NB: The author declares a conflict of interest as he is employed by Cape Bio Pharms.
The World Health Organisation (WHO) announced the coronavirus pandemic on 11 March 2020. Globally, as of writing, there are 626 unique Covid-19 therapeutic and vaccine candidates in development, 223 of which are being tested in clinical trials.
Given this unprecedented response from the global biotechnology industry, why are we still in “lockdown”, “sheltering in place”, and “social distancing”? Why, in biotech’s so-called “finest hour”, is there still no treatment effective enough to embolden our leaders to institute a safe and deliberate return to economic and societal normality?
To address these questions, it is important first to examine the processes of drug, vaccine, and medical device production, and then to investigate the avenues that lead to consumer availability.
The development pipeline
New drug therapies or vaccine candidates developed in university or private laboratories are first tested in a pre-clinical setting – i.e. they are tested in non-human trials. Usually, a particular cohort of animals (rodents, canines, non-human primates) is chosen as the first model in which to evaluate the safety, efficacy, and dynamics of the treatment. A strong ethical code enforced by institutional committees and national law governs how these animals are treated, as well as their living conditions.
Once the safety and efficacy of the candidate product has been established in an animal model, clinical trials follow. These are divided into a number of phases, namely Phase 0, I, II, III, and IV, during which the drug or vaccine is administered under ethically determined conditions to a group of volunteers, each of whom has submitted to a rigorous informed consent process. One or more of a combination of parameters including, but not limited to, safety and efficacy in humans, potential side-effects, and appropriate dosage are then studied.
In Phase 0 clinical trials, participants are administered a very small, subtherapeutic dose of the study drug. These small studies of 10 – 15 people aim to answer questions such as: “Where does the drug go in the body?”, “How does the body metabolise it?”, and “How does the body excrete it?”
Phase I clinical trials are conducted among a larger group of individuals and aim to establish the safety and optimal dosage of the study drug.
Phase II clinical trials investigate treatment efficacy, seeking to answer questions such as, “Does the treatment work compared to a placebo?”
By Phase III, the number of participants in the trial is typically over 1,000. The aim of this phase is to monitor side effects, confirm efficacy, and compare the study drug to alternative treatments that have already been approved, sold, and administered (if they exist).
At this point, in the interim between Phase III and IV trials, the developers of the treatment will apply to a regulatory authority for market approval, which is required for any medical product or device before it can be sold. In South Africa, the regulator is the South African Health Products Regulatory Authority (SAHPRA), our equivalent of the United State’s Food and Drug Administration (FDA) or the European Union’s European Medicines Agency (EMA).
Should the developers of a new drug receive market approval from the regulatory authority, Phase IV clinical trials will continue throughout the course of the drug’s history to monitor its performance and gather additional data.
Given the above, drug and vaccine development is clearly a lengthy process. Apart from clinical trials, regulators such as SAHPRA need to evaluate the risk-benefit ratio of all medical products as no medicines are truly side effect free.
To do this, the regulatory body reviews all the clinical trial data, assesses the conclusions drawn by the researchers, conducts clinical trial site inspections, and inspects the manufacturing facility to ensure that it is compliant with current Good Manufacturing Practices (cGMP), etc.
Regulators may require additional trials or studies to be conducted before market approval. The reality is that fewer than 10% of candidate products investigated in Phase I clinical trials are eventually approved for marketing, and the process at best takes several months, but can take years.
Understandably, the layperson might argue that given the global pandemic, the process of drug and vaccine development should be expedited, and there are some measures in place, such as Emergency Use Authorisation (EUA) and Accelerated Approval, which can reduce the time between clinical trial and market approval.
Drugs which are granted EUA are not formally approved, but they are permitted to be distributed based on the best evidence available and they are used to treat patients in cases where no effective treatment exists.
The now notorious hydroxychloroquine was granted EUA for treatment of Covid-19 by the US FDA on 28 March. But this authorisation was revoked on 11 June due to a lack of proven benefits in a randomised clinical trial, as well as the demonstration of serious cardiac side effects. The actual mechanism of hydroxychloroquine is not entirely clear, but it is believed to inhibit viral entry into cells.
The use of a drug or vaccine is approved by the regulatory authority for pre-specified purposes. If a treatment is used for a different purpose, additional regulatory approval or EUA is required (e.g. hydroxychloroquine, which is traditionally an anti-malarial). Both novel and repurposed drugs and vaccines are being developed for the treatment of Covid-19; the front-running vaccines are from both categories.
Vaccines in the pipeline
Four vaccines – two TB vaccines; the MMR vaccine; and the ChAdOx1 nCoV-19 vaccine – are in Phase III clinical trials. Of these, the only vaccine which is new for Covid-19 is ChAdOx1 nCoV-19. Both the TB BCG vaccine and the ChAdOx1 nCoV-19 vaccine are in Phase II clinical trials in South Africa.
The ChAdOx1 vaccine is based on a weakened, non-replicating version of the common cold virus. It is engineered to present the SARS-CoV-2 spike protein to the body and elicit a protective immune response.
In pre-clinical trials, ChAdOx1-vaccinated monkeys that were infected with SARS-CoV-2 (the virus that causes Covid-19) had a reduced viral load and no pneumonia symptoms.
In addition to South Africa, the ChAdOx1 vaccine is now in Phase II/III clinical trials in various locations around the world. In the UK, 10,000 volunteers are participating in a Phase III clinical trial, and the USA is planning a 30,000-participant Phase III clinical trial in the near future.
The theory behind using existing vaccines such as those traditionally used for protection against TB and measles is that, although these vaccines are not specific for Covid-19, there is some cross-protection.
Other novel vaccines in the late stages of development are CoronaVac (SinoVac) and mRNA-1273 (Moderna), both of which are due to begin Phase III clinical trials in the near future. Furthermore, CanSino Biologics’ Ad5-nCoV vaccine has reportedly been approved for military use in China after promising Phase I and II trials.
Antivirals in the pipeline
Many existing drugs have been redirected for Covid-19 treatment and are currently in clinical trials. These include anti-HIV and anti-influenza drugs. Another antiviral strategy is to treat patients with convalescent plasma, that is, blood plasma containing antibodies (part of the body’s defence mechanism) against the virus taken from patients who have already recovered.
Treatment with convalescent plasma is in Phase III clinical trials in many locations all over the world. South Africa is due to start its own trial in the near future, spearheaded by the South African National Blood Service (SANBS).
Antibody drugs mimic the body’s natural defence mechanism. They are essentially copies of neutralising (effective at inhibiting the virus) antibodies against SARS-CoV-2. Using a variety of production systems, these antibodies can be manufactured on a large scale.
Regeneron’s antibody cocktail, REGN-COV2 is soon to enter Phase III clinical trials. It contains two antibodies that target the virus’s receptor binding domain (RBD) to prevent the virus from entering cells.
An additional drug that has been redirected for the treatment of Covid-19 and has received EUA (by the FDA and EMA) for compassionate use, is Remdesivir, manufactured by Gilead Sciences. It was previously shown to have potential as an anti-Ebola drug and is thought to act by inhibiting viral replication.
Clinical trial data shows that Remdesivir reduced recovery time from 15 days (no treatment) to 11 days (with Remdesivir), although whether it reduces mortality significantly is still unknown. More recent evidence shows that Remdesivir inhibits SARS-CoV-2 in human lung cells.
RT-PCR tests for Covid-19 have been available in South Africa since the early days of the pandemic.
These tests detect viral genetic material (RNA) in nasal secretions. Public and private healthcare providers as well as pharmacies collect a nasal swab. The samples are then sent to a pathology laboratory such as Lancet, Pathcare, or Toga for testing.
RT-PCR is a highly common laboratory technique that involves the amplification of genetic material, i.e. DNA or RNA. However, the procedure takes several hours before completion, quickly leading to backlogs.
Serology tests for Covid-19 require small blood samples and provide results in a matter of minutes. They test for the presence of antibodies against the virus, but these antibodies can take up to two weeks to be produced in sufficient quantities. A Chinese imported (Tip Top Trade (Pty) Ltd.) serological test (Zhejiang Orient Gene Biotech) is available in South Africa and has a section 21 licence or authorisation.
A handful of companies (Medical Diagnostech, LifeAssay Diagnostics, Lateral Flow Laboratories) in South Africa have the capacity to manufacture many thousands of Covid-19 serology tests per month, although, as of writing, their tests await SAHPRA authorisation.
SAHPRA’s stance as of 30 March is that serological tests are not suitable for the diagnosis of acute Covid-19 due to the unknown time between antibody generation after infection, and that these tests are better suited for viral-surveillance studies. The utility of Covid-19 serological tests at this stage in the pandemic remains controversial.
Once the efficacy of a treatment or test has been established, national distribution and cost depend on if the product can be manufactured locally or will need to be imported.
For all novel Covid-19 late-stage vaccines, manufacture will most likely have to take place in other countries and be imported. According to Prof Shabir Madhi, Professor of Vaccinology at Wits University, Biovac in Cape Town “do[es] not have [the] technology to produce gene-based or vector-based vaccines” such as ChAdOx1 nCoV-19.
However, antibody drugs can be manufactured locally by companies such as Cape Bio Pharms*, pending cGMP certification. Other frontline antivirals such as Remdesivir will likely need to be imported.
As the clinical trials reveal their data, the distance to a highly efficacious treatment or combination of treatments grows shorter. The equitable access to the most promising Covid-19 treatments both globally and nationally requires the attention and proactivity of the South African government. DM
Timothy Dennis is a research scientist at Cape Town-based biotech company, Cape Bio Pharms.
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