Development regulation

Hello Everyone! My name is Dr. Gabriel Castro. I am the CEO of Taipei Medical University, Joined Clinical Research Center. The title of this course is “clinical trials”.

In this course, we will follow and focus on the terms and aspects of the research on drugs as it provides a good example of what to assume, prepare, and follow while conducting a clinical research either in drugs, devices or diagnostics. As we can see, clinical

researches breakdown in: phase 1, phase 2, phase 3, phase 4. Extensive literature is describing the timeline, milestones involved in each phase of the clinical trial and what is the success rate while developing a given pipeline. Regardless of the taking time, the main point, is the

focus on: what is the objective of the research? Because all aspects of the research will be around this objective.

As far as the research advance through each phase, the complexity of the

resources used: manpower, subject population, and infrastructure relatively increase. Young basic researchers, trained to be more active at early stages while Pharmacy, Biotech, or similar institutions will be more prevalent at late stages.

Phase 1 clinical trials are conducted in humans. It’s the 1st step with humans, and they will, in these trials, they will test the compatibility, the pharmacokinetic, the pharmacogenomics, and the Bioavailability of the drug. Usually takes 2 digit healthy

volunteers: 10, 20, 30, 40 patients and the goal is to establish the dose range tolerated by healthy volunteers or patients.

80 to 90 % of drug candidates will fail during this phase 1 stage.

Prior to the clinical trial, the study protocol must be ready. The company or the investigators should file an application for an IND with a regulatory authority. The regulatory agency also has to be satisfied with the preclinical animal data, does not show an acceptable safety risk.

For a clinical trial, phase 2, will be the first test with patients. During this stage, the goal of the research is to establish efficacy, dose, the pharmaceutical form, the science phase, the interactions. Usually, we’ll take 3 digits patients.

80, 90, 100 patients. The goal is to value the efficacy and safety with selected patients, dose response and frequency with safety. During this stage, 50% of the drug candidates fail.

Prior to the clinical trials, the study protocols must be ready again and the company, all the regulatory authorities related to the IND with the regulatory authorities and the preclinical animal data, the same as phase 1 studies, should not show an acceptable safety risk.

Phase 3: During this stage, it is an intensive test with patients. The frequency will be proven on a wide base and the goals as to provide a clear data about the safety and the harmlessness of the candidate drug. Usually the trial will use the placebo or standard treatments and in comparison with the investigation of product. During this stage, 4 digits patients will be necessary to prove the safety to demonstrate the safety and efficacy in a larger patient population. This means 200, 300, 400 or thousands of patients even. During this stage, 10 to 20% of the drug candidates fail.

The same as any other trials, all the regulation, all the IND regulatory related forms, and all the safety and risk-benefit balance should be clearly shown in the protocol. This is major because this will, the major part of the submission to the regulatory authority. This will complete, will be part of our submission to NDA, MAA to FDA, EMEA, MHLW.

Phase 4: Phase 4 relates to pharmacovigilance or is a long term monitoring of the investigation of protocol. Seldom, during this stage, the IP seldom have side effects and will be tested in everyday life condition. The goal during the phase 4 is to demonstrate safety and efficacy again in a larger patient population to confirm. I will also provide some marketing data to possibly develop new indications.

As I say before, for any clinical trials, the study protocol must be ready and the company should follow the regulatory authority requirements and should continue follow the safety, data mining, reports periodically in a given reporting, forms, and timelines.

So what are the assumptions to do a clinical trial? The main assumptions are the clinical investigations should distinguish the effect of the investigation of product from other influences such as a spontaneous change in the cause of the disease, placebo effect, or biased observation.

Adequate and well controlled clinical trials are conducted by experts to provide valid scientific evidence. That means the research should have clear statements of the objectives, methodology and intention to report the results. It should describe the proposed methods of analysis and should prove or show that the investigation of product is a standardized identity, strength, quality, purity dosage form.

But what is an adequate and well controlled clinical trial? Basically the investigation results are significant the subject selection is accurate to the disease and treatments. Subjects are allocated, considered minimized bias and assured confirmed viability. Subject assessments and data are reasonable, scientific, well defined, and reliable. Outcomes should explain the variables measured, the methods of observation and criteria used to assess response.

Finally, the regulatory requirements. Basically, as I’ve mentioned before, the sponsor of the investigator should submit an IND or IDE investigation of the Biased Exception. Also the investigator or the sponsor should comply with all applicable requirements by local or global regulation. For example, the 21 CFR parts of the FDA or the ICH E6 GCP guidelines with respects to trial conduction.

Investigator also can have their own investigation. IITs, investigator initiated trials with also should be in compliance with all applicable requirements by local, global regulation.

To have further references, the investigator or the sponsor should refer to all standards like the ICH E6 or the clinical medical guidance opened to the public in FDA or EMA websites.

The public also can refer to the websites, the FDA approved products or the FDA device advice websites in which you will find extensive research related to the biased regulation and guidance.

Thank you for your attention