By Dean Willis, Lecturer in Neuroscience Physiology & Pharmacology at University College London
The outbreak of SARS-CoV-2 which causes the infectious respiratory disease COVID-19 as now been with us for around 4 months. While the initial viral infection was localised to Wuhan in China it has now spread globally. The impact of the disease is staggering, ranging from effects on the world’s health, welfare, educational and economic systems. The phrase “once in a generation event” is often banded about, but in this instance it appears totally justified.
One of the biggest challenges that the world is now confronted with is the development of an effective therapy to treat the current outbreak of the virus and any subsequent waves of infection. It is hoped that in the near future, an effective vaccine against SARS-CoV-2, or a drug which can reduce the replication of the virus can be developed. However at times like these we would do well to remember the words of the German scientist who was the father of chemotherapy Paul Ehrlich. Ehrlich stated that to be successful in finding a new therapy you needed the 4 G’s: Geld, Geduld, Geschick & Glück, or Money, Patience, Skills & Luck.
Globally, governments as well as public & private organisations have been pouring resources into vaccine and drug discovery programmes for COVID-19 at an unprecedented scale. Will this be enough? The average out of pocket costs for the development of a new drug is $1.4 billion. To fully fund the various vaccine programmes against COVID-19 costs are placed between $750 million and $3 billion. While these are large numbers, it is estimated that the global economy could lose between $1 and $4 trillion because of COVID-19. Finding the Geld & Geschick to develop a new therapy for COVID-19 will probably not be a problem. So what about Glück?
The role that luck plays in the design or identification of new therapies is debatable. Did an individual make a scientific breakthrough because they worked harder or could see further than their colleagues? Or was it just luck? The role of luck, is therefore difficult to define let alone quantify in vaccine/drug discovery programmes. So let us take a statistical view on the role luck may play in these programmes. On average, luck will contribute no more or no less in the discovery of new therapies for COVID-19 than it as in any other development programmes. Probably not that enlightening; suffice to say we should not overplay luck.
So this brings us to Geschick or Patience. Typically a successful vaccine or drug discovery program takes 10-15 years to come to fruition. It is hoped that the money and skills being directed towards the various COVID-19 therapy programmes will shorten this time significantly, but patience is required.
In the current atmosphere, good news is at a premium so every report on the development of a new vaccine or anecdotal evidence for the effectiveness of a repurposed drug brings new headlines. This can give the perception that a new “game–changing” treatment is around the corner. But it is at this moment of optimism that we must show patience. The success rate for drugs entering clinical trials and finally being approved is around 10-14%, for vaccines it is slightly higher at about 16%. These numbers also vary depending on the disease that the new therapy is intended to treat. Sepsis, a life threatening condition which can also develop in some COVID-19 patients, is notorious for the number of new therapies which have failed clinical trials. This low success rate of drugs passing through clinical trials also contributes to the high costs of new therapy development. Patience is required because many drugs and vaccines will fail in clinical trials. So what is involved in a clinical trial for a prospective new therapy?
After pre-clinical development of a drug or vaccine, they enter clinical trials which typically involves four phases. Phase 1 is usually carried out in a small number of healthy individuals to test the safety of the treatment. Trial participants are allocated different sub-therapeutic doses of the new therapy with lowest dose tested first. The majority of drugs & vaccines, 70-75%, pass Phase 1 and while this hurdle has the lowest attrition rate during clinical development severe consequences can occur when things go wrong.
On 13 March 2006 a Phase 1 clinical trial for TGN1412, a CD28 super–agonist antibody, resulted in the six young (19-35) heathy male participants of the trial developing life-threatening cytokines release syndrome and multiple organ dysfunction. Luckily all 6 participants of the trial survived after receiving treatment at Northwick Park hospital London. This episode demonstrates that while all precautions are taken regarding a therapy’s safety there is inherent risk when a new vaccine or drug is investigated for the first time in humans.
Once it has passed Phase 1 the new therapy moves to Phase 2. In this phase the effectiveness of therapeutic dose of a drug or vaccine is evaluated in a small number of patients, usually 100-300. Phase 2 trials also evaluates the safety of the therapy in the patients it is intended for. This may be a particularly important aspect for drugs against COVID-19 were the safety profile of a new drug may be very different for young healthy individuals compared to older individuals with underling cardiovascular, metabolic or respiratory problems which appear to be more at risk of developing severe COVID-19 symptoms. To test efficacy and safety of the new therapy, the Phase 2 trial usually takes the form of a randomised control study. This works by randomly allocating patients to groups which will receive the therapeutic drugs or a control group which does not receive the therapy, otherwise known as the placebo. The trial may also be carried out blind, meaning the patient and possibly the clinical staff involved do not know which arms of the trial the patients are allocated to.
The purpose of this design is to collect data with the minimum of bias and is considered the basis by which new therapies are assessed. Repurposed drugs such as those considered for COVID-19, usually enter at this stage of the clinical development process. Repurposed drugs have usually been extensively used in human for other conditions, so more human safety data is available. Phase 1 trial is therefore not required thus shortening the whole clinical trial process. The problem is that the majority of drug entering phase 2 do not leave it. Approximately 60-80% drugs fail phase 2 clinical trials.
If a therapy gets past Phase 2 it enters Phase 3. Phase 3 clinical trials are multi–centred randomised control trials. They can involve anywhere between 200-3000 patients and confirm the data collected in Phase 2. In addition Phase 3 trials will often determine the usefulness of a new therapy in a clinical setting by comparing it to the current best treatment or “gold standard” for treatment of the disease the new therapy is targeted at. For COVID-19 this is not an issue. Phase 3 trials are the most expensive part of the clinical development process because of their size and complexity, however approximately 40-60% new therapies still fail Phase 3 trials.
If a new therapy finally passes all three phases, the data is collected and submitted for regulatory approval. This process itself is not straight–forward but if successful, about 85-90% of the time, the new therapy is finally approved. But this is still not the end of the story! The therapy now enters Phase 4, known as post–market surveillance and is subjected to pharmacovigilance. Phase 4 looks at how the therapy acts in the real world, not controlled clinical trials which Phases 1-3 are. It investigates if there are long–term sides effects of the new therapy not detected in Phases 1-3. Does the new therapy behave differently in different sets of patients or does it interact with other drugs a patient may be taking. The length of the Phase 4 is a minimum of 2 years, but the evaluation of a drug’s or vaccine’s safety never stops.
Vaccines and therapies for SAR-CoV-2 infection and the control of COVID-19 symptoms will need to navigate this rigorous but essential process. Unfortunately some of the repurposed drugs for COVID-19 that have entered clinical trials may have already hit the buffers. Two recent reported studies, investigating the potential of using hydroxychloroquine, a repurposed anti-malaria drug, in combination with the antibiotic azithromycin, for COVID-19 have found more side effects, including fatalities, in patients receiving the drugs compared to patient which did not.
It is certain a high percentage of all the programmes developing new vaccines or drugs against COVID-19 will fall by the wayside. This may be at the pre-clinical stage or during clinical trials. But the sheer number of projects, talent and money being invested means, with a modicum of luck, a new vaccine and/or drug should be successfully developed in record time. All we need is a little Geschick.