Clinical Research - Why consider a pre-approval access programme?

Why consider a pre-approval access programme?

Pharmaceutical companies are increasingly incorporating expanded access programmes such as named patient programmes at an early, pre-launch stage in the clinical development of new drugs. Why are these programmes increasing, how do they work in practice and what are their potential risks and benefits? Susan Mayor reports

Expanded, pre-approval access programmes that give patients with unmet medical needs access to unauthorised medicines outside clinical trials are becoming more common in response to the changing environment for new pharmaceuticals. Pressure for this is coming from three main directions: patients and their families, clinicians wanting early access to new agents, and the pharmaceutical industry as development shifts to more specialist products.

This move towards specialist, innovative drugs for secondary care use means the number of patients on a particular drug, and the number of healthcare professionals in that area, tend to be smaller, making named patient programmes (NPP) more feasible, commented Dr David McIntosh, honorary clinical senior lecturer, Imperial College London, at the Pre-Approval Expanded Access Programmes forum held in London at the end of last year. Many novel drugs are designed to meet unmet needs - so clinicians and patients want to be able to use them during early stages of clinical trials. Greater access to information about drug development from the earliest stages - particularly via the Internet and through international conferences - raises awareness about new drugs globally, driving requests for new agents from doctors, patients and advocacy groups worldwide.

Lengthy drug approval times can also lead to delays in access to new drugs which patients and their doctors are keen to bridge with pre-launch access programmes, suggested McIntosh. "In recent years expanded access programmes have enabled thousands of patients with cancer to gain access to investigational drugs before they have been approved by the FDA," he told the meeting. Before changes in regulations in the mid-1990s, patients who had exhausted all standard avenues to treatment were able to obtain investigational drugs only on a case-by-case basis. Expanded access programmes (EAPs) are an extension of more traditional compassionate use programmes and allow patients to receive investigational drugs earlier than Phase III of the clinical trial process, he added.

The underlying principle

There are different mechanisms for early access programmes in different countries, often with different regulations governing their operation, but the underlying principle is to make unauthorised drugs available to patients with unmet medical needs.

In the EU, a compassionate use programme can provide an unauthorised drug to patients suffering from a disease for which no satisfactory authorised alternative therapy exists or who cannot enter a clinical trial. This is a protocol driven clinical trial approach for provision of access to medicines, run under clinical trial regulations and legislation. Drugs can also be requested as part of particular, or named, patient programmes in response to an unsolicited request from a healthcare professional for use by an individual patient on their direct responsibility. At a national level, each country has its own laws governing the importation and supply of pre-launch medicinal products, which vary considerably between different countries.

In the US, investigational drugs that are in clinical trials but have not yet been approved by the FDA can be made available to patients under three types of protocol:

• Investigational new drug (IND) treatment programme. Under an IND treatment programme, the FDA allows expedited access to drugs under investigation for cancer and other serious diseases. They require a treatment protocol, safety monitoring and site approval. Examples of major expanded access programmes for cancer drugs in the US include oxaliplatin (Eloxatin, approved for colorectal cancer) and imatinib (Gleevec [in the US], approved for chronic myelogenous leukaemia).

• Single patient access treatment programme. A single patient access treatment programme is a type of IND treatment programme in which an individual patient can receive an investigational drug. This must be physician driven and each request is determined on a case-by-case basis.

• Group C. A group C protocol is the National Cancer Institute equivalent to an IND treatment programme, administered by the NCI.

Examples of pre-launch programmes

Anagrelide (now available as Xagrid in the EU and Agrylin in the US) was developed by Shire in the 1990s for the treatment of essential thrombocythaemia, a condition in which patients have too many platelets so are at risk of haemorrhage and stroke. The prevalence is 110 per million population and most countries previously had no treatments, with the only option being off-label use of medicines, including hydroxyurea and alpha-interferon, indicated for other conditions. This is a fairly typical situation for many orphan diseases, Tim Tustin, managing director export with Shire Pharmaceuticals, reported at the meeting.

There was a seven-year delay between FDA approval given in March 1997 and EMEA approval in November 2004, because the EMEA requested further data. To bridge this gap, Shire made anagrelide available on a pre-launch programme by supplying the US product in the EU and elsewhere until local marketing authorisations were granted - reaching a peak of 53,097 packs in 2003. This shows the scale of an expanded access programme, even in a rare disease, suggested Tustin. Physicians knew about the drug from meeting at international congresses, so wanted it for their patients, he pointed out.

The company also introduced an early access programme for iduronate-2-sulfatase (Elaprase), the first treatment for Hunter syndrome, an inherited lysosomal storage disorder. The FDA approved the drug in June 2006 and the EMEA granted EU approval in January 2007. Tustin reported that around 70% of patients diagnosed with Hunter syndrome in Western Europe had access to Elaprase within one year of EU approval (see Figure 1). There is regular contact between patients with Hunter syndrome and their families so they had heard about the drug and wanted access to it. Having an expanded access programme helped to ensure there was very rapid uptake, he explained.

Putting NPPs into operation

NPPs can be used to provide patients access to a medicine at several stages of a product's lifecycle:

• During Phase III trials, to patients with unmet medical needs who do not meet the clinical trial inclusion criteria

• Bridging the gap between the end of Phase III trials and market authorisation

• In conjunction with the global launch of a medicine while approval and reimbursement arrangements are being agreed in different countries.

These access programmes can also be used as part of a global commercialisation strategy where a company is not planning a formal launch, in countries where there is no sales infrastructure and where it is not commercially viable to seek marketing authorisation for a drug.

Early planning is essential, suggested Simon Estcourt, global business development director with Idis, a specialist consultancy that works with partners to develop expanded access programmes globally. "Companies need to decide in advance how they will respond to requests for a drug they are developing. The worst situation is where they have not thought about this, and are unprepared to meet requests for a drug in a development programme. We encourage companies to consult early in a product plan, at the time they are planning Phase III, on their strategy for expanded access."

Coordinating with clinical trials

Expanded access programmes need to be carefully coordinated with clinical trials to avoid compromising recruitment. However, delegates agreed that an NPP often serves as a complement to trials for patients who don't meet the criteria but whose doctors consider they would still benefit from a drug. "The aim is to work with clinical trial programmes and absolutely not to get in the way of clinical trials. In many ways, expanded access programmes can support clinical trials," noted Estcourt.

"We have examples of programmes that have run alongside Phase III trials, where we have been able to direct patients meeting criteria into trials as well as offering a solution for those who do not meet the criteria," he said. But it is important to recognise that the aim of an EAP is to provide a drug to patients with an unmet medical need, not to collect data, he pointed out. They can also bridge the gap for a patient coming out of a clinical trial until the drug they have been on is made available commercially.

Early access programme: benefits/risks

The potential risks to avoid when making a drug available on an EAP include reducing candidates for clinical trials, biasing safety data by treating patients with particularly severe illness and those not meeting trial criteria, and being accused of promoting unauthorised medicines pre-launch. Liability may also be an issue, because the company manufacturing a drug will have liability as well as the treating physician. All of these issues should be addressed as part of planning for an effective EAP.

On the other hand, the benefits include early product visibility and development of relationships with physicians, with those using a drug before launch often becoming early adopters. Programmes can provide real life data to support marketing forecasting models, as well as providing opportunities for testing the quality, allocation and supply chain of pre-launch drugs.

Well-planned EAPs enable companies to include a risk management strategy, which facilitates a controlled route to pre-launch medicines. They can protect against drugs being accessed inappropriately, including reducing the risk of counterfeit products and parallel imports. In addition, they guard against a drug being used inappropriately by ensuring that physicians and patients are educated about its correct use. They can also accelerate the uptake of a product after market authorisation and official launch.

"Despite healthy debate about the intricacies involved, there is an overwhelming groundswell that expanded access programmes are a good thing to do," suggested McIntosh, by providing an ethical way to respond to demands for unmet medical needs from patients and physicians throughout the world."

Figure 1: 70% of patients diagnosed with Hunter syndrome in Western Europe had access to Elaprase within one year of EU approval

Figure 1: 70% of patients diagnosed with Hunter syndrome in Western Europe had access to Elaprase within one year of EU approval

Susan Mayor is a freelance journalist based in London