It’s time to include real efficacy data on drug labels

Product labels or summaries of product characteristics are viewed as reliable sources of information for healthcare professionals because they describe the properties and officially approved conditions of use of a drug. The Summary of Product Characteristics is a living document that evolves as more reliable information becomes available. Most changes are initiated by manufacturers, but regulators frequently lead changes in safety. The final wording of the initial summary of product characteristics and any other amendments is usually agreed between the regulatory agency and the manufacturer.

In October and November 2021, the European Medicines Agency (EMA) and Health Canada published updated summaries of product characteristics for AstraZeneca’s COVID-19 vaccine (ChAdOx1 nCoV-19).
1
European Medicines Agency
Vaxzevria, COVID-19 vaccine (ChAdOx1-S [recombinant]). Annex 1. Summary of product characteristics. 20 October 2021.

,

2
Health Canada
Product monograph. Including patient medication information. Vaxzevria, COVID-19 vaccine (ChAdOx1-S [recombinant]). November 19, 2021.

For the first time, these updated summaries included new efficacy data from a large, randomized (n = 32,500) phase 3, placebo-controlled clinical trial conducted in the United States, Peru and Chile ( study D8110C00001; NCT04516746).

In late 2020 and early 2021, ChAdOx1 nCoV-19 was temporarily cleared by many regulatory authorities for people 18 years of age or older, with a dosing interval of 4 to 12 weeks between two doses of the vaccine. This vaccine has been authorized in the elderly (≥ 65 years) – the main target population group – despite the lack of clinical efficacy data from randomized, placebo-controlled trials in this age group.
3
When is it reasonable to extrapolate during a pandemic? : the case of general labeling in the United Kingdom for the AstraZeneca COVID-19 vaccine.

Several months later, the clinical efficacy of ChAdOx1 nCoV-19 was estimated in the elderly (≥ 65 years) via real-world mass observational studies performed in the UK, with individuals receiving one or two vaccine doses (with a 12 week interval to maximize initial coverage).

4
Public health England
COVID-19 vaccine surveillance report. Week 37. Sep 16, 2021.

In September 2021, the interim results of study D8110C00001 were published; for the first time, the vaccine’s efficacy was estimated to be 83.5% (95% CI 54.2–94.1) in the elderly.

5
  • Falsey AR
  • Sobieszczyk ME
  • Hirsch I
  • et al.
Safety and phase 3 efficacy of the Covid-19 AZD1222 vaccine (ChAdOx1 nCoV-19).

In the updated summary of product characteristics of EMA, the efficacy of the vaccine in the elderly is only discussed in the study description section D8110C00001.
1
European Medicines Agency
Vaxzevria, COVID-19 vaccine (ChAdOx1-S [recombinant]). Annex 1. Summary of product characteristics. 20 October 2021.

The statement regarding the lack of clinical data preventing an estimate of vaccine efficacy in the elderly, which was introduced in the first published summary of product characteristics, has been deleted in this updated version. Therefore, it must be assumed that, for the EMA, the results of study D8110C00001 filled this gap.

The updated summary of product characteristics shows that the EMA has recognized the ChAdOx1 nCoV-19 safety data in the real world, but has chosen to ignore the clinical efficacy data. The safety information in the summary includes all side effects that have been described after the massive deployment of the vaccine in Europe. For example, the EMA considered a review of individual cases and an observational (network cohort) study (EUPAS40414) based on analyzes from computerized primary care records.
6
European Medicines Agency
Committee for Medicinal Products for Human Use. Evaluation report. Procedure under Article 5 (3) of Regulation (EC) No 726/2004. Invented name: Vaxzevria. Active substance: chimpanzee adenovirus encoding the spike glycoprotein of SARS-CoV-2 (ChAdOx1-S). Procedure number: EMEA / H / A / -5 (3) / 1507. September 16, 2021.

for the evaluation of thrombosis with thrombocytopenia syndrome. Conversely, no efficacy data from real-world observational studies were included. Observational studies have well-known limitations and constraints, but one of their primary goals is to provide post-authorization confirmation of the efficacy of conditionally approved products, such as ChAdOx1 nCoV-19.

seven
WHO
Evaluation of the efficacy of the COVID-19 vaccine. Provisional guidance. March 17, 2021.

We contend that vaccine efficacy data should be included in the summary of product characteristics for ChAdOx1 nCoV-19 for three main reasons. First, the clinical utility of ChAdOx1 nCoV-19 against COVID-19 in the elderly is beyond doubt. Shortly after vaccination rates began to reach relevant percentages, the number of hospitalizations and deaths declined dramatically and remained low for many months among those vaccinated.
4
Public health England
COVID-19 vaccine surveillance report. Week 37. Sep 16, 2021.

Thus, death from COVID-19 has become very rare in fully vaccinated elderly people.

8
  • Barn Z
  • Buelo A
  • Sullivan C
  • et al.
Characteristics and risk of death from COVID-19 among fully vaccinated people in Scotland.

Second, the data from British observational studies meet European methodological standards for this type of research,

9
European network of pharmacoepidemiology and pharmacovigilance centers
EncePP guide to methodological standards in pharmacoepidemiology. 14.2.2. Efficacy of the vaccine. October 28, 2021.

are very reliable and line up in the same direction, with similar estimated effect sizes across the studies, which depended primarily on the SARS-CoV-2 variant prevalent at the time of assessment. Finally, since no new efficacy data from randomized controlled trials (RCTs), except those from study D8110C00001, were included in the updated summaries of product characteristics, it must be assumed that having new efficacy data based on the RCT in elderly people who have received doses of ChAdOx1 nCoV-19 within a 12-week interval will be impossible. Therefore, further information on clinical efficacy will only be available from observational research.

Inclusion of vaccine efficacy data from observational studies in the summary of product characteristics for ChAdOx1 nCoV-19 would be aligned with current EMA thinking regarding the complementary role of real-world evidence in public emergencies.
ten
  • Cavaleri M
  • Sweeney F
  • Gonzalez-Quevedo R
  • Carr M
Shaping European drug regulations in the post COVID-19 era.

Any well-designed, conducted and reported observational study should be considered, although the evaluation of this type of study is more difficult than the evaluation of RCTs. By including actual data in the summary of product characteristics, healthcare professionals will understand that the 12 week interval between vaccine doses in the elderly is evidence-based: not RCT data, but on data from observational studies. This approach should also be considered by the WHO and regulatory agencies in countries such as Australia and the United Kingdom which have not yet included the results of study D8110C0001 in their summaries of product characteristics for ChAdOx1. nCoV-19 and therefore continue to report the vaccine’s lack of efficacy. data in the elderly.

When clinical efficacy data are not available, such as for ChAdOx1 nCoV-19 and the 12 week dosing interval in people 65 years of age or older, regulatory authorities worldwide should begin including reliable clinical efficacy data from observational studies on product labels. whether these data can support claims without justifying the RCT data.

We do not declare any competing interests.

The references

  1. 1.
    • European Medicines Agency

    Vaxzevria, COVID-19 vaccine (ChAdOx1-S [recombinant]). Annex 1. Summary of product characteristics. 20 October 2021.

  2. 2.

    Product monograph. Including patient medication information. Vaxzevria, COVID-19 vaccine (ChAdOx1-S [recombinant]). November 19, 2021.

  3. 3.

    When is it reasonable to extrapolate during a pandemic? : the case of general labeling in the United Kingdom for the AstraZeneca COVID-19 vaccine.

    Eur J Intern Med. 2021; 87: 1-2

  4. 4.

    COVID-19 vaccine surveillance report. Week 37. Sep 16, 2021.

  5. 5.
    • Falsey AR
    • Sobieszczyk ME
    • Hirsch I
    • et al.

    Safety and phase 3 efficacy of the Covid-19 AZD1222 vaccine (ChAdOx1 nCoV-19).

    N Engl J Med. 2021; 385: 2348-2360

  6. 6.
    • European Medicines Agency

    Committee for Medicinal Products for Human Use. Evaluation report. Procedure under Article 5 (3) of Regulation (EC) No 726/2004. Invented name: Vaxzevria. Active substance: chimpanzee adenovirus encoding the spike glycoprotein of SARS-CoV-2 (ChAdOx1-S). Procedure number: EMEA / H / A / -5 (3) / 1507. September 16, 2021.

  7. seven.

    Evaluation of the efficacy of the COVID-19 vaccine. Provisional guidance. March 17, 2021.

  8. 8.
    • Barn Z
    • Buelo A
    • Sullivan C
    • et al.

    Characteristics and risk of death from COVID-19 among fully vaccinated people in Scotland.

    Lancet. 2021; 398: 1799-1800

  9. 9.
    • European network of pharmacoepidemiology and pharmacovigilance centers

    EncePP guide to methodological standards in pharmacoepidemiology. 14.2.2. Efficacy of the vaccine. October 28, 2021.

  10. ten.
    • Cavaleri M
    • Sweeney F
    • Gonzalez-Quevedo R
    • Carr M

    Shaping European drug regulations in the post COVID-19 era.

    Lancet Reg Health Eur. 2021; 9: 100192

Sara H. Byrd