Medical ethics, public safety and the DOH
Since I wrote my first column on the matter, I have been receiving from several sources, more documents related to the unethical drug tests conducted on the drug ActRx Triact. Triact is a combination of the anti-malarial drugs artemether and artesunate and the herbal berberine. The documents show that studies conducted by the Department of Health under recently resigned Secretary Enrique Ona were flawed and unethical. These were opposed by the Food and Drug Administration from start to finish. The documents showed that at the very least, Ona was gullible and incompetent, or at worst, in league with a bunch of scammers.
The story is a shameful one. Shameful because it makes the country look like a failed state whose agencies can be rented for profit by racketeers. Shameful because the very agency meant to protect people from unethical and harmful experimentation, in fact, perpetrated this sort of grevious harm.
My second column dealt with the dubious nature of the manufacturer of the unproven drug, ActRx and its local distributor, Preferred and Proven Therapies, Inc. It also dealt with the scientifically and ethically indefensible trials conducted by Department of Health personnel at the behest of AxtRx and PPTI. On the same day my column was published, the Philippine College of Physicians (PCP) and the Philippine Society For Microbiology and Infectious Diseases (PSMID) published a joint statement that did a more thorough critic and rejection of these clinical trials.
In this third column, I shall tell the story of how these trials came to be undertaken by the Department of Health. Before I begin, I will have to beg the reader's indulgence. I will be reporting from documents leaked to me along with the request for anonymity. I must say that the leaked documents come from two or three reliable sources. None of the documents should be difficult to access because they should be public documents. But they remain inaccessible.
Thus, I take the time to explain why I am taking the unusual step of writing 3 columns on this matter with the third column being from sources the readers cannot directly verify.
My only motivation is that, as a medical professional, I find it abhorrent that Filipinos, and in this case even young children, were subjected to unethical testing. Furthermore, that the results of this testing were to be used to promote a drug that is potentially dangerous to those who take it and would have, in terms of creating malarial strains that would be resistant to therapy, put the health of many more of our people in danger.
A bad beginning
Our story begins with a letter by Secretary Ona dated March 9, 2012. The letter is addressed to Robert L. Steele, Chairman of the Advisory Board of The ActRx Foundation. It is copied to Assistant Secretary Enrique A. Tayag, FDA Director Suzette H. Lazo and Director Remigio Olmeda of the Research Institute for Tropical Medicine. The letter acknowledged a letter dated February 4, 2012 from ActRx Foundation Chairman and Executive Director Robert. H Barron. It talked also of Ona's recent meeting with Mr. Steele as facilitated by former Senator Heherson Alvarez.
It then stated: “It is with great interest and enthusiasm that I accept and approve in principle your offer to forge a Public-Private partnership with the ActRx Foundation and Preferred and Proven Therapies, Inc.” In this regard the letter also said that, “I have formally endorsed your exclusive distributor Preferred and Proven Therapies, Inc. to the FDA for the purpose of securing the appropriate licenses and permits required under Philippine law.”
The last piece of important information revealed in the letter is that ActRx Triact be subjected to clinical trials for both dengue and malaria.
This fact is important for two reasons. First, Dr. Ona should not have approved the trials on ActRx Triact for malaria from the very start. As the PCP-PSMID joint statement noted: “Unwarranted and widespread use of artemether and artesunate in the community promotes malaria resistance to the drug – a serious public health problem.” Dr. Ona should have known that this combination goes against WHO guidelines for malaria. As for the use of the same combination for dengue, he should also have known that given the nature of malaria and dengue, its use even just for dengue still increased the risk for the development of malarial resistance.
The next step
The next step in our document trail is a memorandum of agreement between the Department of Health, PPTI and ActRx for the conduct of 100 “clinical trials” of the ActRx treatment for both dengue and malaria.
The MOA stated that ActRx Foundation shall donate an initial 500 treatment packs for malaria. One wonders how this initial 500 doses were computed considering that in the Miranda study on dengue referred to in my previous column, the dosages used for the test would have required at least 600 packs for 100 patients.
The proposed memorandum of agreement also stated that another 1,000 packs of the drug would be donated after the worldwide publication of clinical trial results. We must look at this in the light of the statement of the spokesperson of Acting Secretary Janette Garin who ordered the discontinuation of the trials. The statement noted that no other tests on the ActRx drug had been undertaken anywhere in the world. Considering further that ActRx drug patent holder Anthony Fedele Musso was already selling this drug online, I conclude that the DOH had lent itself to provide something ActRx could not obtain elsewhere: legitimacy.
The proposed memorandum of agreement is interesting also because it was signed by Robert Steele for ActRx and Atty. Justice Anthony A. Foz for PPTI. But it was not signed by Ona. What was attached to the document is a routing slip from FDA Director Suzette Lazo dated March 13, 2012, stating that Ona must not sign the agreement. Dr. Lazo argued that the protocols must go through ethical review and noted that there was a need for proof of efficacy of the drugs for dengue.
This makes a memorandum to Ona from Health Assistant Secretary Nicolas B. Lutero on August 31, 2012 puzzling. Lutero, a lawyer, suggested a revision to a draft letter of understanding between DOH attached agencies, San Lazaro Hospital and the Philippine Institute of Traditional and Alternative Health Care, and ActRx. The memorandum stated that “inasmuch as the Department has already agreed to conduct the clinical trial for malaria and dengue treatment,” the letter of understanding should be modified so that ActRx should take sole and complete liability for any adverse effects on trial participants “as indicated on page 10 of the study.”
A non-ethical review
On October 25, 2012, Alma F. Rivera, chairman of the Ospital ng Palawan Research Ethics Committee, wrote Robert Steele that the committee has approved the study entitled, “A Study Demonstrating the Efficacy and Safety of Artemether + Artesunate in combination with Berberine in Malaria Patients Admitted in Palawan, Philippines.” The letter said that Efren M. Dimaano is the principal investigator while Edna A. Miranda and Talitha Lea V. Lacuesta are sub-investigators. I note here that the title of the study seems to pre-suppose a positive finding even before the study has been undertaken.
A letter by Assistant Secretary Entique A.Tayag, Dr. Jose Llacuna, Jr. and copy furnished to Dr. Louie Ocampo, Provincial Health Officer of Palawan, said that a DOH endorsement was no longer necessary to continue with the proposed clinical trials because a Palawan review board had already approved the study.
Note here that there was a substitution for FDA and PCHRD ethical review for the Palawan Hospital review board. As of today we have no proof that these two bodies, which should have had jurisdiction over these trials, ever gave approval. In the case of the FDA I will discuss later how it in fact moved to stop the trials upon discovery that these were ongoing.
The next document in my files is a letter of understanding between ActRx, Preferred and Proven Therapies, and the Department of Health, PITAHC, several government hospitals, and the city governments of Subic and Olongapo. This document is incomplete because it is supposed to have attached to it the protocol for a malaria study. Its significance however is that it is now signed by all the stakeholders, including a certain Dr. Efren M. Dimaano as principal investigator. Also significant is that this notarized document was signed and dated by Ona on November 13, 2012. My copy however bears the notation “Revised February 2013.”
With Department Personnel Order No. 2012-4943, dated November 7, 2012, Ona ordered Drs. Dimaano, Miranda, Lacuesta and Jason T. Suquila to conduct a training conference on the clinical trials. The order stated that expenses shall be paid for by ActRx Foundation and Preferred and Proven Therapies.
A November 15, 2012 letter by Dr. Dimaano to Dr. Rivera requested that they be allowed to do something unethical: revise their experimental protocol so that they may include children, 5 to 9 years old, in the study. As the joint PCP-PSMID statement noted, “it was unethical for the investigators to test drugs in children without first testing them in adults.”
To the rescue
A letter to Ona from Palawan Provincial Health Officer Dr. Louie Ocampo dated December 4, 2012 reported the implementation of the study despite certain conditions not being met: namely that an endorsement from the National Program Manager of the Malaria Control Program was needed; that the research protocol pass ethical review; and that Dr. Ona endorse the study. It also noted that the advice of Atty. Lutero that ActRx be liable for adverse outcomes was not indicated in the study protocol. Dr. Ocampo requested the suspension of the study until these conditions were met.
In March 2013, Dr. Ocampo issued a more definitive order to municipal health units in Palawan strongly suggesting the cessation of the trials.
The trials, however, did continue until FDA Director Kenneth Hartigan Go issued an order in June 2013 to suspend not only the clinical trials but also the principal researcher and the ethics review board of Palawan. This is based on data gathered by an investigation team formed by the FDA because of reports about the trials, including those of Dr. Ocampo. The actions of those suspended violated the standards of good clinical practice for clinical trials issued by the FDA which are in compliance also with WHO standards. I urge the reader to compare the processes discussed in those guidelines to the processes I have narrated here to see how badly these were violated.
ActRx and PPTI then filed a motion for reconsideration and countercharges against Dr. Hartigan Go.
A bad ending
The document that caused a great deal of sadness is Department Order no. 2013-0299 dated October 1, 2013. Here Ona transferred supervision of the study from the FDA to the PITAHC, essentially undermining Dr. Hartigan Go's order to stop the trial and suspend the researchers.
My document trail ends here. For some reason the public never heard of the malaria trials. It would seem from the dates of the documents I found about the dengue trials, those were started after the malaria trials came to an end. I have no idea why the DOH put such trust in ActRx and PPTI that it persevered not just with one set of unethical trials but with a second set.
I write this report not because I have any political agenda. I write it because regulatory mechanisms that ensure that medical ethics, the core values of my profession and one of the bedrocks of public protection, cannot fail. And if the documents I possess paint the correct picture, then there were heroes who stood their ground despite a prevailing laxity of moral standards cultivated by those in power. But there were also those who were responsible for the ethical violations that cannot be simply forgotten.
If we are to build social institutions that people can trust, I hope that our criminal justice system is able to verify and clarify the picture painted by my sources, who, because their conscience could not let them be quiet, gave me a glimpse of the unethical swamp that our Department of Health had become.
I hope that culprits be brought to justice and that the gratitude of our nation be expressed to those who tried to protect us. – Rappler.com