i get asked why i bother to blog again and again on ActRx TriAct when no one seems to be reading, much less agreeing; mostly, the comments only echo, insist on, what kill-the-cocktail proponents feed an unthinking mediocre media.
meron naman akong readers, heh, or so my site stats tell me, and dr. stuart and i have been receiving email thanking us for the posts and the research and wishing that mainstream media would pick them up, publish them as well, so the public may know. yeah, we wish.
but even if i had just a handful of readers, or even if no one agreed with the sentiments expressed herein, i would continue to blog, if only for the record. i would continue to share my thoughts and reactions on an issue such as this that has national and worldwide significance. dengue is a global public health concern, after all, and let it not be said, now and in the future, that pinoys, one and all, sat back and allowed the killing of a promising anti-dengue cocktail without question or resistance.
which is also to say that it is dismaying, nay, disturbing, nay, scandalizing! that the public discourse is so one-sided. except for dr. tony leachon, speaking for the philippine college of physicians and the philippine medical association, and dr. sylvia claudio in her online column – both pro-garin, it would seem — we are not hearing any dissent from the medical community. no doubt there are dissenters, but unfortunately they choose to not make public their informed opinions (along with their identities), they choose to not engage in, contribute to, an exchange of expert views, whether for or against. ask them why, and they’ll invoke the politics, the dirty politics; they’d rather not get involved.
but surely the good doctors know that their silence has political repercussions, too, giving the impression that they’re all okay (as in, all right) with acting DOH sec garin’s godawful decision to stop the ActRx TriAct clinical trials?
yeah, the devil is in the politics.* and on this blog, we dare confront that devil.
Dr. Stuart: I received anonymous emails with links to articles on the position of the Philippine Medical Association (PMA) and the Philippine College of Physicians (PCP), in support of the cancellation of the expanded clinical trials of the anti-dengue drug, ActRx TriAct. One was accompanied by a link to the WMA (World Medical Association)’s Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects.
What the media reported on the PMA POSITION was a nitpicking criticism, full of text extracts from Dr. Calimag, without even the briefest elucidation on the censured design and analysis flaws.
In contrast, The WMA DECLARATION OF HELSINKI: ETHICAL PRINCIPLES FOR MEDICAL REASEARCH INVOLVING HUMAN SUBJECTS was an interesting read. I wondered which of the 37 articles the ActRx TriAct study violated. I likewise wondered if maybe it was sent in support of the ActRx TriAct study.
The last article was especially compelling: Unproven Interventions in Clinical Practice — “…where proven interventions do not exist or other known interventions have been ineffective, the physician, after seeking expert advice, with informed consent from the patient or a legal representative, MAY USE AN UNPROVEN INTERVENTION IF IN THE PHYSICAN’S JUDGMENT IT OFFERS HOPE OF SAVING LIFE, RE-ESTABLISHING HEALTH OR ALLEVIATING SUFFERING.” Compelling — because it advocates the use of the medicine for compassionate use.
I don’t want to belabor the fact. The components of the ActRx TriAct anti-dengue therapy are old drugs, being repurposed or repositioned for new uses. Repositioning or repurposing drugs is one way of significantly shortening the process of drug studies and trials. Yet, criticisms continue to express incredulity on why the ActRx TriAct therapy did not take the usual 12 to 14 years of new drug development.
The PCP POSITION also slammed the people behind the clinical trial for including some children as subjects. Why are doctors so horrified or against testing the efficacy of the treatment on children? Ladies and gentlemen, it is the children who are most vulnerable, it is in the children’s sector where most fatalities are found in a 2011 study. From January to September, there were a total of 86,662 cases, with 65,000 (74%) occurring in all confirmed cases. 36% of these occurred in children aged 1-9 years, resulting in 265 deaths, representing 60% of deaths due to dengue in 2011.
CRAP? There was also a public status on facebook posted by Dr. Claudio, that “the science supporting Ona’s anti-dengue miracle drug is crap.” In the course of public discourse, that the best argument a doctor in her position can offer is that the study is “crap,” is sad, unprofessional, disreputable, and downright juvenile. The study is crap!—and that’s it? We take her word for it? We deserve better than that. She should not have called a study “crap” based on reports she is privy to but she is not willing to divulge. Such criticism is crappier than crap.
The medical voices or the guardians of truth charged with informing the public is burdened with the responsibility of providing explanatory answers, not silently agreeing to pronouncements of “crap.”
We need a clear judgment and resolution on this controversial matter from a really independent scientific review board — if that is at all possible — not rantings from the bully pulpit or DOH press releases dutifully published by kowtowing media, repeating, ad nauseam, pronouncements from on high without looking deeper into or researching the issues.
GAME OVER? But is it all moot now? Has the circus left town? Dr. Ona has resigned, silenced, lips politically zipped? The pneumonia vaccine issue abandoned to die a quiet death? The anti-dengue drug vilified as crap? The study criticized as unethical, diagnostically inaccurate, no endorsements, dubious paper trails, poorly designed, flawed data analysis, blah blah blah? Were these a fagot of separate political issues—of demolition, positioning, wheeling-dealing, and a clashing of government egos—really meant to get Ona out of the picture?
Or is this partly issuing from the great disdain by many in the medical community of anything that has to do with alternative medicine? Remember, many of the medicines that grace the pharmaceutical landscape are plant derived, and many more are waiting to be discovered, many a lot safer, without the toxicities of synthetic pharmaceuticals.
In the ActRx TriAct study of 290 patients — 145 received the drug treatment, 145 did not — there were no deaths in both groups of patients. The PCP concludes that because no one died in the 145 who didn’t take the drug, the “experimental drug added nothing in preventing deaths.” This is a valid scientific conclusion? Or just a position intent on seeing the cup half empty rather than half full.
In different studies, dengue deaths ranged from one for every 185 to 250 cases. In the ActRx TriAct study of 290 patients (145 with treatment, 145 without), taking the optimist position, the absence of death might suggest the benefit of prevention of at least one fatality.
Calimag also said: “the lack of adverse events in a small sample size is not conclusive evidence of the absence of harm.” Taking the optimist position, the absence of adverse effects might suggest the absence of toxicity — three drug components that have already undergone extensive toxicity evaluation — and the absence of deaths, albeit a small sample size, should support further expanded study and testing, especially in the many provinces that have attained malaria-free status.
THE CAT IS OUT OF THE BAG. Even here in the boondocks, a local alternative healer has asked me about it. In places like these, what is to keep the local healers from accessing the separate components of the drugs for the occasional desperate families seeking any possible treatment for dengue stricken family members?
Is the study dead? I hope not—because the anti-dengue drug treatment has NOT been debunked. And calling it “crap” doesn’t kill it. Perhaps, dissenting voices from the medical community might still surface and dare to disagree with the powers that be, provide a badly needed and audible point of view.
If it is a bad study, tweaked or falsified, or in the end, proven as crap, I’ll be glad to help pull the trigger and kill it. BUT if the potential to save lives still exists, the testing and expanded use must be allowed to go forward. This year, from January to September 2014, there have been about 60,000 reported cases of dengue in the Philippines, with about 242 deaths (4 deaths for every 1,000 cases). These numbers cry out.
What a shame if in the end ActRx TriAct is taken elsewhere, and the drug is shown to work.
my pet theory is, the demolition job on ona and ActRx TriAct is in aid of that dengue vaccine for which a huge pharmaceutical company has spent $1.5 B on research and development, soon to be out in the market. as i’ve blogged before, we could use both ActRx TriAct AND a dengue vaccine. dr. stuart tells of the vaccine’s limitations here.
and if you’ve read this far, good for you, i saved some juicy tidbits for last. over the holidays, different grapevines were buzzing with anti-garin stories: how she wants the post so badly, sorry na lang si ona, and how she’s not even qualified for such a high post — she’s more a politician daw than a physician, much less, a scientist (check out her wikipedia profile).
but the juiciest story, a sweet stab of sarcasm from ona himself, came via inquirer’s christmas day report, Ona: Loss of Aquino’s confidence prompted me to quit
When asked about his relationship with the acting health secretary, Ona said he thought it was “very ideal.’’
… “My personal things were brought to my house even before I officially announced my resignation and there’s only one person in DOH who could make such order,’’ Ona said.
whew, what a game she plays. this is the same aquino-appointed acting DOH sec who brazenly disobeyed the quarantine rules imposed on families of travellers from ebola-stricken countries, the very same one, still unmasked, whom our senators welcomed to their august halls with beso-besos to boot.
the anarchy proceeds apace. in the highest places yet.
*
* “The devil is in the politics” is how i ended the book Revolutionary Routes: Five stories of incarceration, exile, murder, and betrayal in Tayabas province, 1891-1980 (2011)
Best wishes to you, Angela, and to everyone.
Angela,
I’m glad to know there are still some people who think about the welfare of the masses (as opposed to politics for self-interest). I wish you and your family a safe and a fruitful New Year.
I believe that we Filipinos deserve better. Better health, better environment, better government, better economy.
manigong bagong taon rin, bert at dok margel, at sa lahat ng nagbabasa nito. here’s to an enlightened year ahead, and may pope francis knock some sense into us all :-)
“DOH dengue trial protocol approved by PCHRD” by Dr. Rafael Castillo
Six years ago, Dr. Renato Dantes, one of the country’s top lung specialists and researchers, died due to dengue shock syndrome, which he likely got while on an out-of-town volunteer mission. He also got dengue a year before his death, but this did not deter him from continuing his pro bono work every time he felt his services were needed.
He was promptly diagnosed with dengue fever again and was still stable when admitted, but within 48 hours, his condition progressively deteriorated. His doctors, all experts in the field, felt helpless as they watched him bleed profusely, go into shock and breathe his last.
That was in 2008. Six years hence, we still don’t have any known effective cure for dengue. Thousands of Filipinos are still dying yearly due to the complications of dengue, supposedly a self-limiting viral infection transmitted by a mosquito bite, but in a significant proportion of cases, it can cause life-threatening complications like bleeding and dangerously low blood pressure (shock).
Clinical trial issue
Dr. Dantes came to mind when this issue on the ActRx TriAct clinical trial was brought up recently by acting Health Secretary Janette Garin.
My first impression was: Who cares about possible side effects in the future of a potential cure for a disease with no known cure, when you have a high-risk patient before you whose chance of dying is high? I have always considered myself an evidence-based physician, but in such cases, I would give the drug a try if the patient and his/her relatives would also consent after a detailed explanation of the pros and cons.
Acting Secretary Garin ordered the suspension of an ongoing clinical trial evaluating the effectiveness and safety of an herbal combination of artemether, artesunate and berberine, shown in an initial “pilot” study to offer remarkable benefits in dengue patients.
The second or confirmatory clinical trial or drug research was approved by Health Secretary-on-leave Enrique Ona sometime in September of this year, and was being conducted under the supervision of the Philippine Institute of Traditional and Alternative Health Care (PITAHC) through a multihospital, prospective study in six Department of Health (DOH)-retained hospitals.
‘Double blind’
A prospective study, especially when bias is eliminated by “blinding” the researchers or clinical investigators and providing a control group, is a reliable way to demonstrate the effectiveness and safety of a drug or product.
It’s called “double blind” when neither the investigators nor the enrolled patients know whether they’re receiving the active drug or not. All patients in both active-drug and placebo (dummy pill) groups receive the known beneficial supportive treatment for the disease, so no patient is left untreated and the participating patients are not being exposed to more risk than what he/she already has. The only difference is that one group gets the drug being studied, the other group does not; and the outcomes at the end of the study are compared in both groups. When the last patient has completed treatment, that’s the time when they open the “code” and the trial is “unblinded.”
Contrary to what has been said in some news reports, the protocol or research plan was actually evaluated thoroughly by the Philippine Council for Health Research and Development (PCHRD), which is recognized as the government’s expert arm in doing scientific health-related researches. From what I could gather from copies of communications between the DOH and the PCHRD on this research project, Dr. Ona requested the PCHRD sometime in April 2014 to review the results of a “pilot,” or initial study, which showed remarkable benefits of the product in dengue patients. The pilot study was done in 288 patients confirmed to have dengue at the San Lazaro Hospital.
New treatment modality
After doing a thorough technical review, Dr. Jaime Montoya, PCHRD executive director, confirmed the potential of the compound to be a new treatment modality for dengue, “which is a disease that remains to have no accepted or proven cure.” He noted that there were also no significant unfavorable or negative effects observed among the 288 patients included in the study.
Because of the apparently positive results of the initial clinical trial, an expanded and confirmatory follow-up trial, using a more stringent protocol (research plan) was called for. Dr. Ona again passed on this protocol to the PCHRD for review. The research experts at the PCHRD noted some areas in the proposed research protocolfor improvement, and for the results to be more conclusive, they proposed that the clinical trial should involve a bigger number of cases or patients. These recommendations were then relayed to Secretary Ona, PITAHC director general Dr. Jovencio Ordona and head of technical division Theresa Mendoza on April 22, 2014.
The research proponents followed the suggestions of the PCHRD, and developed an enhanced protocol, which Secretary Ona again requested the PCHRD to review sometime in July of this year.
Reviewing the final version of the research protocol, the PCHRD found it to be “complete in form and content based on the prescribed format.” It was also noted to be “scientifically valid and sound” to be carried out in hospitals. However, Dr. Montoya also stressed that “it is the responsibility of the research proponents to ensure that the appropriate ethical review and approval is obtained from the participating hospitals. The research proponent should comply with all pertinent and relevant procedural requirement, as required by concerned regulatory and monitoring agencies.” This evaluation and recommendation report was communicated to Secretary Ona in a letter by Dr. Montoya on Aug. 7, 2014.
No perfect research
There is no such thing as a perfect research. I have had the privilege to be invited to “peer-review” the research outputs of well-known and seasoned researchers before their papers are accepted for publication in some international journals or presentation in international conventions, and one can always find “methodological infirmities” or flaws in some of their researches. It’s so easy to be an expert evaluator in retrospect or hindsight, when the research project is already ongoing or has already been completed.
You can always find a loophole here or there. But you still appreciate these researchers for carrying out these clinical trials or research undertakings because their grit and determination fuel the engine of scientific advances and medical progress. If we would not allow researches until everything is perfect and no perceived adverse effect is seen, we will never be able to encourage any meaningful research in this country, and we will remain at the bottom of the list of nation-achievers in innovations, scientific research and development.
I appreciate the passion of acting Secretary Garin and I’m sure she means well. I have always admired her from a distance even since her first term in Congress, and I recall requesting Arvin Reyes, our senior editor then of Health & Lifestyle (H&L) magazine, to feature her on the cover, so she could be a role model to Filipino doctors and inspire them to be not only health champions but social advocates as well.
Critical decisions
But in the last six weeks that she’s at the helm of DOH while Secretary Ona is on extended leave, I think she has been doing things overenthusiastically, and some of her critical decisions could have benefited from a more dispassionate way of looking at both sides. It would also seem that some of her decisions, like her reorganization of the DOH and reversal of Secretary Ona’s decisions, were made with the perception or prior knowledge that Dr. Ona would already be asked to resign and she would be appointed as health secretary.
Among seasoned top executives in the private and government sectors, there are such traits as patience, humility, prudence and empathy for others. Aggressiveness, passion and overenthusiasm are tempered with these traits. Once Dr. Garin has fully learned these, I’m sure in the future, she would make a great health secretary and senator, or who knows, possibly president of the country. Meanwhile, just like Sen. Grace Poe, she has to be humble enough to accept that some lessons still have to be learned. (december 13, 2014)
http://business.inquirer.net/183492/doh-dengue-trial-protocol-approved-by-pchrd
Greetings!
I am one of the co-investigators of study..
In behalf of the medical research team, we would like to express our gratitude in your support to our cause!
The reason why we, as medical practitioners and researchers, have not gone out to the press and release our statements is because first of all, we do not want to involve ourselves in politics. Secondly, we have not received any formal complaint against us or the study. All issues being thrown at us are all allegations and speculations.
Last November 30, the DOH has released a statement with regards to the suspension of the DOH Department Order 2014-0161 regarding the implementation of the Clinical Trial on Dengue. We got hold of the said statement and we have answered everything point by point. I will be sharing to you a copy of our response to the DOH statement.
1. Berberine was used in the studies even without specific and definitive scientific bases for the researchers’ claims that in can cure malaria or dengue
SCIENTIFIC BASIS BEHIND DENGUE
In a study done by Jia, F., et al, entitled Identification of palmatine as an inhibitor of West Nile virus published 2010 in Arch Virol, it was found out that palmatine, which is a member of the protoberberine class isoquinoline alkaloid, was able to suppress West Nile Virus without detectable cytotoxicity. The study has shown that the compound is able to “block the activity of NS3 protease which flaviviruses like the West Nile Virus and Dengue Virus encode.”
West Nile Virus is member of the virus family Flaviviridae wherein the dengue virus is also a member. It can also be noted that the article suggests that the compound “might be a potential candidate for treatment of flavivirus infections (including dengue).”
It is the objective of the researchers to test the hypothesis that berberine has an anti-viral effect on dengue virus.
Artemisinin Derivatives, such as artemether and artesunate, also have established effects as an anti-viral drug. In an article that was published by Efferth, et. al., in the Clinical Infectious Diseases in the US last 2008, entitled, The Antiviral Activities of Artemisinin and Artesunate, it expounded on some of the different anti-viral properties of artemether and artesunate. Some of the viruses listed in the article include CMV, Herpes, HBV, HCV, even HIV-1. “The value of this compound is not limited to the treatment of malaria, and a wealth of studies have demonstrating the activity of artemisinin and its derivatives against…various viral diseases.”
With this premise, the researchers would like to study if artemisinin and its derivatives also have anti-viral properties against dengue.
SCIENTIFIC BASIS BEHIND MALARIA
In a research conducted by Sheng, et. al., which was internationally published in 1997 by the East African Medical Journal entitled “Treatment of chloroquine-resistant malaria using pyrimethamine in combination with berberine, tetracycline or cotrimoxazole,” results showed that berberine has a greater clearing effect than the other treatment arms.
Since there is proof that berberine has anti-malarial properties, the researchers now aim to test whether berberine plus artemether, artesunate, and primaquine may be efficacious for the treatment of malaria
2. The use of artemether and artesunate is considered as “artemisinin monotherapy”, which increases the prevalence of resistance to anti-malarial drug.
The ActRx Malaria study does not use an artemisinin monotherapy, rather, it utilizes a combination of artemether, artesunate, primaquine, and berberine. The purpose of the study to be able to develop a new combination of drugs that would be an available alternative treatment that the filipino malaria patients would be able to use. The use of the artemether plus artesunate, primaquine, and berberine might be the combination we are looking for to prevent the development of resistance from the “artemisinin monotherapy.”
3. The combination of berberine, arthemether, and artesunate may have long-term effects that have not yet been studied adequately.
Review of literatures do not show any data that proves that the individual drugs have long-term deleterious effects.
The research team have data to show that berberine is safe for use for all ages. In a study done be Gupte, et. al. last 1971, entitled The of Berberine in Treatment of Giardiasis, a total of 137 subjects with ages ranging from 5months to 14years of age received berberine as a treatment of giardiasis, which is an intestinal parasite causing severe diarrhea.
In another study done by Zhang et. al., in 2006, Assessment of taste development in 62 newborn infants they administered berberine to assess the taste reaction of neonates 90 minutes after birth. This proves that berberine is safe for consumption even for neonates.
4. By not complying with the International Conference on Harmonization Guidelines for Good Clinical Practice, the 2012 malaria study lacks strong scientific merit and study participants were not afforded their due protection.
ALL of the studies being questioned have undergone ethical and technical review by the independent review boards of the participating institutions wherein the studies were conducted, as this is the requirement by the International Conference on Harmonization Guidelines for Good Clinical Practice.
ALL of the subjects were also afforded their due protection since all subjects were covered by a deed of legal undertaking wherein any form of complications that would be directly related to the test drugs would be the responsibility of the sponsor of the study.
ALL of the subjects, based on the International Conference on Harmonization Guidelines for Good Clinical Practice, have been given and have signed the informed consent and assent forms. The informed consent means that all subjects were informed of the study protocol and have willingly consented to become part of the study. Patients who did not sign the informed consent were not included in the study.
5. The 2013 dengue clinical study was noted by the Philippine Council for Health Research and Development (PCHRD) to have the following deficiencies:
Missing baseline characteristics of study participants;
The baseline characteristics were included in the research report handed to the members of the review board.
Lack of scientific justification for the use of artemether and artesunate for dengue treatment;
Answers from number 1
Absence of pre-clinical studies on each of the three drugs (berberine, artemether, and artesunate) as to which drug has anti-dengue properties
Each of the three drugs have already scientific bases that show possible effects in the treatment of dengue from other clinical studies. Answers can be found in number 1.
This item also seems contradictory to the updated memorandum that the PCHRD has released last December 1
6. In addition to all these, to date, ActRx TRIACT has not been registered with the FDA whether as a drug or as a food or a supplement. Thus, it has no legal basis to be present in the Philippines, especially for clinical trials.
ActRx TriAct is NOT registered as a drug or as a food or a supplement basically because it is still undergoing clinical trials to have a basis for the registration to the FDA. The Philippine FDA has approved the use of the drug for clinical research purposes only.
7. This is highly irregular and dangerous because in not following and complying with the basic protocol of scientific experiments using human subjects, the researchers are endangering the lives of the Filipino people who were given ActRx TRIACT without any accountability and transparency.
Upon review of literatures, there were NO evidence that showed that the use of these drugs are irregular and dangerous. Further review show that there are strong evidences that Artemisinin derivatives and berberine are very safe for the consumption of the general population. Examples of these are sited in number 1.
8. If something happens to those who had taken the ActRx TRIACT months or years from now, how and where do they seek legal remedy?
All subjects enrolled in the study are covered by the Deed of Legal Undertaking and Informed Consent and Assent between the subjects, the researchers, and the sponsors.
Also, let it be known that the investigators are members of Good-Standing of the Philippine College of Physicians(PCP) and of the Philippine Society for Microbiology and Infectious Diseases(PSMID). We would like to express our concern on how the societies have released a statement in the newspapers without consulting the concerned people. The joint statement by the PCP and PSMID was released in newspaper advertisements “so that the public may know”, yet up to present, we have not released any letter of communication from our societies. If they were really concerned of how we have conducted our clinical trials, they should have talked to us and not the media.
There was even another statement from Dr. Leachon urging the Senate to probe the people behind the study. If Dr Leachon really believes we have done something illegal, why doesn’t he himself file a case against us? Why urge the senate to probe if they know that something was wrong? And on what grounds are being charged? The Medical Research Team behind the study is ready and willing to go through any investigation and answer all accusations against us.
Again, in behalf of the research team, we would like to express our sincerest gratitude in your support of continuing medical education. Rest assured we would will continue to strive to provide our patients a better regimen for the treatment of dengue.
Sir Dennis, thanks for coming out to clear the doubts hovering the contentious issue on the ethical and legal protocols which were followed during the research test on this anti-dengue drug. i am sure as a member of the research team you will not compromise your expertise to validate a medical break-through beyond your field of study.
“Ona ‘aghast’ Garin stopped anti-dengue drug trials” http://www.abs-cbnnews.com/focus/01/05/15/ona-aghast-garin-stopped-anti-dengue-drug-trials
OMG GMA NewsOnline!!! WHAT KIND OF JOURNALISM IS THIS? mag-research naman muna / magbasa, magisip, so you can give the thinking public an objective appraisal of the issue. or is GMA News in the pocket, along with other kill-the-cocktail proponents, of vested interests? how about a public trial instead of garin and her co-hort physicians, including unthinking journalists, who would kill an anti-dengue drug that hasn’t killed anyone and could more likely save lives and therefore deserves expanded trials???http://www.gmanetwork.com/news/story/400692/news/nation/trial-sought-for-proponents-of-controversial-anti-dengue-drug
Good Morning Mam. I hope you dont mind, can I get your personal email so I can send you docs and info. please send me a reply via the email provided above. Thanks.
At last more people are coming out. It looks like the medical researchers really know what they are doing. Of course, this is what I expect. Before a research proposal will be approved and allocated a budget, it has to be subjected to scrutiny by the funding agency. It turns out that PCP and PSMID is involved in politicking. Thank you Sir Dennis and Save Life.