By: Ma.Sophia Editha Cruz-Abrenica and Glaiza Narvacan  

          In a bid to strike a balance between saving lives and reviving the economy, a number of countries have begun to ease lockdown measures[1].  In the Philippines, for instance, many parts of the country have already been moved to a more relaxed form of community quarantine, allowing selected industries to resume operations and permitting limited movement of people[2]. But while the relaxation of restrictions has been much anticipated, many approach this new phase with worry[3] given the fact that we will be navigating it while vaccines and specific therapeutic drugs targeting the deadly SARS-CoV-2 are still not available[4]. Nevertheless, with pharmaceutical and biotech companies, start-ups and research establishments rallying together to battle the virus[5], hope is on the horizon, and it is only a matter of time before we see tangible results. On the vaccine development front however, wherein scientists have essentially started from scratch, the results may take longer and as such, we may see Covid-19 medications or treatments sooner than we will a vaccine[6]. But even developing a medication will not be as fast as we need. Drawing from the lessons of the thalidomide disaster[7], even considering that the urgency of the pandemic called for work on finding a solution to progress in unprecedented speed[8], the work cannot be overly rushed. What follows is a look at the current processes and regulatory framework in the Philippine setting, that help ensure the development of Covid-19 treatments that are not only effective, but also safe.

          Currently, there are three (3) broad categories being investigated for the treatment of Covid-19: (1) antiviral drugs that arrest SARS-CoV-2’s ability to thrive inside the body; (2) drugs that can moderate the immune system to prevent collateral damage to the body when fighting the disease; and (3) antibodies, either from a survivor’s blood or synthesized in the laboratory, that can attack the virus.[9] Regardless of the category, treatments under investigation will have to undergo stringent clinical trials before they reach the pharmacy shelves. So, what then is a clinical trial?

A clinical trial is a research study involving human volunteers to determine the safety and efficacy of a particular treatment or vaccine (“investigational product”)[10]. In drug development, it is the next step after a new compound shows promising results in the laboratory and animal study stages.[11] Clinical trials are conducted by phases (I-IV) wherein each phase has a different purpose and design, and will answer particular research questions. In Phase I trials, only a small group of people (around 20-100) will be involved. These trials will evaluate the investigational product’s safety such as safe dosage range and side effects. In Phase II, a larger group of people (generally 100-300) will be recruited to further evaluate the investigational product’s safety and to see if it is effective and safe. In Phase III trials, an even larger group of people will be asked to participate (usually 1,000-3,000) to confirm the investigational product’s effectiveness, monitor adverse effects, compare the same to other commonly used medications and to collect information that will allow the safe use of the product under investigation.[12]

Typically, a drug may be applied for regulatory approval and marketing after a successful Phase III trial[13]. However, Phase IV trials (post marketing studies) are still usually conducted so that additional information including the risks, benefits and optimal use of the drug are delineated.[14] It is to be emphasized that the clinical trial “should only be initiated and continued only if the anticipated benefits justify the risks”. [15] Given the arduous journey to be traversed before a drug can reach the marketplace from initial discovery, it is not difficult to imagine that drug development sometimes takes a decade or more[16]. Considering the urgency of the pandemic situation however, this timeline will have to be dramatically compressed. Nevertheless, it must be done without compromising the quality and integrity of the drug development and safety assurance processes. One time-saving option, which has in fact been explored, is to focus on medications that already exist in the market to be “repurposed” as Covid-19 treatments[17].   

Clinical trials are conducted in different parts of the world and are governed by both local regulations and international guidelines. These measures are in place to provide assurance to the public, among others, that the rights, safety and well-being of human volunteers are protected above all, that the clinical trial design is scientifically sound and that the clinical trial data generated from these research studies are handled such that accurate reporting and verification are allowed[18]. For instance, the available guidelines provide strict requirements for the informed consent process to ensure that clinical trial participants are not being coerced to join clinical trials and that they are informed of their rights as trial participants.[19] The guidelines also provide safeguards such as monitoring requirements to ensure that the trial is being run according to protocol and applicable regulations, and that trial data are not fabricated and are verifiable.[20] In the Philippines, the conduct of clinical trials is primarily regulated by the Food and Drug Administration (FDA), under the Department of Health (DOH)[21]. All clinical trials require approval from the FDA to ensure that they conform to the prescribed ethical and technical standards of clinical research[22]. In addition, the policy-making body for research ethics in the Philippines or the Philippine Health Research Ethics Board (PHREB)[23] was given a mandate under Rep Act. No. 10532[24], to ensure that the universal principles for the protection of human participants in research are adhered to. In line with this mandate, clinical trials research protocols of drugs for FDA registration must be cleared by an ethics review committee (ERC) that has a Level 3 accreditation from PHREB[25]. The PHREB (together with the Philippine National Health Research System[26]) also issued the National Ethical Guidelines for Health Research (NEG) which includes special guidelines on clinical trials[27]. Furthermore, through an FDA Circular, the Philippines adopted the International Conference on Harmonization (ICH) Safety and Efficacy Guidelines.[28]  These ICH guidelines include specific guidelines for Good Clinical Practice (ICH-GCP) which aims to provide a unified standard for the conduct of clinical trials in the European Union, Japan and the United States (ICH-GCP regions) so that there can be mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.[29]  The adoption of ICH-GCP by other countries, such as the Philippines, provides a way for the ICH-GCP regions to accept clinical trial data generated from trials conducted in these other countries.

Usually, clinical trials are set up and monitored by pharmaceutical companies (more commonly referred in clinical research as “sponsors”) or by contract research organizations (CROs). If a trial is to be conducted by such entities in the Philippines, they must obtain from the FDA a License to Operate (LTO) for such purpose.[30] Sponsors and CROs contract medical teams, led by a “principal investigator” who is a medical doctor with proven experience and expertise in the therapeutic area involved (e.g. for Covid-19 clinical trials, infectious diseases specialists will be tapped to spearhead clinical trial teams), to recruit volunteers and execute the clinical trial protocol. When the clinical trial has commenced, regular monitoring visits and audits are performed by the sponsors or the CROs to ensure that the clinical trial is conducted according to the trial protocol, local regulations and international guidelines (ICH-GCP). Inspections by regulatory bodies are also periodically scheduled to check the same.[31] Clinical trials may be suspended or prematurely terminated for reasons such as the poor safety performance of the investigational product[32] or serious protocol, ethical or ICH-GCP violations. As such, strict adherence to protocol and regulations must always be practiced, except where a deviation is warranted to eliminate immediate hazards to the trial participant[33].

All in all, it can be said that clinical trials cannot be conducted without stringent regulations. Though these measures may sometimes slow down drug development, they are necessary in order to ensure that we are using drugs that were thoroughly evaluated in ethical research studies and backed by verifiable efficacy and safety data.

          At present, the Philippines has green-lighted the country’s participation in “Solidarity Trials”, a global megatrial launched by the World Health Organization (WHO) which will test the safety and effectiveness of four (4) possible COVID-19 treatments, compared to standard of care. The four drug candidates are antiviral Remdesivir, antimalarial drug Chloroquine or Hydroxychloroquine, antiretroviral drugs Lopinavir with Ritonavir, and Lopinavir with Ritonavir plus Interferon beta-1a.[34] Knowing that regulatory measures for clinical trials have been in place in the country for years, and that the Philippines has established clinical trial experience[35], we can look forward to our country’s significant contribution in the race to find a Covid-19 cure. In the meantime, we wait until a cure is found, in due course.

~o0o~  

This article is intended for informational purposes only and should not be considered as legal advice.