Dr Joy Duffen has been representing The Cure Parkinson’s Trust (CPT) on a number of important panels looking at improving the means by which we may bring new Parkinson's (PD) treatments forward. Having a clear regulatory and commissioning pathway is critical to enable potential new treatments for PD to be easily accessible to people living with the disease.  March 2017 update.

How do we get better drugs to patients?

Whilst the old and established medications that are favoured in the treatment of Parkinson’s might be expected to be amongst the armoury of any good consultant and probably familiar to and widely prescribed to patients, what about the more unusual, new or completely unheard of options? CPT supports much innovative research notably focussing on projects that are very close to clinical translation i.e. could yield new treatments for patients within five years or sooner. These new treatments will not have been in use for other conditions so the knowledge base on their safety and efficacy is limited; they have to go down a route of obtaining a new licence in any country where they are to be marketed. A marketing authorisation or licence is issued by the regulatory authority for controlling the use of drugs in the UK - the MHRA (Medicines & Healthcare products Regulatory Agency) and or through European and/or USA equivalents. The licence is the most reassuring status for patients and prescribers but the development of a new drug from the stage of interesting chemicals in the laboratory to a product can take over 15 years and costs in excess of £1 billion. The fallout rate is high and the licensing requirements onerous.

In the last few years there have been a number of schemes that try to address the frustrating rate of innovation. In terms of new drugs the regulators have developed several routes that can streamline or make less onerous the process of obtaining a licence especially in the case of a drug that can claim to offer a breakthrough in treating a condition which is poorly served; a truly disease modifying treatment for PD could well fall into this category. Orphan Drug Status (EU and USA versions) can facilitate a quicker or smaller trial where a very low number of responders are investigated, generally because the disease is rare but certain subgroups of patients may also qualify i.e. those with a clear genetic predisposition to the effects which the drug is targeting. There is also an Early Access to Medicines scheme which can provide an early indication of potential success of a drug and allow some patient access prior to completion of a marketing authorisation and Adaptive Licensing introduced by the European Medicines Agency to allow a progressive authorisation process as more data is collected.

CPT continues to try to keep in touch with and contribute to developments in the multiple potential routes for taking an exciting new drug candidate to patients in a safe yet expeditious route.

Repurposing

In recent years CPT’s efforts have been focussed on investigating the potential for drugs that already have a licence and a track record of use in other conditions where new understanding of the mechanisms involved in PD indicates that they could have the potential to be disease modifying treatments in this condition (what we term 'repurposing'). Often this theory can be backed up by investigating the drug in various animal models and examining epidemiological data. Drug candidates that have a marketing authorisation/licence have been thoroughly evaluated in terms of the balance of risk and benefit to patients and they have a wealth of preclinical and clinical (human) data to back them up; taking a drug of this type and repurposing it has these obvious attractions as well as others; speed of development and cost being high on the list.

There are still risks associated with using a drug in a previously unfamiliar group of patients and thus the pursuit of a new licensed indication with the accompanying large scale trials to support it is still the gold standard to aim for but where there is good evidence that a repurposed drug can have potential benefit in another unlicensed indication there is the option for registered prescribers to give the drug “off label”, indeed prescribers have the legal power to prescribe any drug or treatment to patients whether it has a licence or not. “Prescribers” include all GPs, consultants and various other specialised health professionals.

In the UK most commonly prescribed drugs for PD are also now off patent (i.e. are no longer the solely owned commercial product of the originating pharma company) and although that means that the cost of their prescription is not likely to be high this and other issues can affect their availability if prescribed off label. The fact that the drug is off patent (or at least there is no longer any exclusivity for a company marketing a suitable form of the drug) means there is little financial incentive for a company to take the drug forward for a new licence as it cannot be sure of recovering its costs.

The most common use of off label prescribing is in paediatric medicines where approximately half of the commonly used drugs have never obtained a licence for specific use in the very young (or the very old!). This is largely related to the difficulty of conducting sufficient clinical trials in the specific age group. Nevertheless most of these drugs will have been thoroughly evaluated and have a long safety record of their use in their primary indication and gradually establish an acceptable track record in those of a different age group. Prescribers in these fields are generally comfortable with this level of off label use but where the practice is less established more caution is evident. The guidance from the General Medical Council is very supportive of off label use but is clear that where there is a licensed alternative that drug should be the first to be considered.

Off label use is patchy and inconsistent. Surveys have indicated that in some cases prescribers are unaware of the flexibility in their right to prescribe off label, the Clinical Commissioning Groups (CCG’s) that determine regional budgets vary in their acceptance of such procedures and therefore their willingness to pay and there was a perception by some to be a reluctance of prescribers to prescribe off label because of the personal liability that this engendered. A lack of effectively disseminated knowledge was also seen to be a limiting factor.

In the UK in the last few years at least two relevant private members bills have been generated as a response to this situation; The Off Patent Drugs Bill was driven by a desire to oblige the government to provide a formal route for drugs to obtain a new marketing authorisation/licence for the new indication when the drugs were already in receipt of such for one indication and proven to be effective in another; and The Medical Innovations Bill instigated originally by Lord Saatchi attempted to find a means of providing greater clarity for off label prescribers i.e. to overcome reluctance to do so where provoked by the perceived liabilities to the prescribing individual. The main provisions of this latter bill were however deemed to be flawed by the relevant stakeholders although a much modified and reduced version - the Access to Medical Treatments (Innovation) Act 2016 - was eventually passed into law in Feb 2016; it provides for the formation of a database sometime in the future.

Both were very well intentioned bills and a campaign of support especially for the off patent bill but more importantly for the requirement to find non-legislative solutions to the unequal access of patients to valuable off label drugs has been led throughout by Breast Cancer Now and supported by CPT and notably AMRC members generally. Ultimately the off patent bill failed but it and its contemporary did provoke considerable debate and resulted in a promise from the Department of Health’s Medicines Pharmacy & Industry Division -

to gather the key stakeholders together to talk this through and identify what further steps might be taken to support prescribers and patients.

Constructive meetings have been held regularly since and much progress has been made; the final meeting was held in Feb 2017 and a comprehensive report and recommendations are being prepared. The Department of Health has also responded positively to pressure from the group to continue with this work until certain aspects notably a “Pathway for Repurposed Drugs in England” is completed; this is contingent upon current changes to commissioning policy that are on-going and the final input and commitment from NHS England and others whose participation is critical.

There have been however many very positive and constructive changes that have been instigated as a result of this consultative exchange. One of the main objectives was to see how to improve the consistency and adoption of new treatments that were yet to fulfil the gold standard of a new licence and/or provide a realistic route to obtaining such when the drug is a generic. All stakeholders agreed that there were many things that could be done within the existing frameworks of legislation and commissioning.

Licence/Marketing authorisation for a new indication: 

In the case of a licence the main problem is the lack of commercial incentive where the drug is off patent. Progress made:

• The regulators are willing and able to offer more and better guidance to not for profit groups willing to undertake the complex and expensive process of obtaining a licence. Charities such as CPT or academic institutions may be able to support the conduct of definitive studies and possibly even pursue a licence directly, ideally supported by a group with the resources and experience to manage the manufacture, distribution, marketing and post marketing surveillance (following up on safe use in practice),

• The British Generic Manufacturers Association (BGMA) announced that they are keen to pilot a licensing programme for repurposed off-patent drugs by partnering with charities. They think they can do this without resulting in a huge increase in the price for the drugs concerned. The Association (26 members) has prepared a paper recommended applying for licenses as part of a HM Revenue & Customs (HMRC) research and development tax relief system. This could offer the medical research charities a way to work collaboratively with the BGMA where existing capabilities, infrastructure and knowledge could be shared. Discussion continues with HMRA.

Development of a repurposing pathway:

Where it is unlikely that any new licence will be sought:

• To support use through other routes proposals focussed around the better utilisation of current groups e.g. recommendation of research results from the NIHR, an MHRA review of safety and efficacy and/or a NICE update to its guidance or use of other review mechanisms. Emphasis is on providing sufficient information to prescribers for them to make a decision with their patients and a need for the drugs concerned to be subject to some sort of uniform financial support i.e. to avoid the need for an individual business case to be made to commissioning bodies each time the instance of use arises.

• The British National Formulary (BNF) has already started a revision of its content to include reviews of many more off label use indications. The BNF is the supportive reference guide for all prescribers and drugs listed in it are much more likely to find acceptance amongst prescribers. NICE and the BNF have also committed to greater collaboration and improved review procedures for off licence drugs and the GMC has raised off label prescribing as a “hot topic” - see more here: gmc-uk.org/guidance. The GMC's general prescribing guidance can be accessed here.

• National Institute for Health and Care Excellence (NICE) is responsible for providing guidance on the best use of drugs and devices. It does not review every new drug or indication that receives a new licence but it does have extensive Guidelines on the best management of conditions which are regularly reviewed to take account of the latest practices and evidence. This includes the use of off label drugs. NICE guidelines provide strong support for off label or licensed use of drugs but only one form of appraisal carries legislative force; a positive technical appraisal (TA) carried out on some drugs results in a legal compulsion on all CCG’s to make that drug available to patients if prescribed. Although at present NICE cannot commit to an extensive revision of its practices to support off label drug use it would be a critical contributor to the proposed new pathway. NICE appraisals do address economic benefit.

General

In the meantime, the other more general review of Innovation in the UK has been progressing and is now published by George Freeman MP led by Sir Hugh Taylor - “The Accelerated Access Review” - for the Department of Health on accelerated access to transformative drugs, devices and diagnostics for NHS patients.

Currently the next most interesting overview of practices in the health policies of the nation is in the governments proposals on “Industrial Strategy” consultations which are on-going until mid April 2017 and AMRC have been drafting many recommendations some of which are very pertinent to the above.

Dr Joy Duffen – March 2017