Service-Based Research in Drug Development
Currently, there are still many Indonesians who have not been able to critically evaluate the viability of information on health products that promise to cure or prevent disease.
Not long ago, it was reported that the government stopped local development of a Covid-19 candidate vaccine at the phase I clinical trial stage. Subsequently, the government decided that this vaccine candidate would be developed in the context of "service-based research".
This policy needs to be assessed very carefully. If service-based research in drug development means that vaccines that have not passed the clinical trials can be used for the public while their safety and effectiveness are to be studied later, this process goes against the logical process of drug development.
Aside from having the potential to endanger people’s lives, practicing this kind of research is also not in alignment with the prevailing ethicsl principles.
Currently, there are still many Indonesians who have not been able to critically evaluate the viability of information on health products that promise to cure or prevent disease. Many people want to use such products as soon as they hear these promises.
This kind of situation often occurs when uncertainty arises because of a lack of an effective treatment for a disease. Today, we can also see how excessive enthusiasm is spreading for health products that promise to cure Covid-19, such as hydroxychloroquine, oseltamivir, convalescent plasma and ivermectin.
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Although no strong scientific evidence exists on the efficacy of these drugs in treating Covid-19, many people feel the need to joing the rush to buy these products. This kind of hastiness can be dangerous, because people often don\'t realize when side effects or even deaths occur from their use. This would certainly be different if the drugs have been developed through rigorous research, wherein the drug’s use is carefully monitored by doctors or experts in their fields.
The current global standard for drug development is “research-based service”. That is, the effectiveness and safety of a new drug must first be proven through systematic research. After the efficacy and other properties are proven, the drug may then be sold commercially and used to serve the public.
Systematic research starts from the drug manufacturers conducting laboratory tests on animals. If the results are good, the drug manufacturer will submit the results of the animal trial to the office of regulatory operations (ORO) in the relevant country – in Indonesia, this is the Food and Drug Monitoring Agency, or BPOM. After all of the trial phases have been passed, the ORO will give the drug manufacturer permission to run human trials (clinical trials) under an established system.
In the phase I clinical trials, the drug is first tested on a small group of healthy volunteers. The aim is to determine the movement, effect, toxicity and the dosage level that can be accepted by a healthy human body. If the results are good, ORO will give permission to "scale up" to the phase
II clinical trials. In this phase, the new drug may be tried on a small number of sick people under very close supervision.
The drug manufacturer again reports the results to ORO. If the results are deemed good, ORO will then grant permission to advance to the phase III clinical trials, in which the drug is tested on a large number of sick people under conditions similar to the drug’s intended use in normal treatment.
Under normal circumstances, this entire process usually takes about 10 years.
If the results are safe and effective, ORO will grant marketing authorization. After all these steps are completed, the new drug can finally be used in health services. Under normal circumstances, this entire process usually takes about 10 years. However, during a pandemic, specifically in the development of drugs and vaccines for Covid-19, this process is accelerated and simplified.
The permission ORO grants under this accelerated process is called emergency use authorization (EUA). However, even if a distribution permit has been granted, drug manufacturing companies are still required to conduct post-marketing surveillance. The main objective is to obtain more complete data on safety during the drug’s actual use.
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At this stage, what you want to know is whether there are rare side effects (especially dangerous ones) from using the drug. This entire series of studies shows how rigorous ORO is in ensuring the effectiveness and safety of a new drug before it can be used for serving the public. So, it is clear that research-based service is a concept that is arranged in a logical order and is based on strong ethical principles in order to maintain human safety.
Reverse concept
Now, the problem facing Indonesia is the application of the concept in reverse, namely "service-based research". This concept gives rise to questions in terms of both ethics and logic. From an ethical point of view, the questions are: "Is it ethical for us to use a health product whose effectiveness and safety are not yet known?”, or “What if the product is sold to the public even though the benefits and safety have not been proven?"
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From a logical point of view, it is certainly illogical if someone says, "use this new drug/vaccine product in public health services, but the efficacy and safety of the drug is not known with any certainty because the research is only just beginning". Therefore, the concept of service-based research can lead to misinterpretation. If the interpretation is as above, this clearly violates the system of research that has been developed so far, and also violates research ethics.
Furthermore, this kind of interpretation will lead to research bias because it may not involve a comparison group, randomization, blinding and other procedures during the clinical trials. When the results of this study provide the basis for a statement that a new drug or vaccine has been proven “safe and effective”, of course that statement does not have a strong scientific basis. Therefore, it is not surprising that this conclusion is biased.
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Then, what should be the correct interpretation of this “service-based research” concept? To answer this question, the most important thing to do is to look at the drug to be studied. Is this drug really a drug that has been in use for a long time (conventional) in public health services, or is it a new drug? It is then necessary to look at the purpose of the study.
Such studies usually arise because of curiosity as to whether this long-used drug is effective and safe as treatment. These two factors are the basis for conducting service-based research.
The following is an example to explain service-based research. Dialysis in public health services is a routine service provided to patients with chronic kidney disease. The cost of dialysis creates a heavy burden for the Healthcare and Social Security Agency (BPJS Kesehatan) because each dialysis session incurs quite a large cost of Rp 800,000 to Rp 1.5 million. Dialysis can be provide as hemodialysis or peritoneal dialysis. The BPJS wants to know which of these two methods is more cost-effective. Here, service-based research can be carried out.
Here is another example. In the ancient health system of 2000 BC, Chinese people frequently used a plant called qinghaosu (Artemisia annua L.) to treat fevers. However, around the 1960s, many countries experienced a problem with malaria parasites presenting resistanc to the conventional drugs used at that time, namely chloroquine and sulfadoxine-pyrimethamine.
This discovery eventually led to the 2015 Nobel Prize for Prof. Tu You-you.
To solve this problem, Chinese scientists conducted research on medicinal plants that had been used for centuries and finally discovered a new antimalarial drug, artemisinin. This discovery eventually led to the 2015 Nobel Prize for Prof. Tu You-you.
These two examples clearly illustrate how service-based research can be applied in a logical and ethical manner.
Herbal medicine
Then, what about the development of herbal medicine? In Indonesia, the development of medicinal herbs and plants is included in the context of herbal medicine, which is studied using the service-based research approach (Health Ministry Decree No. 003/2010). Here, traditional herbal plants are well-known and have been regularly used in daily health services. Examples of the commonly used herbs include curcuma, meniran (Phyllanthus urinaria) and keji beling (Strobilanthes crispa).
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If these herbal plants are to be developed into a medicinal drug with clear scientific efficacy through service-based research, of course, there is no problem. However, this does not mean that all herbal ingredients are safe and that they can automatically be included in service-based research. Examples for this include Derris elliptica, which is used as a tuba (poison) for fish, or the tea parasite, which is said to be effective in treating cancer.
We do not know the exact effectiveness or safety of Derris elliptica or the tea parasite. Even if it really is effective, the Derris elliptica plant is usually classified as a toxin. At this time, we also know that vincristine, atropine, strychnine, arecholine and others are toxic compounds of plant origin. Therefore, ingredients from medicinal herbs that are not regularly used in traditional medicine should not be included automatically in a service-based research scheme.
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From a financial point of view, it should also be noted that if a drug or vaccine is developed outside of internationally accepted mechanisms, the resulting product will be difficult to export because destination countries will usually evaluate several factors, such as the quality of the data, how the product was developed, and if there is a distribution permit for the product in the country of origin.
If developers cannot provide satisfactory data, importers tend to refuse to grant a distribution license. If this happens, the products developed in Indonesia can only be sold domestically. Developers will also find it difficult to get back their investments.
In conclusion, I would like to point out that this service-based research policy can be easily abused by drug and vaccine developers that look for shortcuts. If deviations are tolerated, this will set a bad precedent, and if it turns out that the resulting product has insufficient effectiveness and safety, the people will be the victim. This is what we must avoid!
Rianto Setiabudy
Rianto Setiabudy, Member of the National Health Research and Development Ethics Committee
(This article was translated by Kurniawan Siswoko)
