Re: Covid-19: Order to reschedule and delay second vaccine dose is “totally unfair,” says BMA
Dear Editor
Irrespective of the scientific rationale for delaying a second vaccine dose, doing so may create legal uncertainties both for vaccine manufacturers and for those healthcare professionals charged with administering them.
---
It is a well-established principle that drug manufacturers receive civil immunity when their products are prescribed outside of the terms of the license (prescribing ‘off-label’). Companies cannot prevent off-label use, hence making them accountable would be like chasing carmakers for parking-tickets.
Covid19 vaccines are being granted temporary authorisation under Section 174 of the UK’s Human Medicines Regulation (HMR), which pertains to the spread of pathogenic agents. Use of this provision also activates HMR Section 345, which confers immunity upon not only manufacturers and suppliers, but also upon the healthcare professionals administering the injections.
Providing immunity to doctors and nurses seems entirely necessary given that they are being asked to use a medicine that does not yet have a complete evidence package. It seems even more necessary when you consider that the same is being asked of myriad other professions – from physiotherapists to dieticians – whose unions and professional indemnity insurance are unlikely to offer much protection in the event of problems.
Without this immunity, suppliers might refuse to supply, and vaccinators might refuse to vaccinate.
---
Last autumn it was realised that HMR s174 did not allow the MHRA to specify the terms of temporary licences, also known as the Product Information (PI or SmPC). Therefore, Section 174A was added which states that the licensing authority “may attach conditions” to temporary authorisations.
However, 147A was drafted in such a way that the validity of a temporary licence, and of the immunity, is contingent on all parties demonstrating continued adherence to the newly created ‘conditions’.
The conditions for the Pfizer vaccine are codified in Conditions of Authorisation [1] and also, by virtue of cross-reference, in Information for UK Healthcare Professionals [2]. The latter resembles a standard PI, specifying who may be vaccinated (age, gender, diagnosis etc.) and how they should be vaccinated (dose, frequency, route etc.). Therefore, using the vaccine off-label would seem to breach the licence conditions and, in turn, invalidate both license and civil immunity.
---
Could any of this impact manufacturers or vaccinators? Absolutely.
When first licensed, the Pfizer/BioNTech PI specified a treatment regimen of “two doses (0.3mL each) 21 days apart”. Accordingly, administering the second dose up to 12 weeks later would surely breach the temporary licence conditions. To negate this problem, the PI has simply been changed to “two doses (0.3mL each) at least 21 days apart”. Unfortunately, the manufacturer does not seem to agree.
Product Information is normally arrived at via a process of negotiation. Indeed, the temporary licence states that “Pfizer/BioNTech must liaise with the Agency to provide suitable instructions for usage” and that “the instructions that will be agreed with Pfizer/BioNTech are to be considered as conditions of this authorisation.”
We therefore have the unusual situation of the PI making recommendations for which the manufacturer has no supportive data, and seem to dispute, yet they must ‘recognise’ if they are to continue supplying the vaccine and enjoying civil immunity.
It is not entirely clear how these positions can be reconciled. The dichotomy will only be deepened if patients do indeed receive different vaccines for their first and second doses; a possibility that has been raised by the Joint Committee on Vaccines and Immunisation (JCVI).
---
What of the healthcare profession?
The circumstances under which vaccinators might lose immunity are more complex, requiring not only a breach of the conditions but also a “risk of death or personal injury that is wholly or partly attributable to that breach”. Nevertheless, the issue of off-label vaccine use has been causing consternation for some time.
Minutes [3] from the JCVI’s July meeting, held prior to any licence having been issued, show NHS England asked whether the committee would consider recommending Covid19 vaccines for “off-label use for under 18s or pregnant women”. JCVI responded that it would “consider off-label use, as had been done with other vaccines.”
At the time, it was reasonable to doubt that MHRA would recommend the use of the Covid19 vaccines in children, because they had no data for under 12s and little for under 18s. Precisely why under 18s might be a priority was not documented but when, on November 27th, draft guidance on Covid19 vaccine prioritisation was published (Greenbook Chapter 14a), it acknowledged the potential to prescribe to persons under 18 who are working in residential care-homes.
A few days later, the Pfizer/BioNTech vaccine was licensed and the PI was published. Somewhat surprisingly, given that paediatric data were scant, it permitted treatment of patients as young as 16 years of age, rather than 18. This effectively removed the potential problem of off-label prescribing to some care-workers, who can be as young as 16. When Greenbook Chapter 14a was subsequently finalised, it simply aligned itself with the license conditions.
Now, the issue has returned. While amending the PI to state “at least 21 days” partly addresses one issue, others have, and will, continue to appear. In fact, Greenbook 14a has just been amended again, now proposing that children with neuro-disabilities might still receive vaccination, even if under 16.
Instead of changing the PI again, the Greenbook attempts to resolve this conflict another way: by advising that vaccinating children would constitute use of a ‘special’ under HMR Section 167. Unfortunately, this too appears to be a conflict, because MHRA guidance [4] on Specials specifically excludes any medicine authorised in response to a pathogenic agent from scope.
---
Clearly, there are operational challenges associated with the availability and roll-out of Covid19 vaccines, dealing with which can throw up some conflicts. However, due to the delicate interplay between science, law and public confidence, attempting to resolve these conflicts by varying the terms of licence may not be the best solution. Doing so could erode confidence and introduce still greater uncertainty for healthcare professionals, industry, and patients alike.
Competing interests:
I work as a consultant to industry and have previously undertaken strategic work for both the pharma industry, including Pfizer, and the MHRA. All views expressed in this letter are entirely my own.
Rapid Response:
Re: Covid-19: Order to reschedule and delay second vaccine dose is “totally unfair,” says BMA
Dear Editor
Irrespective of the scientific rationale for delaying a second vaccine dose, doing so may create legal uncertainties both for vaccine manufacturers and for those healthcare professionals charged with administering them.
---
It is a well-established principle that drug manufacturers receive civil immunity when their products are prescribed outside of the terms of the license (prescribing ‘off-label’). Companies cannot prevent off-label use, hence making them accountable would be like chasing carmakers for parking-tickets.
Covid19 vaccines are being granted temporary authorisation under Section 174 of the UK’s Human Medicines Regulation (HMR), which pertains to the spread of pathogenic agents. Use of this provision also activates HMR Section 345, which confers immunity upon not only manufacturers and suppliers, but also upon the healthcare professionals administering the injections.
Providing immunity to doctors and nurses seems entirely necessary given that they are being asked to use a medicine that does not yet have a complete evidence package. It seems even more necessary when you consider that the same is being asked of myriad other professions – from physiotherapists to dieticians – whose unions and professional indemnity insurance are unlikely to offer much protection in the event of problems.
Without this immunity, suppliers might refuse to supply, and vaccinators might refuse to vaccinate.
---
Last autumn it was realised that HMR s174 did not allow the MHRA to specify the terms of temporary licences, also known as the Product Information (PI or SmPC). Therefore, Section 174A was added which states that the licensing authority “may attach conditions” to temporary authorisations.
However, 147A was drafted in such a way that the validity of a temporary licence, and of the immunity, is contingent on all parties demonstrating continued adherence to the newly created ‘conditions’.
The conditions for the Pfizer vaccine are codified in Conditions of Authorisation [1] and also, by virtue of cross-reference, in Information for UK Healthcare Professionals [2]. The latter resembles a standard PI, specifying who may be vaccinated (age, gender, diagnosis etc.) and how they should be vaccinated (dose, frequency, route etc.). Therefore, using the vaccine off-label would seem to breach the licence conditions and, in turn, invalidate both license and civil immunity.
---
Could any of this impact manufacturers or vaccinators? Absolutely.
When first licensed, the Pfizer/BioNTech PI specified a treatment regimen of “two doses (0.3mL each) 21 days apart”. Accordingly, administering the second dose up to 12 weeks later would surely breach the temporary licence conditions. To negate this problem, the PI has simply been changed to “two doses (0.3mL each) at least 21 days apart”. Unfortunately, the manufacturer does not seem to agree.
Product Information is normally arrived at via a process of negotiation. Indeed, the temporary licence states that “Pfizer/BioNTech must liaise with the Agency to provide suitable instructions for usage” and that “the instructions that will be agreed with Pfizer/BioNTech are to be considered as conditions of this authorisation.”
We therefore have the unusual situation of the PI making recommendations for which the manufacturer has no supportive data, and seem to dispute, yet they must ‘recognise’ if they are to continue supplying the vaccine and enjoying civil immunity.
It is not entirely clear how these positions can be reconciled. The dichotomy will only be deepened if patients do indeed receive different vaccines for their first and second doses; a possibility that has been raised by the Joint Committee on Vaccines and Immunisation (JCVI).
---
What of the healthcare profession?
The circumstances under which vaccinators might lose immunity are more complex, requiring not only a breach of the conditions but also a “risk of death or personal injury that is wholly or partly attributable to that breach”. Nevertheless, the issue of off-label vaccine use has been causing consternation for some time.
Minutes [3] from the JCVI’s July meeting, held prior to any licence having been issued, show NHS England asked whether the committee would consider recommending Covid19 vaccines for “off-label use for under 18s or pregnant women”. JCVI responded that it would “consider off-label use, as had been done with other vaccines.”
At the time, it was reasonable to doubt that MHRA would recommend the use of the Covid19 vaccines in children, because they had no data for under 12s and little for under 18s. Precisely why under 18s might be a priority was not documented but when, on November 27th, draft guidance on Covid19 vaccine prioritisation was published (Greenbook Chapter 14a), it acknowledged the potential to prescribe to persons under 18 who are working in residential care-homes.
A few days later, the Pfizer/BioNTech vaccine was licensed and the PI was published. Somewhat surprisingly, given that paediatric data were scant, it permitted treatment of patients as young as 16 years of age, rather than 18. This effectively removed the potential problem of off-label prescribing to some care-workers, who can be as young as 16. When Greenbook Chapter 14a was subsequently finalised, it simply aligned itself with the license conditions.
Now, the issue has returned. While amending the PI to state “at least 21 days” partly addresses one issue, others have, and will, continue to appear. In fact, Greenbook 14a has just been amended again, now proposing that children with neuro-disabilities might still receive vaccination, even if under 16.
Instead of changing the PI again, the Greenbook attempts to resolve this conflict another way: by advising that vaccinating children would constitute use of a ‘special’ under HMR Section 167. Unfortunately, this too appears to be a conflict, because MHRA guidance [4] on Specials specifically excludes any medicine authorised in response to a pathogenic agent from scope.
---
Clearly, there are operational challenges associated with the availability and roll-out of Covid19 vaccines, dealing with which can throw up some conflicts. However, due to the delicate interplay between science, law and public confidence, attempting to resolve these conflicts by varying the terms of licence may not be the best solution. Doing so could erode confidence and introduce still greater uncertainty for healthcare professionals, industry, and patients alike.
Sincerely, Tom Macfarlane.
[1] https://assets.publishing.service.gov.uk/government/uploads/system/uploa...
[2] https://assets.publishing.service.gov.uk/government/uploads/system/uploa...
[3] https://www.gov.uk/government/groups/joint-committee-on-vaccination-and-...
[4] https://assets.publishing.service.gov.uk/government/uploads/system/uploa...
Competing interests: I work as a consultant to industry and have previously undertaken strategic work for both the pharma industry, including Pfizer, and the MHRA. All views expressed in this letter are entirely my own.