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Shining a light on orphan medicines

Orphan diseases represent one of the most exciting and emotive areas in modern medicine and need a communications strategy that covers a spectrum of issues
Shining Light

Interest in orphan diseases has increased substantially in recent years. This interest has been fuelled by the attractive development environments created by the US Food and Drug Administration and the European Medicines Agency (EMA) since 1983 and 2000, respectively, and the success of companies such as Shire Human Genetic Therapies (HGT) and Genzyme, which have focused resources in this area.

However, development and licensing of therapies for orphan diseases are not without their challenges and, all too often, companies fail or are delayed in bringing novel effective therapies to market. But just what are the potential barriers to orphan drug development and how can they be overcome (see infographic).

Laying the groundwork
For any drug to be approved and taken up by the medical community, it must be clear why it is needed in the first place. What is the natural history of the disease being treated? How many people are affected by the disease? What is the humanistic, societal and economic burden? What are the limitations of existing approaches to disease management? 

In the case of orphan diseases, these pieces of information are rarely in the public domain, so it is important to build a compelling argument for the benefits of the new agent and to lay a solid foundation for regulatory approval, prescription and reimbursement.

Simply put, it is essential to have a well-thought-out communication strategy that includes plans for promoting disease awareness, clinical development and market access activities.

Demonstrate an unmet medical need
As we know from observing the furore surrounding the development and launch of BioMarin's Firdapse for Lambert–Eaton myasthenic syndrome (Nicholl DJ, Hilton-Jones D, Palace J et al. Open letter to Prime Minister David Cameron and Health Secretary Andrew Lansley. BMJ 2010; 341: c6466 and Quartel A, Lennertz J. Biomarin Europe replies. BMJ 2010; 341: c7006) you have only one chance to introduce your product to the medical community.

No matter how effective and well-tolerated your product, there is a real risk that its benefits will be underappreciated or, worse, unnoticed if you don't explain why it is needed and how it can make a difference to patients' lives. 

With this in mind, the first step in any communication plan must be to create awareness of the existing unmet medical need. This includes consolidating all available information on the natural history, disease burden, current management approaches and economic impact of the disease, before filling gaps in knowledge and building a coherent scientific platform on which to base the development of a novel therapy. 

Early engagement with specialist physicians, caregivers and patient associations is an essential part of this evidence-gathering process, as individuals within these groups often have an unrivalled understanding of the humanistic and social burden of the disease.

Natural history studies can also play an important role in broadening understanding of rare conditions. This is exemplified by the realisation that heterozygous female patients with Fabry disease do develop life-threatening disease manifestations, rather than simply acting as asymptomatic carriers (as was thought previously), thanks to a study of 60 female patients by MacDermot and colleagues (MacDermot KD, Holmes A, Miners AH. Anderson–Fabry disease: Clinical Manifestations and Impact of Disease in a Cohort of 60 Obligate Carrier Females. J Med Genet 2001; 38: 769–75).

Natural history studies can also provide insights to potential biomarkers and other measures of clinical outcome, which can be invaluable later in the drug development process.

Define the size of the problem
A key obstacle in the development and licensing of an orphan drug is achieving orphan designation. For this to be granted, the sponsor must demonstrate that: 

  • The target indication is medically plausible and qualifies as a rare disease (ie, it affects fewer than 200,000 people in the US or fewer than 1 in 2,000 people in a given European population) 
  • The disease is life-threatening or debilitating 
  • There are no satisfactory existing methods for preventing or treating the condition or, if such methods exist, the new medicinal product will be of significant benefit to individuals with the condition. 

It is generally advisable to apply for orphan drug designation as early in the drug development process as is feasible; that is, when there are sufficient preclinical and/or preliminary clinical data to show proof of concept. 

Applying for orphan designation before such data are available, although possible in theory, is likely to lead to an unfavourable verdict. Similarly, the ability to demonstrate the rarity of the target indication is a critical success factor for orphan designation applications. 

Authoritative epidemiological data for orphan diseases are often scarce or non-existent, so alternative sources are needed. For example, data from other regions may be extrapolated to the population of interest, provided that sufficient justification is given for the validity of such an assumption. 

Consideration must also be given to the potential for bias, and data should be weighted accordingly. This can be a complex process that requires the implementation of a variety of statistical methods to give a valid estimation of disease prevalence in the population of interest.

Fortunately, the EMA is willing to offer advice on how to optimise the probability of a successful application with the available data. 

Pre-submission meetings or teleconferences with the EMA are free of charge and give the sponsor the chance to fine-tune its application and to form a working relationship with those who will review the final application.

Demonstrating therapeutic value
Once it is clear that new medical therapies are needed to treat a given condition, the next step is to demonstrate the therapeutic value of the novel compound. 

Clearly, the first challenge when initiating clinical trials for an orphan drug is finding patients to participate. This again underlines the importance of fostering disease awareness: if clinicians don't know what to look for, how can they identify and refer patients? Similarly, if patients are unaware of the limitations of their current treatment, how can they be motivated to enrol in a clinical trial?

Assuming that there are sufficient patients willing to participate in a clinical trial, the next challenge is designing a study that ticks all the necessary boxes. It is important to consider whether the study entry criteria are representative of the population that the new therapy is aimed at, taking into account the full spectrum of disease severity, patient age, ethnicity and geography likely to be met in real clinical practice. 

Owing to the heterogeneity of many orphan diseases, different populations may respond in different ways to treatment or require different management strategies; therefore a balance needs to be reached between sub-categorising patients (eg, according to renal function or gender) and having enough patients to ensure that the study is meaningful.

Prospective natural history studies carried out early in the drug development process provide one way of exploring these issues.

The first step in any communication plan must be to create awareness of unmet need

The next consideration is how to ensure that the study is sufficiently powered to detect changes in disease activity among treatment groups. Studies of orphan diseases typically have fewer than 50 patients per treatment group, whereas studies of more common conditions may have several hundred or thousands of participants.

Furthermore, it may not be acceptable ethically to include a placebo control group owing to the life-threatening nature of many rare diseases. Hence, the choice of primary and secondary endpoints is crucial. 

As well as being sensitive enough to detect changes in disease activity over a six- to 12-month period, they must also reflect the disease in real life; significant improvements in a given end point are worthless if the overall disease burden is not reduced. They must also be quantifiable; patient-reported outcomes certainly provide useful information regarding health-related quality of life and symptom severity, but they cannot be used exclusively. 

Surrogate markers, such as those found in urine and blood, are often used because they provide quantitative measures of disease activity and are easier and less invasive to collect than direct measures like tissue biopsies. However, such markers must be validated and shown to be sufficiently robust before being used in a clinical trial.

Animal models may be useful for identifying potential markers of efficacy, but the validity of any candidates would need to be investigated fully in humans before they could be considered for use as endpoints in clinical trials. 

Finally, the parameters being measured must be appropriate to the patient population under investigation. For example, the six-minute walk test is used commonly to evaluate endurance and joint function in adults, but may be difficult to carry out in young children or patients with severe neurological manifestations. 

Cultural differences, poor patient adherence and concomitant medications may also make it difficult to measure end points.

It is important to bear in mind what adverse events are likely during clinical trials and post-marketing authorisation. With so few patients participating in orphan disease clinical studies, regulators often ask sponsors to carry out post-approval studies to monitor the long-term safety and efficacy of the therapy as a condition of marketing authorisation.

Rather than being seen as an additional obstacle for sponsors to overcome, this can be beneficial to all stakeholders, because it enables the collection of valuable natural history data, maintains engagement with investigators and provides opportunities to publish clinical data and thus keep the new drug in the minds of treating physicians. 

Patient registries such as the Pfizer International Growth Study (KIGS), Pfizer International Metabolic Study (KIMS), Pfizer's ACROSTUDY database for patients with acromegaly, and Shire HGT's Fabry Outcome Survey (FOS) and Hunter Outcome Survey (HOS) are examples of how the systematic collection of outcomes data can be of benefit to the manufacturer, physicians, patients and regulatory bodies.

Creating a value proposition
From a payer perspective, the approach to demonstrating value for an orphan drug is different from that required of treatments for more common diseases. For a start, the pricing of orphan drugs is driven primarily by the need to recoup significant research and development costs from a small patient population. 

The prices of orphan drugs are thus invariably higher than those of treatments for common diseases, but are not necessarily reflective of the benefits and potential cost offsets that may be obtained with treatment. Therefore, while the activities described above to prepare the market and demonstrate therapeutic value are essential for supporting pricing and reimbursement as well as registration, the payer perspective requires additional elements to be taken into account before patient access to a new orphan drug can be assured.

Define the uniqueness of the drug
Not all orphan drugs are the same. Most of the early approvals under orphan drug designation were for drugs indicated for a condition with no existing treatment, and that would have no use for any other condition (eg, enzyme replacement therapies for lysosomal storage diseases). 

However, advances in personalised medicine have led to a marked increase in the number of orphan drug designations in cancer (40 per cent of orphan drug designations are now for oncology indications), in which the drug in question may not be the only treatment available for that indication. 

Moreover, the potential for off-label use of the drug, or expansion into additional licensed indications, is considerably greater. These issues are of considerable concern to payers, who desire a predictable and manageable budget impact. 

The level of innovation of an orphan drug therefore becomes a major determinant of value, with payers likely to challenge high prices for a drug that is not the only option for a particular indication and/or that may be used off-label. 

Nevertheless, orphan drugs that represent the first and only treatment for a condition, and that are unlikely to exhibit 'indication creep', should still have the potential to command a high price.

Be aware of variations
It is also worth bearing in mind that the criteria used to assess the value of an orphan drug differ markedly across regions, and so the evidence required will differ accordingly. 

Canada and Scotland put orphan drugs through the same health technology assessment (HTA) process as all other drugs; in contrast, Belgium and several other countries waive a full pharmacoeconomic evaluation for orphan drugs. The evidence-generation plan for a new orphan drug must therefore provide data to address a range of demands in different countries.

A particular challenge for the funding of orphan drugs – and one that is magnified for ultra-orphan drugs, defined in the UK as treatments for diseases affecting fewer than 1 in 50,000 people (National Institute for Health Clinical Excellence. NICE Citizens Council Report Ultra Orphan Drugs. London, NICE, 2004) – is that the distribution of the small population of eligible patients is rarely homogeneous. 

Moreover, diagnosis and treatment are often limited to a handful of specialist centres. The budget impact of a new orphan drug therefore tends to fall unequally across regions, and funding treatment for even a handful of new patients may represent a significant proportion of resources for a budget-holder at a local level.

Anticipating potential regional and local funding issues is therefore essential. Robust evidence on the epidemiology of a rare disease and close engagement with key clinicians and specialist centres can provide accurate local forecasts of the number of treated patients and budget impact. Engagement with regional policy-makers can then help to drive provision of the necessary funding and resources to meet the future need.

Demonstrate the humanistic and societal impact of the disease
Evidence of the indirect or societal costs of a rare disease (such as lost income and work productivity, caregiver burden and health-related quality of life) is becoming increasingly important, even though in most countries it is not considered by HTA bodies in the evaluation of drugs for the treatment of common diseases.

The level of innovation of an orphan drug is a major determinant of value ...

While quantitative data should be collected through questionnaires as part of the evidence-generation process, the value of case studies must not be underestimated. Direct testimony from a caregiver or patient – perhaps incorporated as a video file within a submission document or presented at an appraisal committee meeting – can have a significant impact, making this an option worth exploring at all stages of the evaluation process.

Orphan diseases represent one of the most exciting and emotive areas in modern medicine, and the rewards for success, for both those developing novel therapies and those receiving them, are great. 

Although this promise is counterbalanced by the medical, economic and social challenges associated with treating these conditions, there is a sense that effective and well-tolerated therapies will nevertheless reach those in need. It is now in the hands of the individual biotechnology and pharmaceutical companies to put their propositions forward.

Learn how an orphan drug reaches market in this infographic

Article by
Dr Jonathan Morton and Dr Richard White

Dr Morton is Communications Director of the Rare and Orphan Diseases Practice and Dr White is Consulting Partner and Director of the Value Demonstration Practice both at Oxford PharmaGenesis

25th February 2013

From: Sales, Marketing, Regulatory, Healthcare



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