Author – Ratfink


Clinical trials explained. 

Reading some of the recent posts on the Mesoblast threads at HC it has become apparent that a few of the new people getting involved in the threads don’t have much of an understanding of what clinical trials are and how they work. 

To address this, I’ve used material from a number of sources to compile this rough outline of how it all works.


What is a clinical trial?       

Clinical trials are research studies that investigate whether a medical treatment or device is safe and effective for humans. Clinical trials show us what works and what doesn’t in medicine and healthcare. 

Before you even get to a clinical trial there are a number of other processes and studies to be undertaken.  

Firstly, there are Pre-clinical studies, which often involve cell studies and animal studies. After that is completed, an IND, or an investigational new drug application must be sought from the regulatory body, usually the FDA. These two processes can take significant time and resources before you can even begin a clinical trial. 


Types of clinical trials 

Clinical trials come in a number of different formats, these are called phases. Usually there are 3 phases, sometimes 4. 

Each phase has a distinct purpose and helps researchers answer a variety of questions on safety, effectiveness and the right dose to use. 


What Are the Four Phases of Clinical Trials?  

Clinical trials advance through three or four phases to test a treatment, find the appropriate dosage, and look for side effects. If, after the first three phases**, researchers find a drug or other intervention to be safe and effective, the FDA approves it for clinical use and continues to monitor its effects.  

Clinical trials of drugs are usually described based on their phase. The FDA typically requires Phase I, II, and III trials to be conducted to determine if the drug can be approved for use.  

  • A Phase I trial tests an experimental treatment on a small group of often healthy people (20 to 80) to judge its safety and side effects and to find the correct drug dosage.  Time taken ~3 months to 1 year.
  • A Phase II trial uses more people (100 to 300). While the emphasis in Phase I is on safety, the emphasis in Phase II is on effectiveness. This phase aims to obtain preliminary data on whether the drug works in people who have a certain disease or condition. These trials also continue to study safety, including short-term side effects. This phase can take several years
  • A Phase III trial gathers more information about safety and effectiveness, studying different populations and different dosages, using the drug in combination with other drugs. The number of subjects usually ranges from several hundred to about 3,000 people. and can take from 2 – 4 years. If the FDA agrees that the trial results are positive**, it will approve the experimental drug or device. 
  • A Phase IV trial for drugs or devices takes place after the FDA approves their use. A device or drug’s effectiveness and safety are monitored in large, diverse populations. Sometimes, the side effects of a drug may not become clear until more people have taken it over a longer period of time. 

Before, during, and after a clinical trial, there are a number of terms that get used frequently when companies or regulators talk about clinical trials.

What do the terms placebo, randomization, and blinded mean in clinical trials?

In clinical trials that compare a new product or therapy with another that already exists, researchers try to determine if the new one is as good, or better than, the existing one. In some studies, you may be assigned to receive a placebo (an inactive product that resembles the test product, but without its treatment value). 

Comparing a new product with a placebo can be the fastest and most reliable way to show the new product’s effectiveness. However, placebos are not used if you would be put at risk — particularly in the study of treatments for serious illnesses — by not having effective therapy. Patients will be told if placebos are used in the study before entering a trial. 

Randomization is the process by which treatments are assigned to participants by chance rather than by choice. This is done to avoid any bias in assigning volunteers to get one treatment or another. The effects of each treatment are compared at specific points during a trial. If one treatment is found superior, the trial is stopped so that the most volunteers receive the more beneficial treatment. 

Blinded” (or “masked“) studies are designed to prevent members of the research team and study participants from influencing the results. Blinding allows the collection of scientifically accurate data. In single-blind (“single-masked“) studies, you are not told what is being given, but the research team knows. In a double-blind study, neither you nor the research team are told what you are given; only the pharmacist knows. Members of the research team are not told which participants are receiving which treatment, in order to reduce bias. If medically necessary, however, it is always possible to find out which treatment you are receiving. 

**It should be noted that the FDA will often require two phase 3 clinical trials before approving a new drug. The second phase 3 is to validate the positive data from the first. There are exceptions to this, mostly for oncology drugs, which I will discuss another time.

This info in this post should go some way toward answering some of the most common questions that get asked by people that are new to biotech.

Email me if there’s any subject you would like to hear about in a blog post, or if you would like to write a blog post.

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Celestial · September 10, 2020 at 5:02 pm

I am looking at the section on this poster about Phase IV Clinical trials.
It says
“Phase IV
Purpose: when a medical approach is being marketed, continue gathering information on its effects.
Number of people: thousands.”

So, this is what they meant at the ODAC (Oncological Drugs Advisory Committee) meeting a few weeks ago which was about Ryoncil (Remestemcel-L) for pediatric patients, when the FDA suggested that if Ryoncil was approved then Mesoblast should perhaps consider a phase IV trial to compare Ryoncil with another treatment/drug. A Phase IV trial is a means of continuing to gathering information from thousands of patients while the product is being marketed.

That information was not clear to me before. I have heard some people suggesting that a phase IV trial might create further delays but that is not correct.

Ratfink · September 10, 2020 at 6:19 pm

That’s right. It’s to shore up the safety and efficacy data post approval.

Obviously the pediatric GVHD phase 3 trial was only on 55 kids, not many compared to most phase 3 trials, so it would come as no surprise if they asked for a confirmatory phase 4 on the first few hundred kids treated. But as this is post approval there would be no delay getting to market.

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