COVID breaks the chain

COVID breaks the chain

“A wise human would have an understanding of the supply chain and how the pieces fit together. But it’s against our nature to think about it. (Paolo Bacigalupi)

There is no denying that the COVID-19 pandemic has ravaged the globe, leaving in its wake death and severely ill patients. The novelty of this virus and the speed of its spread have meant there is no specialised cure. Instead, health professionals and pharma companies alike have struggled to repurpose existing drugs in an attempt to treat those that have contracted the disease.

This has resulted in many countries having to break from the authorised prescribing practices in their efforts to find a drug or combination of drugs to defeat the virus or treat its varied symptoms.

From a pharmacovigilance perspective, this unique situation presents many opportunities that could result in a reduction in patient safety. To ensure this does not happen, major regulatory authorities including the FDA, the UK MRHA and the EMA have revised guidelines, set up special reporting websites and pleaded for all and any, valid or suspect, adverse events to be reported, particularly related to COVID-19 treatments.

So – while the regulatory authorities are encouraging patients and healthcare practitioners to be vigilant with safety related to COVID-19, there is also a growing concern for safety issues relating to continuity of treatments for conditions not related to COVID-19. These concerns stem from:

  • the interruption in the supply chain for Active Pharmaceutical Ingredients (APIs) and manufactured novel and generic drugs
  • the unfounded fear that certain medications for cardiovascular and rheumatic diseases could increase the chances of contracting COVID-19.

There is a strong possibility that the financial burden forced on healthcare systems caused by the COVID-19 pandemic will increase prescription of generic rather than branded drugs in an attempt to cut costs and contain budgets.

The irony is that the enforced boarder closures and the prolonged lockdowns first in China and then in India has had a huge impact on the ability of these two dominant countries to produce and distribute both generic agents and the APIs they are manufactured from. China and India are responsible for more than 80% of the APIs used to make drugs sold in Europe; together they host 31% of the world’s FDA-registered API-manufacturing plants. Furthermore, India supplies 40% of the World’s generic drugs, and before it was affected by the pandemic, was making strides to increase its API-manufacturing capacity to become less reliant on China for its chemical supplies.

The reality that the world is majorly reliant on two countries for its ability to provide pharmaceuticals is a concern, especially when we see how quickly the supply chains were impacted by enforced lockdowns.

Interestingly, even before the outbreak of COVID-19, Europe was keen to bring back drug manufacturing to its home lands so not to rely so heavily on imported materials. In the US, however, the concept of drugs made in America is being met with some resistance. Perhaps the huge disruption COVID-19 has had in terms of being able to heal and protect ourselves, maybe the catalyst required to rethink the concept of putting all our drugs in one basket.

With respect to generics, there is a misconception that they do not “work the same way” as branded medicines. Small molecule generics need only demonstrate bioequivalence to a reference product within an accepted 80%-125% margin of difference; generic agents do not have to demonstrate bioequivalence with each other. There is a concern two generic agents can legitimately have a 45% difference in their bioavailabilities. However, the FDA has stated over a 12-year period the average difference in drug absorption between branded and generic agents was 3.5%.

Adverse events occurring in patients switching to, or between generic agents is not unheard of, and in some cases it is the excipients and bulking agents that are the culprits. In an attempt to avoid drug shortages, some countries have changed to prescribing practices permitting only one instead of three months’ supply. This could result in more frequent “generic swapping”, particularly as the duration of the pandemic extends. If this happens, we must rely on patients and healthcare practitioners to report their experiences. And for generic manufacturers extra vigilance regarding literature monitoring is prudent since generic products may be more frequently prescribed than before.

It is not only generic drugs per se that may be cause for concern. The FDA recently highlighted the importance of drug packaging in terms of safe use. In response to a shortage of a neuromuscular blocking agent, required for intubation of COVID-19 patients, the temporary production of a similar drug was permitted without the usual warnings on the bottles. Although the two contain the same active ingredient, Propoven 2% (the drug under EUA) is double the concentration of the FDA-authorised Diprivan; the lack of warnings could lead to accidental overdose if practitioners are not aware of the temporary replacement.

I believe that, especially in the wake of the COVID-19 pandemic, “pharmaco-extra-vigilance” practices are necessary regarding literature monitoring to ensure all safety events, particularly those categorised as special situations, are captured. Not only for drugs directly involved in the treatment of the virus and its pathological symptoms, but also for branded and generic drugs that will have been impacted by the global disruptions in the supply chains resulting from the waves of lockdown that have swept the globe.

Image by Shaojie on Unsplash.

COVID causes chaos and special situations

COVID causes chaos and special situations

“Order brings sameness. Chaos brings newness every moment. The problem is first overcoming our fear of chaos, and then mining for the great ideas and bringing them back home.” (anon.)

Since the start of 2020, and the dawning realisation that something was “not quite right” with the world, chaos has indeed reigned. Bringing with it fear, not only of the chaos, but also of the cause….the novel coronavirus SARS-CoV-2 (COVID)

The COVID-19 pandemic has necessitated the unprecedented use of a number of pharmaceutical agents not only in an attempt to find an effective treatment for the viral infection itself, but also to manage the severe and varied nature of the symptoms associated with this deadly virus.

This has resulted in an increase in the number of (often emergency) situations where drugs have been used off-label and/or resulted in cases of pregnancy exposure or lack of efficacy. From a pharmacovigilance perspective, these “special situations” must be closely monitored to ensure the emerging safety information relating to the use of drugs in such cases, is appropriately recorded and analysed so that subsequent interventions can happen to ultimately guarantee patient safety.

From our experience, the proportion of special situations identified in the literature is approximately 15% of Individual Case Safety studies (ICSRs) reported. During the first half of 2020, the proportion of special situations associated with COVID-19-related drug use has increased by a further 10%…. and this is only the beginning.

Unfortunately, while the virus has increased the number of drug safety events worldwide, it has simultaneously reduced the resource and potential to record what will become an important phase in the history of global drug safety.

This was recognised by the US FDA when it recently updated its guideline related to post-marketing adverse event reporting during a pandemic.

To ensure that safety data related to medicinal use during the COVID-19 pandemic are captured, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) has set up a designated website, and the EMA has taken a similar approach with its call to action for all patients with COVID-19 to report any adverse events relating to the use of medicinal products they may receive, since it is important to understand the potential drug interactions that patients may experience.

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

This agile approach has been demonstrated by the FDA when it issued two Emergency Use Authorisations (EUAs) for off label use of Remdesvir and also for chloroquine phosphate and hydroxychloroquine sulfate; then, just 11 weeks later, the EUA for chloroquine and hydroxychloroquine was revoked, based on on-going gathering of evidence that indicated these agents may not be effective for the treatment of COVID-19.

Use of azithromycin to protect healthcare workers from the virus was fleetingly entertained in the UK; this glimmer of hope was short lived as evidence emerged to indicate azithromycin was not effective and may have an unfavourable risk-benefit profile especially when given in combination with hydroxychloroquine. This was supported by National Institutes of Health that issued guidelines strongly recommending against the combined use of hydroxychloroquine plus azithromycin, citing potential toxicities, and also against the use of HIV protease inhibitors without evidence of clinical benefit against the disease. Although disappointing, this information is important for patient safety, and in terms of pharmacovogliance the lack of efficacy observed with these and other repurposed drugs will contribute to the growing volume of valuable safety literature.

At the beginning of 2020 an increase in special situation literature safety reports began to emerge as the pandemic swept the globe and the world looked for an effective treatment for this disease. A search of the AdisInsight Safety database confirms that off-label use of lopinavir and ritonavir, alone and combination was associated with adverse events in patients located in China, Japan, Poland France Iran and the US. And pregnancy exposure, to a variety of drugs, was evident particularly in China and the US.

With the unfortunate possibility that we will experience a second wave of COVID-19 infections in countries that seem to have already conquered the disease, hopefully we can learn from the safety information generated during the initial wave and can put it to good use.

The global impact this disease has had on the use of pharmaceutical products is yet to be fully realised. I believe that the volume of safety-related literature is set to soar over the next few years as the information regarding this unique situation is processed and published.

Image: Morning Brew on Unsplash.

Artificial Intelligence: organised chaos or chaos ordered?

Artificial Intelligence: organised chaos or chaos ordered?

I recently attended the 7th DIA India Pharmacovigilance (PV) Conference in Mumbai. One of the sessions was dedicated to the Impact of Artificial Intelligence (AI) and Predictive Sciences in the world of PV. The session was moderated by Moin Don and Anju Agarwal; the panel comprised Mengesh Kulkarni, Saikat Biswas, Retesh Kumar and Saurahb Khurana.

The interaction between the panel of guest speakers and the open floor reminded me of the Mumbai traffic: it was frenetic, loud, comprised of many different thought vehicles and yet despite all this – it traveled in the same direction without any head-on collisions! Continue reading “Artificial Intelligence: organised chaos or chaos ordered?”

DIA India 2019: Regulatory Trends in Clinical Safety & Pharmacovigilance (An EU perspective).

DIA India 2019: Regulatory Trends in Clinical Safety & Pharmacovigilance (An EU perspective).

This first session of the conference, chaired by J Vijay Venkatraman, gave the audience a broad overview of the state of flux in pharmacovigilance, essentially resulting from changes initiated in Europe – the impact of evolving Eudrovigilance, Brexit and E2B R3 were the focal points. Continue reading “DIA India 2019: Regulatory Trends in Clinical Safety & Pharmacovigilance (An EU perspective).”

DIA India 2019 – Keynote Presentation: India Implements Initiatives to Encourage Domestic Clinical Trial Activity and Increase Safety

DIA India 2019 – Keynote Presentation: India Implements Initiatives to Encourage Domestic Clinical Trial Activity and Increase Safety

It may not have been his outright intention, but Dr Y.K. Gupta certainly set the scene and piqued the interest of the eager audience ready to receive information regarding multiple aspects of pharmacovigilance that would be lively debated throughout the following two days. Continue reading “DIA India 2019 – Keynote Presentation: India Implements Initiatives to Encourage Domestic Clinical Trial Activity and Increase Safety”

Planning and strategizing in the face of evolving regulatory guidelines: Report from the DIA Pharmacovigilance and Risk Management Strategies Conference (PVRMS19)

Planning and strategizing in the face of evolving regulatory guidelines: Report from the DIA Pharmacovigilance and Risk Management Strategies Conference (PVRMS19)

The PVRMS19 was presented at the Omni Shoreham Hotel, Washington DC, January 2019. During the packed three-day event, we learned that many aspect governing the development and subsequent safe and effective use of medicines are in a state of flux… and so they should be. As we learn by our actions (triumphs and failures) we make adjustments to enhance the future investigations and create medicinal agents that are effective and safe, or more precisely, have a benefit that outweighs the risks. Continue reading “Planning and strategizing in the face of evolving regulatory guidelines: Report from the DIA Pharmacovigilance and Risk Management Strategies Conference (PVRMS19)”

Avatrombopag (Doptelet®): First Global Approval – Reducing the bleeding risks of invasive procedures in patients with Chronic Liver Disease

Avatrombopag (Doptelet®): First Global Approval – Reducing the bleeding risks of invasive procedures in patients with Chronic Liver Disease

Avatrombopag (Doptelet ®) received its first global approval in the US; this was reviewed in detail in the First Global Approval report in Adis’ journal Drugs[1], based on the development milestones tracked in AdisInsight[2]. Continue reading “Avatrombopag (Doptelet®): First Global Approval – Reducing the bleeding risks of invasive procedures in patients with Chronic Liver Disease”

Erenumab (AIMOVIG™): First Global Approval in US followed by Positive CHMP Opinion – Once-monthly prophylactic approach for adults with Migraine

Erenumab (AIMOVIG™): First Global Approval in US followed by Positive CHMP Opinion – Once-monthly prophylactic approach for adults with Migraine

Erenumab (AIMOVIG™, erenumab-aooe) was launched in the US in July 2018, following its first global approval in the region in May, which was reviewed in detail in the First Global Approval report in Adis’ journal Drugs[1], based on the development milestones tracked in AdisInsight[2]. Also in May 2018, the agent received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP). Continue reading “Erenumab (AIMOVIG™): First Global Approval in US followed by Positive CHMP Opinion – Once-monthly prophylactic approach for adults with Migraine”

Durvalumab (Imfinzi®): CHMP Positive Opinion for NSCLC in Europe

Durvalumab (Imfinzi®): CHMP Positive Opinion for NSCLC in Europe

In July 2018 durvalumab (Imfinzi ®) received a positive opinion from the Committee for Medical Products for Human Use (CHMP). The committee recommended marketing authorisation for the agent in Europe for the treatment of locally-advanced, unresectable non-small cell lung cancer (NSCLC) in adults whose tumours express PD-L1 on ≥1% of tumour cells, and whose disease has not progressed following platinum-based chemotherapy and radiation therapy. [1] Continue reading “Durvalumab (Imfinzi®): CHMP Positive Opinion for NSCLC in Europe”