CRL
Complete Response Letter. Basically a letter explaining why the FDA is not approving a drug. The Food and Drug Administration (FDA) is amending its regulations on new drug applications (NDAs) and abbreviated new drug applications (ANDAs) for approval to market new drugs and generic drugs (drugs for which approval is sought in an ANDA).  The final rule discontinues FDA’s use of approvable letters and not approvable letters when taking action on marketing applications.  Instead, we will send applicants a complete response letter to indicate that the review cycle for an application is complete and that the application is not ready for approval.  We are also revising the regulations on extending the review cycle due to the submission of an amendment to an unapproved application and starting a new review cycle after the resubmission of an application following receipt of a complete response letter.  In addition, we are adding to the regulations on biologics license applications (BLAs) provisions on the issuance of complete response letters to BLA applicants.  We are taking these actions to implement the user fee performance goals referenced in the Prescription Drug User Fee Amendments of 2002 (PDUFA III) that address procedures and establish target timeframes for reviewing human drug applications.

Fast Track
Fast track is a process designed to facilitate the development, and expedite the review of drugs to treat serious diseases and fill an unmet medical need.  The purpose is to get important new drugs to the patient earlier. Fast Track

addresses a broad range of serious diseases.

Determining whether a disease is serious is a matter of judgment, but generally is based on whether the drug will have an impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one.  AIDS, Alzheimer’s, heart failure and cancer are obvious examples of serious diseases.   However, diseases such as epilepsy, depression and diabetes are also considered to be serious diseases.

Filling an unmet medical need is defined as providing a therapy where none exists or providing a therapy which may be potentially superior to existing therapy.

Any drug being developed to treat or prevent a disease with no current therapy obviously is directed at an unmet need.  If there are existing therapies, a fast track drug must show some advantage over available treatment, such as:

• Showing superior effectiveness
• Avoiding serious side effects of an available treatment
• Improving the diagnosis of a serious disease where early diagnosis results in an improved outcome
• Decreasing a clinically significant toxicity of an accepted treatment

A drug that receives Fast Track designation is eligible for some or all of the following:

• More frequent meetings with FDA to discuss the drug’s development plan and ensure collection of appropriate data needed to support drug approval
• More frequent written correspondence from FDA about such things as the design of the proposed clinical trials
• Eligibility for Accelerated Approval, i.e., approval on an effect on a surrogate, or substitute endpoint reasonably likely to predict clinical benefit
• Rolling Review, which means that a drug company can submit completed sections of its New Drug Application (NDA) for review by FDA, rather than waiting until every section of the application is completed before the entire application can be reviewed.  NDA review usually does not begin until the drug company has submitted the entire application to the FDA, and
• Dispute resolution if the drug company is not satisfied with an FDA decision not to grant Fast Track status.

In addition, most drugs that are eligible for Fast Track designation are likely to be considered appropriate to receive a Priority Review. Fast Track designation must be requested by the drug company.  The request can be initiated at any time during the drug development process.  FDA will review the request and make a decision within
sixty days based on whether the drug fills an unmet medical need in a serious disease.

Once a drug receives Fast Track designation, early and frequent communication between the FDA and a drug company is encouraged throughout the entire drug development and review process.  The frequency of communication assures that questions and issues are resolved quickly, often leading to earlier drug approval and access by patients.

FDA Action Date
The action date tells when an FDA regulatory action, such as an original or supplemental approval, took place.

New Drug Application (NDA)
When the sponsor of a new drug believes that enough evidence on the drug’s safety and effectiveness has been obtained to meet FDA’s requirements for marketing approval, the sponsor submits to FDA a new drug application (NDA). The application must contain data from specific technical viewpoints for review, including chemistry, pharmacology, medical, biopharmaceutics, and statistics. If the NDA is approved, the product may be marketed in the United States.  For internal tracking purposes, all NDA’s are assigned an NDA number.

Orphan Drug Status
The Orphan Drug Act (ODA) of January 1983, passed in the United States, with lobbying from the National Organization for Rare Disorders, is meant to encourage pharmaceutical companies to develop drugs for diseases that have a small market. Under the law, companies that develop such a drug (a drug for a disorder affecting fewer than 200,000 people in the United States) may sell it without competition for seven years, and may get clinical trial tax incentives.

Orphan drugs generally follow the same regulatory development path as any other pharmaceutical product, in which testing focuses on pharmacokinetics and pharmacodynamics,dosing, stability, safety and efficacy. However, some statistical burdens are lessened in an effort to maintain development momentum. For example, orphan drug regulations generally acknowledge the fact that it may not be possible to test 1,000 patients in a phase III clinical trial, as fewer than that number may be afflicted with the disease in question.

PDUFA
The Prescription Drug User Fee Act (PDUFA) was enacted in 1992 and renewed in 1997 (PDUFA II), 2002 (PDUFA III), and 2007 (PDUFA IV).  It authorizes FDA to collect fees from companies that produce certain human drug and biological products. Since the passage of PDUFA, user fees have played an important role in expediting the drug approval process.

Priority Review
Prior to approval, each drug marketed in the United States must go through a detailed FDA review process.  In 1992, under the Prescription Drug User Act (PDUFA), FDA agreed to specific goals for improving the drug review time and created a two-tiered system of review times – Standard Review and Priority Review.

Standard Review is applied to a drug that offers at most, only minor improvement over existing marketed therapies.  The 2002 amendments to PDUFA set a goal that a Standard Review of a new drug application be accomplished within a ten-month time frame.

A Priority Review designation is given to drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists.  A Priority Review means that the time it takes FDA to review a new drug application is reduced.  The goal for completing a Priority Review is six months.

Priority Review status can apply both to drugs that are used to treat serious diseases and to drugs for less serious illnesses. The FDA goal for reviewing a drug with Priority Review status is six months.

The distinction between priority and standard review times is that additional FDA attention and resources will be directed to drugs that have the potential to provide significant advances in treatment.
Such advances can be demonstrated by, for example:

• evidence of increased effectiveness in treatment, prevention, or diagnosis of disease;
• elimination or substantial reduction of a treatment-limiting drug reaction;
• documented enhancement of patient willingness or ability to take the drug according to the required schedule and dose; or
• evidence of safety and effectiveness in a new subpopulation, such as children.

A request for Priority Review must be made by the drug company. It does not affect the length of the clinical trial period.  FDA determines within 45 days of the drug company’s request whether a Priority or Standard Review designation will be assigned.  Designation of a drug as “Priority” does not alter the scientific/medical standard for approval or the quality of evidence necessary.