto do the placebo-controlled trial.

A third type of argument points tothe difference in “standard of care” indeveloped and developing countries.Currently in developing countries,the standard of care for HIV-infectedpregnant women is to receive notreatment to prevent perinatal trans-mission. A clinical trial is ethical if itdoes not make those enrolled in thetrial worse off than they would be ifthey were not enrolled. If some preg-nant women enrolled in a clinicaltrial are given placebo, they are notmade any worse off than they wouldbe if they were not enrolled in thetrial at all. Therefore, it is ethical toconduct placebo-controlled trials incountries where pregnant women donot receive any treatment.

A fourth type of argument looksat the satisfaction of procedural re-quirements. If ethically adequate pro-cedures are used in the approval andimplementation of research proto-cols, and if properly informed con-sent is obtained, it is ethical to con-duct the studies. The placebo-con-trolled perinatal transmission studieswere approved by ethical review com-mittees in the developed countriesthat sponsor the trials and in the de-veloping countries where they arebeing carried out. Women who areenrolled in the studies are being askedto give their voluntary, informed con-sent to participate. Researchers fromthe developing countries are carryingout the studies in their own coun-tries. Therefore, since the placebo-controlled trials are following proce-

dures that are ethically adequate, theyare ethically permissible.

Arguments Opposing the Trials

The argument that it is unethicalto conduct placebo-controlled

trials to prevent perinatal transmis-sion can take several different forms.The first version does not rely on anycomparison between developed anddeveloping countries. It rests on theobligation to minimize harm to re-search participants. A proven regimenexists that can reduce the rate of ma-ternal HIV transmission and conse-quently can prevent the deaths ofsome infants who will be born toHIV-infected mothers. The provenregimen can be made available underresearch conditions in developingcountries. Researchers are under anethical obligation to minimize harmto research participants. A researchdesign that uses placebo instead ofthe proven regimen knowingly failsto minimize harm to research partici-pants. Therefore, a placebo-controlledtrial is unethical in this instance.

The second argument explicitlycompares developing and developedcountries and presupposes an unvary-ing ethical standard in internationalcollaborative research. A proven regi-men can reduce the rate of maternalHIV transmission. The proven regi-men is the standard of care for preg-nant women in developed countriesand therefore it would be unethical toconduct a placebo-controlled trial inthose countries. To do so would allowsome infants to be born with a fataldisease when their deaths could beprevented if pregnant women did notenroll and instead received the stan-dard of care. If it is unethical to con-duct a placebo-controlled study in adeveloped country, it would be un-ethical to conduct that same study ina developing country because itwould involve applying a lower stan-dard of research ethics. The samestudy, using the proven regimen, canbe conducted in developed countries.Therefore, it would be unethical to

conduct a placebo-controlled trial indeveloping countries.

The third argument claims thatother study designs are possible, mak-ing placebo controls unnecessary.Clinical trials can be designed to an-swer important questions other than“Is the affordable, experimental regi-men better than placebo?” One hy-pothetical study uses 076 as the con-trol arm and asks: “How much lesseffective is the new experimental reg-imen than 076?” This design wouldgive an indirect answer to the ques-tion whether the experimental regi-men is better than placebo, since the076 protocol demonstrated thatplacebo is one-third as effective as the076 regimen. This study relies on the076 results and assumes that extrapo-lation from 076 is possible. Admit-tedly, it assumes that 076 and placebowould behave the same in the devel-oped country as in the trials carriedout in the United States. Another po-tential flaw is that when things arenot directly compared, there may beother factors unaccounted for.

Another hypothetical study com-pares two different oral regimenswith doses lower than those used in076. It compares the “optimal” dose,that is, the maximum affordable regi-men in the developing country wherethe regimen is being tested, with amuch lower dose. There may be somebenefit to those receiving the lowerdose, but that is not known in ad-vance. A larger sample size would berequired for this study than for aplacebo-controlled trial. If the “opti-mal” dose is more effective than thelower dose, the study would showthat an affordable regimen is effec-tive. If no difference is shown be-tween the two doses, then govern-ments can save money by introduc-ing a regimen with the lower dose.This study, like the first, relies on thebackground data from the 076 studyto suggest that one or both of thesedoses are more effective than placeboin reducing transmission.

A third hypothetical study is nota randomized controlled trial butemploys an observational methodolo-


gy using “untreated” controls. Themethod requires picking a represen-tative sample in a community thatwould receive the affordable experi-mental regimen. This group wouldthen be compared later to the ratesof maternal-infant transmission ofwomen in the community who werenot enrolled in the study and who re-ceived nothing. A difficulty with thisdesign is the follow-up of the babiesfrom the community; it would benecessary to find a representativesample six months to a year later.However, this design makes possiblea genuine comparison between wo-men who received an experimentaltreatment and those who truly re-ceived nothing. A placebo is not“nothing.”

These studies are less methodolog-ically rigorous than a randomizedcontrolled trial that undertakes tomake direct comparisons. However, amethodological compromise is neces-sary in situations where the best sci-entific design is not ethically accept-able. The study design using an activecontrol arm instead of a placebo isactually being conducted in Thailandby a research group from HarvardUniversity. According to its chairper-son, the Human Subjects Committeeat the Harvard School of PublicHealth considered a placebo arm tobe unacceptable.9

Weighing Arguments

Opponents and defenders of theplacebo-controlled trials dis-

agree on a number of critical proposi-tions, some of which pertain to scien-tific methodology, some to politicalor policy matters, and others to ethi-cal judgments and value priorities.On questions of scientific methodol-ogy, opponents contend that alterna-tive methodologies can provide a sat-isfactory answer to the question ofwhether an affordable, practical treat-ment regimen exists. Defenders saythat only a placebo-controlled trialcan answer that question.

Opponents also contend that suf-ficient evidence existed that some

AZT is better than none in prevent-ing transmission. Defenders say therewas insufficient evidence for thisclaim.

Opponents contend that govern-ments may be willing to introducetreatment regimens even if placebo-controlled trials showing that a newtreatment regimen is better thanplacebo are not carried out. Defend-ers say this is the evidence health pol-icy officials would insist upon.

Opponents question whether gov-ernments are likely to make even theaffordable regimen as widely avail-able as defenders claim they will,once the placebo-controlled trials arecompleted. Defenders are confidentthat once the trials are completed,governments in developing countrieswill make the affordable treatmentswidely available.

Opponents say these placebo-controlled trials are unethical despitetheir approval by ethical review com-mittees in the sponsoring countriesand in the countries where the re-search is being done. They claim thecommitment of U.S. funds and U.S.researchers requires adherence to U.S.standards. Defenders claim that ethi-cal approval in the countries wherethe research is being done demon-strates that the trials meet the ethicalstandards in those countries.

Opponents contend that it is un-ethical to withhold from participantsin research an effective treatment thatcan reduce the number of deaths re-sulting from HIV transmission. Theharm done to HIV-infected babiescannot be undone; AZT must be ad-ministered to their mothers withinsome definable range at the end ofpregnancy and at delivery. Defendersclaim that a much large number oflives will be saved if placebo-con-trolled trials are carried out rapidly.

Opponents contend that research-ers’ obligations to participants in a re-search study outweigh the obligationsto society in general. Defenders saythe chief obligation is to provide ef-fective preventive treatments in devel-oping countries that have a high bur-den of disease. This may be seen as a

difference between a clinical careethic and a public health ethic.

Opponents of the study contendthat the actual harm that will resultfrom placebo-controlled trials is cal-culable and certain, whereas the ben-efits that might accrue from the studyare only probable and remain uncer-tain. Defenders argue that the highestpriority is to conduct as efficiently aspossible the highest quality scientificstudy in order to maximize benefits.

Opponents contend that referenceto the “standard of care” in develop-ing countries to justify placebo-con-trolled trials is ethically suspect.When people receive no treatment atall, there can be no “standard” of care.Defenders say that women in the trialwho receive placebo are not beingmade worse off than they would be ifthey were not in the trial at all. Thatis what is meant by “standard of care”in this context.

The arguments supporting place-bo-controlled trials emphasize thepublic health need to develop afford-able interventions, the lack of re-sources in developing nations, the ef-ficiency of placebo-controlled stud-ies, and political assessments aboutthe evidence needed to convince gov-ernments to allocate resources andpharmaceutical companies to supplydrugs at lower cost. The argumentsagainst such trials, on the other hand,stress a concern for the welfare of theindividual subject (and in this case,her infant); and the importance ofminimizing risk and preventing harmin the course of gaining scientificallyvalid, generalizable knowledge. Thesearguments are also skeptical aboutpromises made by governments anddrug companies, especially for long-term support of public health inter-ventions.

Keenly aware of the need for effec-tive interventions in the developingworld, I nevertheless believe that inthis instance placebo-controlled trialsplaced economic goals, valid thoughthey may be, ahead of individual sub-jects’ welfare. The evidence that AZTworks to prevent HIV transmission isso conclusive that it is hard to justify


the trials on scientific grounds alone.The risk is serious disability and even-tual death; there was more than pre-liminary evidence suggesting stronglythat the new therapy was more effec-tive than placebo; and in this case,there was only a short window of op-portunity to prevent the disability.The subjects were pregnant women,vulnerable in most societies, and par-ticularly so when the fate of their ba-bies is at stake. Women are certainlycapable of making informed decisionson behalf of themselves and theirchildren, but a lack of power and ac-cess to medical care, as well as to sci-entific information, at the very leastputs them at a disadvantage com-pared to investigators. Women insuch situations deserve special con-cern in research design and the con-sent process. Sixth Lesson Learned:This case is an example of a true eth-ical dilemma on which thoughtfuland reasonable people can disagree.

When an ethical dilemma resistsresolution by agreement, the nextbest approach is a procedural solu-tion. The way procedural resolutionsusually work is that those who havethe authority, the power, or themoney are the ones who make thedecisions. In the case of HIV/AIDSresearch, an ethically appropriate pro-cedural mechanism could be used: aprocess of community consultation.That process is poorly defined andunderstood, there is little experienceto go on, and considerable workwould be required to establish a work-able mechanism midway through on-going trials. Although it is true thatinvestigators from the developingcountries are conducting the researchand local or national IRBs have ap-proved them, one relevant “commu-nity” has been omitted: the womenfrom whom subjects will be drawnand to whose infants the benefits ofthe completed research will apply.

Some such process should be de-veloped leading up to the design andimplementation of future research.The most immediate opportunity isin the area of AIDS vaccine trials,which are already underway in some

settings and will be expanded in thefuture.

For the Future

Even with the Thai data, manyquestions remain. What will be

the fate of those babies who escapedHIV infection during pregnancy?Will the benefits of AZT be undoneby breastfeeding, a known method ofHIV transmission? What will be theimpact on future pregnancies of HIV-infected women who receive AZT?Will a drug-resistant HIV strain de-velop? Is the oral dose used in thetrials the optimal dose or could evenlower doses be effective? Even asGlaxo Wellcome cuts the price forAZT to be used in developing coun-tries to prevent HIV transmission (butnot for long-term treatment), otherquestions about the role of pharma-ceutical companies in designing drugtrials for new markets arise.10 Apartfrom the cost of drugs, the medicalinfrastructure problems remain adaunting obstacle to widespread useof AZT to prevent HIV transmission.Impressive and welcome as the tech-nological achievement of preventingHIV transmission is, there is still nocomparable response to the millionsof children whose mothers are dyingof AIDS in Africa, Asia, the Carib-bean, Latin America, and the UnitedStates, and Europe, as well. Address-ing the needs of this generation ofchildren will truly be a test of ethicalcommitment.

Final Lesson (To Be) Learned:Technological advances, welcomeand impressive as they are, do noteven begin to address some of themost basic social, health, and humanrights questions raised by the globalAIDS epidemic.

Acknowledgments

I have benefited from discussionswith many ethicists, investigators, andadvocates on this challenging topic. Iwant especially to acknowledge RuthMacklin and Robert Klein for theirthoughtful and precise comments,

while absolving them of responsibilityfor the views expressed in this article.

References

1. Sheryl Gay Stolberg, “Placebo UseSuspended in Overseas AIDS Trials,” NewYork Times, 19 February 19 1998.

2. Susan A. Fiscus et al., “Perinatal HIVInfection and the Effect of ZidovudineTherapy on Transmission in Rural andUrban Counties,” JAMA 275 (1996):1483-88.

3. World Medical Association, “Declara-tion of Helsinki,” JAMA 277 (1997): 925-26.

4. Nuremberg Code, Principle 6.5. Carol Levine, Nancy Neveloff Dubler,

and Robert J. Levine, “Building a NewConsensus: Ethical Principles and Policiesfor Clinical Research on HIV/AIDS,” IRB:A Review of Human Subjects Research 13,nos. 1-2 (1991): 1-17, p. 8.

6. Council for International Organiza-tions of Medical Sciences, InternationalGuidelines for Biomedical Research InvolvingHuman Subjects (Geneva: CIOMS, 1993).

7. Christine Grady, “Science in the Ser-vice of Healing,” Hastings Center Report 28,no. 5 (1998): ____; Harold Varmus, DavidSatcher, “Ethical Complexities of Conduct-ing Research in Developing Countries,”NEJM 337 (1997): 1003-1005.

8. Howard W. French, “AIDS Researchin Africa: Juggling Risks and Hopes,” NewYork Times, 9 October 1997.

9. Troyen A. Brennan, MD, letter toDonna Shalala, Secretary of Health andHuman Services, 10 June 1997.

10. Michael Waldholz, “AZT Price Cutfor Third World Mothers-to-Be,” WallStreet Journal, 5 March 1998.


Documents

Placebos and HIV Lessons Learned