Yay!!! Three more days and we're free!!! I mean, boo...three more days and we have presentation! Apparently we were told that most of the mentors who taught us are going to be the audience, plus our lecturers are also coming (maybe to also see whether they chose the right people for IPEP?), what else is worse than that?
Anyway, morning was intense, which we covered Global Clinical Trials Organization (GCTO). Clinical trials are projects at such a huge scale that there is a separate subsidiary in the company just to cater to this need. Normally a NCE is patented for about 20 years. With pre-clinical trials, clinical trials and registration amounting up to 15 years, many a time companies only get to sell products for a short 5 years before the patent expires and every other company can grab away your market shares by copying your innovator products. So now there is a challenge for future clinical researchers to shorten the clinical trials years and optimize the patent period.
As we have learned in medicinal chemistry, there are millions of compounds in the corporate library, and when a therapeutic target is identified, validated (showing that the target is linked to the disease), then over 10000 compounds are derived which are similar to the target. After some modifications and screening, only about 250 compounds reach the pre-clinical stage. These compounds are tested in-vitro (in beakers or test tubes), in-vivo (animal studies) on their pharmacokinetics, i.e. ADME.
After that, only about 5 compounds are deemed fit for in-vivo use, which then proceeds to Phase 1 of the clinical trials. Phase 1 involves a few healthy patients who volunteer themselves. This phase is very important as it is conducted in high-tech facilities meant to keep subjects for overnight monitoring. So it's like those movies whereby the subject is connected to a machine for real-time monitoring of the subjects over a few days. Phase 1 is normally conducted in modern countries such as U.S., UK and even Singapore, but Malaysia has yet to establish on that aspect. Even before Phase 1, sometimes there may be Phase 0 (microdosing), which involves even smaller number of patients on really small doses of the drug. This phase is normally for critical drug compounds to ensure that they are fit for human use.
If Phase 1 is proven successful, Phase 2 then proceeds, this time with a population of patients. Phase 3 is an even bigger population of patients from many different medical centres. In Malaysia, these clinical trials are conducted in accredited Ministry of Health trial sites such as USM hospital, UM hospital etc. This is to reduce bias from any pharma companies that are sponsoring the trials. In phase 3, the labeling of the drug compound can be done. Is it only suitable as a stand-alone drug in the treatment (monotherapy), is it suitable for combination with other drugs? Is it better to put it as 1st line of treatment, or second line?
I think we have mentioned before, that in Phase 3 and other pre-launch clinical trials, the data obtained can only show statistical significance, which is a good estimate of the outcomes that the drug will give. However, it can never be the same as clinical significance which only can be obtained from post-marketing clinical trials, whereby the patients are not subjected to standardized conditions of the trials. Much more rare side-effects can be picked up from post-launch studies as variability between subjects are not minimized as this stage. For example, patients may be taking grapefruit juice which triggers a rare side effect when taken with the drug. In pre-launch studies, patients will need to adhere to a protocol on their diet as well as many other things.
Sometimes, the economical aspect of the trials also significantly influences the development of a new drug compound. Say if a new drug has a totally new therapeutic profile that was never preceded by any other drugs, or is much safer and efficacious than competitior drug compounds, but if it's too expensive or too difficult to manufacture in large quantities, companies would most often opt for the next best choice.
We also learned a famous saying by a famous chemist Paracelsus, who said that "All things are poisons, and nothing is not poisons. Only the dose permits something to be poisonous or not poisonous". Even apples, rice, water....anything can be poisonous at a certain dose. True?
So if all the research lab are in America, why do we need a clinical trial unit here? Again, there is a "bidding" process, much like an open tender. Whenever there is a proposed clinical trial from HQ, the branch countries will give their "quotations" on things like whether they have the population of patient, whether there are qualified investigators (doctors who have been trained to be clinical trials investigators) fit for the trial, whether there are adequate resources to import the new drug etc.
Some countries like China, Japan, Taiwan and South Korea have certain requirements for registration of new drugs. In the Dossier files, the clinical trials need to include a certain number of local patients in the sample population of the trial. Like for Japan, a totally new trial comprising of Japanese patient population needs to be conducted to show that the drug also works for Japanese, then only it can be submitted for registration. Therefore, when planning a clinical trial, this aspect is very crucial as if you include these countries into your regional study, it can take quite a while to get ready these sites for the trial; whereas if you exclude these countries, your new drug may not be able to penetrate those key markets where healthcare industry thrives.
The clinical trial department in pharma companies also help to ready the trial sites. They will have to go around looking for appropriate clinics and hospitals and to ensure that the investigators are clear about the protocols of the trials (which can be 200 pages long). They also need to ensure that the environment is suitable for the trial, such as room temperature, which may affect drug stability and hence the validity of the trial data. They also need to ensure that the subjects are well-informed and consented before beginning the trial. If the patient is illiterate, a third-party witness needs to verify that the doctor has explained thoroughly about the protocols. Pharma company staffs and trial sponsors cannot deal directly with the subjects, therefore they need to work closely with these investigators.
The Clinical Research department associates (CRA) also ensures that everything has an audit trail. This means that every single discussion, shipment, data collection etc. needs to be documented as regulatory agencies may do a random "spot-check" audit on clinical trials that are ongoing and even those that has already been finished. So sometimes we may get news that a certain medicinal product is not as efficacious as previously proven if the clinical trials are found to be flawed and unreliable after retrospective audits are done.
CRAs also carry out source data verification (SDV) at the trial sites. This is the checking of medical data of patients and making sure that it tallies with the recorded data from nurses, doctors and prescribers. CRAs also ensures that blood extracted from subjects are kept properly and sent to the central lab in other countries which handles blood testing for that particular trial. Everything must be done according to the protocol, and if any events deviate from the protocol, it must be reported and rectified, otherwise the trial will be deemed statistically weak.
Sometimes for these double-blinded trials, things can go wrong. For instance, the patient's glucose level may be uncontrolled and the doctor needs to know is the patient taking the active drug or the placebo in order to choose the right treatment plan. In this case, "unblinding" is possible, but this will also affect the reliability of the study. So in general it is recommended that we do not do "unblinding" unless circumstances requires us to do so.
Some things may go wrong for a clinical trial outcome. If protocols were not strictly adhered to, the trial may give a false positive or false negative result. False positive meaning the trial showed that the new drug works better but is actually non-superior. When it is launched into the market, it seems to not enhance treatments of the patients. If it's a false negative, meaning the trial showed that the new drug has no potential but it actually does works, it may cause a loss of a new drug that could save the world. How tragic is that!
Another two terms we learned today. To ensure quality of the trial, there is Quality Control (QC) and Quality Assurance (QA). Both may seem very similar but are actually very distinct from one another. QC is the monitoring process and site visits, whereby you go to the actual place and make sure everything is as documented. On the other hand, QA is the auditing (spot check) of documents, whereby you ASSURE that quality control is being carried out.
Being in the Clinical Research department of any pharma company involves a lot of documentation. The pre-clinical studies in laboratories are mostly overseas, so if you're really interested in the experimental part, you might want to consider working overseas. Over here, although you don't get to put your name as author in the clinical papers, you still get to really understand and appreciate how a real scientific experiment should be documented and implemented...not just "cincai-cincai" copy data and trying to straighten the graph line. Cheers!
Signing the consent forms
