Lamotrigine Review: Appendix 2 – Associate Professor Doogue’s advice
From: A/Prof Matthew Doogue
Department of Medicine
University of Otago
To: Dr Jonathan Coates
19 April 2020
Re: Independent Review of PHARMAC’s Lamotrigine Sole Supply Decision
I am a qualified medical practitioner with vocational registration in the specialties of Clinical Pharmacology and Endocrinology (NZMC Registration No. 22733). My qualifications include MBChB and FRACP. I am employed by the University of Otago – Christchurch as Associate Professor of Medicine and by the Canterbury District Health Board (CDHB) as a Senior Medical Officer in Clinical Pharmacology and General Medicine and as Clinical Director of the Department of Clinical Pharmacology.
Clinical Pharmacology is the scientific discipline that involves all aspects of the relationship between drugs and humans. The clinical speciality includes all aspects of quality use of medicines. My academic role includes teaching clinical pharmacology from undergraduate to specialists and my research interests include adverse drug reactions and clinical decision.
I have been asked to provide clinical advice for the Independent Review of PHARMAC’s Lamotrigine Sole Supply Decision. More specifically, I was asked to explain, bioequivalence and interchangeability. I was further asked to comment on aspects of the decision to move to one brand and to comment on implementation planning and risk mitigation. I was further asked to comment on PHARMAC’s response to Medsafe’s submissions and on quality assurance. I was provided with copies of PHARMAC documents pertaining to the matter and I accessed published literature and reports relevant to the questions asked. I have not listed these. I have selectively cited a small number of key references that are important to the questions asked.
I have read the terms of reference for the independent review of PHARMAC’s lamotrigine sole supply decision. I note the parameters of the review state:
The review is intended to be an “end to end” review of the systems and processes followed by PHARMAC in relation to the sole supply decision. In particular, it will address:
- all preliminary steps which led to the sole supply decision,
- all steps since taken to implement the decision,
- all steps responding to subsequent events.
For the avoidance of doubt, the review is not intended to be a reassessment of substantive decision making, but will include matters such as the sufficiency of the information provided to the decision maker.
The issues raised here are not new and have been extensively discussed and documented many times. However, the level of knowledge and understanding of the issues in the health professions and the public is variable. Differences in perceptions of the issues can lead to differences in views and actions.
Examples of the state of knowledge in New Zealand include a special edition of the Best Practice Journal (BPAC) on generic medicines in 2009. This explains the concepts and issues to a general clinical audience and illustrates the level of knowledge expected of a prescriber. There was a report on brand switches in New Zealand provided by MedSafe to the Medicines Adverse Reaction Committee in 2018. This provides in depth review of previous experience in New Zealand of controversial brand changes. The findings in this review are similar to those in other countries. This can be summarised as, problems relating to brand switching are seldom pharmacological.
There is a long history of concerns about brand changes and of actions to protect the market position of different brands of medicines. In this respect medicines are similar to other widely used products. The difference between medicines and other products is how tightly medicines are regulated.
For a context most people are familiar with using different brands of flour or different brands of petrol. Flour (food) and petrol (fuel) are less tightly regulated than medicines. Food must list its ingredients and be produced in a safe way, this is less strict than for fuel or medicines. Fuel must demonstrate ‘quality’ of product, this aspect is similar to medicines. ‘Quality’ in this case means the product reliably has a certain chemical composition. For medicines there is regulation of both quality of the product AND additionally of the amount (rate and extent) of the drug in the blood of people taking the medicine. This is the concept of bioequivalence.
For medicines different brands must both have same amount of the medicine AND be bioequivalent.
Bioequivalence: taking one brand of a medicine gives the same amount of drug in the body as taking another brand.
Two brands of the SAME medicine are bioequivalent when the SAME dose gives the SAME concentration of medicine in people taking the medicine. Functionally, this means that if two brands are bioequivalent, then the same dose is expected to produce the same clinical effect regardless of which brand is used.
A new (‘comparator’) brand must demonstrate bioequivalence to the existing (‘reference’) brand. The reference brand is usually the ‘originator’ brand, which has had safety and efficacy demonstrated in clinical trials. This process is also regulated.
To establish bioequivalence both steps must be demonstrated. Firstly, the comparator must be manufactured to Good Manufacturing Practice (GMP) standard and contain the same amount of the active ingredient. Secondly, a bioequivalence study is undertaken to demonstrate equivalent bioavailability to ensure the comparator has the same pharmacokinetics as the originator.
The requirements of the bioequivalence study are that both the maximum concentration achieved and the area under the concentration-time curve of the comparator have geometric mean values and 90% confidence intervals within 80-125% of the mean values of the originator. For narrow therapeutic index drugs (including lamotrigine), a tighter value of 90-111% is used.
This is measured by studying a group of people given a dose of the comparator brand one day and a dose of the reference brand on another day. The concentration of the active drug in their blood is measured several times after each dose. The concentration of the drug in the people is compared between the two brands.
Medsafe is responsible for establishing that approved generic medicines are bioequivalent to the originator. It is the responsibility of the pharmaceutical company wishing to market and distribute the comparator in New Zealand to provide the information to MedSafe in an application for approval. This includes evidence of GMP and the bioequivalence study, or studies. The processes for this are rigorous and New Zealand is very similar in to Australia and Europe and similar to USA and Japan.
For clarity, Medsafe is not responsible for unapproved products.
In the case of lamotrigine, bioequivalence between Logem and Lamictal was established prior to Logem being distributed in New Zealand. After reports of issues after switching brands this was reaffirmed by MedSafe in a Prescriber Update.
Because lamotrigine brand change has been previously associated with uncertainty, differences (or not) between brands of lamotrigine has been more thoroughly studied than for most medicines. In addition to bioequivalence studies there are randomised trials that have demonstrated equivalent effects of different brands of lamotrigine.,
PHARMAC could reasonably conclude that for patients who take their medicines correctly, switching between brands of lamotrigine would not cause meaningful differences in drug exposure. PHARMAC could reasonably conclude the pharmacological effects of the brands would be the same.
NB: within a brand no two tablets are exactly the same. There can be small differences within batches and between batches. Additionally there can be small changes over time (this is another concept ‘stability’). These are also regulated by Medsafe.
Interchangeability and Substitution
Interchangeability means that two brands are expected to produce the same results when consistently used. Substitutability means that they can be switched. To be substitutable they also have to be available in the same form (e.g. tablet or liquid) and packaging (e.g. blister pack or bottle). These terms are not always used consistently but further discussion is not needed for the purpose of this report. In New Zealand interchangeability of medicines is regulated by MedSafe. MedSafe may gazette a brand as not interchangeable. The regulatory process is such that brand interchangeability is ‘expected’.
Interchangeability is necessary as supply of an individual brand cannot be guaranteed for ever and there are many circumstances when brands may need to be switched. In New Zealand we have very few different brands of medicines because we have a single purchaser, PHARMAC, negotiating with suppliers. In most countries, including Australia, there are usually many brands of a medicine available and substitution of brands is common.
This is particularly visible to consumers for medicines available for general sale or over the counter at pharmacies. On the supermarket shelf you can see two different brands of paracetamol side by side. There are more brands of these available in New Zealand because general sale items are not funded by the taxpayer and hence are purchased by retailers, rather than by PHARMAC.
Interchangeability is determined by the regulator and substitution is undertaken by the pharmacist at dispensing. This is defined in the medicines regulations. In New Zealand when PHARMAC changes funded brands this affects a lot of people at the same time. In Australia each individual pharmacy negotiates with suppliers and changes usually affect a small number of people at a time. Prior to the awarding of sole supply to the Logem brand of lamotrigine there were three brands of lamotrigine available and substitution could occur. For example if a patient went to a different pharmacy they may not have stock of a particular brand. Pharmacists endeavour to maintain brand consistency for patients, particularly for narrow therapeutic index drugs, and make efforts to counsel patients when changes occur. However because there are many different medicines in use and supply changes, brand changes are common.
Interchangeability and substitution poses four potential risks:
- Confusion due to changes in packaging or tablet appearance etc. This can be compounded if a brand change has different strengths available e.g. brand A has 50mg capsules, but brand B only has 25mg capsules and therefore patients need to take two capsules of brand B. Note that Logem and Lamictal have the same strengths and so this is not a relevant factor for lamotrigine.
- Patients have pre-existing preferences for brands which can affect confidence, adherence to regimens and placebo/nocebo effects.
- Bioequivalence is usually established in healthy, young participants. There are physiological changes with age, disease and medicines which alter bioavailability (for example, gastric pH changes with age, disease (e.g. Zollinger-Ellison syndrome) and with medicines (e.g. omeprazole)). Theoretically, some formulations may be more resistant to these changes than others. However this has not been shown in practice. For lamotrigine the randomised controlled trials of brands did not find evidence of this in patients with epilepsy.,
- Bioequivalence is established with population pharmacokinetics. Theoretically, an individual may exhibit a difference masked by the population mean. This has not been shown in practice. An example where I might be concerned would be a patient who had short gut (from extensive bowel surgery) AND it was two different brands of modified release preparations.
The first two risks can be mitigated, but not eliminated, by patient counselling at the time of brand switching. All approved products in New Zealand must follow GMP which mitigates the risk of variability in product quality.
If there are still concerns in particular situations, lamotrigine drug concentrations can be measured in individual patients before and after significant changes in treatment. If unexpected clinical events occur drug concentrations are one of the tests used to investigate the reasons for changes.
NB. For stable patients, the reference concentration would be the drug concentration in that patient prior to switching, rather than the reported population reference range.
Decision to move to one brand
The decision was based on advice of the PHARMAC Neurological Subcommittee. The subcommittee concluded:
1.44 The Subcommittee considered all of the consultation feedback, including the concerns raised by Medsafe with regards to the possibility of an increase in breakthrough seizures attributable to a brand change, and considered that based on a full review of the available evidence, there was no pharmacological reason to suggest there would be a clinical problem with changing brands of lamotrigine for patients with epilepsy or mental health conditions.
1.45 The Subcommittee considered that there would be patients who experience adverse events, e.g. breakthrough seizures, even when there is no brand change. The Subcommittee considered that in the event of a brand change there would be patients who experience adverse events that would attribute these to a brand change, and that factors likely to contribute to this perception could include reduced adherence, nocebo, or other psychological factors
1.46 The Subcommittee considered that ensuring adequate information, education, and reassurance to healthcare professionals and patients would be required to support patients with epilepsy or a mental health condition should there be a brand change for lamotrigine. 1.47 The Subcommittee considered that it was supportive of the proposal to move to one funded brand of lamotrigine (Logem), with implementation support as discussed above”
In my view these conclusions are consistent with and supported by the evidence as cited in this report. As referred to there are ‘social risks’ of brand change.
- The first of these is change in adherence, confusion and consequently not taking the medicine in the same way causing a difference in drug effects.
- A second risk is a change in placebo/nocebo effect – some of the effects of medicines are due non pharmacological factors which are affected by expectations and beliefs.
- A third risk is that events are occurring regardless and that any event occurring soon after a change may be attributed to the change. Association versus causation.
Patients with epilepsy report issues with brand changes more than some other conditions. The reasons for this are not well understood. A characteristic of epilepsy is that seizures are dramatic intermittent events that fluctuate in frequency. Changes to disease control in individuals happen and are not always easy to explain.
I have been asked specific questions related to this issue.
- Please explain the difference between the pharmacological risks and the other management (or ‘social’) risks associated with the move to the one brand (Logem).
- See above
- Do you consider that there were material pharmacological risks (not management/social risks) with this brand change?
- No, see above
- Do you think that PHARMAC, working through its subcommittees, had sufficient evidence to conclude that moving to one brand of lamotrigine was appropriate? (see, for example, the conclusion in the Neurological Subcommittee meeting minutes 11 November 2015 at 7.22).
- Yes, as documented in the minutes of the Subcommittee
- Do you see significance in the Neurological Subcommittee’s inability to reach a consensus as to whether lamotrigine should be in category one, two or three of the UK MHRA categorisation? (see 11 November 2015 minutes at 7,10, 7.12, and 7.21).
- No. The UK MHRA categorisation has been useful. It is not an international regulatory standard, it is rather a categorisation to ‘help’ with decisions. The need for this categorisation has largely been superseded by regulators adopting tighter criteria for narrow therapeutic index drugs. This is illustrated by the more recent American Epilepsy Society position statement, discussed further under implementation.
- Do you think PHARMAC’s original exceptional circumstances criteria was adequate protection for the particular consumer group?
- Insofar as the management/social issues of moving to Logem (as a sole brand) are concerned, how do the foreseeable consequences compare with brand changes in other areas?
- Epilepsy is a particularly difficult condition for brand changes and it is foreseeable that any brand change in epilepsy treatment will be difficult. Another example where difficulties are foreseeable is transplant medicine.
- This is reflected in the additional measures PHARMAC took and also demonstrated by the subsequent problems leading to this review.
- The review by MedSafe of brand changes in New Zealand, cited above, addresses this issue in detail. I have attached it as a supplement to this report because it addresses this, and related issues, in detail.
Implementation planning and risk mitigation
Firstly my response to the specific questions asked.
- Is it correct to say that implementation planning, and risk mitigation strategies, is directed at the management/social risks associated with the brand change to Logem?
- Are there national or international standards and/or guidelines addressing brand changes of medications? Are there any that specifically address brand changes of anti-epileptic drugs (AEDs)?
- Brand changes are a normal rather than an unusual occurrence, as outlined above. Brand changes are largely managed by pharmacists as outlined in the medicines regulations. Other health professionals, including prescribers have a responsibility to understand the issues of brand changes and support patients. There is guidance for health professionals about managing brand changes, for example the BPAC publication cited above.40 BPAC was also one of the avenues used to communicate the change.
- In 2014 the MHRA (UK) issued guidance for the UK re anti-epileptic drugs, which was considered by and referred to by the Neurological subcommittee of PHARMAC. Although often cited, this guidance has been superseded. NB: Even if considered applicable this guidance would not alter the findings of this review.
- In 2016, following the randomised clinical trials of lamotrigine brands, the American Epilepsy Society issued an updated position statement on generic antiepileptic drugs.51 with the following:
- “The AES supports ongoing research by the FDA to study factors (e.g., extended-release products, tablet or capsule color and shape, nocebo effect) related to the generic substitution of AEDs in adults and children.
- The AES acknowledges that drug formulation substitution with FDA-approved generic products reduces cost without compromising efficacy.
- When dispensing medications to patients, healthcare professionals should ensure that a bioequivalent FDA-approved generic product is substituted for the brand or another generic AED. For example, an immediate-release generic product should not be dispensed as a substitute for a delayed-release or an extended-release product.
- Based on data showing that tablet or capsule color or shape and that statements about drug products impact patient adherence and drug response, healthcare professionals should exercise the highest standards of care when substituting generic products (4, 5).
- Patients or caregivers should be informed when substitution of a drug product results in a change in color or shape. Drug products that differ in color or shape should not be mixed in the same prescription vial to avoid confusion by the patient or caregiver.
- Descriptions of generic products for patients and caregivers should indicate that generic products are equivalent to the brand product. Patient counselling should not include descriptions of generic products as being a cheaper or lower-quality version of the brand product.”
- Have you identified any mitigation actions that you would expect to be taken that PHARMAC omitted to take?
- The guidance offered by PHARMAC around switching was sufficient to inform good medicines counselling by doctors, pharmacists and nurses. Therapeutic drug monitoring was suggested as a measure to help if needed. This is an effective measure to manage individuals (as discussed above) and can be used, but is not required, at brand change.
- Of note the brand was in existing use in New Zealand, this was not switching all patients from one brand to another but consolidation to use of a single brand.
Secondly I quote the MedSafe report to the Medicines Adverse Reaction Committee in 2018 cited above.
“6.0 DISCUSSION AND CONCLUSIONS
Brand switches will continue to happen in New Zealand due to the function of Pharmac and the increasing number of generics on the market. Pharmac aligns with international consensus in the economic benefit of generic medicines, however it is apparent from reporting trends that there is a risk of adverse drug reactions when brand switches occur. Currently, Medsafe acts in a retroactive manner to brand switches, where increased reporting encourages reviews of the medicine, media statements and public assurance of safety and quality. Thus, there lies an opportunity to take on a more proactive approach, using general and targeted risk minimisation interventions to enhance public safety, reduce the potential for harm and improve public trust in Pharmac, Medsafe, and the wider government.
On a New Zealand population-level, there is no evidence of issues with brand-switches (35). This is in line with international evidence on the effectiveness and economic benefits of generic medicines. The ADRs that are reported appear to be on an individual level and the causative mechanisms of such ADRs can be difficult to pin point. In the eye of public safety, exploring ways in which Medsafe can approach brand switches to reduce adverse reactions has become important, especially in light of the recent issues with Enlafax (venlafaxine).
The ADRs that occur are likely not of any physiological mechanism, or due to pharmacological properties of the medicine. Theories as to how these come to be may be through negative perceptions and the nocebo effect – where the simple knowledge that the brand has changed may lead to adverse effects. An alternate explanation is that disease-related or non-related symptoms are being attributed to adverse effects associated with the brand switch – these are not true ADRs but are reported and treated as being ADRs. There are rare situations where a patient may have an intolerance to a changed excipient, however these would not be expected to occur at the observed rates.
The media has been shown to play an increasingly important role in the reporting trends. In the early 2000s, brand switches generated ADR reports, but at a much lower number in comparison to recent switches. News was less accessible than it currently is, with online media, social media and discussion boards. Since the Eltroxin formulation issues, the media has started publishing more articles highlighting cases where patients state the cause of their adverse reactions are the brand switch. The validity of these articles are irrelevant to the core issue – media portrayal plays an important role in shaping the public’s perception of the world and will directly stimulate certain trends. High reporting of venlafaxine ADRs directly following media reports is an excellent example of this effect. If only negative effects are [widely] publicised, there is a higher risk of the nocebo effect or misattribution of symptoms.”
The events that have played out with lamotrigine are similar to those on previous occasions and it is possible that media reports contributed to the confusion.
In my opinion PHARMAC’s implementation planning and risk mitigation was of a high standard. Putting additional resources to this would have added cost and been unlikely to reduce risk.
Response to potential adverse reaction notifications
Management of the brand change and supporting patients is the responsibility of clinicians. This includes appropriate management of any reported changes by the patient.
I was asked
- Should any quality control/assurance have been undertaken in 2019, following the adverse reaction notifications, to test the Logem? If so, whose job would this have been?
- The primary responsibility to report potential adverse events sits with health professionals. Reporting is to CARM (Centre for Adverse Drug Reactions Monitoring). If there are specific concerns then a heath professional should undertake further investigations and/or refer onwards.
- If there were thought to be issues of product quality, then this would have implications for approval. The manufacturer has responsibility for product quality and Medsafe has regulatory responsibility. Any concerns about product quality should be raised with Medsafe.
- I have not reviewed the clinical events to be able to comment further. To do so I would need access to other sources of information and an extension of the scope of the review.
Following reports of problems, the media reports and the reported statements of some health professionals may have further contributed to the problem. The possibility of problems was foreseen and the reasons for such problems are known. Attributing the cause of the problems to the pharmacological effects of the Logem brand risks diagnostic error and consequent management errors. This possibility cannot be excluded and needs to be investigated but apriori causality is unlikely.
Following the concerns that were raised, PHARMAC widened criteria for funded access to other brands and provided funding for patient appointment with GPs. The application criteria for other brands are:
- Break through seizures
- Mood destabilisation
- Concerns regarding driving
- Clinical concerns around the patient’s ability to manage a brand change (e.g. previous difficulty with medicine changes, severe anxiety around change
These are broad criteria. While an understandable response to public concern such broad criteria may not be appropriate in future similar circumstances. I would suggest that in future similar circumstances funding an alternative brand may not be an appropriate response.
To illustrate this, consider a patient with another condition treated with a particular brand of a medicine who develops problems. A brand change is not expected to help and would not be an appropriate clinical course of action. A temporal association with brand change understandably raises questions, but accumulated evidence suggests brand change per se is unlikely to cause a biochemical change.
In responding, PHARMACs has broad objectives outlined in the PHARMAC framework including ‘need’ and ‘health benefit’. These include social impacts and managing additional risks such as patients stopping their medicines. The responsibility for individual patients sits with their clinicians.
For lamotrigine, information that no pharmacological consequences were likely was available prior to the brand change. The evidence for this was stronger than for almost any other brand change.
This does not exclude problems occurring. I have not considered what problems occurred and why and detailed examination of each case is required before conclusions can be drawn. This should include careful analysis of clinical events and measurement of drug concentrations. This is outside the scope of this review.
Brand switching of medicines is emotive for patients and health professionals. Epilepsy is particularly challenging as it is a fluctuating condition with dramatic intermittent events. It is understandable and expected that seizures and other events associated with a brand change may be attributed to the brand change. However, to determine causality requires detailed investigation. In previous brand changes subsequent investigation has found that associated events were not caused by the brand changes.
The role and responsibilities of the clinicians and media is not in scope of this review. However, based on previous problems with brand changes, the solutions to avoiding future problems are likely to be with clinicians, media and patient groups, rather than with bodies such as PHARMAC. If there is to be further external scrutiny, this should be considered.
 BPJ SE Generics May 2009 Best Practice Journal https://bpac.org.nz/BPJ/2009/generics/contents.aspx(external link)
 Brand switches in New Zealand. Medicines Adverse Reactions Committee: 13 September 2018
 New Zealand Code of Good Manufacturing Practice for Manufacture and Distribution of Therapeutic Goods https://www.medsafe.govt.nz/regulatory/Guideline/code.asp(external link)
 Some medicines need to be prescribed by brand. Prescriber Update 40(4): 68–69, 2019
 Generic Lamotrigine Versus Brand-Name Lamictal Bioequivalence in Patients With Epilepsy: A Field Test of the FDA Bioequivalence Standard Epilepsia. 2015 Sep;56(9):1415-24. https://pubmed.ncbi.nlm.nih.gov/26201987/(external link)
 Bioequivalence Between Generic and Branded Lamotrigine in People With Epilepsy: The EQUIGEN Randomized Clinical Trial JAMA Neurol. 2017 Aug 1;74(8):919-926. https://pubmed.ncbi.nlm.nih.gov/28654954/(external link)
 New Zealand Regulatory Guidelines for Medicines (Volume 1, Edition 6.16, September 2014)
 PHARMAC. Record of the joint Neurological and Mental Health Subcommittee meeting held on 7 February 2019. 2019. Available from: http://www.pharmac.govt.nz/about/advice/ptac-subcommittees/
 AES Position Statement on Generic Substitution of Antiepileptic Drugs. Epilepsy Curr. 2016 May-Jun;16(3):209-11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913860/
Last updated: 24 June 2020