The road to commence a clinical trial could be long, according to Cynata’s Jolanta Airey. Picture Getty
Health & Biotech
When it comes to healthcare and life sciences investing, there is one area where investors should take notice – research and clinical trials.
For biotech investors, the news of approval of a new clinical trial by a regulatory body such as the FDA is a genuinely exciting milestone.
The FDA is the ultimate gatekeeper for the US pharmaceutical market, which is by far the world’s largest.
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.
A clinical trial in the US can start following an 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.
But what many might not be aware of is that there are multiple steps involved in actually commencing a trial, even after the FDA has given approval.
This can lead to investor frustration, and the misconception that perhaps things aren’t running smoothly when in reality, for complex, multi-centre multinational trials to open all sites for enrolment, it can take up to 12 months post-approval.
Jolanta Airey, chief medical officer of Cynata Therapeutics (ASX:CYP), explained to Stockhead the summary of steps that most biotechs and pharmaceutical companies will need to sequentially work through before recruitment of patients can begin.
The first step, according to Airey, is to put together the development of core study documents.
This includes documents such as final study protocol, Investigator’s Brochure (a collection of clinical and non-clinical data about the investigational product), and Informed Consent Form (a document volunteers sign when they agree to participate in a clinical trial).
Then the biotech company will need to select the Clinical Research Organisation (CRO), i.e. the specialist company that actually runs the clinical trial on behalf of the drug company.
“This involves several bid defence meetings where quotes are analysed, and contract negotiation,” explained Airey.
The third step is to choose the clinical research sites, potentially involving multiple countries.
This is followed by site qualification visits at each site where more detailed assessments are conducted about the site personnel and equipment to ensure the site has adequate resources and patient population for successful study execution.
Next, the biotech will need to negotiate and agree on budgets for individual study sites, and make a submission to the local Regulatory Affairs (RA) and Ethics Committees (EC).
“These bodies review research proposals involving human participants to ensure they meet ethical standards and guidelines,” Airey said.
They will then need to answer questions and any further requests from RA/EC to obtain the approvals.
“Questions can range from pre-clinical package to risk-benefit assessments, and further requests may involve conducting additional experiments,” Airey added.
When those questions have been answered satisfactorily, the company will need to submit more documents to the Research Governance Office (RGO) detailing the sites and the budget for each site.
The Research Governance Office is the office within the hospital that administers the processes used by the institution to ensure that it is accountable for the research conducted under its auspices.
“To be properly governed, research must be conducted according to established ethical principles, guidelines for responsible research conduct, relevant legislation and regulations and institutional policy. This step alone can take up to six months,” said Airey.
When those submission are done, preparation of the study plans can commence and include but are not limited to things such as IP (Investigational Product manual) and PVG (Pharmacovigilance plan), a report on how to assess and report serious adverse reactions.
Then there is the MMP (medical monitoring plan), which is the plan for ensuring safety oversight and reviewing the protocol (e.g., study halting rules), and information about the study as it becomes available.
The biotech in question will also need to prepare crucial planning documents such as a lab manual, clinical monitoring plan, a statistical analyses plan, and a data management plan, amongst others.
All these will need to be built and validated on an electronic data capture (EDC) database, which is a database used to record all the data from the subjects in the trial.
Finally, prior to the first patient dosage, the company will conduct site initiation visits which involves training the team on study protocol, adverse event reporting, data recording in EDC, and other systems to be used during the study.
“As you can see, it’s not a short nor simple process,” said Airey.
“And, within this process, some of the steps may take multiple iterations even if appropriately undertaken.
“I appreciate that it’s difficult for already patient investors to continue to be patient but at the end of the day, designing good clinical trial strategies to ensure they have the best chance of reaching the intended end point and move to commercialisation is imperative,” she added.
When all the boxes have been ticked, the process moves to the clinical trial stage, which are conducted in a series of steps known as phases.
According to the FDA, the Phase 1 study usually involves 20 to 100 healthy volunteers or people with the disease/condition.
The length of the Phase 1 study is usually several months, and approximately 70% of drugs move to the next phase.
In Phase 2, the study participants will increase and involve up to several hundred people with the disease/condition.
The purpose of Phase 2 focuses on the efficacy and side effects of the drug.
The average length of a Phase 2 study is several months to two years, and according to FDA data, approximately 33% of drugs will succeed Phase 2 and move to the next phase.
In Phase 3, the number of participants are ramped up, enrolling around 300 to 3,000 volunteers who have the disease or condition.
The purpose of Phase 3 is to evaluate the efficacy of the drug further on a bigger population, and to monitor any adverse reactions.
At this stage, only 25-30% of drugs will succeed and move to the next phase, statistics have shown.
And finally in Phase 4, several thousand volunteers who have the disease/condition will normally participate.
The main focus of this final phase is on safety and efficacy on a much bigger population of patients, and no statistics were given by the FDA on the success rate of Phase 4 trials.
Note this list may not be exhaustive.
In December, Neuren announced the submission of an Investigational New Drug (IND) application for NNZ-2591 in Prader-Willi syndrome.
NNZ-2591 has been tested in the Magel2-null mouse model, which mimic the behavior and metabolic profile of Prader-Willi syndrome in humans.
In the mice study, treatment with NNZ-2591 for six weeks showed normalisation in all behavioural deficits in the mice.
The mice treated with the low dose of NNZ-2591 showed partial reversion to normal levels.
Immuron also submitted an IND application to FDA for Travelan in December.
Travelan is an orally administered immunotherapy that reduces the likelihood of contracting travelers’ diarrhoea, a digestive tract disorder that is commonly caused by pathogenic bacteria and the toxins they produce.
In Australia, Travelan is a listed medicine on the Australian Register for Therapeutic Goods.
Apart from travelers’ diarrhoea, Travelan is indicated to reduce the risk of minor gastro-intestinal disorders.
Radiopharm Theranostics (ASX:RAD)
In December, Radiopharm received IND approval for its αVβ6 Integrin (RAD301) technology.
RAD301 is part of Radiopharm’s Integrin platform technology, invented by world renowned integrin expert, Professor Johannes Notni.
The protein αvβ6-integrin is found in many challenging types of cancer, including pancreatic cancer.
RAD301 is said to suppress the high levels αvβ6-integrin by using PET imaging.
The FDA approval will allow Radiopharm to begin a Phase 1 imaging trial in ambulatory patients with pancreatic cancer, targeting commencement at the end of Q1 CY23 with an estimated close by Q3 CY23.
An IND application for the ISLA-101 Phase 2a PEACH clinical trial has been filed with the FDA in December.
ISLA-101 is a well known drug candidate that is being repurposed for the prevention and treatment of dengue fever and other mosquito (or vector) borne diseases.
Presuming the IND is cleared by the US FDA, Island’s PEACH clinical trial could begin screening and enrolling subjects starting this month.
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