Bangkok Post - January 4, 2001
Nusara Thaitawat

Thailand's top experts in HIV vaccine research have been struggling with this question for the past year since the conclusion of a Phase II trial involving nearly 300 volunteers. Strangely, the issues appear to have become less and less scientific after each meeting of concerned experts and authorities, and more and more political.

At a meeting of the National Aids Committee on December 26, respected virologist Dr Prasert Thongcharoen of Siriraj Hospital told Prime Minister Chuan Leekpai of the political pressure being exerted on experts to endorse the results of the trial and approve a proposal for a more advanced trial with 10,000 volunteers.

The proposal was presented by the Phase II study researchers, led by Vina Churtboonchart, an associate professor at the Department of Pathobiology, Faculty of Science, Mahidol University and owner of the Trinity Medical Group Inc (TMG).

Dr Prasert, a member of the National Aids Committee and formerly the chairman of its sub-committee on vaccine evaluation which has monitored the trials of Remune from their inception, finally articulated the muted frustration of many experts over the past year.

"We've always received political support and commitment [for HIV vaccine research], unlike in this case where there is only political pressure," Dr Prasert told the prime minister. Vina Churtboonchart, an associate professor at the Department of Pathobiology, Faculty of Science, Mahidol University and owner of the Trinity Medical Group Inc (TMG). Vina, who holds a PhD in Pathobiology, is a successful businesswoman with strong connections in many sectors in the country.

Dr Prasert cited the latest scientific meeting held the day before which turned out not to be scientific at all. The chair was Health Minister Korn Dabbaransri, a political figure who specifically asked for a resolution of the issue "Thai style among Thais".

It is unclear what Korn meant, since trials of this type must follow international standards of research in order to be recognised and the vaccine to be marketable worldwide.

Korn's presence caused obvious uneasiness among ministry officials who seemed to play it safe by keeping as quiet as possible. The experts from various institutions around the country also remained mostly silent during the three-hour meeting. One expert volunteered a short comment that the meeting was not in keeping with the stated purpose in the invitation letter.

The issues in contention are:- The principal investigator of the Phase II trial and the proposed advanced trial is also an investor in the company which manufactures the vaccine and thus a conflict of interests could arise. - According to the Trinity Medical Group Inc quarterly report of August 21, 2000, compiled by the Investor Research Centre and posted on Edgar Online, a copy of which was circulated at last week's meeting of experts, TMG signed two agreements with the US-based Immune Response Corporation (IRC), the manufacturer of Remune, in September 1995.

The first agreement is to develop and market Remune in 10 Southeast Asian countries: Burma, Cambodia, Indonesia, Laos, Malaysia, Philippines, Singapore, Sri Lanka, Thailand and Vietnam.

The second one is a stock purchase agreement for one million shares. TMG purchased 333,334 shares of IRC stocks at $15 (about 375 baht at the time) per share on April 30, 1996. It will buy an additional 333,333 shares at $15 per share upon receiving the required official approval for the marketing of the drug.

Another 333,333 shares will be bought at the same price when it receives the licence to manufacture Remune. The quarterly report also stated TMG paid IRC $5 million in cash to secure the rights to develop and market Remune in Southeast Asia.

The share price having been fixed at $15 clearly indicates the confidence in the vaccine and the expected high demand among millions of HIV-infected people in Southeast Asia. A warehouse to store Remune, to be built at a cost of $5 million, was also envisaged.

The second issue is that of good clinical practice. Vina did not follow her own protocol and has come under fire by the sub-committee on vaccine evaluation whose mandate is to keep researchers in line with their protocol and with rules and regulations.

They could not accept her change of methodology to evaluate the end results of the trial.

"It is a must to stick to your own protocol. If you want to change the methodology, you have to follow set procedures and inform the sub-committee. But you can't change the methodology and re-evaluate the results of your study as you please," said one member.

This is an absolute, especially considering that the methodology stated in the original protocol, used to evaluate the results by independent and internationally recognised researchers from Harvard University, has not shown any significant difference between volunteers who were given Remune and those who were given a placebo.

After several inconclusive rounds of talks between the sub-committee and Vina and her team of researchers, sub-committee chairman Dr Natth Baramapravati, Thailand's foremost virologist and mentor of Vina, suggested the results of the trial should be presented for publication in an internationally recognised medical journal.

This means the results of the trial would be reviewed by an independent panel of experts. Acceptance for publication means a certain level of recognition of the trial's methodology and results.

Submission and review by a number of journals took several months. Finally, Vina's research was published in the September issue of the Clinical and Diagnostic Laboratory Immunology.

Vina told the meeting on December 25 that she did not understand what the problem was, as she did what she was told and her article was published.

Mentioned at the meeting, however, was a letter from world-renowned clinical statistician from Harvard University Dr Stephen Lagakos to the editor of the journal, contesting Vina's research results. He sent copies of the letter to Korn and all members of the sub-committee on vaccine evaluation.

In his cover letter, he told the minister, "When I read the published paper, I found it to give a misleading account of the study, overstating the benefit of Remune."Dr Lagakos also wrote that he and Drs Soyeon Kim and David Glidden were involved in the initial planning of Vina's trial at the request of Dr Natth.

They assisted Vina in implementing several modern standards of clinical trials, including a double blind design, use of the independent Data and Safety Monitoring Board to review interim results of the study, and an analysis plan that described how the study would be conducted and analysed to assess the efficacy of Remune.

Specifically discussed were the problems of post-hoc analyses of study results and the need to specify how the data will be analysed prior to examining the study results. An analysis plan was worked out with a primary method of analysis of the main study outcome (a comparison of Remune and placebo groups with respect to changes in the CD4 cell count), and secondary methods of analysing CD4 count.

The plan was accepted by Vina at the time, wrote Dr Lagakos.

"Consequently, in our final report of the study, we noted that some of the secondary analyses of CD4 count suggested that Remune possibly did have some effect, but the study overall failed to demonstrate that Remune significantly improved CD4 count over the placebo group.

"We believe that this accurately reflects the results of study, and that experts in clinical trials would agree with our assessment," he wrote.

In her published article, Vina wrote: "There was a significant difference in changes in CD4 cell counts that favoured HIV-1 Immunogen treated group compared to those for the adjuvant-treated control group."These two main issues in contention became more complicated with the release last month of the results of a large-scale trial of Remune in combination with anti-rival drugs in North America involving some 2,500 volunteers, which also shows that there was no significant difference between those on the vaccine and those on a placebo.

Thai experts say that these results strike a heavy blow to Vina's hopes for approval for her protocol for a large scale trial. This is because the concept of a therapeutic vaccine is based on its combined use with anti-viral drugs. The anti-viral drugs suppress the HIV viral load to the lowest level possible, and finish off the job with HIV-1 Immunogen which is intended to boost the immune system.

Vina's trial is a mono-therapy trial in which only Remune is used. Because they are very expensive, anti-viral drugs remain mostly out of reach for Thais infected with the virus.

At the December 25 meeting, Vina's team of researchers spent considerable time attacking the results of the North American trial even though just a few months ago, Vina proposed to the sub-committee that they jump to a Phase IV trial as a Phase III trial was already being done in the US.

Remune consists of two basic components. The first is the non-activated, or killed, HIV that has been stripped of its outermost protein, called gp120, but retains most of the common HIV protein that can be recognised by the immune system and may help the body learn to respond more broadly to HIV.

The second component is a potent stimulator of immune cells. This mineral oil emulsion is commonly referred to as an adjuvant, which enhances the response of the immune system to the rival proteins in Remune.

Vaccine trials are usually conducted in three to four phases after laboratory and animal tests. Phase I aims to find out whether the vaccine is safe while Phase II tests whether and how it boosts the immune system.

Phase III, which involves thousands of volunteers, seeks to prove whether the immune response obtained in Phase II is capable of actually protecting the body from infection.

A Phase IV or post-marketing trial is conducted with tens of thousands of volunteers and aims to find out any other side effects in a large population.

Senator Jon Ungphakorn, an advocate of the rights of people with Aids and formerly a member of the National Aids Committee, agrees with the sub-committee on vaccine evaluation.

"I've been following the issue with concern from the start," he told Outlook.

He commented that the sub-committee should not even have approved Vina's proposal for the so-called extended study of Phase II which was given the green light a few weeks ago.

The study involves the same volunteers. The reason given for continuing to administer Remune to the volunteers who were given the vaccine as well as those who were on a placebo in an earlier trial was "compassionate use", as Vina claimed that to discontinue its use would only deteriorate the condition of the volunteers who had shown positive results.

"This is a scientific research," said Mr Jon. "The data on the effectiveness of Remune is unclear and therefore the term 'compassionate use' is public relations intended to benefit the manufacturers more than the volunteers. Vina's trial should be discontinued and her proposal for a large-scale trial involving 10,000 volunteers should not be approved. We should be supporting more promising projects."Mr Jon stressed the rights of the volunteers in the trial. "They have the right to know the facts of the trial, if not they will be nurturing a false hope about the effectiveness of Remune."He said that Remune had been advertised among people living with Aids for some time. "It's been advertised as a vaccine able to help those with HIV. Whether it was advertisement or words of mouth from one person to another, it gives false hope without scientific data to support it."Since Thailand decided to join international effort to develop a vaccine for HIV about a decade ago, it has received a lot of praise for its leadership in the fight against the spread of HIV and its efforts in the complicated scientific fields of diagnosis, treatment, and research.

Among the four countries which the World Health Organisation had identified as sites for vaccine research, Thailand is known as the most advanced, with its political commitment, financial contribution and promulgation of laws to facilitate and regulate research.

However, the past year or so saw increasing comments from international researchers as to "how easy" it has become for foreign firms and scientists to do research on humans in Thailand.

According to several researchers, there seem to be only two options for Vina, both of which have been made known to her for a long time. One option is for her to re-do a Phase II trial with new volunteers without being its principal investigator. The other is for her to acknowledge the scientific data from her own trial and from those conducted by leading international scientists that Remune does not produce the hoped-for results.

It is clear that the sub-committee on vaccine evaluation cannot unanimously support her claims regarding the results of the Phase II study and her protocol for a Phase III as it is.

Supporters of Vina's trial argued that there was no need to repeat the Phase II trial because the use of a larger group of volunteers would produce clearer results showing the benefit of the vaccine.

"We don't agree with the move to suspend the [large scale] trial because it has been proven that the vaccine was safe," they said.

The National Aids Committee will automatically dissolve with the completion of Mr Chuan's term in government with the forthcoming elections on January 6. Members of the sub-committee on vaccine evaluation are feeling the pressure to approve Vina's large scale trial before that date.

All, except Dr Natth, have signed the motion to suspend the protocol pending redesign. A few have already submitted their resignation to show that they cannot support a large scale trial involving 10,000 lives without enough evidence that the vaccine might be useful.

"I won't be able to live with myself if this trial goes through. We're talking about human lives and the false hopes that we will give to millions of people with HIV," commented one observer.

In his letter to Korn and sub-committee members, Dr Lagakos said: "We realise that publication of our letter may cause some readers to (incorrectly) form opinions about the quality of research being done in Thailand. This troubles us greatly because we know numerous outstanding Thai scientists and medical researchers and are aware of excellent clinical studies which have and are being conducted in Thailand.

"Furthermore, we have worked over the past four years to develop quantitative expertise in the area of clinical trials in Thailand. However, as scientists we felt that we had no choice but to see that the full results of the trial were made public."

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