Clinical trials are crucial to advancing medical science

Clinical trials are crucial to advancing medical science

How do you know that the drug you are ingesting, being injected with or applying to your body is safe?

After all, we call both aspirin and cocaine drugs. But obviously, one is medicinal in nature (and legal), while the other is not.

A further difference would be that medicinal drugs - especially those discovered in the past couple of centuries - would have most likely undergone clinical trials to establish their safety and efficacy.

According to the World Health Organization, a clinical trial is defined as "any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes".

As Universiti Malaya (UM) Faculty of Medicine senior lecturer Dr Muhammad Muhsin Ahmad Zahari explains: "Usually, clinical trials are a reference to pharmacological trials.

"But medical research is very wide; clinical trials can be about investigating prevention, diagnostics or treatment for patients."

This can include methods like surgical or radiological procedures, blood tests, and behavioural modification, among others.

As the cost of discovering and testing these new substances or procedures can run up to billions of (US) dollars, clinical trials are usually financed by pharmaceutical companies.

Other bodies such as government agencies, academic institutions, non-governmental organisations, and even, private individuals, also do provide grants for clinical trial research, especially in developed nations.

However, the limited number of such grants make them highly competitive to obtain, and are likely to be insufficient to cover the entire cost of the study.

Clinical trial phases

The clinical trial aspect of medical research is actually the third stage out of four for drug development. (See Drug development)

Explains Dr Muhsin: "When we talk about clinical trials, it has to be backed by (scientific) literature to suggest that this is the best way (to treat the disease), or show that it can do more good, or less harm, than the current method."

Interventional cardiologist Dr Rajesh P. Shah says: "It's usually a pharmaceutical company with a particular molecule that they have tested out at the pre-clinical stage."

Pharmaceutical companies usually have a "library" of unique molecules that have different properties, which may lend themselves to treating or diagnosing various diseases.

Based on the initial research results, scientists will then further explore the safety, efficacy and bioavailability (the proportion of the molecule that actually reaches the targeted cells in the body) of the molecule via laboratory and animal studies.

Only when the drug has been established as safe and effective in animals does the research move onto human subjects, ie the clinical trial stage.

"Clinical trials can be divided into four phases: I, II, III and IV," explains Dr Muhsin.

"In phase I, a few healthy people will be carefully selected to receive the product, to determine how safe it is to be used in humans. So, it is a very meticulous process.

"Sometimes, for phase I patients, they need to stay in the hospital for up to five days, and we monitor all their vital functions and do regular blood tests on them."

Once the safety of the product, including the safe dosage range and side effects, has been established, then the research can move on to phase II of the clinical trials.

According to Dr Muhsin, this second phase delves deeper into the effectiveness and mechanics of how the product actually works and reacts in human beings.

The number of participants involved in this phase are increased, and consist of patients with the condition the new product is meant to affect.

Phase III is the stage where the numbers are increased to thousands of patients, and the study is frequently expanded to multiple medical centres across several countries.

In this phase, the new product is compared to either the current standard treatments or tests, or a placebo.

The results are then analysed statistically, and have to show a statistically significant difference in outcome in order to prove the new product's superiority over what it was compared against.

IV is when the product has already been rolled out and is available on the market. This phase is also known as the post-marketing phase, says Dr Muhsin.

Among the areas monitored in this phase are any common side effects of the product, as well as its interaction with other drugs or products for patients on multiple medications.


Regulations and ethics

Because of the potential danger in introducing a new chemical substance or mechanical device into humans, clinical trials must undergo stringent regulatory and ethical approval procedures.

Pharmaceutical company MSD's Southeast Asia Global Clinical Trial Operations director and lead Dr Nazrin Azli explains that there are two big regulatory agencies in the world: the US Food and Drug Administration (FDA) and the European Medicines Agency.

"Before we start any study, we usually consult them first, because every regulatory authority in the world will follow them," he says.

In Malaysia, all clinical trials involving humans that are conducted at Health Ministry hospitals or clinics, have to have their applications approved by the ministry's Medical Research and Ethics Committee (MREC). These applications have to be submitted via the online National Medical Research Register (NMRR).

Clinical trials conducted at places like university hospitals and private hospitals also have to be reviewed and approved by each institution's or hospital's ethics committee.

So, for example, any clinical trials Dr Muhsin wishes to run, have to first be reviewed by the UM Medical Centre Medical Ethics Committee.

These ethics committees are responsible for ensuring that the clinical trials are run in accordance to the Malaysian Guidelines for Good Clinical Practice, and usually comprise of both physicians and laymen.

Researchers are also ethically governed by the Declaration of Helsinki, which is "a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data" developed by the World Medical Association, and the Nuremberg Code, a set of medical research principles that grew out of the World War II Nazi experimentation on Jews and other minorities, among others.

There are, however, no specific legal provisions governing the conduct of clinical trials in Malaysia.

While the National Pharmaceu-tical Control Bureau (NPCB) is the sole regulatory body overseeing clinical trials in Malaysia, they draw their authority from the laws that regulate the sale and control of drugs alone.

Doctors and patients

Most of the clinical trials conducted in Malaysia are phase III trials, which are nowadays run as international multi-centre trials.

Physicians with an established reputation and track record are usually approached by the pharmaceutical company organising the trial to help run it in their respective medical institutions.

Says Dr Muhsin, who has been involved in several psychiatry-related clinical trials at UM Medical Centre: "They will appoint a principal investigator (PI), who leads the research at that particular place.

"We also have co-investigators, research assistants (RA), and clinical research associates (CRA), who help run the trial."

However, as Dr Shah, who practices at a private hospital in Penang, shares, the scenario in the private sector can be quite different.

"I am the only doctor seeing the patients. I do everything, including filling out all the paperwork," he says.

While public hospitals have a large pool of patients to select from for a clinical trial, the choices in private practice are definitely less.

In addition, Dr Shah shares: "People say, 'I'm coming to a private hospital; I'm paying so much money, and you want me to be part of a trial?'

"I've had so many rejections because of this."

But he always explains to his patients that the drug has passed the "guinea pig" stage by this phase of the study, and that this is an opportunity to contribute to the body of knowledge that can benefit patients like themselves worldwide.

"As I see patients daily, I will check them against the inclusion criteria of the trial.

"After I select the patient, I will tell them about the trial, try to convince them to participate in it, and give them some literature on it.

"After one week, they come back with lots of questions, which I will answer, and tell them everything they want to know. There's no hiding of anything.

"It is very important that they go through the whole informed consent process. I tell them that they can opt out at any time, but that I hope that they won't," he explains. (See Questions to ask)

Following the patient's agreement, there is usually a short period of about two weeks, where the patients are given the new drug, and monitored closely to see if they can tolerate it.

If all goes well, then the patients are subsequently randomly selected (by a software programme) to receive either the placebo or current standard treatment, or the new drug.

As most studies are double-blind, this means that not even the doctor knows which patient is receiving which treatment, in order to eliminate any bias in the trial.

Dr Muhsin says that he usually informs suitable patients that there is an optional treatment available under study, which, while they are not obliged to take it, will benefit the rest of mankind, if they do.

He adds that clinical trials also offer an option for treatment for patients who have exhausted all conventional therapies.

At the end of the day, Dr Shah shares that he always shows his patients the published results of the clinical trial they participated in, and reminds them of their contribution - no matter how small - to it.

"They are usually very happy to feel that they are a part of medical advancement, and some of them even ask me if there are any more trials to participate in," he says.

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