The South African Health Products Regulatory Authority (SAHPRA) this week announced that doctors will be able to apply for access to the experimental COVID-19 treatment ivermectin in terms of section 21 of the Medicines Act. section 21 is a mechanism that allows for access to medicines that SAHPRA has not yet approved.
In allowing section 21 applications as part of a controlled compassionate access programme, SAHPRA has essentially shifted the responsibility for deciding whether the anti-parasitic ivermectin is safe and effective enough to be used in the treatment of COVID-19 to doctors. This places an enormous responsibility on doctors, since doctors who do decide to prescribe the drug will be responsible for any potential side effects.
How it will work
The SAHPRA guidelines for the use of ivermectin, a schedule 3 drug, require that medical practitioners apply for approval to prescribe for every patient they wish to treat. While SAHPRA aims to respond to applications within 24 hours, it remains to be seen whether they can meet this target, especially if large numbers of applications are received. It also remains to be seen which specific companies will be allowed to supply the drug.
The guidelines released this week were thin on details, but the prescribing doctor will have to provide evidence of the drug's registration and use in other countries and motivate for it as a treatment for their patients. They will need to provide package inserts and information on risks. They will also need to get patient consent. While these steps are required for any section 21 or unregistered drug application, such as cannabis or cannabinoids, many medicines used off label usually have more robust efficacy and safety profiles in place to draw on.
The guidelines do not stipulate the dosages of ivermectin to be prescribed, as there is not enough data to support one dose over another. It also does not contain any warnings of what dosages might be considered toxic. This means that doctors will decide the dosage and for how long the treatment is required with no guidance from SAHPRA. While SAHPRA wants doctors to report on side effects, they also did not provide any guidance on what doctors should be on the lookout for.
Some early stage studies (mostly not published in reputable journals) have suggested ivermectin is safe at a low dose, but there is also some evidence suggesting that higher doses are required for efficacy. How high is high enough to kill the virus and when does it become toxic to humans? This has not been answered conclusively and doctors who prescribes the drug will to some extent be working in the dark. Presumably it will come down to a doctor's clinical experience, particularly with the treatment of infectious diseases.
Ethical doctors who do decide to prescribe ivermectin will probably stick to low doses taken only a few times and will carefully have to monitor patients for any potential side effects. Such doctors will need to have independently studied the available evidence of the use of ivermectin in COVID-19 and be satisfied that the evidence supports their decision to prescribe it. They will after all be going against the advice of most leading regulators and health bodies that advise that ivermectin should not be used to treat of COVID-19, except in clinical trials.
It is obviously a decision doctors should take professional responsibility for, but whether doctors can be held liable if anyone suffers ivermectin-related complications is not clear. Although unlikely, given public interest in ivermectin, in the worst-case scenario a doctor could be called before the Health Professionals' Council of South Africa.
On the positive side the compassionate access programme could help flag safety concerns with ivermectin, if doctors report side effects as they are required to, and if SAHPRA has the capacity to pull together and analyse all the safety reports - which may end up being very many.
The programme will however not tell us anything about the drug's efficacy since there is no control group or systematic study being conducted as part of the programme. There is however a real risk that confirmation bias will bolster people's belief in the drug's efficacy. It is estimated that around 90% of people diagnosed with COVID-19 do well with no intervention; they get better. That's not even including asymptomatic cases. In other words, many people who will be given ivermectin who get better would have gotten better, anyway.
Authorities say not enough evidence
SAHPRA has said it cannot definitively say whether ivermectin has a significant risk or benefit for patients with COVID-19, which is why it is only providing pre-approval access in terms of section 21 at the moment. It has said it will look at a longer-term access protocol while awaiting scientific data from ongoing trials. Our understanding is that SAHPRA received no applications for full registration yet, but reading between the lines it is clear based on the currently available evidence they would not register the drug to treat COVID-19 should they receive such an application.
The World Health Organization, America's Food and Drug Administration, the European Medicines Agency, Australia's Therapeutics Goods Administration and the UK's Medicines and Healthcare Products Regulatory Agency, after having reviewed the data have all decided not to authorise ivermectin for COVID-19 neither for prevention nor treatment until more data is available.
Assessing available evidence, the National Essential Medicines List Committee of the Department of Health found ivermectin trials, thus far, to be of low quality and recommends that the drug not be used generally for COVID-19. Instead it recommends the drug be considered in a trial setting only.
Why then, if most leading health authorities advise against it, has SAHPRA said they would allow pre-approval access outside of a clinical trial?
In indicating that they will issue section 21 authorisations for ivermectin, SAHPRA has buckled under, first, the social pressure for access to the drug and, second, the legal responsibility on them to track and prevent the illegal importation and use of the drug - an enforcement function SAHPRA seems not to have the capacity for.
Stories abound about the drug being sold in many places including hardware stores at astronomical prices, and even then it is uncertain that what a person is purchasing is in fact ivermectin. It seems that by instituting a section 21 process, SAHPRA will at least ensure that only products from reputable manufacturers are permitted - something that may well reduce the potential harm from products that are not quality assured.
But social and political pressure may also have played a role in the decision. Some doctors have already been suggesting to their patients that they use the drug. Some have advocated on webinars and in opinion pieces for wider access to ivermectin. Many have taken up the battle for access to ivermectin on social media - where proper evidence unfortunately often plays second fiddle to anecdote.
Some doctors are justifiably desperate for new means to treat patients in the face of devastatingly high caseloads. There is virtually no recourse for them, especially without the assurance of enough doses of vaccines for the general population. They have argued that, faced with high COVID caseloads and the highly transmissible variant in South Africa, we cannot wait for the data on large double-blinded, randomised placebo-controlled trials and that in the meantime ivermectin is a risk worth taking.
Other doctors, probably the majority as far as we can tell, feel they want to be guided by the "best science" and will only change their minds on prescribing ivermectin when robust evidence is available. These doctors will most likely not apply for access to ivermectin for their patients.
Either way, the jury is still out.
Will ivermectin prove to be the miracle cure for COVID-19 that some believe it is or will it go the same way as Vitamin C, Vitamin D, Remdesivir and Hydroxychloroquine? It remains to be seen.
Whether SAHPRA has struck the right balance in allowing a controlled compassionate access programme while the data on ivermectin is still so uncertain also remains to be seen.
*Adele Baleta is an independent science writer, media consultant and trainer.