When it comes to healthcare and life sciences investing there is one area where investors should take notice and that is research and clinical trials.  An understanding of how the trial process work, important bodies and terminology is useful investing information in this unique sector.

In the first of our series on Clinical Trials 101 we look at what exactly they are and the process. What is a placebo and blinded study? Who approves clinical trials? What protocol? What is the aim of a phase 1, 2 and 3 study? Who takes part in trials?

Whether you’re new to the sector and wanting to know more or wanting a quick resource to review before striking up a conversation with any biotech experts at a summer barbie, our clinical trials process 101 should have you covered.

You’ll notice we refer a lot to US resources including the National Institutes of Health and the Food and Drug Administration (FDA).

The US is the largest pharmaceutical industry in the world across key metrics including drug development and production, revenue generation and acceptance. In 2021, the US market accounted for 47% of the world’s pharmaceutical market, while the country is home to many of the world’s top pharma companies.

Clinical trials involving the use of unapproved therapeutic goods (i.e. drugs, medical devices and biologicals) are subject to laws and regulations jurisdictions which they are conducted.

Each jurisdiction such as Europe, the US, China and Australia have their own regulatory bodies and protocols for a clinical trial which will need to be vetted (approved).

In the US a clinical trial can start following the FDA review of the investigational new drug application (IND) and ethics approval from an institutional ethics committee (EC), known as institutional review board (IRB) in the United States.

While it wouldn’t necessarily be the case that a US protocol agreed with the FDA would be approved by the European regulator there will often not be much difference and increasingly they are working closer together.

Key bodies in Australia

In Australia theTherapeutic Goods Administration (TGA) is the body responsible for administering the Clinical Trials Notification (CTN) and Clinical Trials Approval (CTA) schemes, while the National Health and Medical Research Council (NHMRC) is the main statutory authority of the Australian Government responsible for medical research.

According to its website, aside from funding, the NHMRC advises the Australian Government, facilitates networking in the research community,  builds commercial literacy among researchers and works to protect intellectual property.

In Australia, Human Research Ethics Committees (HRECs) review research proposals involving human participants to ensure they meet ethical standards and guidelines.

The guidelines include the National Statement on Ethical Conduct in Human Research, which if you want to delve deeper you can read more about here.

The NHMRC requires HRECs who receive their funding to conduct research in line with the national statement. This is where I introduce our guest lecturer Bioshares analyst Mark Pachacz who puts what the industry refers to as “site onboarding” simply.

“Even though the TGA will say you can do the trial you still need to find a hospital who will say you can do it and so once you get ethics approval then you can start recruiting patients,” Pachacz said.

Medlab Clinical (ASX:MDC) CEO and managing director Dr Sean Hall said NHRMC funding or similar in other jurisdictions is important and that without it companies have to fund research themselves.

Medlab is currently preparing for a Phase III trial for its lead asset NanaBis for cancer bone pain.

“Depending on the trial it can cost tens of thousands, hundreds of thousands or even millions,” Hall said.

He said the sponsor –  usually the company – needs to ensure they have the cash whether through raising capital or grants, which can be highly competitive.

The Australian Clinical Trials website provides the nitty gritty of conducting clinical trials and getting approval in Australia, while the NIH provides information on different jurisdictions globally.

Clinical research vs clinical trials

Let’s take one step back to clinical research (not trials) as it’s important to note the difference.  According to the NIH clinical research includes all research that involves people.

Types of clinical research include:

  • Epidemiology

Improves understanding of a disease by studying patterns, causes, and effects of health and disease in specific groups.

  • Behavioural

Improves understanding of human behaviour and how it relates to health and disease.

  • Health services

Looks at how people access health care providers and health care services, how much care costs and what happens to patients because of this care.

  • Clinical trials

Evaluate the effects of an intervention on health outcomes.

Different phases of clinical trial

So now let’s delve deeper into clinical trials, which are conducted in a series of steps known as phases.  After researchers test new treatments or procedures in the lab and in animals, then promising treatments are moved into clinical trials. According to the NIH these include:

  • Phase I trials

Researchers test a drug or treatment in a small group of people (20–80) for the first time. The purpose is to study the drug or treatment to learn about safety and identify side effects.

  • Phase II trials

The new drug or treatment is given to a larger group of people (100–300) to determine its effectiveness and to further study its safety.

  • Phase III/Pivotal trials

The new drug or treatment is given to large groups of people (1,000–3,000) to confirm its effectiveness, monitor side effects, compare it with standard or similar treatments and collect information enabling the new drug or treatment to be used safely.

Healthcare and life sciences expert Scott Power said after successful Phase III trials companies can apply to have a drug approved for use in the public by the US Food and Drug Administration (FDA).

 “Other countries have their own regulatory bodies, Europe is the known AS CE Mark and Australia has the Therapeutic Goods Administration but given the US is the biggest market this is where most companies target,” he said.

  • Phase IV trials

After a drug is approved the NIH said researchers continue to track its safety in the general population, seeking more information about a drug or treatment’s benefits, and optimal use.

Orphan drug development

But we can’t move on before learning about orphan drug development, so stay in class please everyone.

“Some companies look for orphan indications which is where the patient population may be 30,000 or even 10,000 worldwide so it means you don’t have to run as big trials,” Pachaz said.

Companies can also be incentivised to find treatments for rare diseases.  The FDA orphan drug designation program provides orphan status to drugs and biologics for rare diseases that meet certain criteria.

Pachaz said orphan drug designation provides incentives such as tax credits for qualified clinical trials, improved dialogue with the regulator and intellectual protection.

According to the FDA website, orphan drugs receive a seven-year period of exclusivity from product approval effective on the date of FDA approval of a marketing application.  For seven years, FDA will not approve a subsequent sponsor of the same drug for the same disease.

“If you have a phase III trial for an orphan indication you may be able to run a trial, then you may need to run it with just 100 or 200 people,” Pachaz said.

“The more common the indication (condition) the larger the study needs to be.”

Examples of ASX companies focusing on orphan drug development include Neuren Pharmaceuticals (ASX:NEU), which is close to launching the first ever drug for Rett syndrome.

Dimerix (ASX:DMX)  is also undertaking a phase III trial for its lead product DMX-200 in the study of rare kidney disease Focal Segmental  Glomerulosclerosis  (FSGS).

Here’s a link if learning more about the FDA Orphan drug development program has struck your interest.

Getting crucial protocol right

Protocol is designed to balance the potential benefits and risks to participants and answer specific research questions. A protocol describes the following:

  • Goals
  • Eligibility
  • Protections against risks to participants
  • Details about tests, procedures, and treatments
  • Expected duration of trial
  • Information to be gathered.

Hall said it was important to point out that clinical trial protocol write-up is really technical and specialised.

“Bad trial design can mean recruitment failure, trial endpoint failure, trial endpoint success but data not usable for regulatory submission, ethics and or DSMB failure or participant death,” he said.

“So good clinical trial protocol write-up requires significant insight and input by the clinician, clinical trial experts, regulatory people and market access people who understanding what is needed to get a drug to market.

“In Australia they also understand co-pay, where the government is paying for the patient’s medicine so the real cost might be $1000 but out of pocket cost could be $20.”

Now a quick note on a Data and Safety Monitoring Board (DSMB). A DSMB is a committee of experts responsible for reviewing clinical trial data on an ongoing basis to ensure the safety of study subjects and validity and integrity of the data. The NIH provides a good overview of a DSMB and their role.

“As a point of reference, on average it will take us 4-5 months to finalise a protocol and then submit to HREC or Institutional Review Board (IRB) for approval,” Hall said.

“The more principal investigators you have, the more time it takes as each hospital has varying nuisances.”

“After approvals expect up to 3 months to onboard the trial into a public health facility; experienced teams can sometimes shorten this.”

“All trials also need medical insurance which can be costly with specialised insurers such as Chubb or Newline.”

How are trials conducted? 

There are three ways a trial may be conducted including:

  • Placebo
    • Simply put, a placebo is a treatment that appears real but is designed to have no therapeutic benefit.
    • The NIH said comparing a new product with a placebo can be the fastest and most reliable way to show its effectiveness.
    • However, the NIH said placebos are not used if trial participants would be put at risk, such as for serious illnesses by not having effective treatments.
    • Participants are told if a placebo is being used in a trial.
  • Randomised control study
    • In these trials participants are assigned to different trial arms rather than choosing to avoid bias in getting one or another.
    • The NIH said effects of each treatment are compared at specific points during a trial.
    • If one treatment is found to be superior, the trial is stopped so the most participants receive the more beneficial treatment.
  • Blinded or masked trial
    • In a single-blinded or single-masked study participants don’t know what they are being given, but the research team knows.
    • In a double-blind study, neither the research team or participants are told what is being given and only the pharmacist knows.
    • However, if medically needed, the NIH said it is always possible to find out which treatment a patient is receiving.

Who takes part in trials?

One of the higher profiles trials of recent times has surrounded the Covid-19 vaccines and treatment.  As the world grappled with a pandemic which brought the world to a standstill, the race was on among pharmaceutical companies to provide a preventative vaccine and effective treatments.

Different types of people take part in clinical trials, mostly patient volunteers hoping for a better treatment outcome. A patient volunteer has a known health problem and takes part in research to better understand, diagnose, or treat that disease or condition.

Generally, before a first in-human study is conducted, animal toxicology has been undertaken which Hall said is to build up “so-called comfort factors” before use in human to determine safety levels.

Research with a patient volunteer helps develop new knowledge. Depending on the stage of knowledge about the disease or condition, these procedures may or may not benefit the study participants.

In some instances healthy volunteers are used to collate pharmacokinetic data commonly known as PK studies. Hall said this enables models of absorption, metabolism and excretion in healthy people to be compared with a target population of patients with a particular condition.

“Basically how drug reacts in a healthy person will be different to that of a person with a particular condition,”  he said.

“It’s like building a benchmark against a benchmark and it gives fundamentals for safety and when we repeat the medication in people with the condition we start to see big movements in peak concentration of the maximum amount it takes for that drug to be present in the blood.

“We also see big movements in how long it takes to reach that peak concentration in the blood and for the drug to be excreted from the body.”

He said from PK studies you can work out for example how often to give medications, dosages, whether to give medication with a meal or after a meal.

“For example with cannabinoids taken by mouth we know that PK data for healthy people changes drastically based on whether they ate before or after dosage,” he said.

“We know also that repeating PK in people with particular conditions that same problem carries through which leads us to a better understanding on dosing.

“Generally healthy people won’t be given drugs that could put them at risk and ethics reviews offer safeguards.”

Although these studies may provide direct benefit to patient volunteers, the main aim is to prove effects and limitations of the experimental treatment.

Researchers follow clinical trials guidelines when deciding who can participate, in a study known as inclusion/exclusion criteria based on factors such as age, gender, the type and stage of a disease, treatment history, and other medical conditions.

In the next article we will look at just what the regulators are looking for in approving a drug and key points investors should note.

At Stockhead, we tell it like it is. While Dimerix and Medlab Clinical are Stockhead advertisers, they did not sponsor this article.