Twelve years ago, University of Adelaide researcher Dr Mohammed Alsharifi began experimenting with a vaccine against Streptococcus pneumoniae, a bacteria commonly found in the nose and throat, and responsible for life-threatening illnesses such as sepsis, pneumonia and meningitis.
He started as most researchers do: by identifying the problem, trying to find the solution, and then figuring out how to make it happen. “How do I build a team? Where do I get the funding for proof of concept?” Alsharifi tells Cosmos.
This process alone took up to 4 years, and can sometimes go beyond it, he says. Even after you have your initial research team assembled (made up of PhD students and postdoctoral researchers) the team changes as the research develops.
“We need funding to pay for consumables, salaries for researchers, the experiments, the animals and so on.”
The pre-clinical stage of drug or vaccine development is conducted on animals under ethical guidelines, called the Code and overseen by the National Health and Medical Research Council (NHMRC). For vaccines, mice are widely used due to the similarity of their immune system to humans and the quick development of the drug, Alsharifi says.
This is the stage where researchers need to show the product is working. If so, they need to then test it on another animal for safety.
While we are making good progress, it has been much slower than initially anticipated.Mohammed Alsharifi
“The first animal model would have given you enough data to show its effects, but to progress you need to show the data, to transfer the knowledge and technology, to a third party to ensure the product has no adverse effects,” he says.
In this second animal trial (still pre clinical), the materials need to be reformulated to resemble those that will be used on humans. This should provide the essential information on the effects of the drug on vital organs, including lack of toxicity at different doses. Only after that can the drug progress to testing in humans…phase 1 can begin.
But already it has cost “millions of dollars,” Alsharifi says. “You need to patent your invention and look for investors to back you to do the work. In general, the manufacturing [of the drug or vaccine] is complicated, and you need skilled, third-party people to develop your product.”
The vaccine against Streptococcus pneumoniae is not Alsharifi’s first rodeo. For the last 18 years, he has also been working on a universal flu vaccine, the “holy grail” of vaccines.
“While we are making good progress, it has been much slower than initially anticipated,” he admits. It seems he and his team are stuck in the preclinical stage until they figure out how to manufacture it at large scale. It works in animals – but getting it to the human trial stage is still a puzzle.
“The methods to produce suitable materials for animals won’t work in humans: there are different qualities and controls in place,” he says.
When asked how he keeps going, Alsharifi laughs ruefully.
“You have to be very, very patient and you have to have the passion to do it – this is the key factor.” You also have to believe in your product so fiercely that you’re willing to put everything on the line for it, he says.
“You have to prioritise your work in many parts of your life – essentially, making a vaccine happen becomes your life.”
This is the first time a new drug is studied in humans, and it requires 50 to 80 healthy adult volunteers.
You have to prioritise your work in many parts of your life – essentially, making a vaccine happen becomes your life.Mohammed Alsharifi
“In this phase, we check if the product is safe and well-tolerated by humans,” Alsharifi explains. “You start with a very small dose and monitor for safety, and gradually increase the dose while making sure there are no side-effects.”
This phase, however, can take some time to complete. Professor Laurent Billot from the George Institute for Global Health says how quickly people are recruited to trials depends on the condition being studied (e.g. rare or common); the context (e.g. hospital vs community); potential competition (e.g. other trials recruiting a similar population); and financial incentives (to recruiters/investigators, not participants).
“In my experience, which is mostly based on academic trials, so not leading to a regulatory submission, recruiting patients in a clinical trial is often a challenge,“ he says.
Researchers are continuously trying to improve the process by finding new ways to engage with participants, as well as leveraging existing registries which helps identify potentially eligible participants, as well as minimise additional burden linked to data collection, Billot adds.
If safety concerns associated with dosing are considered acceptable, the product then enters phase 2.
Alsharifi, who started on this journey 12 years ago, is about to complete Phase 1 clinical trial of the resulting Gamma-PN pneumococcal vaccine, with a team at the biotech GPN Vaccines.
This phase mainly focuses on the benefits of the drug or vaccine, so whether it improves outcomes or minimises the effects of the condition it is trying to treat.
Recruiting patients in a clinical trial is often a challenge.Laurent Billot
This is done in a much larger population of still healthy individuals — as many as 500, or 10 times the number in phase 1, says Alsharifi — and often requires financial backing from large pharmaceutical companies.
“Most small biotechnology companies can accord phase 1, but once they pass this phase and show some biological function, they aim for big pharma to take over so they can do the big studies with hundreds of volunteers,” he says. In Australia, volunteers may be reimbursed for participating in medical studies, which can vary from gift cards up to thousands of dollars, depending on the study and a variety of other factors.
Phase 2 trials typically explore a range of doses of the new drug. If it’s found to be acceptable in terms of the side effects and shows some benefit to patients, then it progresses to the third phase.
In this phase the original researchers, as well as multiple third party operators, seek definitive answers on whether the product is safe and effective. The number of volunteers increases 10-fold again, which will often reveal any side-effects that may have been missed in a smaller population.
How trials are conducted
Clinical trials, especially in phases 2 and 3, are usually conducted according to the randomised controlled trial (RCT) design. Here, participants are randomly assigned to groups where they will be given either the treatment, or the control (so no treatment at all, or a placebo). Both sets of participants go through the same procedures, after which outcomes are compared.
Some RCTs are also double-blind studies, meaning that neither the participant nor the research team know who is receiving the drug or control treatment. The aim is to reduce bias in the reporting of benefits and side effects. If you don’t know which treatment you’re having, the results are less likely to be influenced by you or your doctor’s views.
Regulatory submission (to the TGA)
If these trials are successful the next step is to apply to the country’s regulatory body (in Australia, this is the Therapeutics Goods Administration, or TGA), responsible for regulating prescription medicines, vaccines, sunscreens, vitamins and minerals, medical devices, blood and blood products.
The process of application is complex and also requires many steps — and millions of dollars — before a drug or vaccine can be prescribed. The TGA only registers about 40 new prescription medicines containing new substances each year.
If you don’t do everything the way the TGA expects you to, you can run afoul of the process.Tony Whittaker
Tony Whittaker, former researcher at Melbourne and Monash Universities and employee at the TGA turned pharmaceutical consultant, helps companies navigate the intricate bureaucracy associated with getting a product approved in Australia.
“I work with a lot of researchers who are so excited because they have this potential new drug or product they’ve been working on for decades, but they don’t realise how exacting and bureaucratic the process is to get it registered,” he says.
“If you don’t do everything the way the TGA expects you to, you can run afoul of the process.”
There are 3 main types of applications a sponsor (the person or company wanting to register the drug) can enter: the first is to register a ‘new medicine’ containing a new active substance not currently approved in Australia; second, to register a ‘new combination’, where 2 or more already approved medicines are combined into a single product; and thirdly an application for a ‘new indication’, or additional therapeutic use, for an already approved medicine.
However, Whittaker points out there are more subtypes including generics, new types of products, new routes of administration (e.g. injection, tablet, patches) and more. In short, a minefield.
As for the length of time? Well, it’s a long time. While there may be some exceptions (think Covid) where vaccine or drug development moves at lightning speed, TGA only registers drugs after years of research and development, and following a comprehensive review by its own scientists and clinicians of the medicine’s quality, safety and efficacy.
As Australian experts point out in this article for The Conversation, generally speaking, studies in phase 1 are completed in a few months, phase 2 in a year or 2, and phase 3 may take up to a number of years. “It takes a total of 9 to 12 years on average from drug discovery in the laboratory to approval by a regulatory body,” they write.
In the meantime, many more researchers and companies will try to reach that holy grail.