How, Why, and When to Apply for an Orphan Drug Application

This article is written by Hema Balasubramanian and Mamta Puri-Lechner.

In the rapidly evolving landscape of medical innovation, securing a U.S. Food and Drug Administration (FDA) special designation marks a pivotal achievement for any life science company. These designations are tailored to facilitate and expedite the development and review of drugs that address unmet medical needs in the treatment of serious or life-threatening conditions. These conditions are critical for companies at the cusp of breakthroughs, especially when they have promising clinical data, are at a development inflection point, or have recently secured funding to scale their operations and move with speed. Orphan Drug Designation (ODD) is an example of one such special designation offered by the FDA and other health authorities across the world.  

But at what point should a clinical trial sponsor apply for orphan disease designation? We field this question often from clients and industry colleagues. If you’re in the early phases of developing a drug product with strong nonclinical proof of concept or mechanism of action data in in vitro cell lines or in vivo data in an appropriate animal model or with preliminary but promising readout from an early phase clinical trial and believe your candidate will improve an orphan disease, you likely have the same question. 

In other scenarios, perhaps you’ve just finished your phase one clinical trial in all comers (in oncology patients, for example) and you have collected some biomarker data indicative of the efficacy, in one of the rare tumor types, and are pausing to think about an orphan indication, but do not know how to apply, when to apply, and are unaware of the advantages and watch-outs for this pathway. 

In this article, you (as a clinical trial sponsor) will learn strategic considerations for targeting an orphan drug designation and associated logistics to consider when choosing such a designation from the onset. 

Applying for Orphan Designation – Strategic Considerations 

To quote CFR 316.23, “A sponsor may request orphan drug designation at any time in its drug development process before the time that sponsor submits a marketing application for the drug for the same rare disease or condition."

However, there are several considerations that a sponsor should consider when planning to apply for organ drug designation. These include: 

• The population affected by the disease/condition needs to be less than 200,000, because, by definition, an orphan disease must affect fewer than 200,000 people in the U.S. The prevalence information should be calculated after a thorough review of all acceptable sources of information including SEER (for oncology indications), NORD, and other literature references. Prevalence calculation is one of the most critical aspects of an orphan application and should portray an exhaustive and systematic search of all available resources. Only when there is no U.S. data available, should ex-U.S./global data be used to justify prevalence numbers. It is also important that all key references used for this calculation be provided to the FDA at the time of submission. In our recent experience, the FDA seems to default to the highest number in the literature (not necessarily the most recent). If the highest number is an outlier, this should be addressed proactively in the ODD request. Moreover, if a drug is intended for the diagnosis or prevention of a disease, the sponsor will need to estimate the number of people eligible to receive the drug annually. 
  
  

• This includes the disease pathophysiology, etiology, treatment options, and prognosis. The sponsor must explain and justify the unmet need or gap in those therapeutic options for the patients, and how their drug will help address the unmet need. 
  
  

• The sponsor must provide scientific data to demonstrate how their drug’s mechanism of action plays a role in the prevention or treatment of the specific disease or condition, by way of blocking or inhibiting certain biological pathways responsible for the disease or condition. 
  
  

• Clinical data provides the strongest justification for the drug to be effective in the relevant disease or condition. If no clinical data is available, animal studies conducted in a relevant animal model of disease may be considered. However, if the animal study did not assess endpoints that are relevant to the clinical endpoints of the disease being studied, the FDA may not accept the animal data as justification for the ODD. When there is no relevant animal model, in vitro data, ideally utilizing human cell lines from patients with the disease or condition, may be used to support the scientific rationale and a strong justification for why there is no relevant animal model should be included. Thus, the FDA provides some flexibility to the sponsor in terms of the evidence required (i.e., clinical or in vivo or in vitro data) provided the sponsor presents a strong scientific rationale, enabling the sponsor to strategically plan the application. In our recent experience, however, it has been challenging to obtain ODD with solely in vitro data. This seems to be more in line with the ODD requirements by the EMA and other health authorities. 

• Note that the FDA can come back during the 90-day review with an information request that the sponsor needs to address to avoid the rejection of the application. Depending on the nature of the information requested, the sponsor may need to either provide a scientific rationale or may need to generate additional experimental data to address the FDA’s query (i.e., generation of proof-of-concept data in a relevant animal model of disease. If your candidate does not bind to the disease-specific model, you may still need to demonstrate that to justify your application). 

Suggestions for Expediting Clinical Development Once Orphan Drug Designation is Granted 

Sponsors must be aware that based on the low prevalence or incidence of orphan disease, patient recruitment can take a long time, often years compared to more common diseases. There are few opportunities for sponsors during their early planning phase to ensure they can bring speed and efficiency to their orphan disease program, propelling timely availability to patients. These opportunities include: 

• Listen to patients and the caretakers. Engage with patient advocacy groups and patient registrations during the early planning phase to understand what matters most to these patients, while understanding the natural history of the disease. 

• Including patient-reported outcomes is valuable in rare disease trials and close engagements with patients and/or caregivers will enable you to develop this document meaningfully. 

• Valuable information on the standard of care can be obtained through the interactions with the patients and/or caregivers, and hence, building relationships with the patient groups is very critical. 
  
  

• This approach will help plan sponsors’ clinical studies efficiently and optimally given the low number of patients available, while gaining agreement on the right endpoints for rare disease patients. 
• Equally important is ensuring you follow through on the advice you receive from the regulators. 
  

Explore partnering with the right Clinical Research Organizations (CROs) and vendors

• Engage with the right CROs (and CDMOs) who have demonstrated experience and a successful track record in the therapeutic area you are pursuing. 

• Think outside the box. Consider using artificial intelligence and machine learning-powered digital health technologies, tools to identify rare disease patients, screening and recruiting patients, and endpoint selection.
  
  

• This approach is encouraged to enable the recruitment of the right patients, monitor disease progression, and prevent patients from getting exposed to less effective treatments. 

Is There a Downside to Applying for Orphan Drug Designation Early On? 

When sponsors choose to apply early on for orphan designation, the worst outcome is a rejection of the application. This decision, however, is not public information. This rejection comes with feedback from the FDA regarding their application, including what they consider ‘missing’ from the application. Sponsors can then absorb FDA’s feedback, generate/collect the data requested, and then submit an amendment to their initial application. 

Receiving a rejection on the initial application is not necessarily harmful for sponsors, considering there is no fee associated with the application, and the valuable feedback provided. The downside of a rejection occurs only if a sponsor has promised designation by a certain timeframe, or publicly communicated they are targeting orphan drug designation and are therefore accountable to external stakeholders. 

Ultimately, the timing is up to the sponsor’s development strategy, timeline, and commitments to external stakeholders, including investors. 

Halloran typically files on average seven orphan drug designation applications per year on behalf of our clients. Most of these applications are granted, and while some were not, this insight gives Halloran unique insight into current FDA expectations and trends. 

To discuss your orphan drug designation application strategy, contact Halloran.