Small pharma companies and drug development consultants are a mighty powerhouse when it comes to the creation of treatments for rare or orphan diseases. Undeniably, big pharma companies have historically disregarded rare diseases on the basis that they were unlikely to generate enough profit to give a reasonable return on investment, largely because of the small number of patients involved.

Yet around 30 million people in the U.S. (i.e., 1 in 10 Americans) are affected by an estimated 7,000 rare or orphan diseases. Worldwide, some 350 million people are living with a rare disease that does not have adequate, if any, treatment available.

The first legislation in the U.S. that intended to encourage the development of drugs to treat rare diseases was the Orphan Drug Act, which introduced compelling incentives for the development of drugs to meet unmet patient needs.

Understanding the legislation is fundamental to navigating the process for small pharma companies in the field of orphan drug development, which are clearly vital to a small but collectively large and disadvantaged section of the U.S. patient population.

Defining rare and orphan diseases

According to the FDA, a disease is considered rare if there are 200,000 or fewer affected patients in the U.S. There are more than 7,000 known rare diseases with new discoveries being made each year and 95 percent of these have no available treatment. The FDA has granted 6,058 orphan drug designations for drug and biologic products intended to prevent, diagnose, or treat a rare disease or condition.

The majority of rare diseases are genetic indicating lifelong, and often highly debilitating conditions. Others may result from infections, allergies and environmental causes. Most of these rare diseases have no recognized treatment and therefore there is a high level of unmet medical need.

Some examples of orphan diseases include:

• Progeria—a fatal genetic condition of childhood with features resembling premature ageing;
• Amyotrophic lateral sclerosis (ALS)—a progressive nervous system disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control; and
• Mobius syndrome—a congenital condition that results from underdevelopment of the facial nerves that control eye movements and facial expressions.

Notably, certain types of cancers including pancreatic cancer and glioblastoma are also classified as rare diseases, and the few treatments currently available are limited in their efficacy.

The importance of developing orphan drugs

Just five percent of known orphan diseases have any type of treatment available and rare diseases are often misdiagnosed, emphasizing the urgent need to bring new and effective medicines to the market to treat rare conditions.

Many factors contribute to why rare diseases have unmet medical needs. Primarily, development costs are very high for several reasons, including specialized disease characterization and costly analytical and clinical development. In addition, small patient numbers make recruitment to clinical trials challenging, and often mean it is impossible to demonstrate statistical significance.

Moreover, the cost to develop a treatment can far outweigh any commercial return. Reimbursement factors may present a challenge, and because pharma companies are ultimately businesses, it can be tricky to ensure the product will provide a business case, resulting in upside down financials.

Big pharma companies undoubtedly have the wherewithal to develop novel treatments for rare diseases but, due to their reluctance to invest in the area, the onus is very much on smaller pharma and academia to fill the gap.

The frontrunners in the rare disease drug development sphere are commonly small start-ups or biotechs with a vested interest in a specific therapeutic area. Such organizations often work very closely with patient advocacy groups, and help to raise awareness of those groups to regulators and engage with potential trial subjects.

While embarking on the development of an orphan drug provides small companies with the opportunity to showcase their novel technologies and approaches, the challenge lies in putting together a team capable of getting a new treatment on the market. This is where the expertise of experienced drug development consultants is essential to help develop the asset through all phases of its development.

The orphan drug designation process

The issue of unmet medical need for patients with rare diseases has led to increasingly powerful lobby groups persuading regulatory authorities to put measures in place to stimulate research into these diseases.
To qualify for orphan drug status in the U.S. one of the following conditions must be met:

• The number of people in the U.S. affected by the disease or condition for which the drug is to be developed is less than 200,000; “prevalence” is defined as the number of persons in the U.S. who have been diagnosed as having the disease or condition at the time of the submission of the request for orphan-drug designation; and
• The disease affects more than 200,000 in the U.S. and there is no reasonable expectation that the cost of developing and making the drug available in the U.S. for the disease will be recovered from its sales in the U.S.

Supporting the development and evaluation of new treatments for rare diseases is a key priority for the FDA. Orphan drug designation qualifies sponsors for incentives including:

• Tax credits for qualified clinical trials;
• Exemption from user fees; and
• Potential seven years of market exclusivity after approval.

Sponsors seeking orphan designation for a drug must submit a request for designation to the FDA. The request must be supported by the sponsor’s own data and information, especially in the case where the sponsor is requesting designation of the same drug for the same rare disease or condition as a previously designated product.

Orphan drug designation is a separate process from seeking marketing approval, and drugs for rare diseases are subject to the same rigorous scientific review process as any other drug for marketing approval.

The process is highly individualized for each application, and the FDA and the sponsor work together to address the challenges of development with the shared goal of meeting patient needs with new treatments.

The FDA also funds the Orphan Products Grants Program which has provided funding support for rare disease research. The program’s goal is to foster rare disease product development leading to more available treatments.

The complexities of developing orphan drugs

Having obtained orphan drug designation, the next set of hurdles involve evaluating the drug in the necessary non-clinical and clinical studies.

Owing to the genetic nature of many rare diseases, enrolment in clinical trials may sometimes involve entire families. With multiple family members undergoing trials, the issue of informed consent becomes more complex; it is vital that everyone involved fully understands the nature, significance, implications, and risks of the trials in which they are participating.

For rare diseases, patient advocacy is particularly important within the context of clinical trials, where advocates are key to increasing success rates. Indeed, patient advocates can provide regulators, clinicians, and other medical staff with reassurance about the acceptability of trial procedures, as well as educate patients on clinical trial processes and results.

Due to limited knowledge about many rare diseases, it can also be a challenge to identify clinical biomarkers or surrogate endpoints (measurable indicators used as a substitute for a direct measure of how a patient feels or functions). As such, engagement of patients can be vital in educating key stakeholders (regulators) on the importance of proposed biomarkers or surrogate endpoints for their condition, increasing the chance of gaining agreement on a shorter clinical development path, which would result in all patients with the rare disease being able to access a clinically efficacious product more quickly.

Cost continues to be an important consideration when a drug makes it through clinical trials to market approval. If the patient population is unable to afford or access the medication or treatment, the product becomes moot.

As with any clinical trial, patient safety is the key priority. However, patients with rare diseases often have comorbidities, yet with few patients available to study, it can be difficult to formally assess the potential for drug-drug interactions. Moreover, as many rare diseases are chronic, treatments may have undesirable long-term effects.

Another challenge is that, typically, the identification of an appropriate comparator can be problematic, for instance when there is a lack of clinical consensus on standard of care treatment, or regimens differ across regions where the study is being conducted. Further, use of placebo in clinical trials for rare disease is often not ethical or appropriate.

The very nature of rare diseases and the lack of scientific knowledge, information, and data available about them, means that research needs to be international to facilitate collaboration, and the pooling of relevant resources and expertise across clinicians and researchers is essential.

Working with drug development and regulatory consultants

Drug development consultants have proven to be an invaluable and often essential addition to a development team. They can work closely with organizations looking to submit a request for Orphan Drug Designation to the FDA, assisting with all aspects of the process, from request preparation and submission to agency correspondence, product initiation and filing, as well as further full program management for all related applications.

One of the key advantages of using an experienced external consultant is their in-depth understanding of the evidence and data required by regulators, as well as their knowledge of the diseases the drugs are trying to treat. With experience supporting a range of orphan drug submissions across various therapeutic areas and product types, a good consultant can provide strategic recommendations for what has and has not been successful in the past.

A supportive team of external consultants will support small pharma and academic groups with the development of medicines, working with them every step of the way from program management through to the setting up and management of global clinical trials, preparation of regulatory submissions and liaising with the regulatory authorities.

Looking to the future

Going forward, increased patient advocacy, greater personal interest from privately held pharma and biotech companies, and the FDA’s incentives programs are all set to drive greater orphan drug development.

The “bench to bedside” approach to research is becoming increasingly prevalent and, although the US is not yet fully technologically and regulatorily structured in these areas, innovation and persistence of the sponsors involved will help inform this approach and set a research precedent. 

Better accessibility of real-world data will provide authenticated, relevant evidence that will support orphan drug development where datasets are limited.

Although each orphan drug application is specific, there is relief in numbers, and more applications and experience beget a smoother development path for future sponsors.

There is a long journey ahead in the development of treatments for rare diseases, but this is a growing and highly promising area that is of increasing interest to both researchers and investors. This momentum will lead to the successful development of many more medicines to treat rare diseases in the years to come. 

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Katy Rudnick has 20 years of regulatory and quality experience in the U.S. market, is highly experienced in managing business-critical projects with proven first cycle application approvals and possesses a well-rounded perspective of the global drug development market having worked in all therapeutic areas and dosage forms. A specialist in Regulatory Affairs strategy, and project pipeline and portfolio development and implementation of process flow standardization and efficiencies, Katy has experience with integration activities and special business partnerships. As Boyds’ VP and Head of U.S. Regulatory Affairs, Katy utilizes her knowledge of the global pharmaceutical industry to support our US-based clients and facilitate interactions with the FDA. Boyds provides specialist consultancy services to an international client base, supporting development of cutting-edge medicines for patient benefit. For more information, visit www.boydconsultants.com.