Orphan Drug Application

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The Orphan Drug Act

One of the largest obstacles to jump-starting research for a rare-disease drug therapy is the lack of financial incentive for the developer. Because the populations affected by these diseases are relatively small, pharmaceutical companies would, in most cases, be unable to recover the drug development costs through sales alone. The group of conditions lacking therapies for this reason is collectively known as “orphan” diseases because they have not been “adopted” by the pharmaceutical industry. Their therapies are likewise referred to as “orphan” drugs.

To address this problem, the United States Congress passed the Orphan Drug Act (ODA), P.L. 97-414, in 1983. The aim of the ODA is to provide financial incentives to those companies and investigators that choose to develop orphan drugs. Congress amended ODA in 1984, 1985, and 1988 to further the scope of the legislation. The incentives provided to drug developers by the ODA include:

7-year market exclusivity for developers of approved orphan drugs
A 50% tax credit for the costs associated with testing the drug in humans
Food and Drug Administration (FDA) assistance in developing clinical trial protocols
Research grants for clinical trials

The ODA is applicable to drugs that treat conditions that meet one of the two criteria set out in the legislation:

The condition affects less that 200,000 people in the United States, or
The condition affects more than 200,000 people in the United States, but the sponsor successfully demonstrates that there is no reasonable expectation that the costs of development will be recovered solely from profits resulting from sales.

The FDA is responsible for the administration of the ODA and is solely responsible for reviewing applications that seek orphan designations and research grants. The Office of Orphan Products Development (OOPD) within FDA carries out these responsibilities. Once a drug has been developed, it must then be approved by the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER) in order to go to market. It is important to note that the OOPD is not involved in drug approvals. The Internal Revenue Service (IRS) administers the sections of the ODA dealing with tax credits once an orphan designation has been made by the OOPD.

The ODA has been successful in encouraging the development of orphan drugs. In the ten years prior to the passage of the ODA, only thirty-four orphan drugs moved to market. In the ten years after passage, 100 orphan-designated drugs went to market and an additional 620 orphan designations were made by the OOPD. Since then, the number of market approvals and orphan designations has increased. As of November 3, 2008, the OOPD had made 1,857 orphan designations. While most orphan designation sponsors are pharmaceutical and biotechnology companies, individuals and organizations can sponsor an application. The OOPD has clear guidelines and expectations for the submission orphan designation applications, which will be reviewed here.

It is important to note that much of the application’s fate will hinge on the scientific evidence presented. As such, it may be helpful to first conduct an exhaustive search of the scholarly literature to determine the current thought on the condition and therapies related to your application. This could be the most difficult aspect of preparing the application. It may be helpful to consult with a medical professional throughout the process of preparing your application and before submitting your application to make sure that the presentation of scientific information and reasoning are sound.

Conducting a Literature Search

The goal of conducting a literature review is to ascertain where the field is right now:

What is known about the etiology and manifestation of the condition?
What is known about the therapy? How does it relate to the condition?
Who are the major researchers in this field? They may be helpful contacts as you prepare your application and attempt to learn more about the field.
Is there sufficient evidence for the assertions you will make in the orphan status application? What needs to be studied further? It is important to find information that may support or dispute your assertions.

Necessarily, a literature should begin broadly. This may be as simple as typing the name of the condition into an Internet search engine. It is important, however, that one considers the sources of information as he or she moves through the literature. In science, the peer-review process is the gold standard for establishing validity of research. Thus, it is best to consider articles and papers from peer-reviewed journals and cite these as authoritative sources. The OOPD expects that the scientific foundations of the application are sound and based on scholarly research and clinical evidence. These websites offer specialized scientific search functions that will include authoritative resources in the results:

Many academic journals require high-priced subscriptions and fees to view content. Fortunately, many public and academic libraries have access to most of these journals and services. In addition, all journal articles reporting on federally funded research are required to be deposited in PubMed Central no later than 12 months after publication. These you will be able to access through PubMed Central.

It can be daunting to review scientific literature, especially if you have not had much experience in the scientific field. Here are some tips that may help:

If there is a specific term or concept that you do not understand, use an Internet search engine to determine its meaning. There are many resources on the Internet that explain medical and scientific information.
Begin by searching in secondary sources (encyclopedias, science magazines, etc.) to familiarize yourself with the necessary ideas and jargon.
Consult with someone who has experience in the field and with the literature. Their help can be invaluable in putting technical concepts and language into understandable terms.
Summarize articles and papers in a few sentences after reading them. This will help you to synthesize the information and to easily find the conclusions of each reference later.

After a broad survey of the field, it will become necessary to narrow the search. Determine what information is needed in order to provide convincing evidence that the drug will be effective and safe in treating the condition. Here are some tips:

Many times drugs and therapies have been used for other conditions or mentioned as possibly being useful in treating other conditions. Determine whether evidence for the treatment of those conditions can likewise be applied to the orphan condition.
What are the molecular mechanisms of action of the drug and how do those relate to treatment of the condition? This theory could prove convincing in the application, especially if the field lacks a lot of clinical data that studies the effectiveness of the treatment for a specific indication.
If the drug has already been developed, is it being used in an off-label fashion already to treat your disease? Search for published scientific evidence of its effectiveness or safety. If this evidence does not exist, consider surveying the disease community to determine the experiences of those who have received the treatment.

Once the scientific evidence has been gathered, the next step is to prepare the application for review by OOPD.

Preparing the Application

OOPD reviews orphan status applications and has developed guidelines for what information must be included. It is important that all requirements are present and complete in the final application. The application must include nine statutorily mandated components:

The sponsor must make a statement that demonstrates the intent to seek an orphan drug designation for a rare condition. It is important that the condition be specified as specifically as is possible.
The name, address, and phone number of the sponsor must be included. If an organization is sponsoring the application, the same contact information must be supplied for a primary contact person. In addition, the sponsor must identify the generic and market names of the drug for which they are seeking an orphan designation. If the producer of the drug is not the sponsor, then the sponsor must supply the name and the address of the drug manufacturer as well.
A clinical description of the disease must be provided. The sponsor must also identify the indications for which the drug would be used as treatment as well as the reasons for using the drug.
The sponsor must then provide a description of the drug as well as the scientific reasoning for using the drug to treat the indications specified in part 3. Cite all clinical and nonclinical data regarding the drug and its use, whether it is supportive, detrimental, or neutral in regard to the assertions made in the application.
If the drug for which the sponsor seeks an orphan designation is the same as a drug that already has an orphan designation for the same disease, then the sponsor must demonstrate that its drug is clinically superior.
If the designation is being sought for a subset of individuals that have a particular condition, then the sponsor must demonstrate that the subset is medically plausible.
The sponsor must provide a summary of the regulatory history of the drug both in the United States and in other countries. Include information about what indications the drug is approved for, what further indications are being studied, results of treatments with the drug (beneficial and adverse), etc.
The sponsor must state whether or not he is the interested party in the development, production, or sale of the product.
The sponsor must assert that the disease is one covered by ODA by documenting that the condition

affects fewer than 200,000 people in the United States, or
affects more than 200,000 people in the United States, but that there is no reasonable expectation that the costs of development will be recovered solely from profits resulting from sales.

Suggestions for Preparing the Application

OOPD provides the following tips for preparing the application:

Number the items on the application, 1-9.
Particular emphasis is placed on items 4 and 8.
In Item 8, be sure not to confuse prevalence with incidence. OOPD is interested in the former.
Include hard copies of every reference with the application.
In Item 7, provide an Investigational New Drug Application (IND) number or the New Drug Application (NDA) number if either is available.
References can be either numerical or parenthetical. If they are numerical, provide a bibliography in that order and place the copies of the reference materials in that order. If the references are parenthetical, provide an alphabetically ordered bibliography and place the copies of the reference materials in alphabetical order as well.
Place tabbed dividers between the copies of the reference materials.
Place each copy of the application in separate binders before sending them to OOPD. All materials should be the same in both applications, including cover letters.

Application Submission

Sponsors must submit two hard copies of the application. Be sure to include copies of all cited articles and papers with each application. The application should be submitted to OOPD:

Director, Office of Orphan Products Development

Food and Drug Administration, HF-35

5600 Fishers Lane, Room 6A55

Rockville, MD 20857

The contact person in OOPD for orphan designation applications is Jeff Fritsch, (301) 827-0989.