Rational pharmacotherapy in times of pandemic

(Shortened version for ISDB Newsletter of April 2020)

Dr. Dick Bijl,¹ Alan Cassels²

1. Former general practitioner-epidemiologist, president International Society of Drug Bulletins. Vredenburgplein 40, NL-3511 WH Utrecht. e-mail; dick.bijl@hetnet.nl

2. Communications Director, Therapeutics initiative, University of British Columbia. 2176 Health Sciences Mall Vancouver, BC, Canada V6T 1Z3 Alan.cassels@ubc.ca

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The urgency caused by the COVID-19 pandemic accelerated the demand for rapid development of drugs and vaccines. Many studies of drugs and vaccines were launched, but some had serious methodological problems which undermine the ability to draw valid interpretations and conclusions. The International Society of Drug Bulletins calls for the principles of rational pharmacotherapy to be maintained. Even in a pandemic, the vital principles of in dubio abstine (in case of doubt, don’t do) and primum non nocere (first do no harm) must be rigorously observed. This means that drugs and vaccines should be evaluated, wherever possible, by proper randomized double-blind, placebo-controlled trials.  

The current pandemic is caused by a typical virus from a strain that have been around us for many decades and perhaps longer and are one of the viruses that cause influenza-like illnesses (ILI’s) in winter. These illnesses are also caused by other viruses like adenovirus and influenza viruses which are indistinguishable on clinical grounds. The COVID-19 virus was thought to be highly contagious and very virulent and the public was warned that this Coronavirus could cause severe, sometimes fatal lung diseases. The intensive care units of many hospitals in western countries were overcrowded with many severely injured patients and the majority of those admitted to intensive care units or died were mostly older people with comorbidities and consumers of multiple prescription drugs.

For vaccines the process to receive a marketing authorization is essentially the same as for drugs, involving phase I-, II-, III- and IV-studies, a process that usually takes many years to complete the animal and human testing. Both in the European Union (EU) and the United States (US) there are exemptions to the regulatory process and due to the pandemic’s perceived urgency and severity there was a huge push to expedite the process. Fast track procedures have been developed where manufacturers were not required to fulfil all the requirements for their vaccines, and drugs, a fact which simply increases the risk of insufficiently studied drugs and vaccines.  

We have seen past examples where hasty use of treatments without sufficient study has hurt patients. Even during the Spanish flu which killed many millions of people, some of those deaths were caused by injudicious use of aspirin, which was administered in excessive doses (8 to 21 gr).  According to microbiologists this treatment may have been responsible for many fatal haemorrhagic pneumonias. In the last few decades, antivirals to combat influenza were promoted by manufacturers based on dubious claims they could prevent the spread of the virus even in times of a pandemic. The antiviral oseltamivir (Tamiflu) showed a minimal effect in shortening the duration of flu symptoms yet millions of doses were purchased and stockpiled by governments around the world. Today its manufacturer is facing expensive lawsuits for making misleading statements of the drug’s effect.

 Currently, the position of many governments around the world is that unless there is mass vaccination campaigns against Covid-19, social restrictions and limitations cannot be relaxed. This seems the wrong message: The right statement to make is that we need an effective and safe vaccine, one that is proven to prevent illness, complications and death. What effects are we looking for? (See Box)

What would an effective vaccine do? (related to a flu vaccine but also pertinent to coronaviruses)

1. Provide antibody production. It is absolutely necessary that an efficacious vaccine generates sufficient numbers of antibodies against the virus, thus protecting the person against contracting a future virus.

2. Protect against the viral illness. This is efficacy, and is the extent to which the vaccines (shown in the laboratory) can prevent viral infection (or its complications).

3. Protect against flu-like illnesses. This is the concept of effectiveness which means the extent to which vaccines (shown in the laboratory) can prevent flu-like illnesses or their complications.

4. Reduce absenteeism. The extent to which the vaccination can reduce the number of workers losing work due to sick days.

5. Prevent infection and disease in caregivers. Vaccination of staff working with the elderly could lead to a reduction in viral infections and less illness in that population.

6. Provide proper match between virus and vaccine. A flu vaccine’s composition is determined well before flu seasons begin yet its capacity to match actual circulating viruses that season, becomes apparent in the flu season itself. A poor match will lead to poor efficacy, and vice versa.

7. Preventing complications and death. Although vaccination should reduce numbers of infected people, the ultimate goal is to prevent complications and death. Most viral infections are generally harmless to the general population, and healthy infected people are often able to mount an effective immune response.

In the case of the seasonal flu vaccine, Cochrane reviews have repeatedly shown that the NNT (Numbers needed to Treat or Vaccinate) of preventing one case of flu are quite high. For elderly people the NNT of a flu shot is 30, for healthy adults 71 and for people working in health care and caring for the elderly NNT could not even be determined. There are no documented effects on the prevention of complications, spreading of the virus and on mortality.

Unfortunately these NNTs are extremely high and do not justify the amount of public money invested in annual flu vaccine programs by many government. For any Coronavirus vaccine the same data on hard clinical endpoints need to be generated, independently evaluated and then judged on its own merits whether it is effective, and safe. Unfortunately, authorities do not demand data on hard clinical endpoints and clinical relevance.  

WHAT WE KNOW:

• Degree of effectiveness in preventing coronavirus infection. AstraZeneca’s vaccine effectiveness (VE) is more than 60%, Pfizer and Moderna’s VE is more than 90%.  NNT might be over 100.
• Few serious short-term side effects (up to 2 months), especially local transient side effects.

WHAT WE DON’T KNOW (YET): 

• Effects on ICU admissions, complications and mortality.
• Effects on transmission (transmission) of the virus.
• Effects on pregnancy, breastfeeding and fertility.
• Effects considered long-term and serious. 
• Duration of effect: How long the vaccinations work
• Effects against mutated viruses.

When a vaccine is approved it is naïve to think that this will be enough to stop the pandemic. A vaccine that works must be safe, effective and acceptable to the population and show that it is effective in reducing complications and deaths. A vaccine that does little more than prevent some cases of rhinitis is not what the world needs now, but sadly regulatory authorities around the world may compromise their standards, not giving us the science-backed and vital vaccines that the world is waiting for.