Recognizing the challenges of drug development, the US FDA has established several special designations and expedited pathways to accelerate the development and approval of innovative therapies, particularly those addressing serious medical conditions with unmet patient needs.
Some of these special designations and approval pathways include:
- Orphan Drug Designation
- Fast Track Designation
- Breakthrough Therapy Designation
- Regenerative Medicine Advanced Therapy Designation
- Accelerated Approval
- Priority Review
These not only provide hope for patients awaiting breakthrough treatments but also offer biotech and pharmaceutical sponsors strategic opportunities to bring life-changing medications to market more efficiently.
Having gathered key expert insights, we’ve put together this comprehensive guide of these FDA special designations, providing insights into the various pathways that can potentially transform the drug development process and ultimately improve patient care.
1. Orphan Drug Designation (ODD)
The Orphan Drug Designation program is a pathway designed to promote the development of promising drugs for rare diseases and conditions. Its primary purpose is to provide incentives for sponsors to invest in treatments for medical conditions that affect a small number of patients.
Eligibility criteria and timelines
To qualify for ODD, a drug must target a disease or condition affecting fewer than 200,000 people in the US. Examples of typical orphan diseases/conditions:
- Duchenne muscular dystrophy (DMD): ~15,000 individuals
- Familial adenomatous polyposis (FAP): ~50,000 individuals
- Idiopathic pulmonary fibrosis (IDF): ~100,000 individuals
The FDA will also consider drugs that may not be profitable within seven years of marketing approval. When evaluating an ODD request, the FDA requires preliminary evidence demonstrating the drug’s potential effectiveness.
Sponsors can request ODD at any point before submitting a New Drug Application (NDA) or Biologics License Application (BLA). In fact, ODD is unique among special designations because it can be requested even before an initial Investigational New Drug (IND) application. Experts recommend requesting ODD as early as possible once sufficient preliminary evidence of effectiveness is available.
Submission process
The submission process involves two primary methods. Sponsors can either use the CDER NextGen Portal, create an online account, and fill out an online application, or email the required information to orphan@fda.hhs.gov. Most of the time, sponsors use the FDA Form 4035, which provides a standardized template for the designation request.
When an ODD request is submitted, the FDA will review the request and provide a decision within 90 calendar days.
If granted, the designation offers several significant benefits. These include seven years of market exclusivity for the specific orphan indication, a tax credit for the drug development costs, and a waiver of the application fee. Additionally, sponsors become eligible to compete for specific research and development grants through the Orphan Products Development Office.
Basic elements of an ODD request must include:
- Administrative information
- Drug product information
- Explanation of the disease or condition
- Scientific rationale
- Clinical superiority (if applicable)
- Population estimate to demonstrate that the disease or condition is rare (<200,000)
- Regulatory status/marketing history
Scientific reasoning is particularly crucial, requiring sponsors to explain the drug’s mechanism of action clearly and provide supporting data from human, animal, or in vitro studies.
It’s important to note that meeting the basic eligibility criteria does not guarantee ODD approval. The FDA carefully evaluates the specific characteristics of the drug, its mechanism of action, and its potential effectiveness in the targeted rare disease population.
2. Fast Track Designation (FTD)
The Fast Track Designation is a strategic FDA pathway designed to expedite the development and review of drugs targeting serious conditions with unmet medical needs. To qualify for FTD, a drug must demonstrate preliminary evidence of effectiveness in preventing, diagnosing, or treating a specific disease or condition.
Eligibility criteria
There are two key eligibility aspects. First, the drug must address a serious condition, which the FDA evaluates based on its potential impact on patient survival, day-to-day functioning, or the progression of a medical condition if left untreated. Sponsors must proactively make a compelling case for why their targeted condition meets the “serious” criteria, as there is no rigid, predefined definition.
The second key requirement is addressing an unmet medical need. This can be achieved in several ways. If no existing therapies are available, developing a new treatment satisfies this requirement. When alternative therapies already exist, sponsors must demonstrate a clear advantage over current options. These advantages could include superior efficacy, reduced side effects, decreased toxicity, or the ability to enable earlier diagnosis. Additionally, the potential to address emerging or anticipated public health needs can strengthen the FTD application.
Submission process and benefits
Sponsors can request FTD as early as submitting their initial IND application. However, sponsors are recommended to submit the request no later than the End of Phase 2 meeting. The FDA typically takes 60 calendar days to review the FTD request.
If granted, FTD offers significant benefits to drug developers. These include more frequent communication with the FDA, eligibility for accelerated approval and priority review, and the ability to utilize a rolling review process. The rolling review allows sponsors to submit their BLA or NDA in modules, enabling the FDA to begin reviewing sections as they are received rather than waiting for the complete application.
Preliminary evidence supporting the FTD request can come from various sources. While clinical data is ideal, the FDA recognizes that such data might not always be available at the time of application. Sponsors can still request FTD with strong non-clinical evidence demonstrating the drug’s potential effectiveness.
3. Breakthrough Therapy Designation (BTD)
The Breakthrough Therapy Designation is a pathway for expediting the development of promising drugs that demonstrate substantial potential to address serious medical conditions. While sharing some similarities with the FTD, BTD has more stringent requirements and offers more comprehensive support from the FDA.
Eligibility criteria
To qualify for BTD, a drug must meet two criteria.
First, it must be intended to treat a serious condition. Second, and most importantly, the drug must have preliminary clinical evidence indicating a substantial improvement on a clinically significant endpoint compared to available therapies. Unlike FTD, BTD requires clinical study data and cannot be based on non-clinical studies alone.
Timelines and endpoints
It’s recommended that sponsors submit the request no later than the End of Phase 2 meeting. The FDA cautions that requesting BTD after Phase 2 may provide limited benefits, as the designation’s advantages become less impactful in later stages of drug development.
The FDA typically reviews and responds with a decision to BTD requests within 60 calendar days. If granted, BTD’s benefits include all previous fast track designation features, plus intensive guidance on an efficient drug development program, organizational commitment involving senior FDA management, and an initial comprehensive meeting (Type B).
A key aspect of BTD is the focus on clinically significant endpoints. These typically measure effects on irreversible morbidity, mortality, or serious disease symptoms. Acceptable endpoints can include overall survival, progression-free survival, or other findings that strongly suggest potential meaningful clinical effects. The FDA looks for evidence of substantial improvement over existing therapies, which has become increasingly challenging as more advanced treatments enter the market.
Common reasons why BTD requests are denied
Many BTD requests are denied due to common issues such as insufficient clinical data, lack of demonstrated substantial improvement over available therapy, or reliance on biomarkers that the FDA does not consider predictive of clinical benefit.
However, while the FDA may occasionally suggest that a sponsor request BTD, it is recommended that sponsors proactively assess their own data and development plans, the onus is on the drug developers to demonstrate the exceptional potential of their therapeutic approach.
4. Regenerative Medicine Advanced Therapy (RMAT) Designation
The Regenerative Medicine Advanced Therapy Designation (RMAT) represents a specialized FDA pathway designed specifically for cutting-edge regenerative medicine therapies. Unlike other special designations, RMAT has a unique requirement that the drug must be a specific type of advanced therapy product, which distinguishes it from other expedited development pathways.
RMAT covers a broad range of innovative medical technologies, including:
- Cell therapies
- Therapeutic tissue-engineered products
- Human cell and tissue products
Eligibility criteria
An RMAT therapy must meet three critical criteria. First, the drug is a regenerative medicine therapy. Second, the drug intends to treat, modify, reverse, or cure a serious or life-threatening disease/condition
Third, preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs.
Submission process
Sponsors can request RMAT Designation as early as submitting their initial IND application. However, sponsors are recommended to request the designation no later than the End of Phase 2 meeting. The FDA typically reviews RMAT requests within 60 calendar days, providing a decision to grant or deny the designation.
If granted, RMAT Designation offers benefits similar to FTD and BTD. Some drugs may even be eligible to receive both RMAT and BTD simultaneously. However, sponsors should note that even with multiple designations, they are only entitled to one initial comprehensive meeting with the FDA.
5. Accelerated Approval Pathway
The Accelerated Approval Pathway is designed to expedite the availability of promising drugs for serious medical conditions with unmet needs. This innovative approach was put in place to address approval processes that can be extremely time-consuming, often requiring 5 to 10 years to demonstrate a drug’s ultimate clinical benefit.
Eligibility criteria
There are two key criteria for this pathway.
The drug must treat a serious condition that fills an unmet medical need. Additionally, the drug must demonstrate an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on an intermediate clinical endpoint that can be measured earlier than irreversible morbidity or mortality (IMM) that is reasonably likely to predict an effect on IMM or other clinical benefit
Surrogate vs. clinical endpoints
A surrogate endpoint is a laboratory measurement, radiographic image, or other indicator that is believed to predict clinical improvement, even if it does not directly measure patient outcomes.
For example, in oncology, tumor shrinkage can serve as a surrogate endpoint. Instead of waiting years to determine whether a cancer treatment extends patient survival, the FDA can assess and potentially approve a drug based on its ability to reduce tumor size. After receiving accelerated approval, drug companies must still conduct confirmatory studies to validate that the surrogate endpoint truly predicts meaningful clinical benefits.
Intermediate clinical endpoints offer another pathway for accelerated approval.
These are therapeutic effect measurements that are considered likely to predict clinical benefit. In multiple myeloma, for instance, minimal residual disease (MRD) has gained attention as a potential intermediate endpoint. MRD measures the number of cancer cells remaining after treatment, with sustained MRD negativity demonstrating a strong correlation with improved patient outcomes.
Benefits and challenges
The FDA can conditionally approve a drug based on these surrogate or intermediate endpoints, allowing the medication to be marketed sooner. The conditional approval can be converted to standard approval once confirmatory studies validate the initial findings. This is particularly impactful in oncology, where accelerated approval can potentially bring treatments to market three to six years earlier than traditional pathways.
However, the pathway is not without challenges. Sponsors must work closely with the FDA to align on acceptable surrogate or intermediate endpoints. The FDA will carefully evaluate the scientific support for these endpoints, requiring adequate and well-controlled studies. What works as a valid endpoint for one disease may not necessarily apply to another, even if the conditions seem similar.
Sponsors must be prepared to present comprehensive scientific evidence justifying their chosen endpoint. The FDA requires comprehensive data demonstrating that the proposed endpoint truly predicts meaningful clinical benefits. This often involves complex statistical analyses and longitudinal studies that establish a clear correlation between the surrogate marker and patient outcomes.
6. Priority Review
Priority review is a pathway for expediting the assessment of groundbreaking pharmaceutical treatments. This FDA mechanism provides a streamlined approach for reviewing drug applications that demonstrate significant potential to improve patient care.
Eligibility criteria
To qualify for priority review, a drug must offer significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard therapies.
Submission process
Sponsors can request priority review at the time of their NDA or BLA submission. The FDA responds to these requests within 60 calendar days, providing a relatively quick initial assessment of the drug’s potential for expedited review.
If granted priority review, the FDA commits to completing the comprehensive drug application review within six months, compared to the standard ten-month timeline. This four-month reduction can significantly accelerate the potential availability of innovative therapies to patients who may desperately need new treatment options.
Evidence requirements
To successfully secure priority review, sponsors must provide robust scientific evidence demonstrating the drug’s meaningful improvements. This might include data showing increased treatment effectiveness, better safety profiles, improved patient compliance, or evidence of safety and efficacy in specific patient subpopulations. The goal is to prove that the new therapy represents a meaningful advance in medical treatment.
By offering this accelerated pathway, the FDA encourages pharmaceutical innovation and helps bring promising new therapies to patients more quickly, potentially making a critical difference in patient outcomes and quality of life.
Key Strategic Considerations
Sponsors should prioritize requesting special designations as early as possible in the drug development process. The benefits of these designations are most impactful when pursued promptly, ideally no later than the End of Phase 2 meeting. Waiting too long to request these designations can significantly diminish the potential advantages and incentives offered by the FDA.
Successful acquisition of special designations demands seamless collaboration across multiple teams. The regulatory, clinical, and non-clinical teams must work in close coordination to develop a comprehensive development plan. This integrated approach ensures that the necessary data supporting designation requests are collected and evaluated at the most appropriate stages of drug development. Different designations have varying eligibility criteria, so teams must carefully strategize when and how to pursue these opportunities.
It’s also important to note that the FDA does not publicly disclose denials of special designation requests. While approvals may be shared online, sponsors can confidently pursue these designations without concern about potential public scrutiny of unsuccessful requests. This discretion allows companies to explore expedited development pathways without fear of negative public perception.
Leveraging HiRO’s regulatory expertise
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