Multiple sclerosis (MS) is an immune-mediated inflammatory condition that affects the central nervous system (CNS). The inflammatory process causes areas of demyelination, scarring and neuronal damage throughout the CNS, causing symptoms and accumulating progressive disability, which is dependent on the areas of the CNS that has been affected (MS Society, 2020).
Medications available for multiple sclerosis in England
In 1997, Beta-interferon 1a (Avonnex) was licenced in the European Union (EU) for RRMS to reduce the impact and disease process of MS. Today there is a mixture of tablets, injections and infusions available on the NHS for RRMS. It was hoped that Ozanimod would be added to this list and to be the first oral medication to be given after one relapse in 1 year (Comi et al, 2019).
The pharmacokinetics
Pharmacokinetics is a word that is used to describe how a medication passes through the body. This identifies the therapeutic effect of a medication and its safety profile by looking at the time and route the medication takes to be absorbed, distributed, metabolised and excreted (Surapaneni et al, 2021). This is important because certain factors can affect the absorption of a medication and therefore its effectiveness.
Ozanimod is a once-daily oral medication that is absorbed by the gastrointestinal tract. After administration, it is metabolised mainly in the liver via Cytochrome P450 system using CYP 2C9 and 3A4 enzymes. Therefore, the prescriber has to be aware of interactions with other medications that induce or inhibit these enzymes. This is because two medications acting on these enzymes at the same time could increase or decrease the effectiveness of this medication. Ozanimod is distributed in high volumes (meaning that the majority of the active ingredients remain active when changing to metabolites), its metabolites bind well to plasma proteins (98% effective) and its half-life is 17-21 hours (Surapaneni et al, 2021).
Pharmacodynamics of ozanimod
Pharmacodynamics is concerned with a medication's molecular and biochemical makeup that affects the action of the medication. Ozanimod is a Sphingosine 1 phosphate receptor inhibitor. A Sphingosine 1 phosphate receptor is found on lymphocytes, dendritic cells cardiomyocytes and vascular endothelial cells these cells. This receptor is responsible for the regulation of chronic inflammation.
It is thought that by inhibiting this receptor, ozanimod causes downregulation of the S1P1 receptors. By downregulating these cells, it is thought that it reduces the amount of circulating T and B lymphocytes (Surapaneni et al, 2021)
Ozanimod is also active at S1P5 and it is thought that by acting on this receptor, it helps to protect oligodendrocytes, thus helping to protect the blood-brain barrier. It is thought that its role in decreasing the impact of some of the disease markers in RRMS is a result of the reduction of lymphocyte cells that are circulating and migrating into the central nervous system (Sekhar et al, 2021). Unlike its sister drug, Fingolimod, it binds with more affinity to S1P 1 and S1P5 rather than all S1P receptors, thereby reducing the risk of cardiac complications.
Trials in ozanimod
Before trials can begin to find out the effectiveness and safety profile of a medication, Celgene, the company responsible for ozanimod, would have applied for preauthorisation for clinical trials to the European Medicines Agency (EMA) and the Food and Drug Administration (FDA).
Two trials were considered and put forward by Celgene to gain its marketing authorisation and to look at gaining NICE approval.
Radiance
This looked at the efficacy and safety of ozanimod when used with people who had RRMS. The trial was divided into two parts. Part A looked at the safety profile by comparing ozanimod with placebo. It was a phase 2, 24-week randomised double-blinded placebo-controlled study that had three arms. Two different doses of ozanimod were compared with placebo.
Participants were between 18-55 years old, had an Expanded Disability Status Score under five and met the McDonald criteria (Polman et al, 2011), and had had one relapse within the last year or one relapse within 2 years as well as having one gadolinium-enhancing lesion. The McDonald 2010 criteria tool is used to diagnose MS using an MRI scan, looking for lesions that have spread across a period of time. This means that the MRI scan can show if the lesions found have occurred at different times in different places in the CNS (Polman et al, 2011).
Part B was a phase 3 randomised parallel controlled study that compared the clinical effectiveness of two different doses of ozanimod against interferon beta-1a (IFN β-1a) (Avonnex) over a 24-month period. The trial had 1320 participants and was conducted at 147 medical centres in 21 countries including the EU, America and South Africa. The trial took place between 2013 and 2015. The primary outcome measures were annualised relapse rate and secondary measures were the number of new enhancing T2 lesions, number of gadolinium-enhancing lesions, and the onset of confirmed disability progression at three months and at six months.
The trial showed that ozanimod was safe and there were minimum adverse effects. It showed statistical clinical effectiveness at reducing relapse rate (0.17 38% reduction compared to Avonex). Both doses showed a reduction in the number of new or active lesions (Cohen et al, 2019).
Sunbeam
This was a randomised double-blinded double-dummy controlled phase 3 trial that took place in 152 medical centres in 20 countries with 1346 participants. This was a 12-month study with the same enrolment criteria and the same primary and secondary outcomes as Radiance. The outcomes of this trial were that ozanimod was well tolerated and that ozanimod had a statistically lower relapse rate than IFN β-1a. The higher dose of ozanimod was shown to reduce relapses by 48% compared to Avonex. This study did not show any statistical difference in the changes in brain volume between ozanimod and avonex. This led NICE to conclude that there were no data to suggest a reduction in confirmed disease progression (Comi et al, 2019).
Licencing of ozanimod
When ozanimod went through the licencing process, the UK was part of the EU and so to get licencing approval it had to go through the EMA. The EMA was founded in 1995, 2 years after the EU was formed. The purpose of the EMA was to centralise and harmonise the process of medications and medical equipment being licenced. Before this date, all 28 EU countries had their own licencing criteria and agencies. This was not only chaotic, but for the pharmaceutical companies, this meant that they had to apply for licencing for each individual country, which was a timely and costly experience. The EMA has a member from each of the now 27 countries on the committee, and the EMA uses a synthesised approach by consulting with each of these countries as to whether or not a medication or medical product should be granted a licence (Gillert and Jupp, 2021).
Ozanimod was given marketing approval by the EMA in May 2020, 2 months after it was approved by the FDA. Both the EMA and the FDA walk a fine line between safety efficacy and the timeframe to make a decision and the impact this has on the targeted population. Both these organisations are exposed to external pressures from the public, health authorities and pharmaceutical companies to decide within a short timeframe. There have been calls from critics to process the licencing of medications when they are still in phase 2 of trials and to gather the safety data once the medication is available to the general public, because of the length of time clinical trials and then licencing of the medication takes. However, this raises substantial safety concerns and the risks of patients not wishing to participate in a trial once the medication is on the general market, which would make follow up more difficult (Barham, 2021).
An example of this, and of the pressure put on licencing and authorisation authorities such as the FDA, EMA and NICE, is the risk-sharing scheme. In 2002, NICE made the decision not to recommend Beta interferon and glatiramer acetate on the NHS in patients with relapsing-remitting multiple sclerosis (Pickin et al, 2009). The department of health overturned this decision because of public outcry and came up with a 10-year risk-sharing scheme in which the medications could be used in a post-marketing trial to determine efficacy cost-effectiveness and quality of life. It was decided that if, at the end of the 10-year period, the medications had not been shown to have saved £36 000 per annum per patient in terms of quality of life, then the companies would reimburse the NHS (Pickin et al, 2009). However, in practice, it was an impossible task, with patients lost to follow up and difficulties in measuring quality of life, as it was difficult to establish how the patient would have been without this medication. Therefore, the post licencing trial was not able to draw a conclusion and the medications continue to be available and have been shown effective for this condition today (Melendez-Torres, 2018).
The National Institute for Health and Care Excellence
NICE was established in 1999 to ‘improve outcomes for people using the NHS and other public health and social care services’ (Wyatt, 2004). Its role has been expanding and changing since it was developed, but today it provides this by:
- Providing evidenced guidance for health and social care practitioners
- Developing quality standards and performance criteria to assist with providing and commissioning public health and social care services
- Using technology appraisals to assess the suitability for medications and medical devices to be used within the NHS.
NICE is recognised for its robust processes and effective consultations with several different concerning bodies to determine the effectiveness and safety profile of a medication or medical device (Barham, 2021). Many countries look to NICE evidence and guidance to determine whether a medication or device would be beneficial for its own population. NICE is seen by the World Health Organization as the international gold standard in terms of its policies, guidance and technical appraisals (Barham, 2021).
Although other countries have similar institutions to NICE, such as France who have the Haute Autorité de la Santé (HAS) and Scotland who have the Scottish Medicine Consortium (SMC), they do not have the same influences that NICE has gained on an international scale. Ozanimod was reviewed by the SMC, which lead to it becoming available for use in Scotland for RRMS in February 2021 (Scottish Medications Consortium, 2021) (Figure 1).
NICE technical appraisal of ozanimod
Ozanimod gained marketing authorisation by the EMA and FDA for active disease defined by clinical or imagining features. This was specified as one relapse within the last year or one relapse within the last 2 years and at least one gadolinium-enhancing lesion. Once a medication gains marketing approval, NICE aims to assess whether it should be recommended for use in the NHS. The consultation period includes a submission from the company, stakeholder's views including commissioning groups, patient groups and professional groups, and information is then collected by the committee. It can take up to 49 weeks if an appeal against the decision is initiated (Figure 2) (NICE, 2017).
In terms of ozanimod, once NICE finished its appraisal, the company had 15 days to appeal against that decision. After the appeal, if the decision is upheld then the pharmaceutical company can take this to the high court for an appeal. They had 3 months to do this, as the guidance against ozanimod use in the NHS is now in the public arena, it is felt that the company decided against this step.
NICE's decision on ozanimod
Its statistical analysis in terms of confirmed disease progression, where it modelled other comparators, the way it compared and analysed data and the companies cost-utility model all led to ozanimod's downfall when it came to gaining approval from NICE.
These factors led the committee to believe that the company had oversimplified data analysis. The main findings by the committee were there was a lack of comparators for ozanimod and the company was unable to provide information as to why it had changed its marketing stance from firstline to first and second without including any second-line comparators. The committee felt that the disease-modifying therapies being put forward by the company for analysis were substantially less effective than what it would be competing against, were it to enter the NHS market (NICE, 2021).
The committee felt that analysing 3-month data rather than 6-month data in regards to confirmed disease progression was too short a time scale and would not rule out disability because of relapse rather than disease progression. It was felt that the cohort of patients in the trial may have had a milder disease process or that the trial process was too short to show statistically significant differences. This meant that ozanimod could not be shown to be more effective than Beta interferon A at reducing disease progression. It should be noted that Beta interferon A is classed as one of the least effective disease-modifying therapies (NICE, 2021).
The way the data was analysed meant that the committee felt that the cost-effectiveness of ozanimod could not be seen, as it did not show any unique benefits vs its competitors. In 2017, a budget impact test was applied to all medication recommended by NICE. The rationale behind this test was to reduce the impact on the NHS and make access to treatments fairer and more cost-effective.
Once a medication is authorised by NICE, the NHS has 90 days to implement this medication by law. Before the budget impact test was applied, the NHS had to find the money from their budget, which in some cases could amount to tens of millions of pounds. This test allows NICE to work with the pharmaceutical companies to look at ways a drug can be implemented at the best possible price (NICE, 2017).
After a period of consultation with the company and interested parties, NICE's committee concluded in May 2021 that ozanimod would not be recommended for use in the NHS under its current marketing authorisation.
Changes to marketing authorisation in the UK and NICE since Brexit
When part of EU, NICE worked closely with the EMA to determine whether a medication would receive a licence. Since the UK left the EU, these ties have been severed and there is no reason for them to work together. NICE has to work with the Medicines and Healthcare Product Regulation Agency (MHRA) who became responsible for licencing of UK medications in January 2021. Northern Ireland remains under the EMA. This is a new role for the MRCA and it has developed a plan called ‘putting patients first’ in 2021, which looks at how it will work with other agencies both nationally and internationally to try to ensure that the UK can remain at the forefront of medical innovation and management (gov.uk, 2020; Holmes, 2021).
On 7 April 2021, Ofatumumab by Novartis was the first medication to be licenced for use for RRMS in the UK since the new process was put in place. The MHRC is now solely responsible for the licencing of medications in the UK since the UK's exit from EU. The EMA continues to be responsible for the licencing of medications in the EU. The MHRC aims to improve efficiency and encourage pharmaceutical companies to seek UK approval of their medication. To achieve this, it has developed a quicker processing system that will assess and decide on the outcome of whether a medicine will receive licencing within 150 working days. The EMU take 210 days to decide on the fate of a medication (Bailey, 2020; Taylor, 2020) It is recognised and reflected by the MHRA and NICE that they have to work together and put compelling guidelines and policies in place to persuade pharmaceutical companies of the worth of marketing their products in the UK. This is not an easy task, especially as the UK market only represents 2% of the global pharmaceutical market, while EU represents 20% and America 70% (Underwood, 2021).
Conclusion
As it stands, ozanimod is available for use in RRMS in America, Europe and Scotland. Ozanimod did not meet the standards required in the comprehensive review to be given authorisation for use on the NHS. It will take time to see whether NICE and the MHRA uphold their position as a global influencer in the healthcare world or whether pharmaceutical companies will feel that the cost, preparation and robust comprehensive review in the UK are still necessary to compete in an ever-changing world market.
Key Points
- Ozanimod is a medication that is thought to help reduce relapses in multiple sclerosis by modulating the immune system and reducing the inflammatory processes thought to cause demyelination and damage to the central nervous system
- There is a journey a medication needs to take to gain licencing approval and to be made available on the NHS, which is explained in this article
- The journey from the submission of a medication to approval for use on the NHS takes 49 weeks. If it is approved for use in the NHS as part of the NHS constitution the NHS has 3 months to then make this medication available
- This can cause pressures on NHS trusts in terms of the service that is required to get this medication up and running especially if there is lots of monitoring involved with starting the medication or if it needs to be started in hospital
- NHS trusts, therefore, must have funding available, hospital beds, staff, and equipment to provide the service within 3 months of the medication being approved this can cause pressure on NHS trusts.
CPD reflective questions
- How long does a NICE technical appraisal take to complete?
- When was the
- rst disease-modifying therapy licenced?
- How is Ozanimod thought to work at reducing the impact of RRMS?