Report: Early access in practice – a joint Clinigen and BIA post-event report from BIO-Europe

On 3 November 2014 Steve Bates, Chief Executive Officer of the BioIndustry Association (BIA) chaired a panel at BIO-Europe in Frankfurt, Germany entitled, “Mind the GAP? Meeting an emerging demand for access to medicines in late-stage clinical trials, prior to commercial launch.”
The panel was organised by Clinigen Global Access Programs (Clinigen GAP) and looked
at how to practically meet the demand for new therapeutic alternatives for patients with unmet medical needs, specifically through enabling pre-launch access to drugs. The panel brought together experts from pharma, biotech, a provider of access programmes and a patient advocacy organisation to discuss, debate and share experiences of the role they each play in delivering drugs to the patients that need them.

Executive summary

Early access is a mechanism that enables patients with an unmet medical need to be provided with access to a medicine, prior to it being made available in that country. The definition sounds simple enough, but understanding and successfully navigating the rapidly evolving and highly regulated, regional early access space is challenging. There is increasing pressure from informed, mobilised patients and their physicians as a result, in part, of more transparency of drug-development pipelines online.
Therefore, pharma and biotech companies need to carefully consider their early access strategy to be prepared in advance, even if they are yet to receive a request for access to a medicine. However, providing access to investigational products can be a complicated business.
The BIO-Europe panel members represented the wide range of stakeholders involved in getting unlicensed drugs to patients, and shared their first-hand experiences of the challenges and opportunities of early access.

Panel members

Henrik Balle Boysen is the Executive Director of HAEi (Hereditary Angioedema), an international patient organisation for C1 Inhibitor deficiencies. Henrik was diagnosed with HAE1 at the age of 17 and is working to establish mechanisms to enable access to unlicensed or investigational treatments for the disease for all patients world wide.

Dr Markus Kosch is the Commercial Portfolio Lead Oncology for Europe, Africa and the Middle East at Pfizer. Markus is a medical doctor by training who spent nine years specialising in nephrology and oncology. At Pfizer, Markus focuses on market access and regulatory matters in the EMEA region.

Dr Morgan Conn is Executive Director, Business Development at PTC Therapeutics. PTC Therapeutics has recently initiated its first early access programme for Translarna™ (ataluren), the first approved therapy for the underlying cause of nonsense mutation Duchenne muscular dystrophy (DMD).

Mark Corbett heads Clinigen’s Global Access Programs business and has implemented over 120 international access programmes for companies ranging from niche biotech to top 10 pharma. In 2013/14 Clinigen GAP delivered 58,000 units of drugs to over 75 countries.

The panel was chaired by Steve Bates, CEO of the BIA and a leading voice in the campaign to raise awareness of early access in the UK and of the UK’s Early Access to Medicines Scheme (EAMS) which was launched in April 2014. Six months on, the panel evaluated the scheme as a case study of a regional mechanism to provide access to unlicensed medicines, and compared this to other models in Europe.

Access programme landscape

There are patients all over the world who are in urgent need of a new treatment but for many, access to new medicines via traditional, well-defined clinical trial processes or commercial channels is not an option. For some, the wait for a new therapeutic option to become commercially available can simply be too long.

A number of mechanisms exist to enable access to drugs that are in clinical development, unlicensed in particular markets, or awaiting Marketing Authorisation approval in a regulatory compliant and ethical manner.

However, navigating the early access space can be a complex and daunting prospect. The first challenge is often how to make sense of the many different terms used from country to country; from expanded access to named patient programmes to compassionate use. These terms can mean different things to different people and it is easy to become confused.

Whilst all these mechanisms are designed to make a drug available to a patient prior to commercial launch, the challenge companies face is the significant variation in processes, terms and routes to access.

Two key considerations to address before initiating an early access programme are the regulatory routes available for each country in terms of how to make the drug available in a compliant manner, and whether to charge for access to the drug. In some countries it is possible to do this but in others, like Germany, it has to be made available free of charge whilst the drug is still in clinical development and prior to receiving a marketing authorisation anywhere worldwide.

The UK Early Access to Medicines Scheme

Launched in April 2014 the UK’s Early Access to Medicines Scheme (EAMS) has been in place for just over six months. EAMS is a three part stepped process, the first enables a company to bring a drug, with phase I/II data, to the Medicines and Healthcare products Regulatory Agency (MHRA) and request a Promising Innovative Medicine (PIM) designation. The second step is then to gain a Scientific Opinion from the MHRA, and step three is commissioning of the drug in the NHS.
For companies considering a global access programme encompassing multiple countries, the UK scheme should be viewed as part of a wider access strategy including the regulatory requirements, timelines and crucially costs of each national mechanism.
The staged approach of EAMS brings with it certain costs at each level, for example the PIM application of stage one has a £4,000 fee. The second phase of Scientific Opinion assessment costs £29,000 for one year, and the filing required to achieve this opinion is considerable and similar to what you would expect to submit for a drug registration. If this stage takes over one year to complete there is a £14,000 fee for each following year.
When viewed across Europe or on a global scale there is a significant volume of different documentation to collate, processes to follow and associated costs.
Unlike other countries such as France, Spain and the USA, in the UK a company must provide an early access drug through EAMS free of charge and therefore cannot generate revenue, or cover the costs through the programme.
Mark Corbett of Clinigen GAP believes the intentions behind EAMS are absolutely right and it marks a positive step forward in the UK for patients to gain access to potentially life saving drugs, but there are some fundamental practical elements that require review – most significantly, reimbursement.

The patient perspective

Patients and patient organisations are increasingly aware of and are actively engaging with early access. Patients are also becoming better organised and are finding out more about which drugs are available to them.
Technology and social media has played a big part in the empowerment of patients and their ability to mobilise and put pressure on industry players and regulators. It has also provided the capacity to share information across continents and to raise awareness of access programmes across international patient organisations and the medical community, as many key opinion leaders and physicians are also strong advocates for early access.
There are many areas of unmet need that an access programme could meet. For the HAEi international
patient organisation for patients with C1 Inhibitor deficiencies, there are currently five therapies approved for the treatment of HAE but there are many patients in areas of the world who do not get access to them as they are not commercially available in their country. To address this, the HAEi is working to establish access programmes for all five drugs and to raise awareness of this mechanism among the patients who need them.

Pharma

For pharma, initiating an early access programme is often highly complex. A company faces a range of different regulations for each territory. For example, the legal and logistical challenges involved in dispatching a drug to a single patient within 24 or 48 hours of receiving the request are significant challenges even for a top 5 pharma company
like Pfizer.
Running an access programme can also be expensive. A recent large scale early access programme involving the supply of a Pfizer oncology therapy for hundreds of patients across Europe was very costly. Costs included the commitment to continue supplying the drug for many years afterwards to patients who responded well. Patient need is the key driver for most companies in providing early access
to a drug but even considering the scale of the organisation, without the prospect of reimbursement or the indirect prospect of a benefit such as a NICE assessment for example, there can sometimes be limited financial incentive for a company to take on the costs of providing a drug free of charge.
The duration of the reimbursement process for the commercial launch of new drugs is also becoming an increasing issue for pharma; it can take up to 22 months to agree reimbursement for a drug after a Marketing Authorisation has been approved in a therapy area such as oncology. This is a long time for a drug to be approved but not made commercially available. Access programmes can help accelerate access to patients in countries during the period when pricing and reimbursement negotiations are taking place and prior to launch in that country. This needs to be considered when a company is considering the duration of their access program, and the exit strategy.
For Dr Markus Kosch of Pfizer, the first step in setting up an access programme is to establish whether there is a regulatory route to access already established by government in a country. A government programme acknowledges the gap and the need for the drug, but the lack of such a programme can make things more difficult as there is no framework to follow.
It is also important to time the start of the programme well
in terms of the value of data generated by early access versus a clinical trial, and to balance the risk of making a drug available which has less clinical evidence than one which has followed the traditional trial and approval channels.

Biotech

Approaching early access from a biotech perspective, the experience is generally very different to that of pharma.
The same regulatory and legal hurdles exist but the challenge of providing 24/7 access to a drug, and making sure that the logistical framework exists to get it to patients in time can be an even greater demand on the resources of a smaller company. There is a huge amount of thinking, planning and goal-setting involved before making the decision to manage a programme in-house.
The ability to be reimbursed for drugs prior to commercial launch is a key factor for biotech companies like PTC Therapeutics. PTC recently initiated a European early access programme for the personalised Duchenne muscular dystrophy (DMD) therapy TranslarnaTM which received Marketing Authorisation in Europe this year and will complete a confirmatory phase III trial in the fourth quarter of 2015.
As PTC’s lead product, the company currently has no sales, and due to the continuing clinical studies, is providing several hundred patients with the drug free of charge, so reimbursement is key as the company works towards the official launch.
For PTC, the motivation to provide TranslarnaTM to patients in advance of commercial launch came from the very high degree of unmet medical need in DMD. Ensuring early access to a drug that could potentially make a huge difference to the lives of young boys is a strong priority for Dr Morgan Conn of PTC, “it’s our goal to get the drug to everybody who may benefit as fast as possible.”

Benefits and risks

Benefits

Crucially, early access programmes provide companies with an ethical route to get potentially life-saving drugs to patients when there is no other alternative and which would otherwise not be available to them, and is seen as positive and responsible practice. This also benefits physicians who are able to provide their patients with the critical drugs they need, and therefore provide better treatment.
Other benefits include a broader range of physicians and patients using the drug prior to launch which will help when commercialising the product. If a company is charging for the drug pre-launch it can also set a price precedent in a number of countries which can be helpful at the pricing and reimbursement stage.

Risks

The key concern during the set up and management of an early access programme is ‘what if something goes wrong?’ It is important to anticipate where these risks could occur and to take action to prevent them from occurring.
Inappropriate use of the drug, inappropriate patients or unwanted safety events are key risks of early access but correctly managed the risks can be mitigated. Add to this a well planned, clear exit strategy and the risks can be overcome and are outweighed by the benefits.

Best practice

Agree your objectives at the outset

The objectives for initiating an early access programme are often different for biotech and pharma companies but it is important to be clear on what these are at the start and what you are looking to achieve by making products available.
The reasons for initiating a programme can often be very simple, if you present promising data at phase II or phase III you often have an ethical obligation if there is an area of unmet medical need to position yourself in that space. Early access programmes can in fact be seen as a valuable mechanism for companies that wish to make their drug available on a compassionate basis whether at a cost or free of charge.
In Henrik Balle Boysen of HAEi’s experience, “in the past, many companies have wanted to make a drug available but the problem was often that just giving away medication in a compliant manner is a hard thing to do.”

What is the exit strategy?

Another other important strategy that both pharma and biotech need to consider is once the access programme has started and the product is made available, at what point should you stop? Similarly, if you make the drug available free of charge, when do you expect people to start paying for it? A clear pathway to how you get out at the end of the programme is key.
One of the most fundamental factors to consider is the amount of the drug available. At the point of offering early access a company will not be manufacturing the drug on a commercial scale and must be sure that if a patient has a chronic or long term condition, it can ensure uninterrupted supply of that drug in the future.
If providing a drug through an early access scheme free of charge, management of physician expectations as to when the drug will start to be charged, and patients will move onto commercial supply is important. Most physicians understand that drugs come at a price, but transparency of the exit strategy is crucial.
Withdrawing potentially life-saving drugs from patients following early access via clinical trial is an example of the damage that a poorly planned exit can do. One of the worst things that can happen to a patient taking part in a trial is that they will be on a drug which is withdrawn when the trial ends. There is established protocol and clear guidance on how to work in this area and it is a situation where a responsible, considered early access programme can help.

Consider the risk

There are many benefits in making products available prior to launch, especially to patients, their physicians, and to biotech and pharma companies, but companies should consider the level of risk they are willing to take. Once there is an agreement on the level of risk, you can then begin to look at how to mitigate it.

Identify and engage with internal stakeholders

By nature an early access process is inherently complex, relying on cross-functional working and involving input from almost every part of a company including supply chain, regulatory, medical, commercial, quality. Therefore it is important to ensure engagement from all stakeholders at the outset so that everybody involved is aligned, understands their role and believes in the same objectives.

Does your business model work?

The structure of the organisation must also be such to enable
a company to physically execute the programme in a compliant manner. Factors such as the ability to react to requests for the drug when you don’t know where the requests will come from, or the unpredictability of the volume of requests must be addressed at the outset.
Early access is very much an unsolicited process; you cannot recruit patients as you would for a clinical trial. You must be confident that as a company you can put the processes, infrastructure and resource in place to be able to respond quickly enough to physically get a product sent out in a compliant manner. Due to the nature of drugs supplied by early access programmes, there will often be a physician waiting in a hospital and needing the drug within a matter of hours to treat their particular patient.
Although big pharma has considerable resources at its disposal there are certain requirements of an access programme, such as making small quantities of a particular therapy available 24 hours a day, seven days a week that are very expensive, and do not fit with how these companies are set up.
This is an area where outsourcing to a specialist service provider can be a solution. For Pfizer, the commitment to finding individualised early access solutions tailored for every drug and every country can be so complex that it is beyond what can be supported internally. In these cases the company has brought in partners to support this element of the business.

Conclusion

This is a time of emerging demand on the industry for access programmes. The rise of the proactive, informed and campaigning patient means that it is feasible that any biotech company could receive a request for their investigational drug from a patient, or a physician on behalf of a patient, from anywhere in the world, regardless of whether they have an access strategy in place. How a company deals with that request could become critical.
In order to be prepared, Mark Corbett of Clinigen GAP believes every biotech and pharma company whose drugs meet a high degree of unmet need, should have an early access strategy of some form in place as a prerequisite of their drug completing phase II trials. Even if the strategy is to say no, a clear, considered, practical plan is must.

About the BioIndustry Association

Founded 25 years ago at the infancy of biotechnology, the BioIndustry Association (BIA) is the trade association for innovative enterprises involved in UK bioscience. Members include emerging and more established bioscience companies; pharmaceutical companies; academic, research and philanthropic organisations; and service providers to the bioscience sector. The BIA represents the interests of its members to a broad section of stakeholders, from government and regulators to patient groups and the media. Our goal is to secure the UK’s position as a global hub and as the best location for innovative research and commercialisation, enabling our world-leading research base to deliver healthcare solutions that can truly make a difference to people’s lives.
For further information, please go to www.bioindustry.org follow us @BIA_UK or join our LinkedIn community

About Clinigen Group

The Clinigen Group is a specialty global pharmaceutical company headquartered in the UK, with offices in the US and Japan. The Group, dedicated to delivering ‘the right drug, to the right patient at the right time’, has three operating businesses; Specialty Pharmaceuticals (Clinigen SP), Clinical Trials Supply (Clinigen CTS), and Global Access Programs (Clinigen GAP).
Clinigen GAP develops and implements global access programs for biotechnology and pharmaceutical companies and has provided access to unlicenced, licenced and end-of-lifecycle products to thousands of patients. Clinigen has experience in the implementation of more than 40 access programs worldwide.