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The Thai Trial Controversy

Published onNov 22, 2022
The Thai Trial Controversy

It’s not very common for success to be diminished into disappointment so quickly, as was the case for the HIV vaccine clinical trial known as the Thai trial, or RV144. As part of the still on-going global search for a HIV/AIDS vaccine, the trial was conducted from 2003 to 2006 in Thailand. The significance of this trial was the combination of two vaccines, ALVAC-HIV and AIDSVAX, that had failed to provide enough efficacy on their own. Though the trial had an underwhelming efficacy of 31% it created optimism among some researchers as it had resulted in the highest level of protection until then.[1][2][3][4] Yet the Thai trial faced much criticism, of which three aspects will be discussed in this article. The first aspect will deal with the flaws of the study, the second will go into depth on the results and the third will focus on the presentation of the data itself. 

The trial, sponsored by the US Army and the Thai government, involved 16,402 participants aged 18 to 30, who were split into two groups: a control group and vaccine group. ALVAC-HIV was administered four times, followed by two booster shots with AIDSVAX B/E.[2] Afterwards, the volunteers were monitored for three years to measure the number of participants who then tested positive for HIV. 51 HIV infections were discovered among the vaccine group and among the control group, 74 were infected with HIV within the three years of monitoring from which the efficacy of 31% could be derived.[1][2] 

When the team of researchers first presented their results at the AIDS Vaccine Conference in Paris on October 20, 2009 and subsequently published them in the New England Journal of Medicine, it generated a myriad of responses among the health science community. One cause for disappointment was the difficulty in identifying exactly which immune responses provided protection, the so-called “correlates of protection”. This aspect is vital in order to conduct further research with the aim of developing more specifically targeted vaccines in general. Equally difficult to determine was the mechanism behind the two vaccines combined. However, optimism was also shared among scientists who saw this as a step closer to developing a vaccine that could potentially be approved by the FDA in the near future. 

The statistical analysis of the results also faced criticism. The results were statistically categorized into three different infection rates. With an infection rate of 26 %, there were 20 fewer infections within the group that had received the vaccine than in the control group. This type of analysis is known as the ITT (intention to treat), which yielded no statistical significance. That is to say, the possibility that the results were “by chance” was at 8 % (p-value of 0.08), which was well above the generally accepted threshold of 5 %.[3] The second analysis, "per protocol", which looked at the study in its best case scenario, excluded participants who had not followed the study instructions and had either missed shots or the appropriate timing.[1] This also had no statistical significance and showed an efficacy of 26 %. This led to the reduction of the number of infections in the vaccine group from 56 to 51 in the last method of analysis, "modified intention to treat", which was the only form of analysis that provided enough statistical significance. All three analyses fell short of providing the required efficacy to deem the study a success.[2][3] Were this a vaccine trial for any other disease, it would have been declared an instant failure. Yet for a field that had seen little success the efficacy of 31 % was enough to become the highest level achieved until then and also became the basis for many more trials in the future. A quote from Dr. Fauci, director of the U.S. National Institute of Allergy and Infectious Disease, who commented on the controversies regarding the results, summed up the trial’s contribution to the on-going development of an HIV/AIDS vaccine; "The good news is when you get any degree of efficacy, you can probe into the results and see if you can identify a correlate of immunity and increase efficacy in subsequent trials." [4]

The study had raised concerns even before the results were announced due to the amount of resources that were being invested in the study. These concerns seemed to prove themselves to be justified when the disappointing results were presented. Were the results significant enough? Was it worth the investment of $119 million? [5]

The way the results of the trial were made public only raised more questions. The release of the efficacy results to the press before publishing the study in a peer-reviewed scientific journal made room to question the reliability and quality of the results. This unusual step meant there was no process of having the study be reviewed by third-party experts to not only ensure quality but to provide credibility. Hence, many were skeptical about the true efficacy of the trial. Furthermore, there was the reproval that the three statistical analyses of the study, discussed previously in this article, had not been sufficiently explained. The study was accused of having cherry-picked its results for publication. To its defense, Dr. Fauci and the Thai Ministry of Health provided a response to the allegations. The Thai Ministry of Health felt it owed it to the Thai people to release the data to them first and Dr. Fauci believed that releasing all the results would have been too complex and would have only led to more confusion for the public.[1]

Looking back on a study that began almost 20 years ago, the trial and the circumstances around it are still of great relevance today. In retrospect, transparency was a fundamental issue, a problem that has not been adequately addressed yet. The prerequisite for an objective and more accurate evaluation and interpretation of scientific findings was absent, and thus the concerns and doubts that undermined the trial’s credibility were well-justified. However, by analysing the intention behind publishing results in such a way, it gives us the chance to reflect on several different potential reasons. Have we turned into a post-truth society where the atmosphere of the scientific community has become less accepting of honest results that lay out the reality and instead evolved into one that leans more towards success stories and instant attention that fulfills the expectations of its community?

On the other hand, one could argue that perhaps the personal ambition to stay relevant in the scientific community led to the misjudgment of prematurely releasing only parts of the results. Has there been a shift in the purpose of science? What objectives do we or should we have when diving into the field of research? Perhaps the clash between accepting the results as is and wishful thinking also contributed to the outcomes of the trial.

The way the results themselves caused much controversy, we must ask ourselves, have we reached a point where research and its tangible results are the only determining factors of the importance of a study? If this were true, this would expose another aspect of the dangers thereof. It could, for example, lead to potential scientists selecting fields of research according to their expected success rate rather than the urgency or necessity of certain research topics.

Another aspect that could be investigated is whether an approach aimed to gain positive results in a short period of time lead to a rather hasty outcome. The high expectation or demand of a successful study or even a conflict of interest could be factors that support this statement. Considering the fact that the researchers of this Trial had deemed it unnecessary to go into the individual details of the study for various reasons, this may prove to be true. If so, what does this mean for the medical community? Is this heuristic approach an adequate method to handle data in certain cases?

Moreover, when dealing with issues such as putting an end to the HIV/AIDS epidemic, what moral responsibilities do researchers carry and do they have a moral obligation towards the people, i.e., potential patients? Must scientists carry the burden of creating hope and expectations, and if so, does this duty outweigh the obligation to transparency, as disappointing as the results may be? To what extent did the way of publishing the results affect the outcome and is there ever a justifiable reason for intentionally excluding results? Are such moral duties prerequisites for a successful study?

How independent are research groups when it comes to the process of presenting their results to the public? As mentioned, the Thai Trial was heavily funded by the government of the United States and the logistics were only made possible due to the cooperation of the Thai government, both being entities that are entrusted with matters such as health and science. For governments to encourage such methods, it raises concerns about their insensitivity and attitude towards dealing with science.

Some may argue that the on-going vaccine development has still not come very far from the Thai Trial, though perhaps this is an example of a case where yielding no significant results may be just as essential. Among those who saw the trial as an opportunity, it gave them an impetus to pursue and conduct further trials based on the Thai trial, such as the HVTN-702 Trial conducted in South Africa in 2016.[4] As of 2022, an mRNA-based HIV vaccine, a type of vaccine which gained a great deal of attention during the pandemic, has also shown a promising future and it began its first human trial early this year. 

Title image by Mufid Majnun.

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