In the past 10 years, there has been a sharp increase in research conducted with human subjects. Research with human subjects, including clinical trials, has become more prevalent globally (i.e., outside the United States) and especially in developing countries.

 The increase in clinical trials in developing countries is fueled by the recent push for global commerce. Trends include the pharmaceutical industry's interest in new drugs; new emerging markets; emerging infrastructure from investigators in developing countries in the newly found, home-grown pharmaceutical services corporations; inability to conduct such research in developed countries; and the less costly and less restrictive regulatory environments found in developing countries. There are also trials sponsored by the National Institute of Health (NIH) and the World Health Organization (WHO) for largely humanitarian reasons. Private foundations, such as the Bill and Melinda Gates Foundation and the Wellcome Trust, also sponsor research in the developing world.

The studies contemplated in developing countries fall into three categories: development of new drugs, development of drugs targeted specifically to developing countries; and expansion of existing drugs for other therapeutic uses. These conditions have resulted in rapid growth of research with human subjects without a similar and adequate growth in infrastructure to protect subjects. Therefore, in addition to the concerns in the past 10 years that have plagued U.S. research with human subjects,

 a host of new and unique concerns emerged because of the risk of exploitation of poor countries by the wealthiest nations.

 This is, in part, because a large portion of the population in these developing countries lack infrastructure for basic health care. This results in lack of access to basic health care needs. Thus, citizens are vulnerable to coercion for enrolling in clinical trials. 

The objective of this paper is to address some of the fundamental moral issues faced by industry and organizations conducting research with human subjects, including clinical trials, in developing countries. Suggestions based in large part on the work of others

 will be offered as to the fundamental principles that one must follow to conduct research with human subjects in developing countries. This paper will address the three most important issues when conducting research with human subjects in developing countries: relatedness of the study to the health needs of the host country; the use of placebo; and the availability of the studied drug to the local population after the trial. 

The ethics of conduct of research with human subjects evolved in the past century in response to reports by respected groups about abuses, scandals, and atrocities.  			

The most important event in this area is the Nazi experimentation with human beings. The first report is the result of the tribunals in Nuremberg of the Nazi physicians by the U.S.-appointed court. The court issued 10 principles, now known as the Nuremberg code (1947).

 The first and most enduring principle is the absolute requirement for informed consent. 

Within the United States, the public exposure of the 40-year Tuskegee syphilis study of 400 African-Americans without their true consent has had a profound impact on U.S. bioethics.

 A U.S. national commission deliberated for five years on these troubling issues, resulting in the Belmont Report (1979).

 The Belmont report enunciated three principles of American bioethics: respect for persons; beneficence; and justice. 

Following these events and others, we have now accepted in the United States the existence of several tiers of protections for human subjects. From national oversight (by the federal government), institutional review boards (IRBs) or ethics committees (ECs) as the gatekeepers, and the principle of informed consent, subjects are safer. These protections and principles have influenced other countries as well. However, there may be important differences in the application of each of these tiers of oversight. 

In the past five years, there have been numerous discussions, reports, articles, and committees dealing with issues of clinical trials in the developing world. Two reports from the United States stand out in this regard. One report was from the U.S. Office of Inspector General (OIG)

 on the globalization of clinical trials. The OIG report dealt primarily with the findings of deficits at the regulatory level and proposed recommendations.  

Among the deficits found, the OIG report cited a growing number of studies being conducted outside the United States with oversight by the Food and Drug Administration (FDA). Moreover, there is a noticeable expansion of clinical trials in foreign countries by various sponsors. Furthermore, they found that the FDA was lacking assurance of adequate compliance in foreign countries. In addition, key entities involved in global research with human subjects raised concerns as to the adequacy of oversight by U.S. agencies. The OIG then recommended that the regulatory agencies, such as the FDA or the Office for Human Research Protections (OHRP), help foreign ethics boards (ECs or IRBs) build capacity; encourage sponsors to obtain attestation from foreign investigators (i.e., to adhere to ethical principles); encourage greater sponsor monitoring; develop a database to track growth; and encourage accreditation of IRBs and ECs. These are all sound regulatory solutions to compliance issues. However, the report does not deal with the fundamental ethical issues of conducting research in developing countries.  

In contrast, the National Bioethics Advisory Commission

 addressed the ethical as well as regulatory issues. NBAC proposed 28 recommendations. The commission emphasized the fundamentals of ethical research: prior review, minimization of risk, proper risk/benefit ratios, informed consent; equal regards; and justice. The report further stresses the importance of considering the cultural context of the local area. It warned against using blanket waivers of informed consent, although its permissibility could be considered under special circumstances. These recommendations are a landmark in the development of ethical standards of research in developing countries. However, the effectiveness of these recommendations will have to be judged over time. Nevertheless, initial indications from OHRP and FDA indicate a strong and positive movement in this direction. 

Finally, the 2004 European Directive on Clinical Trials,

 even though it relates to European members states, will have a large and positive impact on research conducted in developing countries. This new directive comes closer to the FDA rules in dealing with clinical trials data in support of a drug license than has previously been recommended. For example, Phase I clinical trials now require prior approval of their equivalent to FDA regulations prior to initiation of the study. 

Unique moral issues for the developing countries

The three Belmont Report principles—respect for persons, beneficence, and justice—are widely considered and, at least in principle, applicable globally. However, differing environments such as those in developing countries may result in important differences when these principles are applied within local contexts. It is important that the ethics of conducting trials in human subjects in research in the developed world is not forced to fit into developing countries without consideration of local values. In other words, we should avoid what is called "ethical or scientific imperialism."

 However, some would consider this is a double standard approach to research, and they instead promote a single standard. Even though one can understand the single standard and universal approach, it should not be absolute (see Resnik

This discussion will begin with each of the issues stated earlier and list the potential problems when various principles are applied within the context of developing countries. In these regions, the lack of health care infrastructure casts a large shadow on these principles. According to Benatar

: "Avoidance of exploitation in clinical research is a major challenge in a globalizing world in which disparities in wealth, health, and disease have reached grotesque proportions." 

Developing countries have very large and pervasive health care needs. This is in large part due to poverty, social ills, and lack of education, compounded in some cases by corrupt political regimes. These regimes squander the country's resources on the governing elites, bringing into stark focus the overriding need for political reforms. The need for reforms is intertwined with any of the collaborative research studies sponsored by a company from western nations. Researchers in developing countries are faced by the realities of influencing and advancing political reforms with western democracies through either research collaboration and exchange of knowledge and personnel, or forcing the issue of instituting reforms prior to initiating such collaboration. This author favors greater research collaboration as a means to influence the political system. The greater the number of the host country's citizens that are exposed to democratic ideas through contacts and personnel exchanges, the more they can influence policy. 							

In 1993, the Council for International Organizations of Medical Sciences (CIOMS) issued (and later revised in 2002) the International Ethical Guidelines.

 These guidelines also address how to conduct research with human subjects in developing countries. Similar to NBAC's recommendations, guideline 10 emphasizes that research be "responsive" to the health need of the local population. In other words, we should not be conducting research on diseases that are not indigenous to the host community. For example, one can justify research on malaria and HIV in most developing countries. But to conduct research on obesity and cosmetic surgery would not be justified. 

 has recently criticized the past approaches of confining the discussion to provide fair benefits to subjects in developing countries. He claims that this "minimalist" approach to justice ignores the linkage between the health care needs of citizens in developing countries from the broad and more important social, economic, and political issues. He further claims that "minimalism" would promote negotiating their research collaboration without considering these broad issues. London advanced the notion that: "[R]esearch initiatives are permissible only if they expand the capacity of the host community's basic social structures to meet the community's health priorities."  

London labeled his approach as the "human development" approach. However, in the same article he recognized the Herculean task he has shouldered upon the research community. London then calls on researchers to attempt to bridge the gap between health needs and social institutions to enhance the health care infrastructure. While I can understand attempts to build health care infrastructure in the host country, I reject the task of linking research to changing the political and social system. It is unrealistic and unworkable, and one may even say it is fanciful. 

Relatedness of the study to the health needs of the host country

There is a general agreement that research in developing countries should address the health care needs of the host country.

 However, there remain important issues of exploitation, risk/benefit ratio, and informed consent, even if the research study addresses the need of the host country. 			

The potential for exploitation of the population in developing countries—by using them primarily for the benefit of developed countries—is of real concern to many. Such exploitation could occur when clinical trials are conducted in developing countries where the outcome will have little, if any, health value to the developed country. In developing countries, the issue of justice has an added dimension. For example, our concern in developed countries is that we distribute the risks to participants in clinical trials to the population at large who would benefit from the outcome. In developing countries, when a trial is conducted without taking into account the health care needs of the host developing country, the issue of distributing risks and benefits to the population is moot since the entire population would not benefit from the trial. Resnik

 argues that this "minimally exploitative" method may be justified when there are other moral considerations such as autonomy of the subject and social benefits. I think one needs to be very careful in tilting the scale towards such exploitative research. 							

A report of a group from developed and developing countries

 objects to the "reasonably available" standard as too stringent and offers the term "fair benefit." They suggest that the "fair benefit" standard will take into consideration 14 factors such as: health improvement, collateral health services, benefit to participants and population during research, public health measures, employment and economic activity, availability of the intervention for the population, long-term collaboration, financial rewards, and transparency. Unfortunately, proposing a laundry list of benefits may pose a risk of adding small, indirect, and at times inconsequential benefits to overwhelm the magnitude of risks associated with the study. At this stage, where there is a lack of education and adequate infrastructure for health care and research, clearer and more straightforward language for compliance with ethical standards is required.

 If the "standard of care" or "the best current treatment" is available in developed countries, the use of placebo in developed countries is usually excluded. However, if the "standard of care" or "the best current treatment" is not available or not practical in the developing country, should we then insist on its use? Should we then deprive the subjects from the use of the best new experimental drug through the trial, or should we just forgo the entire trial? If the answer is to forgo the trial, then we are avoiding potential exploitation of subjects and promoting the concept that standards of care are universal.

 However, we must face the issue of harm and potential for avoidance of harm to the population of the developing country due to the potential benefits of developing a new drug. Therefore, the case for the use of placebo should be considered and not outright rejected. We should, however, assess the risks and benefits. If the difference is tolerable and the benefits outweigh the risks, then it should be permissible. 

The lack of an adequate economic means is a strong motivation for people in developing countries to utilize clinical trials as a means of obtaining an income. This is understandable because motivation to enroll in clinical trials as a source of income, especially for healthy subjects, is even problematic in developed countries among the poor and uneducated population.

 Globally, the lack of economic means could result in exploiting the population of developing countries to the sole benefit of the developed countries. This will be then an injustice on a global scale that could have political ramifications beyond the realm of clinical trials. Moreover, this lack of economic means could result in skewing the risk/benefit ratio for the detriment of human subjects, since they lack the economic and educational means to advocate for their rights. Thus, one can conceive of clinical trials in developed countries in which the risk to subjects is higher than those tolerated in developed countries because of economic issues rather than for issues indigenous to local health needs. 

The risk/benefit ratio may also differ in developing countries from developed countries. Insistence on absolutist standards could do harm to the people of developing countries by the lack of health care progress that results.  			

The problem of malaria in Africa is a good example. The issue of conducting clinical trials with "newer drugs" was the subject of intense discussions recently (see acknowledgment). Malaria is estimated to kill over one million people (mostly children) per year in Africa. In the United States, the death rate from malaria is nearly zero. Thus, one can conceive of clinical trials in Africa in which the risk to subjects of developing malaria or having certain adverse events during a trial could be tolerable (depending on local conditions) while such a risk would not be tolerated in the United States. 

In a poor environment lacking in adequate health care, it is understandable how duress and coercion may play a role in participating in research with human subjects/clinical trials. The strong desire of desperate patients to receive health care would be a strong inducement or coercive incentive to enroll. This "inducement," however, should not be used to eliminate such research because, as Tangwa

 stated, it "would amount to a prohibition of all medical research, which may not be ethical or even rational under the circumstances." Thus, protecting human subjects should be the primary aim,

 and informed consent is a very important step in protecting human subjects when conducting the trial. Informed consent rests on the three components of sufficient knowledge, lack of duress and coercion, and comprehension. In conducting research with human subjects in developing countries, the potential subjects may lack education and general knowledge regarding research principles, techniques, and risks—the investigator may not have even provided this in the local language!  			

One can see that providing the typical information about the clinical trial that we normally provide in the developed countries  would be insufficient in developing countries. Furthermore, comprehension of the protocol and making a reasoned judgment could be deficient. However, it should be noted that providing such information in the language and cultural idiom of the local population is one of the requirements of respect for persons, and it should not be surprising if subjects do not understand "Americanese." Thus, it is imperative that informed consent be administered appropriately culturally and methodologically.

 We need to be flexible in using a variety of methods such as verbal and witnessed, written, or recorded consents. Moreover, we should consider whether it is appropriate to use individual, family or communal consent. 

The use of placebo (i.e., control group) in developing countries remains ethically troubling to many.

 NBAC proposes that the protocol should utilize the established effective treatment regardless of whether it is available in the host country. CIOMS's guideline no. 11, similar to NBAC's recommendation, recommends that in general, research participants should receive "an established effective intervention." It opens the door slightly for the use of placebo, however, if there is no effective treatment, being on placebo will only cause minor discomfort or the research outcome may be invalid without the control group having placebo, or the use of placebo would not add much additional risk to the subject. However, guideline 11 also suggests exceptions to the use of placebo.

recommends "the best current methods," but it does not exclude the use of placebo. 			

The availability of the studied drug to the local population after the trial

In the controversial area of continuation of treatment after the end of the trial, NBAC proposes that a "good faith effort" ought to be made for continuation. CIOMS

 recommendations require that the research outcome (i.e., drug) be made "reasonably available" for the good of the local community (whereas NBAC's recommendation [no. 4.1] is stronger in that it requires "reasonable, good faith efforts" to make it available to all participants). It is hard to see how a pharmaceutical company could provide an open-ended commitment to provide the "successful" drug to all of the participants and/or the local community. One of the important factors for industry is the knowledge of the cost of a project. The open-ended commitment runs contrary to that practical principle. Possibly, a standard upper cost limit for what it would reasonable cost to make the drug available after the trial's end could be included in the proposed study protocol. The ethics committee reviewing the study protocol should consider this and other aspects of the study in its totality during its deliberation and approval. 							

Clearly there is a consensus that research with human subjects in developing countries ought to serve the health needs of the host country. The citizens of developing countries should not become the "guinea pigs" for the developed countries. Therefore, the first criteria for conducting research in developing countries should be that the research must serve their health needs. The persistence of the lack of health care infrastructure in some developing countries raises concerns as to the fundamental problems facing these nations, including poverty, economy, and the political system. Research collaboration could become a tool to expose the host country to democratic ideas through personnel exchanges and research collaborative contacts. These contacts could enhance future reforms. 			

On the issue of the use of placebo in the control group, it is advisable that the default position ought to be to use the current standard of care. However, under unique and compelling circumstances, the use of placebo should be contemplated. It is difficult, if not impossible, to use an absolutist rule in this area. Decisions should be made on a well-reasoned, case-by-case basis as long as we remain within ethical bounds of treating all human beings as morally equivalent. The investigators should justify the unique and compelling circumstances for the use of a placebo where there is the possibility of more than minor discomfort as the CIOMS recommends. In other words, we could use placebo if it is well justified. 

The most difficult issue is what the study sponsor should offer in terms of providing the drug after the trials to the participants and/or local community conclude. How does one define the local community? How does one define the time period? Is it for one year or forever? Unless these questions are answered reasonably, the potential cost to the sponsor could be unlimited. All of the proposals made so far are complex and subject to varied interpretations. Therefore, it will be prudent to suggest that the decision ought to be made on a case-by-case basis. In each case, the sponsors should be required to adequately justify their decisions and should do so on the basis of dialogue with host investigators and their institutions

 prior to the beginning of the trial. Therefore, a good faith effort ought to be made to offer the drug to the participants after the trial if it is economically viable to the sponsor. A part of the consideration to be given when the drug is made available after the trial is whether it will discourage other sponsors from continuing their sponsorship of the trials in developing countries. 

1.  National Bioethics Advisory Commission (NBAC), vol. I, Report and Recommendations (2001), "Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries," Bethesda, Maryland, April 2001, ISBN 1-931022-13-5 (can be accessed at:  

2.  J. Rehnquist, Office of the Inspector General (OIG), DHHS, "The Globalization of Clinical Trials—A Growing Challenge in Protecting Human Subjects, September 2001, OEI–01–00190. 

3.  A.E. Shamoo, "Future Challenges to Human Subject Protection," The Scientist, 35–35 (June 26, 2000).  

Articles

Feature Article

Addressing the health needs of host nations while guarding against subject exploitation and other pitfalls.

Debating Moral Issues in Developing Countries

Producing global submission-quality laboratory data in remote regions of the world is a significant challenge in antiviral drug development. Since viral diseases are endemic in much of the developing world, it makes sense to locate clinical trials there. For example, in sub-Saharan Africa, much of Asia, and the Pacific, most people become infected with hepatitis B virus (HBV) during childhood, and 8%–10% go on to develop chronic infection.

 Current estimates suggest that more than 8% of the Chinese population has chronic HBV.

 Of the 39.4 million adults and children worldwide believed infected with HIV, 82.5% inhabit sub-Saharan Africa, and South and Southeast Asia.

Statistics such as these underscore the reasons for locating antiviral clinical trials in remote regions.  However, the capabilities of many of the local laboratories in these regions to produce submission-quality global laboratory data are limited, and the ability to move the proper stable sample from parts of Asia, the Indian Subcontinent, and South America in a timely manner is a concern. Export permits from China, for example, can take weeks to months to secure and might not be obtainable for samples like whole blood. Within China, the air transport of HIV-positive samples is not allowed. Due to logistical constraints, the ability to develop and implement quality laboratory practices in remote regions is essential to complex clinical development protocols. Therefore, a global central laboratory with regional testing capability is a valuable asset for producing submission-quality data.   

Laboratory data plays a key role in antiviral drug development. It determines the diagnosis, prognosis, and drug choice, as well as the effectiveness of therapy. While the more basic laboratory data (such as viral serological tests) may be sufficient to evaluate the patient clinically, few local laboratories in remote regions have the specialized equipment and trained personnel for nucleic acid testing (NAT). 

In the clinical trial environment, molecular testing (DNA or RNA quantitation) is used to establish diagnosis and prognosis, and is then used for therapeutic monitoring of viral diseases. Nucleic acid amplification techniques, along with sequence determination, are also a means for determining the viral genotype. Therefore, these real-time data generation capabilities are important in research, in understanding the efficacy of an antiviral drug, and in enrolling the correct patient in the clinical trial. 

As a case-in-point, 45%–60% of HBV viruses in Asia, Africa, the Middle East, and southern Europe possess mutations that prevent the expression of HBe antigen.

 When these samples are tested using HBe antigen assays—which are more readily available in remote regional laboratories—these mutants may go undetected, causing clinicians to erroneously conclude that viremia is decreasing and that the infection is resolving. 

As drug resistance becomes an increasingly more important therapeutic issue for both HBV and HIV, genotyping provides vital information that is not available from serological testing. HBV has the ability to develop resistance in one region of virus structure but not in another, complicating potential resistance patterns and drug choice. With the data from genotyping, a clinician is better equipped to target drug therapy instead of being forced to treat empirically. 

The issues in antiviral drug development as described above—mutations and resistance patterns—emphasize the need for high-quality NAT in remote regions of the world

 and the value of an accessible high-quality central laboratory. 

What is required to meet current sponsor expectations of high-quality services? In dealing with viral diseases, laboratory capabilities such as viral load determination, genotyping, peripheral blood mononuclear cell (PBMC) purification, DNA isolation/banking, RNA isolation/banking, biomarker capabilities, and specimen banking facilities are essential. These services must be found in an environment with an audit trail that proves by documentation pre-analytical, analytical, and postanalytical processes meet submission standards. 

The portion of the clinical trial process that has the potential for greatest variation is specimen collection by the investigator site. Pre-analytical control ensures the correct, stable, and properly identified specimen is delivered to the testing location. Metrics show that typically up to 1% of data is lost because the specimens received at the testing location have exceeded stability limits.

 Proper patient identification is a major concern in health care systems. In 2003, one of the National Patient Safety goals of the Joint Commissions on Accreditation of Healthcare Organizations was to improve the accuracy of patient identification.

 One study found a hospital that used a manual patient identification process had an error rate of 2.46% in linking the specimen drawn to the correct patient in 195,850 phlebotomies. When the ID process incorporated a barcode, the rate essentially fell to zero.

The expectation for submission-quality data is a system that links specimen to patient identification with virtually no defects. This level of quality demands a system where all collection materials are barcoded, with a single point for demographic collection and database entry, and for confirmation of patient demographics across patient visits. 

Pre-analytical processes need to be designed to exclude error. Typically, a central laboratory has procedures in place to assure that quality, properly identified, samples are procured for analysis. Sponsor expectations for the Pre-analytical process should include the following

					1) An analytical validation process that precisely defines specimen type and stability (ambient, refrigerated, frozen, freeze thaws permitted)

				2) A standardized collection container (volume, anticoagulant, manufacture, lot number)

		3) A method of expiration date tracking for collection containers

		4) A standardized process for sample collection and transport 

		5) An audit trail to document that a sample is handled in accordance with biomarker validation (i.e., freezing and thawing, heat, timing, etc.)  

					6) A process to assure that the correct specimen is matched to correct demographics and that any demographic revisions are propagated through the system

				7) A definitive audit trail from protocol to lab statement of work to data generation. 			

In the most remote regions, the Pre-analytical control challenge is to ensure that the correct stable sample is delivered to the analytical lab. Monitoring of pre-analytical metrics is one means of documenting the system performance across all geographies and over time. Lab metrics should be measured against an absolute standard such as 6 sigma (3.4 defects per million), be reported in defects per million (dpm), and should also be provided as a sigma value. Table 1 shows an example of the statistics of a typical global laboratory's performance. 

 Table 1. Example of laboratory metrics 			

A submission-quality laboratory also assures tight analytical control. This is accomplished through the documented processes contained in standard operating procedures, personnel training to ensure competency of the analytical procedures, and appropriate choice of reagent systems. 			

Clear documentation of reagent systems is critical in clinical research. PCR primers are important to the analytical process because they facilitate the amplification of nucleic acids. Sometimes, PCR primer changes are necessitated by new findings of genotypes that amplify poorly or not at all with current primers. If a virus has a mutation in the area of the primer, the primer will not anneal to the viral nuclear material and amplification does not occur. This may result in no sample amplification and the inability to accurately quantitate viral load or genotype the samples. To assure accuracy of results, a laboratory needs to use primers that have been appropriately validated; such primers typically have been approved by regulatory authorities and are known to generate reproducible results. A quality laboratory also tracks which primer (reagent version) is used because the choice of the primer may affect the results. Documentation of reagent changes is essential to provide the detailed audit trail required for submission. 

Another analytical issue is the choice of laboratory method. In antiviral drug development, some protocol criteria preclude the use of certain standard laboratory methods. For example, there are multiple NAT PCR techniques that can be used for quantification of viral copies, but their sensitivity varies. The COBAS AMPLICOR HBV (Roche Diagnostics Corporation) has a more limited range (200–200,000 copies/mL)

 than the  COBAS TaqMan HBV (Roche Diagnostics Corporation) range (29–110,000,000 IU/mL or 169–640,200,000 copies/mL).

 Protocol may dictate the choice of one technique over another. A quality laboratory provides multiple techniques in order to meet protocol requirements. 

The laboratory test's upper limit of quantitation and lower limit of quantitation can also be an issue in conducting a trial. For example, at the onset of symptoms, the HBV viral count is typically >1,000,000 copies/mL. For research, a high dynamic range is needed. Therefore a reagent system like the COBAS TaqMan HBV is required in clinical trial research; it offers greater sensitivity and a higher upper end than many other HBV PCR tests. 

For research, the lower limits of quantitation may also be important because as the virus is successfully treated, it drives the quantity of virus to undetectable levels. The choice of assay to monitor viral load determines precision of results. The lower limits of quantitation vary according to test, i.e., the lower limit of the Roche microwell plate HBV assay (AMPLICOR HBV MONITOR Test,) was 1000 copies/mL; the lower limit of COBAS AMPLICOR HBV is 200 copies/mL; the lower limit of the COBAS TaqMan is 169 copies/mL (29 IU/mL).

 A high- quality laboratory will offer the option to use pretreatment techniques to increase the NAT assay sensitivity down to or below 50 copies/mL. 

With multiple techniques and varied lower limits of quantitation, the ability to track the testing method and generate the final result according to the assay required is a complex process. Some protocols start testing using an ultrasensitive analytical technique, while other protocols expect high baseline values and require a standard assay for screening. A well-designed project database provides the appropriate information to manage the protocol correctly and efficiently. Additionally, the database can be designed so methods can be interchanged, depending on the result obtained, to ensure all data is generated with maximum analytical precision. 

A quality laboratory also has processes in place to validate test results. An example of the detailed expectation for viral load data generation is the use of an internal review of patient history with current lab data. If sequential NAT results vary by a variation greater than expected, typically 0.5 logs, testing is repeated. In addition, to produce submission-quality data it is important to track the number of freeze–thaw cycles for a specimen. Numerous freeze–thaw cycles may falsely decrease a viral load result. 

Choice of NAT techniques can affect the absolute final values obtained (Table 2). Different assays provided by the same manufacturer (Method One, Method Two) produce very similar results. Results from a second manufacturer produce results that numerically are very different. The differences in these results are also seen in published external blind proficiency surveys where the same trend occurs across assays. Consequently, it is important for the sponsor to identify expected NAT methods to the performing laboratory. 

Table 2. HCV external control evaluation			

Conversely, the same assay deployed across multiple testing locations can generate very consistent data. Table 3 was generated using a common control material across testing sites on different continents. When all aspects of the analytical procedure are tightly controlled, the three testing locations can be considered to generate identical data.

Table 3. HIV NAT QC results across sites  			

An additional required service for antiviral clinical trial laboratories is the ability to properly genotype the virus. Viral genomics may be an inclusion or exclusion criteria for a study, so genotyping capabilities need to be readily available. From the clinical perspective, line probe-based assays are adequate because they show the clinical viral genotype. However, the information from these assays is limited because they do not permit the documentation of new point mutations. In clinical research, however, the sponsor frequently needs the complete viral sequence to identify new mutations because when the patient does not respond to therapy, a complete genomic sequence helps pinpoint whether the problem is the virus, the drug or patient compliance. 

Because new viral mutations are being consistently identified in clinical research, the ability to review historical data against new mutation information is vital. Consequently, the sequence data (as it is recorded) needs to be highly standardized so it can be reprocessed as new mutations are identified and added to the gene sequence mutation library. Reported genotypes need to have an audit trail to link the genotype result to the library version that generated the genotype, as libraries will change as new mutations are identified. 

The issue of mixed genotypes is also significant in clinical research. Genotyping systems need to be validated to document the ability to identify mixtures of genotypes, as some protocols specify that mixed genotypes are exclusion criteria. 

During genotyping procedures, all steps require a control process. Good quality control dictates utilization of an independent plasma-based external control across all procedure steps and all lots of reagents to assure reproducibility and consistency of genomic data. For example, the use of an external control with the HIV-1 TruGene Genotyping Assay (Bayer Healthcare) provides additional quality assurance through all steps of testing, from sample preparation through sequencing analysis. In comparison to this approach, most manufacturers only provide kit controls for the later stages of testing. Thus, some laboratories currently rely on only limited control processes. 

The additional quality aspect of availability of real-time data to sponsors is important in antiviral drug trials. Laboratory values are used for the clinical trial inclusion/exclusion criteria as well as drug treatment. In some circumstances, turn-around-time for results may be as short as 72 hours, necessitating the appropriate choice of a methodology as well as efficient Pre-analytical processing and testing. 

Required postanalytical capabilities include reporting data in a usable format for the investigator as well as the sponsor. The investigator needs real-time laboratory results to manage the patient according to the protocol specifications. Patient safety alerts, sponsor required alerts, and complex calculations need to be provided to the investigator in real time for patient management. The sponsor may require real-time Internet access to all protocol data with final data summaries provided by computer-to-computer data transfer. 			

The backbone for patient safety alerts, sponsor protocol alerts, and complex calculations is a robust database system, excellent project planning, and database construction. Calculations need to be preprogrammed for all patients' visits as required through the life of the study. In addition, the database and data transfer systems need to have enough capacity to transfer all applicable data (complex genotyping and sequencing data) back to the customer. 

The database system also needs to be able to handle multiple units such as standard international (SI) and conventional units with consistent patient alert and sponsor control flagging for each, as well as interconvertability between units of measurement. The database system and its users need to understand the data generation systems and the method of rounding so it does not influence the accuracy of data. The required outcome is to ensure that patients with borderline data are treated clinically the same regardless of the units used to report the laboratory data. 

Finally, a laboratory must have the capability for archiving samples as specified by the sponsor. Prudent archival policy for NAT samples is to hold them for 30 days after testing has been completed. Some sponsors may require long-term storage of patient samples in order to allow for repeat testing analysis or additional testing before the data lock, which may resolve any identified circumstances. 

In summary, a laboratory with testing that is capable of generating submission-quality antiviral drug data has several attributes. First, it has the technological capabilities to perform services required such as viral load determination, genotyping, PBMC purification, DNA isolation/banking, RNA isolation/banking, pharmacogenomics, and biomarker identification/validation. Second, it has standardization throughout the entire process, from Pre-analytical through analytical to postanalytical processes. Third, it generates a submission-quality audit trail for all activities. Finally, it has the data system capabilities to generate a protocol-specific database, which can then be used globally to control Pre-analytical, analytical, and postanalytical processes and deliver the final protocol data in the specified format. In conclusion, each of the considerations is vital for meeting the goal of furthering global viral research. 			

1. World Health Organization. Fact Sheet No 204. Available at 

www.who.int/mediacentre/factsheets/fs204/enprint.html

2. Geographic Distribution of Chronic HBV Infection. http://

3. HIV/AIDS Facts and Figures. Available at http://

w3.whosea.org/en/Section10/Section18/Section348.htm

4. K. Appold, "Overcoming Hepatitis Testing Hurdles," 

Achieving quality viral biomarker data from around the globe that measure up to standard protocol requirements

Lab Data in Remote Regions: Meeting the Challenge

The concept of informed consent has evolved over the past century. More than just a document, informed consent (IC) has been acknowledged as a process. It conveys information to the potential subjects with—ideally—active discourse between the subject and principal investigator or designee in order to obtain the potential subject's agreement to participate in a clinical trial. But once the form is signed, indicating IC was obtained, can the study team truly assert that the subject has an adequate grasp of the complexities participation in a clinical trial entails? 

Established by the enactment of the National Research Act in 1974 in response to the growing ethical concerns surrounding clinical trials, institutional review boards (IRBs) carefully review clinical trials to assure that the rights and welfare of human subjects are protected. As part of the review, the IRB examines consent forms to ensure that required elements are contained in explicit fashion, as dictated by Title 45 of the Code of Federal Regulations Part 46.

 Adequate explanations of study procedures and fair representation of risk and benefit must be reviewed and approved, plus the consent language must meet a level of readability—usually an eighth-grade reading level.  			

Approval of the form by the IRB is the first step to beginning the IC process. Although the regulatory references, including the ICH GCP guidelines, 45 CFR 46.117a and 21 CFR 50.27, state that an approved written consent form is required to indicate consent, the form does not represent the process nor does the process end with the subject's signature.

 Furthermore, 45 CFR 46.111(a) requires the IRBs to assure that the IC process is taking place in addition to providing adequate documentation. However, responsibility lies with each investigator.  

Given then that the process is ongoing, how is the study team to ensure that the subject is fully informed? First, one must assess the document for adequacy both before and after IRB review. Is the consent form truly readable? According to Golec,

 lengthy consent forms and low readability contribute to poor comprehension. Golec further postulates that IC forms containing recitation of innumerable risks, no matter how minute the incidence, can be as harmful as too little information. Additionally, pages and pages of pure text can be intimidating and overwhelming to the potential subject.

Moving beyond the form, it is incumbent upon the study team to evaluate IC practices. In the traditional setting, the subject is presented with a lengthy legal document to read. An oral explanation of the study procedures follows, along with, presumably, an active conversation with the potential subject to address concerns and to assess understanding. Naturally, presentation styles will vary from person to person and situational influences such as daily workload, the presenter's or the subject's mood that day, or language or cultural barriers can influence how the information is conveyed.

 The end result is that the presentation of the clinical trial is inconsistent and may be inadequate.   

Next, subject attitudes and perceptions will influence the IC  process. If your subject does not ask questions, does that signify full comprehension or utter confusion? Mark Hochhauser,

 a renowned readability consultant, contends that a significant factor in comprehension is "omission neglect," when a subject is unaware of what they do not know. Considering the technicality and complexity of medicine, it is not reasonable to expect the potential subject to be fully cognizant of either their medical condition or to fully understand the procedures that will be involved in the clinical trial. Potential subjects may be intimidated by the situation, may not want to risk embarrassment by asking for clarification or may simply think that participating will appease their doctor.

 All are attitudes and beliefs that lead to "uninformed consent." Conversely, refusal to participate does not indicate full understanding either. Regardless of the subject's decision, full comprehension must be assessed in some manner after the trial is explained to ensure that the subject is making an informed decision.  

Several methods can be employed to foster understanding. Much has been written recently on the use of technology to complement the IC process. Educational materials including DVDs, brochures, and Web sites, all requiring IRB approval, can be used to supplement the informed consent form and assist in conveying complex ideas in a medium that may be more easily understood by the potential subject. In fact, the Office of the Inspector General issued a report in 2002 suggesting that clinical trial Web sites, with proper regulation, may be a promising tool to enhance the IC process.

 Not all supplemental material must come from the sponsor. Academic institutions are taking on a more active role in educating the public. The University of North Carolina at Chapel Hill has published a brochure entitled "Should You Volunteer?" that is available in Spanish and English.

 The brochure provides basic information about clinical trials in general and suggests questions that interested participants may elect to ask during the course of consenting. An accompanying video is also available that further discusses participating in clinical trials. Using multimedia to convey information may increase comprehension for those who have difficulty with the written word. 			

Accurately assessing a subject's grasp of the clinical trial may be difficult, but steps can be taken to ensure that a reasonable understanding is present. Quite often, the person obtaining the consent relies on verbal assurance from the subject; however, as stated previously, this may not reflect the actuality. Therefore, a brief post-test may reveal any misunderstandings. Subjects may be asked to describe the study procedures or answer simple open-ended questions that elicit a narrative response to evaluate comprehension. Documentation of the answers will provide verification that a truly informed consent was obtained. Alternatively, a trusted third party not related to the study team, like a clinic nurse, might question the potential subject to further assess understanding. Once again, documentation of the subject's response is recommended. It is important to remember that IRB approval must be obtained for any post-test questioning.  

In May of 2000, amid a spate of highly publicized ethical violations in research, Health and Human Services Secretary Donna Shalala took clinical trial professionals—including leaders of universities and academic health centers—to task, emphasizing the responsibility they carry to ensure the protection of human participants in clinical trials.

 Ultimately, it is the responsibility of the principal investigator to ensure fully informed consent exists, despite the fact that a designee may have obtained the IC. It is incumbent upon all study staff to take whatever measures are necessary to ensure that the informed consent form represents true understanding and not just a signed form. 

1.  Code of Federal Regulations, Title 45, Part 46 Protection of Human Subjects. U.S. Government Printing Office, Washington, DC. 			

2.  Food and Drug Administration. Information sheet: Guidance for Institutional Review Boards and Clinical Investigators 1998 update. 

3.  L. Golec, "Are You Truly Informed about Informed Consent?" 

4.  J.S. Brady, "Multimedia Delivery Can Enhance the Consent Process," 

5. M. Hochhauser, "Subject Recruitment and Informed Consent," 

6.  Department of Health and Human Services, Office of Inspector General, "Clinical Trial Websites: A Promising Tool to Foster Informed Consent," (DHHS, Washington, DC, May, 2002). Retrieved September 21, 2004, from http://

oig.hhs.gov/oei/reports/oei-01-97-00198.pdf

7.  Office of Human Research Ethics. "Should You Volunteer?" (University of North Carolina at Chapel Hill, Chapel Hill, NC, 2004).  

8. HHS News, "Secretary Shalala Bolsters Protections for Human Research Subjects" (DHHS, Washington, DC, 23 May 2000). 

, RN, CCRC, is a global training specialist with INC Research, Raleigh, NC, email: 

  Prior to joining INC Research, she was project manager in the Office of Clinical Trials at the University of North Carolina at Chapel Hill. 

For truly informed consent, methods should gauge a subject's real grasp of a clinical trial's complexities.

Informed Consent: Imparting Knowledge or Signing a Form?

As pharmaceutical companies around the world search for alternative clinical trial sites due to subject and investigator shortages in North America and Western Europe, they are beginning to discover the potential advantages of a country that many had previously overlooked—the Republic of South Africa. With its modern health care facilities, well-trained medical professionals, large populations of treatment-naïve subjects, and favorable exchange rate, South Africa offers trial sponsors an accommodating environment for cost-effective, high-quality clinical studies. 

Misconceptions about South Africa persist from the past despite the dramatic changes that have occurred throughout the country in recent years. Located at the southern tip of Africa, South Africa today is the richest and most economically developed country on the continent. Although it contains only 4% of Africa's land mass and just 5% of its population—about 44 million people—South Africa accounts for approximately 25% of Africa's total goods and services by dollar value.

The current atmosphere in South Africa is demonstrated by its commemoration in 2004 of the tenth anniversary of the country's first democratic elections, celebrating a decade of remarkable achievements and peaceful transformation. At the same time, South Africa still faces some significant economic and social issues, as well as health care problems such as HIV/AIDS. 

Despite these challenges, South Africa continues to move forward—supporting the optimism expressed in the nation's slogan: "Alive With Possibility." It is this steady progress, combined with an impressive array of clinical resources, which is fueling the growth of South Africa's clinical research industry and prompting pharmaceutical companies and CROs to take a fresh look at the advantages South Africa has to offer. 

 One of the most important advantages of South Africa's clinical research environment is the high quality of its medical infrastructure—both personnel and facilities. The standard of health care is comparable to that of most European countries, with a dual system of public and private facilities. South Africa's rapidly growing private health care sector, with more than 200 hospitals and clinics,

 offers a standard of care that is competitive with the best in Europe and North America. The quality of South Africa's health care system is highlighted by the fact that more than 100,000 tourists from around the world traveled to the country in 2003 for medical procedures,

making South Africa one of the world's leading destinations for the growing phenomenon of "medical tourism." In addition, South Africa's long history of medical achievements and excellent academic medical centers provide a strong foundation for the first-rate training received by physicians, nurses, and other medical personnel there. This medical training is recognized internationally. 			

 More than 50% of South Africa's population is concentrated in urban areas, providing sponsors with ready access to large numbers of potential subjects for clinical studies. A significant portion of this population is treatment naïve—a key factor at a time when shortages of available and qualified subjects constitute a major source of delays in the clinical development process. Another example is South Africa's sizeable population of steroid-naïve asthma subjects that could be of particular interest to sponsors in North America and Europe, where such subjects are increasingly rare. In addition, this subject population is available for studies of seasonal conditions during the North American and European winter months—a factor that could significantly reduce the time needed for studies of such conditions. 

Equally important for some sponsors is the availability of large numbers of healthy, reliable volunteers to participate in Phase I trials in South Africa—unlike the situation in many other parts of the world. 

 As a result of the country's lower labor costs and a favorable exchange rate, South African clinical trials typically provide substantial cost savings compared with those conducted in North America or Western Europe. The cost advantage is one of the reasons why bioequivalence studies for generic drug development are frequently performed in South Africa. Cost effectiveness is particularly important to generic manufacturers due to the high level of competition in their segment of the pharmaceutical industry. The industry also benefits from the availability of local expertise in bioequivalence testing and other Phase I-related services that have evolved rapidly in recent years to meet the needs of generic drug sponsors. The availability of healthy volunteers and treatment-naïveÏs patients provides additional savings of time and money for clinical trials conducted in South Africa. 

 Although South Africa's clinical research industry is still relatively small, it is by no means in its infancy. All of the major global pharmaceutical companies have conducted clinical studies in South Africa for a number of years, and the quantity of trials is increasing rapidly. Currently, about 400 studies are conducted each year in South Africa, across a wide spectrum of therapeutic areas. These trials account for direct annual expenditures of approximately $150 million

—a figure that is projected to triple in the foreseeable future.

 Serving this growing market are numerous contract research organizations (CROs), laboratories, and other support providers with extensive experience in clinical research. Some of these organizations offer specialized expertise in therapeutic areas such as respiratory diseases, HIV, diabetes, and cardiovascular disease. With South Africa's tradition of medical achievements, qualified investigators and other medical professionals are also readily available. 

Experience with good clinical practice (GCP) and International Conference on Harmonisation (ICH) guidelines is widespread in South Africa. The country's Ministry of Health requires adherence to ICH GCP guidelines for the conduct of clinical trials, and the Ministry's Medicines Control Council (MCC)—the regulatory agency that oversees clinical trials in South Africa—enforces national GCP regulations as well. Data from studies conducted in South Africa have been widely accepted by both the U.S. Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products (EMEA). 

 South Africa's Southern Hemisphere location, with seasons that are the opposite of those in Europe and North America, can also provide a significant benefit to trial sponsors. It is particularly valuable for sponsors studying certain respiratory diseases or other seasonal conditions, allowing them to conduct trials continuously throughout the year and potentially reduce time to market. 			

 There are 11 official languages in South Africa, but English is the common language of government, business, and the scientific communities.  

While there are many advantages to conducting clinical trials in South Africa, there is also an acknowledged challenge that must be understood and addressed—the time required to gain regulatory approval to begin trials in the country. The fact that South Africa has a well-established regulatory process based on ICH and GCP guidelines for clinical studies is beneficial for sponsors. However, the review and approval process is relatively lengthy—currently averaging 12 to 14 weeks from the time an application is submitted to the MCC until a decision is rendered. From the submission deadline, there is also a one-week validation process when the MCC can request information omitted from the original submission. Four to five weeks after the original submission deadline, the clinical trials committee (CTC) meets to discuss the application and may provide feedback to the applicant. Another five weeks after this, the MCC meets to discuss the application and responses. The results of the assessment are delivered to the applicant after the MCC meeting. 			

All clinical trials for nonregistered biopharmaceutical products or new indications for registered products must be reviewed by the MCC. A comprehensive application form must be accompanied by the investigator brochure, the completed trial protocol, and the informed consent form, together with a variety of other documentation such as proof of GCP training for the investigators and trial insurance details. There is a fee for each application, which is currently about $900. An approval letter from the MCC allows the study to commence and also permits the importation of the study drug. 

For generic drugs, however, there is an expedited process. Bioequivalence studies using a product that is registered in South Africa are typically approved by the MCC approximately four weeks after an application is submitted. 

In addition to MCC approval, all clinical trials must be approved by an accredited ethics committee (EC). In South Africa, an EC is typically associated with the particular hospital, clinic, or academic center where a study is to be conducted, but there is also an alternative, centralized EC process. The application requirements are similar to those required by the MCC, and a small application fee is typical. The average turnaround time for ethics committee reviews is about two weeks. The MCC and EC application processes can take place in parallel. 

Given the complexities and timeframe of the clinical trial application process in South Africa, it is essential for sponsors to work with a local partner experienced in preparing applications for the MCC and local ECs. An organization that is familiar with the many complex requirements can help draft the regulatory submission to expedite the process and avoid undue delays. 

Expertise in regulatory requirements is one of many reasons why a sponsor should choose a well-qualified local partner when planning clinical trials in South Africa. Whether that partner is a CRO, SMO, a local affiliate, or another type of service provider, selecting the right one is probably the most important success factor for a sponsor conducting trials in any foreign country. 			

What are the essential characteristics of a good clinical trials partner in South Africa? Experience should be the primary selection criterion. A potential partner should have a proven track record of successfully conducting studies in South Africa, with a demonstrated ability to recruit investigators and subjects, meet deadlines, and produce solid data—as well as the capability to obtain regulatory approval for new trials without undue delays. In short, an experienced partner helps a sponsor minimize risks and avoid pitfalls that could increase time to market, jeopardize completion of a study or compromise the integrity of study results. 

Other key attributes a sponsor should seek in a South African partner include: 					

Strong relationships with experienced investigators and qualified sites

Access to extensive databases of potential subjects in various therapeutic areas and healthy volunteers for Phase I studies

Adequate resources in South Africa to perform the functions required, including management resources, trained monitors or other personnel, and facilities

Thorough knowledge of, and commitment to comply with, ICH and GCP guidelines during every phase of a trial

Well-established quality assurance systems, standard operating procedures (SOPs), and other internal controls, processes, and procedures to maintain quality and ensure compliance with all regulations and study requirements

Adequate infrastructure to support the trial, including communications and information technology systems

Ability to work closely with the sponsor by maintaining strong lines of communication and supplying continuous oversight and feedback throughout the trial process.

By selecting an appropriate local partner and understanding the specific challenges of the South African regulatory process, bio/pharmaceutical companies can reap the benefits of the many advantages offered by the clinical research environment in South Africa. This can assist in the successful conduct of cost-efficient, high-quality trials with the potential to reduce the time and cost of bringing new bio/pharmaceutical products to market. 

1. "South Africa in Brief," World Book Online Reference Center, 

3. "2003 Annual Tourism Report," South African Tourism, p. 38. 

4. "The Beare Pharmaceutical Industry Report," South Africa Department of Trade and Industry, 2001. 

5. "The Beare Pharmaceutical Industry Report," South Africa Department of Trade and Industry, 2001. 

MBChB, MMed, FCA (SA), is corporate vice president and worldwide head of clinical pharmacology, PAREXEL International, 200 West Street, Waltham, MA 02451, (781) 434-5305, fax (781) 768-5512, email: 

MBChB, MBA, is senior director of clinical pharmacology, PAREXEL International.

*To whom all correspondence should be addressed.

A high-quality medical infrastructure and low costs make South Africa--largely an untapped opportunity--an attractive alternative for conducting clinical trials.

Discovering South Africa

Women's participation in clinical studies and potential gender differences: these are fashionable topics taken up frequently by the lay media during the last few years. The discussion about women as subjects in clinical research, however, is not new; in contrast, it has a more than   four-decade history, particularly in the United States. But the starting points of the discussion many years ago and the issues of today are very different. What happened in between? 

Several medical tragedies during the 1960s and 1970s prompted public interest in protecting women and consecutively influenced worldwide regulatory authorities. The two most meaningful events will be briefly mentioned: 					

More than 10,000 birth defects between 1959 and 1962 followed the use of the sedative thalidomide in early pregnancy.

 The thalidomide event was the result of both generally insufficient research standards and a relative uncritical use of the drug. Although the drug was used only outside the United States—the (afterwards highly decorated) FDA reviewer Frances Kelsey expressed safety concerns and prevented U.S. drug approval—the thalidomide disaster finally had a major impact on the worldwide intensification of drug laws and, in particular, on the role of women of childbearing age in drug research.

The synthetic estrogen diethylstilbestrol (DES) caused vaginal and cervical clear-cell adenocarcinoma in 0 to 34-year-old daughters of women who received the drug during pregnancy.

Adequate female representation is mandatory, but gender differences should not be overestimated.

Applied Clinical Trials-06-01-2005

Debating Moral Issues in Developing Countries

Lab Data in Remote Regions: Meeting the Challenge

Informed Consent: Imparting Knowledge or Signing a Form?

Discovering South Africa

Women and Trials: When Is Gender a Consideration?

Entering the Realm of Flexible Clinical Trials

Staple Yourself to a CRF

Do More with Less: The New eRO Model

Streamlining Adverse Event Reporting in Trials

A New GCP Bible Is Born

Successful Outsourcing: Tracking the Evolving Use of Full-Service and Niche-Service CROs

Clinical Trial Shipping: The Essentials

Example of an Industry-CRO Partnership