Anti-dengue drug: A medical mystery
It all began with a news article last October about the adoption by the Department of Health (DOH) of a 2-day anti-dengue treatment called ActRx TriAct. It is a combination drug composed of a sublingual spray of Artemether plus tablets of Artesunate and the herbal Berberine. The article reported that the drug had been developed locally.
I was amazed and pleased with this announcement. I was glad that something this important had happened on our shores. Those who have some idea about how a drug is developed understand how breakthrough drugs usually take years of research, expertise and money. A treatment for dengue, a disease that afflicts and kills millions worldwide, would be called a medical breakthrough.
Before a drug can be tested on human beings, a lot of work has to be done. There are many reasons why one might choose a chemical compound to test. One is that people have been using a certain herb for sometime against a certain illness. This was how the drugs Artemether and Artesunate were developed. These compounds can be found in the herbal Qiinghaosu, which was being used for malaria.
Years go into the pre-human testing of a drug. One needs to isolate the compound, try to discover whether it works in the test tube, and try to discover how it works in the human body without actually testing it on people. In many cases the first tests on living creatures are tests made on animals.
Very few compounds actually make it past the pre-human testing stage. When they do, the developer then has to apply to the government, in the Philippines, the Food and Drug Administration (FDA), for a permit to test in humans. The tests are often done in 3 phases, and permission is needed to start with Phase I trials, the first phase.
To get a permit the developer has to submit all the data gathered during the laboratory testing of the compound as well as a clinical protocol about the testing to be done in humans. That clinical protocol is a detailed plan about the experiment to be done. It tells how many human subjects will be recruited, what the compound is and how this will be administered and in what amounts, what tests are to be taken, how the data will be analyzed, how the rights of those who will volunteer will be protected. Aside from the FDA, another group with expertise in human research ethics has to look at the proposed trial documents and give approval. In the Philippines, this ethical body is often the Philippine Council for Health Research and Development (PCHRD).
Is the drug safe?
Phase I clinical trials can proceed with the proper permits. The goal of Phase I trials is usually to assess whether the drug is safe. In other words, it is not a trial to test whether it works; it is a test as to whether it can even be used without killing or seriously injuring a person. Thus Phase I volunteers are healthy subjects who are few in number, say, around 20 to 80 people. What is looked at is how the drug works in the human body, what doses achieve certain effects and side effects.
After Phase I trials, another application to FDA and an ethics review is made to go on to Phase II trials.
Phase II trials seek to determine efficacy and continue to look at issues of safety. Phase II trials involve people who actually have the disease, in the case of ActRx Triact, people with dengue. The subjects are divided into two groups, those given the compound being tested and those receiving another substance, usually a harmless non-active substance called a placebo. To ensure proper results, the researchers administering the "drug" are "blinded" or unaware of whether they are giving the placebo or not. The subjects are randomly assigned to either the treatment or the placebo group, and they also do not know whether they are receiving the drug or the placebo. This process is a rigid one and is referred to as a "double-blind" procedure. Phase 2 studies utilize volunteers of around a few dozen to a few hundreds.
If Phase II trials prove that the drug is both efficient and safe, it is only then that the drug developer can proceed to Phase III trials, and here, FDA involvement is even greater. Ethical review is still strict, especially as these trials often require several hundreds to thousands of people. Drug developers need to coordinate closely with the FDA. Phase III clinical trials look more deeply into efficacy and safety issues. They are still randomized and double-blind.
After Phase III trials, the drug developer needs to apply yet again to the FDA for its approval for manufacture and introduction to the general public. This is often called Phase IV because there is a continuing need to monitor the drug.
In the case of ActRx TriAct, there are several issues. Some experts are of the opinion that Berberine alone should go through its own set of clinical trials to prove safety and efficacy. The use of Artemether and Atesunate for dengue (they have only been tested and approved for malaria) also needs to be looked into. Definitely, the use of the three compounds in combination for dengue should have gone through the rigid testing procedures described.
No evidence of clinical trials
I took some time to explain this all because, as I began to ask around about this breakthrough drug, my surprise turned to mystification and then dread.
I could find no evidence that ActRx Triact has gone through the proper clinical trials. No evidence of PCHRD or FDA approval of any of the clinical studies cited (but never fully presented) by the manufacturer and the DOH.
The document trail instead leads to perhaps an unethical study on ActRx Triact for malaria halted by the FDA. But that is yet another story. What I picked up from this dead-end trail was that the use of this combination, whether for dengue or malaria, goes against World Health Organization (WHO) guidelines. Its use will risk development of strains resistant to Artesunate and Arthemeter. A better discussion of the real dangers can be found here.
For its use in dengue, one can find only an extremely uninformative clinical summary of what they call a Phase III clinical trial on the drug manufacturer's website. The report raises more questions than answers.
First, the authorship of the study is uncertain because it is only stated that the trial was done with the cooperation of Health Secretary Enrique Ona and Director Ordona of the Philippine National Institute of Traditional and Alternative Health Care (PIHTAC). One cannot find the real report, only its summary. I cannot go into how bad this summary is for lack of space. But for one thing, it cites a very small sample of 288 participants. There are also no efficacy rates, no confidence intervals and no actual numbers showing the claimed effects. Given the sketchy nature of this report, one cannot ascertain also whether there was FDA and PCHRD approval.
Dubious paper trail
I can only find one full clinical protocol for a cohort study (not a clinical trial). This is found as an attachment to a confusing DOH Memorandum Circular 2014-0161 entitled, "Policies, Guidelines and Rules Regarding the Implementation of the National Program Utilizing ActRx Triact for the Treatment of Dengue By the Philippine National Institute of Traditional and Alternative Health Care (PIHTAC)."
DOH order 2014-0161 is confusing because the title makes it appear as if a national program for the use of the drug is already being instituted. This order was the basis for news reports announcing that this was already a drug ready for use against dengue. You have to read through the order to understand that what is being undertaken is a multi-hospital study.
The memorandum order also misquotes Dr. Jaime Montoya of the PCHRD to give the impression that there was an ethical review of the research on the drug. Dr. Montoya has since stated that his words were taken out of context.
Annex A of the order is the clinical protocol of the proposed multi-hospital study. But that annex is now inaccessible whereas I found it initially here. The only online copy to be found is the order without its revealing annex on the website of the drug manufacturer.
For lack of space, I cannot go into the details of that clinical protocol except that in the consent form, the explanation of possible side effects is general and quite vague. In this sense it is not a proper consent form. Also in this sense, one wonders whether the data of side effects, is not known because proper clinical trials are unavailable.
Footnote 20 of that annex leads us to the only possible study that might allay our fears about the lack of safety and efficacy of ActRx TriAct.
I cite it now, in hopes that the medical community and public can help me find it: Miranda, et al. "The Impact of the Combination of Artemether and Artesunate plus Berberine in the treatment of Dengue Patients in San Lazaro Hospital of Infectious Diseases," Manila 2014. The fact that my efforts and those of several well-connected and competent researchers cannot surface this document is disturbing. What we did find was the Department Personnel Order 2014-4343 signed by Secretary Ona on October 8, 2014, detailing several people including a Dr. Edna A. Miranda from San Lazaro to PITAHC, to work on the anti-dengue program embodied in DOH memorandum circular 2014-0161.
I am hoping this is the same Dr. Miranda whose missing study might relieve all my doubts.
I am told San Lazaro does not have the facilities to conduct a Phase I trial. Is the Miranda study a clinical trial? Let us hope it is not the Phase III trial that was summarized by the drug manufacturer. Or if it is, that the summary failed to give the study its due.
Because as it stands, this single document carries a very heavy burden of overturning very legitimate and strong doubts. It is the only chance so far, for those who worked on this, to prove themselves to have been aboveboard rather than an unethical bunch of research hacks. Which is why, its absence seems extremely strange.
The doubts caused by the documents we have so far, made me issue a sigh of relief when the dengue program was suspended by the acting health secretary. (Editor's note: Ona is on extended leave)
These same doubts nonetheless lead me to the frightening idea that this medical mystery may yet turn out to be a real horror story, where an unethical drug company and its local partners met with a DOH secretary ready to play fast and loose with the nation's health. - Rappler.com