Can managed access agreements help unlock access through the NICE Highly Specialised Technology Appraisal Process?

The National Institute for Health and Care Excellence (NICE) process for single technology appraisals (STA) has been established for many years with clear cost effectiveness thresholds.

Highly specialised technology (HST) appraisals bring significant challenges for both the marketing authorisation holder (MAH) and for the NICE committee and clinical experts. These are:

• Small clinical trial population data sets
• Clinical trial data may not fully represent all patients included in the label
• Regulatory approval is often granted as conditional approval, perhaps at phase 2, or in the absence of long-term outcomes data (recognised unmet medical need)
• Epidemiological data are often uncertain and what is in the published literature may over-estimate the actual country prevalence
• Disease-specific quality of life measures are often absent or in development and generic quality of life measures may not have been included
• Pharma companies seek premium pricing in the perceived absence of robust clinical data

What then, if any, is the role of the managed access agreement (MAA)?

MAAs have been used in STAs for some time, particularly in oncology. The concept was initially introduced as part of the first interim HST appraisals process for the review of Vimizim® (Biomarin) in an attempt to overcome objections and allow for approval. The goal of the MAA is to help define which sub-populations are most severe and also which are most likely to benefit from the technology. This can allow for systematic ‘real world’ data collection where the available clinical data are limited with the intention being to reduce the ‘risk’ to the NHS that they will invest in a technology that proves over time to be ineffective.

An MAA may also help to remove uncertainty in groups of patients where outcomes are not proven or there is a question of value.

Why is this important?

Payers want predictability of patient outcomes and certainty of budget impact

Patient population x price = budget impact

The more certain we can be about patient numbers, the more confident payers will be about our prediction of budget impact; an MAA may define the number of patients who can access treatment over the life of the MAA, however, appropriate patients need to be defined i.e. there is a need to identify those patients most likely to be responders or most likely to benefit from the technology.

Proving Benefit

An MAA may allow for the collection of health outcomes data reflecting the correct endpoints in the eyes of payers; these may differ from clinical endpoints required for regulatory approvals. The systematic collection of health-related quality of life scores and collection of clinical data in populations covered by the label but not adequately represented in clinical trials, may allow a compelling case for ongoing funding of the technology at the end of the agreed data collection period.

Affordability

There is an increasing need to justify that the benefit really is worth the additional cost and price needs to reflect value. The NHS has placed a cap on rare disease expenditure and so for each HST which falls outside this cap, there is the difficult challenge of how to demonstrate value and how to bring the technology within the boundaries that the NHS can afford. An MAA may help to do this but not all HSTs will require an MAA.

What is an MAA?

An MAA is required to define amongst other things: patients most in need; patients most likely to benefit (these two groups may not be the same); start, stop and monitoring criteria; risk-sharing measures to protect the NHS if the technology does not work; commercial terms mutually agreed by the NHS and the company; quality of life benefits allowing for QALY calculation.

The challenge, though, is that to reach the stage of negotiating risk-sharing measures and commercial terms with the NHS, each MAH must first define the clinical criteria for the MAA and redefine the value proposition for the technology and have these agreed by the NICE committee. However, without robust commercial terms, with revision of costs being part of that, it becomes challenging to redefine the value proposition and so a circular debate may ensue. You will need to have cost/incremental cost effectiveness ratio (ICER) close to or below the £100,000 threshold before NICE is likely to agree to creating an MAA.

It is certainly the case that while the NHS must adopt a positive NICE opinion, they may not like the price that they will be compelled to pay as a result.

Whilst there is now formal NICE guidance on MAAs on their website, the guidance is limited and so it is essential to use precedents. An MAA may be used to limit patient access and reduce the number of patients eligible for treatment or the scope may be narrower than your marketing authorisation.

Vimizim® MAA allowed all patients to start with aggressive ‘stop’ criteria

Strensiq® MAA restricted patient starts to the most severe with the expectation that all children would remain on treatment for the 5-year duration

An MAA is a hybrid document. To begin developing an MAA, you must assume it’s a clinical document, BUT you must have commercial agreement for the end points collected. It’s also highly unlikely that all patients will meet eligibility criteria, so which sub-populations are you prepared to trade off?

Measuring quality of life with an MAA

Including an appropriate quality of life tool will be used to determine population benefit and may be linked to any rebate or discounts you sign up to. Whatever tool is used, it is important that this can be used to calculate QALYs.

High population QALY gain (meeting or exceeding that in your NICE submission) = NHS pays higher (discounted) price for the drug

Lower than expected QALY gains = company rebates a proportion of revenue to the NHS or agrees a lower price up front

Disease-specific tools may also be included but unless these can be translated into the calculation of QALYs, they may have no use as part of an MAA and can be an important cost for the company.

Building in QoL data collection is not straightforward – most NHS clinics do not have the capacity to perform even EQ5D questionnaires – so you may need to perform separate data collection.

How to develop an MAA

Good communication is a major factor in developing and implementing your MAA, both internally and externally. Most clinicians will have little or no experience of the NICE process and creating an MAA. Clinicians and patient advocacy groups will generally need to be educated. Both stakeholder groups, as well as clinical representatives of NHS England are essential to developing an MAA as they will be the ones who need to implement it in clinical practice, as well as champion the concept to the patients with the disease in question.

It’s important to understand that

• An MAA is not a clinical guideline
• The more you put in as start criteria, the more you need to monitor and the more data you need to collect – which is logistically challenging and costly
• You need hard end points with reference ranges
• You will need to include quality of life scores even if clinicians think this is irrelevant to clinical decision making
• What is your baseline? If you are transferring patients from a clinical trial or compassionate use to an MAA do you use the trial entry baseline or MAA entry baseline?

Once agreed with NICE, the MAA is mandatory if patients want to go on treatment. They must sign consent and agree to all the conditions laid out in the MAA; there is no other way to get NHS-funded treatment in England for an HST once NICE has made their decision.

Key learnings

If you are engaged with the NICE HST process an MAA may be required so plan ahead.

1. Be prepared to submit a draft with your dossier – think ahead and get physician and patient group input into the draft ahead of dossier submission
2. Keep it as simple to administer and as clinically relevant as possible – you will have to bear the administration costs
3. Get your patient estimates as close to certain as possible and don’t rely on the literature – it’s probably wrong!
4. Budget impact and cost per QALY are key
5. Ensure any quality of life tool can be converted to allow QALY calculation.
6. Decide what you are prepared to trade off.
7. If you want access for all patients, you will have to drop the price!
8. Learn from past mistakes – speak to companies who have gone through this before

About the author

Emma Harvey is an independent medical affairs consultant specialising in rare disease and biotech. She has been involved in two NICE Highly Specialised Technology (HST) Appraisals, having represented Alexion as clinical lead for Strensiq™ (asfotase alfa) and Kanuma™ (sebelipase alfa). She represented Alexion at the first ever appeal against a NICE Final Evaluation Determination (FED) for an HST, for sebelipase alfa. For both these products she led on the creation of managed access agreements, working closely with expert physicians, patient groups and NHS England. Since becoming independent, Emma has, amongst other things, been advising other companies on their NICE HST clinical dossiers, and whether a Managed Access Agreement (MAA) might help to address unanswered questions.

Emma has worked in industry for 19 years and is a Fellow of the Faculty of Pharmaceutical Physicians and a Member of the Royal College of Physicians.

Emma can be contacted at emmaharveyconsulting@btinternet.com