Pharmaco-Extra-Vigilance: Pandemic Disrupts Pharmaceutical Practices

Wendy McNeely
Adis Pharmacovigilance

he COVID-19 pandemic has necessitated the unprecedented use of pharmaceutical agents in attempts to find an effective treatment for the infection and to manage the severe and varied symptoms associated with it. These activities have increased off-label use of drugs and resulted in pregnancy exposure or lack of efficacy.

From a pharmacovigilance perspective, these “special situations” must be closely monitored to ensure that emerging safety information in such cases is appropriately recorded and analyzed to allow interventions to ensure patient safety.

(In this context, “special situation” means use of a medicinal product during pregnancy or breastfeeding, or in a pediatric or elderly population. Reports of overdose, off-label use, misuse, medication error, or occupational exposure and lack of therapeutic efficacy are also considered special situations.)

From my experience working for a pharmacovigilance literature monitoring service provider, the proportion of special situations identified in the literature represents approximately 15% of all Individual Case Safety Reports (ICSRs). During the first half of 2020, the proportion associated with COVID-19-related drug use further increased by 10%. And while the virus increased the number of drug safety events worldwide, it simultaneously reduced the resource potential to record what will become an important phase in the history of global drug safety.

The increase in safety information combined with the potential for decrease in resources to report it is not ideal, which has been recognized by actions taken by several regulatory bodies: FDA updated its pandemic guideline, the UK’s MHRA opened a designated website for safety reports of new or repurposed medicines for COVID-19, and EMA announced a call to action for COVID-19 patients to report all adverse events associated with any medicines they receive.

These data-capturing processes are essential in our current “trial and error” situation; close monitoring of off-label use of drugs is imperative, now more than usual, to ensure patient safety in the search for an effective treatment in the absence of a purpose-built cure.

This agile approach was demonstrated by the FDA: In March 2020, it issued two Emergency Use Authorizations (EUAs) for remdesivir and for chloroquine phosphate (CQ) or hydroxychloroquine sulfate, but revoked the latter eleven weeks later because of on-going evidence gathering that indicated these agents “may not be effective to treat COVID-19.”

As the pandemic swept the globe, published literature reports began to emerge early in 2020 of tried and failed treatments. In addition to warnings of lack of efficacy with chloroquine phosphate, hydroxychloroquine sulfate, those for azithromycin and lopinavir/ritonavir or other HIV protease inhibitors were also published. Reports of unfavourable outcomes in previously un-investigated drug combinations included azithromycin or remdesivir combined with chloroquine phosphate or hydroxychloroquine sulfate. This highlights the need to be alert for the possibilities of patients being exposed to other un-investigated drug combinations.

In addition to drug safety related to COVID-19, there are growing concerns for safety issues relating to treatments for conditions not related to COVID-19. One is the interruption in supply chains for Active Pharmaceutical Ingredients (APIs) and manufactured novel and generic drugs.

It is possible that the financial burden forced on healthcare systems by the pandemic will increase prescription of generic rather than branded drugs to cut costs and contain budgets. Ironically, the enforced border closures and prolonged lockdowns in China and India have hugely impacted the ability of these countries to produce and distribute generics and APIs. Together, China and India are responsible for more than 80% of APIs used to make drugs sold in Europe and account for more than 30% of the world’s FDA-registered API-manufacturing plants. India alone supplies 40% of the world’s generic drugs.

This dominance was noted before the COVID-19 outbreak: Europe was already keen to bring drug manufacturing back to its homelands, whereas the US seemed less enthusiastic about the concept of making these drugs in America. I would suggest that the global disruption caused by COVID-19 may be the catalyst required to rethink the concept of putting all our drugs in one manufacturing basket.

In some countries, guidelines for starting new medications changed to account for regional availability of branded and generic agents. Dispensing practices have also changed to allow only one month instead of a three-month supply. This could result in more frequent “generic swapping,” particularly as the duration of the pandemic extends.

Adverse events occurring in patients switching to, or between, generic agents is not unheard of. With the likelihood of increased flexibility in prescribing practices, “pharmaco-extra-vigilance” practices are necessary during and in the wake of the COVID-19 pandemic, especially for literature monitoring. This will ensure that all safety events are captured for drugs directly involved in the treatment of the virus as well as for branded and generic drugs impacted by the global disruptions in the supply chains resulting from the waves of lockdown that have swept the globe.