Which Comes First: A Disease or A Cure?

Published on 14th April 2020

What persuaded me to write this piece is the televised press conference given by the officials of the Government of the Federal Democratic Republic of Ethiopia. At the press conference, the officials announced to the public that they have been researching a cure for COVID-19 and now that they have invented a new brand cure. 

I have no intention to belittle anyone or undermine the benefits that natural herbs/traditional medicines offer to society around the globe. First, I am hundred percent sure that there are many Ethiopian scientists and scholars with ample and full-fledged experiences, qualifications, capacities and knowledge to undertake research and invent a drug that can cure a disease so long as their resources and work environments allow them to do so. 

Secondly, there shouldn’t be any doubt when it comes to the roles that natural herbs/traditional medicines play when used as complementary and alternative therapies. Since prehistoric times, humans have used natural products to alleviate and treat diseases and it is evident that many drugs have been derived as a result of inspiration from natural traditional medicine.[1] Notably, not only in Ethiopia but also around the world, there exist diverse herbs and natural products that have drug-like properties and or serve as a stepping-stone to and as a very important resource for the development of modern medicines. 

In Ethiopia, if not the majority, many heavily and widely depend on herbs and traditional medicines to alleviate and treat their ailments, pains and sufferings. Undeniably, there are many herbs with therapeutic values that societies through their long-time experience proved them to be of therapeutic value. Of note, many depend on natural herbs/traditional medicines not as an option but as a matter of necessity because they lack access to modern medicine while many others are using them either as a supplement to or as a last resort after trying and losing hopes on modern medicines; and many others are simply hard-core loyals to herbs/traditional medicines who, no matter what, always want to first and foremost try herbs/traditional medicine before they consider modern medicine as an option. 

There exists a norm, process, and requirements to be met prior to declaring or giving a press release about a product which is claimed to have an indication to prevent or alleviate or cure a very serious disease such as COVID-19.  As everyone is aware, COVID-19 is a new disease, hence is named as a novel/new coronavirus (nCOV-SARS-2).  As of today, there exists no proven vaccine to prevent or a drug to treat this viral disease.

Researchers around the world are working hard, day and night, to invent a vaccine or a drug. The world is desperately looking for a preventive or curative therapy. Until then, the possible interventions in use are implementing and applying strict preventive measures to halt the spread of the virus and helping victims of this virus using a standard of care and or an investigational therapy or a combination of these. 

Normally, a disease pre-exists a cure and then a research to develop a cure/drug follows. Drug discovery starts with due consideration and characterization of a distinguishing feature of a disease. Not only this but also the process demands a pool of knowledgeable and skilled professionals; tremendous amount of resources and years of extensive work; and systematically designed protocols and stages of development including the exploratory stage, pre-clinical, clinical development, regulatory review and approval, and a manufacturing process supported with a continuous internal and external quality controls. 

To just get one hit molecule of therapeutic value, a drug manufacturer performs continuous laboratory analyses on numerous chemical substances and then, carry out a preclinical testing which takes on average an estimated time of six (6) to seven (7) years of synthesis, purification and animal testing. Then, it is only when the outcome of the preclinical testing is promising and shows tolerable toxicities on animal subjects that pharmas move to the next stage, filing an Investigational New Drug Application (IND)/Pre-licensure vaccine clinical trials/A Biologics License Application (BLA) to regulatory agencies. After reviewing and validating the data generated from the preclinical testing, a regulatory agency, for example, the Food and Drug Administration (FDA) in the U.S.  approves the request to allow the applicant to begin a clinical development phase which consists of Phase I, Phase II and Phase III. 

Phase I: The results generated from laboratory tests and animal studies do not always predict when it comes to the drug dose, side effects and toxicities in humans. This is the reason why it becomes necessary to conduct a phase I clinical trial on healthy volunteers where a drug is administered to human volunteers for the first time and the typical number of volunteers range from twenty (20) to a hundred (100). The focus of phase I clinical trial is to determine the basic drug properties and find an appropriate dose of the new drug that can be given to humans safely and without serious side effects i.e. the main concern of phase 1 is safety and thus, investigators are required to closely monitor and observe any serious adverse effects that may appear on study subjects. A phase I clinical trial typically takes about one to two years and it is only when the outcome of a phase I trial shows a greenlight or results in favorable conditions i.e. the drug has acceptable level of side effects or produces no toxic effects on the healthy volunteers that the drug is moved to the next phase, phase II. 

Phase II: In this phase, the drug is administered to volunteers of the target population/patients who have similar disease characteristics to those who will ultimately use the drug. To simply state, the study subjects are patient volunteers with a disease condition that the drug under investigation is intended to treat.  A phase II clinical trial involves a few and up to hundreds of patients depending on whether the disease is rare/orphan or is of abundant incidence and prevalence. This phase focuses on investigating the efficacy of the drug under investigation. The study design is mostly a randomized and blinded type: a group of patient volunteers receive the investigational drug/intervention while another group serves as a control group who receives a placebo or a standard treatment, if available. Relevant to mention is that neither the study subjects nor the researchers know as to who is receiving what. The expectation is that the drug under investigation should show superiority compared to the comparator, a placebo or a standard treatment. Statistically speaking, the data should be strong enough to reject the null hypothesis, which generally states that the effect of an intervention is no different from the control.[2] Phase II clinical trials, in most instances, take up to two (2) years on average. Then, if the result of phase II study supports the intended outcome, then the process pursues to the next phase, which is a phase III clinical trial. 

Phase III: This phase is the costliest, most extensive, and the longest part in the process of drug development. Phase III clinical trial takes several years and may enroll 1,000 to 5,000 or more volunteers across numerous trial sites around the world.[3] Similar to phase II, candidates of phase III should have a condition that the drug under investigation is intended to treat and the intention is to compare the new drug against a current standard treatment. The phase III study design is usually a double-blind and generates statistically significant data regarding the safety, efficacy and the overall benefit-risk relationship.[4] If this is so, a new drug application (NDA) is submitted to the drug regulatory agencies, for example, FDA in the U.S., for approval. The regulatory agency then reviews the results from clinical trials; and decides whether to approve the treatment for use in patients with the type of illness for which the drug was tested or to request for further data. If approved, the drug will be made available in the market.

In a nutshell, new drug discovery, pre-clinical and clinical trials can take, on average, a total of at least 12 to 15 years to finish the journey to the marketplace. However, there is a caveat to this and the caveat is that there are some exceptional situations where drugs can enter the market through what is known as an accelerated approval process which is applicable to drugs intended to treat serious and unmet medical conditions and needs or if a drug obtains orphan designation because of its narrow indication to treat rare, otherwise named as orphan disease. In these situations, the approval is fast and most of the time e, the drug is made available for use without adequate knowledge or established information as far as safety and efficacy of the drug is concerned. 

In addition, a new drug or an existing drug may also be allowed to be used off label in emergency and pandemic situations. The COVID-19 scenario is a very good example. Drugs that include hydroxychloroquine, chloroquine, azithromycin etc. are used in patients who are either enrolled in clinical trials or for compassionate use. These drugs have very well-established indications for other disease conditions, but data is yet to be furnished to justify their use to treat COVID-19. For now, these drugs are in use under close monitoring and when both the patient and physician reach a decision to prescribe by weighing risks and benefits.  

The regulation to develop, market and use of natural products differs from a country to another, ranging from no regulation to imposing some requirements and standards. However, the decision to use or not to use is the discretion of a consumer. A government can support and sponsor a systematically designed research, if intended to benefit the public. However, no regulatory body or a government entity should be persuaded to officially declare or promote the use of a herb or traditional medicine until there is a well-founded and established information. In many parts of the world, herbs/traditional medicines are in use without being subject to rigorous testing processes to prove their safety and efficacy to treat a specific disease condition.  

I am not sure if officials of the Government of the Federal Democratic Republic of Ethiopia, who gave the press conference were talking about COVID-19 cure that belongs to a natural herb to be used as traditional medicine or a drug intended for use in modern medicine. Whatever the case may be, it doesn’t sound right to invent and declare a cure for a new disease, in no time and without even learning and understanding the nature of the disease. As stated above, COVID-19 is a new form of a coronavirus for which scientists haven’t yet fully understood what its distinguishing characters are and how it transmits. In short, there are many more unknowns than knowns about this virus.  The known fact is that as of today there is no proven drug therapy to treat or a vaccine to prevent it. 

The U.S allows manufacturers to formulate natural products in the form complementary and alternative medicine (CAM) therapy which includes but not limited to a variety of dietary and herbal supplements. And it is well documented that CAM therapies are helpful. However, they may also produce harmful effects to humans or interact with or negatively affect how other medicines work in the body when used concurrently.  The U.S. FDA considers CAM to be safe until proven unsafe. This means that unlike drugs manufacturers are not required to test their product/ingredients or supplements in clinical trials prior to making them available in the market. FDA is mandated to stop the manufacture of a dietary or herbal supplement only when found unsafe or cause harm on consumers.  

The only requirement is that the package label of dietary or herbal supplements should clearly say[5]“Not Intended to Treat, Diagnose, Prevent, or Cure Diseases” and may also contain structure/function claims such as: “helps maintain normal healthy structure or improves function of the body, for example, calcium builds strong bones.” However, the label should by no means make any such claims as “treats pain or cures a disease” In addition, the package labels of herbal/dietary supplements should include: the name of the herbal/dietary supplement; name and address of the manufacturer or distributor; list of active and inactive ingredients. 

One thing is clear. The FDA is not involved in any way to promote the use of CAM as there is no pre-clinical and clinical data to support safety and efficacy of such products. 

By G. Amare (Abridged).

Courtesy: Aiga Forum

References

[1] Yuan H. Ma Q,  Ye L, and Piao G. The Traditional Medicine and Modern Medicine from Natural Products. Molecules. 2016 May; 21(5):

559. Published online 2016 Apr 29. doi: 10.3390/molecules21050559. Available at  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6273146/

[2] Singh Ak; Kelly K; Agarwa R. Interpreting Results of Clinical Trials: A Conceptual Framework  Clin J Am Soc Nephrol. 2008 Sep; 3(5): 1246–1252. doi: 10.2215/CJN.03580807. 

[3] PhRMA. Biopharmaceutical Research & Development: The Process Behind New Medicines http://phrmadocs.phrma.org/sites/default/files/pdf/rd_brochure_022307.pdf. 

[4] PhRMA. Biopharmaceutical Research & Development: The Process Behind New Medicines http://phrmadocs.phrma.org/sites/default/files/pdf/rd_brochure_022307.pdf

[5] FDA. Structure/Function Claims and Related Dietary Supplement Claims. https://www.fda.gov/food/food-labeling-nutrition/label-claimsconventional-foods-and-dietary-supplements.


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