Dark Side of Medicine™

The Independent Medicines and Medical Devices Safety (IMMDS) Review was established in 2018 to examine how the healthcare system had responded to concerns about three medical interventions: sodium valproate, Primodos and pelvic mesh.

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Its final report, First Do No Harm, published in 2020, documented serious failures in the way patients had been listened to, risks communicated and safety concerns acted upon.

But returning to the Review several years later has left me with another question.

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What happened to the issue of overprescribing?

How was this possible?

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My interest in this question is informed by personal experience. During the COVID period, serious illness led me to look more closely at my health and treatment as a whole. In doing so, I revisited the devastating consequences of prolonged overprescribing involving two different medicines.

It left me with a deceptively simple question:

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How was this possible?

That question led me back through my own medicine history, but it also led towards a much wider medicine-safety question.

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If excessive prescribing can occur and continue for prolonged periods, what systems and safeguards are supposed to identify it and prevent harm?

It was this question that eventually brought me back to the IMMDS Review.

What did the IMMDS Review say about excessive doses?

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The final report does not appear to develop overprescribing as a distinct line of investigation.

However, the Review's supporting documentation shows that the issue of excessive doses had been brought directly to its attention.

Annex F, which contains the Review's supporting information on sodium valproate, states:

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“One concern that has been raised by patient groups and individuals who have contacted the Review is that some women were prescribed excessive doses of Epilim.”

This is important.

Excessive prescribing is not a question being imposed retrospectively upon the Review. It was a concern raised with the Review itself.

Annex F then examines the historical dosage information supplied to prescribers.#

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The Review records that guidance on the maximum adult dose had never been higher than 2,600 mg per day and was, at the time of the Review, 2,500 mg per day.

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It also records a longstanding principle within the prescribing information: prescribers using valproate alongside other anticonvulsants should aim for optimum seizure control at the lowest possible combined dosage.

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Maximum doses were documented

The Review's dosage table provides a history of this advice.

For 1977, it records that control was usually achieved at 1,000–1,600 mg per day, with a maximum dose of 2,500 mg per day.

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In 1978 the maximum temporarily increased to 2,600 mg per day.

By 1984–85, the information distinguished between monotherapy and combined therapy. For monotherapy, usual control was recorded at 1,000–2,000 mg per day, with increases up to 2,500 mg per day.

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The significance of this is straightforward.

The Review was able to establish what manufacturers had historically told prescribers about dosage and maximum doses.

At the same time, it knew that concerns had been raised that some women had received “excessive doses”.

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Dose also mattered to pregnancy risk

The importance of dose was not confined to whether a manufacturer's recommended maximum had been exceeded.

The Review also documented the developing evidence that pregnancy risk was related to dose.

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First Do No Harm records that advice from 1977 recommended optimum control at the lowest possible combined dosage, with a maximum of 2,500 mg daily.

It records that pregnancy-specific dosage advice was introduced later. By 1994, monotherapy was preferred, dosage was to be reviewed before conception and the lowest effective dose used.

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By 2003, prescribing information explicitly described a dose-dependent risk of neural tube defects, particularly above 1,000 mg daily.

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The Review also records later NICE guidance warning about risks to the unborn child, particularly with high doses of sodium valproate or when it was used as part of polytherapy.

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Dose, therefore, mattered.

It mattered to the treatment being prescribed to the woman.

And it mattered to the level of risk associated with exposure during pregnancy.

What about monitoring?

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The Review contains considerable discussion of monitoring, but monitoring can mean several different things.

There was monitoring of pregnancy risk.

There was monitoring of whether women received appropriate information.

There was pharmacovigilance and adverse-event reporting.

There was consideration of plasma concentrations and clinical monitoring.

There was later monitoring associated with the Pregnancy Prevention Programme.

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Historical prescribing information also shows an important complication: plasma valproate concentrations were not necessarily considered a useful measure of efficacy, and routine plasma-level monitoring was at times described as unhelpful.

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But this is not quite the same question as monitoring prescribing itself.

If unusually high doses were prescribed, what mechanism existed to identify them?

Who reviewed the dose?

How long could a patient remain on that dose?

What happened when prescribing moved beyond recommended parameters?

And was anyone looking at the patient's treatment longitudinally rather than at individual appointments or individual problems?

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These are different medicine-safety questions.

Was this outside the Terms of Reference?

The IMMDS Terms of Reference did not specifically instruct the Review to investigate “overprescribing”.

That distinction is important.

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However, its remit was considerably broader than simply establishing whether sodium valproate caused harm during pregnancy.

The stated purpose of the Review was to improve the healthcare system's ability to respond when concerns were raised about the safety of medicines and medical devices.

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It was asked to examine the historical scientific evidence and the decision-making and actions taken on the basis of that knowledge by manufacturers, regulators, clinicians and policy makers.

For each of the three interventions, it was also asked whether problems could have been recognised sooner and more effectively and whether relevant organisations should have acted upon concerns sooner.

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For sodium valproate specifically, the Terms of Reference included the circumstances surrounding its licensing and “treatment to date for women and girls of child bearing age”, alongside consideration of how developing scientific knowledge was communicated and acted upon.

Those sodium-valproate-specific questions sat alongside the Review's wider systemic remit.

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Perhaps the most important statement for this particular question appears in the description of the Review's approach.

The Review said it would examine:

“processes and safeguards designed to avoid harm to patients, and whether they were effective.”

That sentence deserves attention.

The pieces were there

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When these documents are read together, an unusual picture emerges.

The Review knew that concerns had been raised that some women had been prescribed “excessive doses of Epilim.”

It established historical maximum-dose recommendations.

It documented advice to use the lowest effective dose.

It documented the relationship between increasing dose and increasing pregnancy risk.

It considered clinical decision-making, communication, monitoring, regulation and patient safety.

And its Terms of Reference explicitly included examination of processes and safeguards intended to prevent patient harm.

Yet overprescribing does not appear to have developed into a clear systemic line of investigation.

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Instead, different elements of the issue appear in different parts of the Review.

Excessive doses appear in Annex F.

Maximum-dose recommendations appear in the historical prescribing evidence.

Dose-related pregnancy risk appears in both the supporting documentation and the final report.

Monitoring and safeguards appear throughout the Review.

The pieces were there.

What is much less visible is an attempt to bring those pieces together and ask:

How was excessive prescribing able to happen in the first place?

Touched upon, but not clearly investigated

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This distinction matters.

It would be inaccurate to say that the IMMDS Review ignored dose or knew nothing about concerns over excessive prescribing.

Its own documents demonstrate otherwise.

But identifying pieces of an issue is not necessarily the same as investigating the issue itself.

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From the material I have examined, I have not found a clear systematic investigation asking:

How many women were prescribed above recommended maximum doses?

How high were those doses?

For how long were they prescribed?

Why were maximum doses exceeded?

Were those prescriptions regularly reviewed?

Were adverse effects or emerging health problems considered in relation to dose and duration?

What systems existed to identify unusually high prescribing?

And, if safeguards existed, why did they fail to prevent or correct it?

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These questions concern the women themselves as patients, independently of the additional question of fetal exposure during pregnancy.

That is why this belongs within medicine safety.

An unanswered medicine-safety question

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Medicine safety does not end when a medicine is licensed and its risks are placed in a datasheet or SmPC.

Safety also depends upon what happens afterwards.

What dose is prescribed?

How long does treatment continue?

Does the treatment remain appropriate?

Are adverse effects recognised?

Is the prescription periodically reconsidered?

Can prescribing systems identify when practice moves outside recommended parameters?

And does anyone look across a patient's treatment over time and join those pieces together?

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A safeguard is only effective if it can recognise when something is going wrong.

This brings us back to the words of the IMMDS Review itself: its intention was to examine the processes and safeguards designed to avoid patient harm and determine whether they had been effective.

In relation to overprescribing, that question appears to remain incompletely answered.

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The purpose of returning to this evidence is not simply to demonstrate that excessive prescribing occurred.

The Review itself tells us that concerns about excessive doses had been raised.

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The more important question is:

How was it possible for excessive prescribing to occur and continue, and what should have stopped it?

First Do No Harm asked questions that had too often gone unasked. Its examination of sodium valproate brought together decades of evidence about fetal harm, risk communication and the experiences of affected families.

But within its own supporting evidence are clues to another medicine-safety question.

If excessive prescribing had been identified as a concern, why did understanding how it happened not become a clear part of the systemic investigation?

For me, that is where the next medicine-safety question begins.

 

A note on the evidence used in this blog

The information about historical prescribing guidance, dosage and monitoring discussed in this blog is drawn from the published documentation of the IMMDS Review, including First Do No Harm, its supporting annexes and the Review's Terms of Reference.

This is important because the purpose of this blog is to examine what information was available within the Review itself, how that information was considered and what questions arose from it.

It should not be assumed that the Review's documentation represents the complete historical record. Other source material exists, including historical prescribing information and regulatory documentation, and this may provide additional detail or differ from the way information was summarised by the Review.

Those wider sources require separate examination.

For the purposes of this blog, however, the question is deliberately narrower:

What did the IMMDS Review's own documentation tell us about excessive prescribing, and what did the Review do with that information?

 

References

1. Independent Medicines and Medical Devices Safety Review. Terms of Reference. 2018. In particular: Scope of the Review; Sodium Valproate; Approach.

2. Independent Medicines and Medical Devices Safety Review. First Do No Harm: The report of the Independent Medicines and Medical Devices Safety Review. London: IMMDS Review; 2020. See Chapter 4, particularly paragraphs 4.60–4.62.

3. Independent Medicines and Medical Devices Safety Review. Annex F: Sodium valproate supporting information. 2020. See Section 5, “Information on dosage”, particularly paragraph 37 and Table F.4.

4. Independent Medicines and Medical Devices Safety Review. Annex C: Sodium Valproate Timeline – Key Events. 2020. See entries relating to NICE guidance on high-dose sodium valproate, polytherapy and women and girls of childbearing potential.

5. National Institute for Health and Care Excellence (NICE). The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care (CG137). 2012. Historical guidance as reproduced and discussed within the IMMDS Review documentation.