What happens after a successful clinical trial?
It is a common frustration expressed by individuals that there is a delay in bringing medication from the development stage to the point where it is being given in clinic.
The pathway of progress, from laboratory development to clinical trials, is well documented (see drug pipeline). What is less well known is what happens next, after a successful clinical trial. This article outlines the processes that pharmaceutical companies go through in the UK to get a drug prescribed for an individual in their local pharmacy or hospital.
When a pharmaceutical company is developing medications they spend millions in development in a laboratory, giving doses to animals to check whether it is safe and assessing whether there are beneficial effects. They spend further millions (sometimes billions) developing and running a study to test the product in healthy adults, then in a few individuals with the condition, then in many individuals with the condition in a number of different countries. Finally they analyse the information they have collected and seem to have a treatment that: (1) shows significant improvement in the condition being targeted; (2) is safe to use.
- How does the pharmaceutical company move this medicine out to those who may be helped by it?
- How can the company recoup some of the money invested in developing this drug over numerous years?
It is a process that is not often explained but it involves several important steps which can cause significant delays in getting medication to those who need it. In life-limiting or debilitating conditions, such delays are frustrating and highly emotive.
The first step for a company that would like to sell their medicine is to decide where they want the medicine to be sold. Often, particularly in the case of rare conditions, because of the small numbers involved, companies will seek to sell a product in the USA (in which case they contact the Food and Drug Administration (FDA)1) and throughout Europe (in which case they contact the European Medicines Agency (EMA)2) . Alternatively an individual national licence can be sought via the country’s medicines regulatory body. In the UK this is the Medicines and Healthcare Products Regulatory Agency (MHRA)3. These bodies often work together to approve or advise on medicines.
European Medicines Agency
If a study has been well designed, it will have taken into account and be built around the regulations for approval from the EMA, or its US equivalent the FDA1, 2. These are overarching bodies whose job it is to ensure research into medications is: ‘high quality, done ethically, and authorised appropriately’. The EMA decides whether to issue a licence based on the evidence given to them in the study. The decision depends on how well the study was done, how effective the medication appears to be, and how safe it is. This licence is also called ‘marketing authorisation’4.
According to the EMA, their process takes 210 ‘active (working) days’; this may be longer if they have questions to ask the pharmaceutical company.
Medicines and Healthcare Products Regulatory Agency
The MHRA is a UK body responsible for regulating all medicines and medical devices in the UK. MHRA also regulate and work with companies on the design of clinical trials to test medicines. In terms of licensing, they do a similar job to the EMA; however licences issued by the MHRA only cover medicines to be given in the UK3. In order to be successful in this application, companies must be certain their product is showing clear, significant effects and is safe5.
Once the pharmaceutical company have their licence to market the medicine in the EU from the EMA or in the UK from the MHRA, they can then proceed to sell their medicine to the healthcare providers - in the UK this is the NHS. For this they need to get approval from the National Institute for Health and Care Excellence (NICE) which has to review all the information.
What are the processes in Scotland, Wales and Northern Ireland?
In Scotland, decisions on approval after an EMA licence is granted are taken by the Scottish Medicines Consortium (SMC). Wales and Northern Ireland also have separate processes – although often these two countries follow the decision made by the National Institute for Health and Care Excellence (NICE).
National Institute for Health and Care Excellence (NICE)
NICE is a body which is often in the news for controversial decisions over whether to pay for expensive treatments and whether the treatments are worth the money that the NHS spends on them. In reality, NICE do not make the final decision on whether a medication is sold to the NHS; however they do review the evidence and develop guidelines which ‘assist budget holders’6. Legally this means that if NICE approve a treatment, the budget holders within the NHS have to provide the medication on prescription within three months5.
NICE do not review all of the medications that are licensed in the UK; approximately 40% go through this process, and these are selected based on the cost implications (i.e. is this drug going to cost a lot and need to be given to lots of people). The remaining 60% of licensed medications do not go through NICE as they are unlikely to affect the budget of the NHS overall. In the case of medications for rare conditions, these are almost always expensive. This is because not many people will be likely to need them compared to medications for common treatments, and therefore the pharmaceutical company increases the price to compensate for this6. NICE also negotiate on the pricing of the medication, and can ask companies to reduce the price if they think it is too high for the potential benefits. Usually this is decided based on statistical methods such as ‘Quality adjusted life years’ (i.e. how many years, at what quality of life, would an individual have if they took this medicine – vs the cost).
NICE look at medicines via several routes. The most relevant are: the ‘Single Technology Appraisal’, a standard route that is taken in approval of new medicines, and the ‘Highly Specialised Technology’ (HST) route. The idea of the HST route is to assess medicines for a single purpose in rare conditions. NICE has stated that otherwise medicines for rare conditions could be assessed alongside mainstream drugs which may mean fewer medicines for rare conditions are approved7.
The full NICE approval process (including appeals) takes an absolute minimum of 43 weeks, and this process can be much longer8. NICE also consult with both members of the public and patient advocacy groups to allow the public to have input into the appraisal process.
Local commissioning bodies
In the UK, the NHS oversees commissioning of medicines and services. Regionally, choice of services is led and advised on by a ‘Clinical Referencing Group’ – a group of clinicians, experts, patient advocacy groups and the public. They oversee the commissioning done on a local level in a particular type of medicine (i.e. cancer care). Clinical Commissioning groups (CCGs) decide exactly how a budget is spent locally9. If a medicine is approved by NICE, then the CCGs have to find money in their budget to provide it. If medicines aren’t approved by NICE then CCGs do not have to provide the medication and instead an ‘Individual Funding Request’ (IFR) can be made by a clinician. This is a process by which an individual can make a case for why the drug could help them, as a special case10. Broadly there are two reasons for making IFRs; either: the medicine hasn’t been approved for sale in the NHS yet by NICE but there is an individual who, without the medicine, could get worse very quickly without hope of recovery (this is called ‘critical clinical urgency’), or: that there is an exceptional need for the medication in this individual case, i.e. unlike the other people who could be helped by this medicine, this individual has an added reason. The way to begin this process is to approach the clinician in charge of the individual’s care to discuss whether this is something that is appropriate for the individual in question. The IFR process takes between two to four weeks depending on urgency.
Early Access Programme (EAP)
This is also referred to by the FDA as: ‘Expanded Access Program’. In order to get medications out to patients earlier, some companies may explore the possibility of expanding their trial into an ‘extension study’; providing the medication to more patients before approval by the EMA, FDA or MHRA. In the UK, companies can apply for the early access to medicines scheme which can allow medicines to be given to eligible patients 12-18 months before full marketing approval.
There are benefits to EAPs in that they provide a medication to individuals prior to regulatory approval, and they can also allow the drug company to give the medicine to people in countries where the company would not seek regulatory approval due to the size of the country and cost11. There are also drawbacks to EAPs however - companies will not necessarily have gathered all their results from their ongoing studies, safety reporting will be ongoing, and there are a lot of logistical issues to resolve in order to provide medications.
The process that each new medication goes through can be long and involves many steps before medications get to patients. The regulatory process is in place for several reasons, including safety, confirmation of effectiveness, and negotiation with the pharmaceutical company over cost. It is widely accepted that it should be streamlined as much as possible, so that medicines that are both safe and effective can be provided as quickly as possible.
To see a summary flowchart of this process, please click here.
1. US Food and Drug Administration. 2016. Available from: http://www.fda.gov/
2. European Medicines Agency. Paediatric regulation. 2016. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000068.jsp&mid=WC0b01ac0580925c45
3. Medicines and Healthcare Products Regulatory Agency (MHRA). 2016. Available from: https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency
4. NHS Choices. Medicines information - licensing. 2016. Available from: http://www.nhs.uk/Conditions/Medicinesinfo/Pages/Safetyissues.aspx
5. National Institute for Health and Care Excellence - Technology appraisals. 2016. Available from: https://www.nice.org.uk/about/what-we-do/our-programmes/nice-guidance/nice-technology-appraisal-guidance
6. National Institute for Health and Care Excellence. 2016. Available from: https://www.nice.org.uk/
7. Barham, L. NICE and Highly Specialised Technologies: three years on. 2016. Available from: http://pharmaphorum.com/views-and-analysis/nice-and-highly-specialised-technologies-three-years-on/
8. NICE - Guide to the single technology appraisal Process. 2009. Available from: https://www.nice.org.uk/Media/Default/About/what-we-do/NICE-guidance/NICE-technology-appraisals/Previous%20STA%20Guide.pdf
9. NHS Clinical Commissioners - about CCGs. 2016. Available from: http://www.nhscc.org/ccgs/
10. NHS England - Individual funding requests - a guide for patients and service users. 2016. Available from: https://www.england.nhs.uk/commissioning/wp-content/uploads/sites/12/2015/06/individl-fund-reqts-info-pats.pdf
11. Patil, S. (2016) 'Early access programs: benefits, challenges, and key considerations for successful implementation', Perspectives in Clinical Research, 7(1), pp.4-8.