Fast Track

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Fast Track, Accelerated Approval and Priority Review
Accelerating Availability of New Drugs for Patients with Serious Diseases Speeding the development and availability of drugs that treat serious diseases are in everyone's interest, especially when the drugs are the first available treatment or have advantages over existing treatments. The Food and Drug Administration (FDA) has developed three distinct and successful approaches to making such drugs available as rapidly as possible: Priority Review, Accelerated Approval, and Fast Track. Because each of these approaches implies speed, there can be confusion about the specific meaning of each and the distinctions among them. The following summary describes each element, how they differ, and how they complement each other. Fast Track Accelerated Approval Priority Review Comparison of Approval Times for Priority and Standard Review Drugs between 1993 and 2003

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.

Accelerated Approval

When studying a new drug, it can take a long time - sometimes many years - to learn whether a drug actually provides real improvement for patients – such as living longer or feeling better. This real improvement is known as a “clinical outcome.” Mindful of the fact that obtaining data on clinical outcomes can take a long time, in 1992 FDA instituted the Accelerated Approval regulation, allowing earlier approval of drugs to treat serious diseases, and that fill an unmet medical need based on a surrogate endpoint. A surrogate endpoint is a marker - a laboratory measurement, or physical sign - that is used in clinical trials as an indirect or substitute measurement that represents a clinically meaningful outcome, such as survival or symptom improvement. The use of a surrogate endpoint can considerably shorten the time required prior to receiving FDA approval. Approval of a drug based on such endpoints is given on the condition that post marketing clinical trials verify the anticipated clinical benefit.

The FDA bases its decision on whether to accept the proposed surrogate endpoint on the scientific support for thatendpoint. The studies that demonstrate the effect of the drug on the surrogate endpoint must be “adequate and well controlled” studies, the only basis under law, for a finding that a drug is effective. Use of a surrogate can save valuable time in the drug approval process. For example, instead of having to wait to learn if a drug actually can extend the survival of cancer patients, the FDA might now approve a drug based on evidence that the drug shrinks tumors because tumor shrinkage is considered reasonably likely to predict a real clinical benefit. In this example, an approval based upon tumor shrinkage can occur far sooner than waiting to learn whether patients actually lived longer. The drug company will still need to conduct studies to confirm that tumor shrinkage actually does predict that patients will live longer. These studies are known as phase 4 confirmatory trials. If the confirmatory trial shows that the drug actually provides a clinical benefit, then the FDA grants traditional approval for the drug. If the confirmatory trial does not show that the drug provides clinical benefit for patients, FDA has regulatory procedures in place that could lead to removing the drug from the market.

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.
SUMMARY

Fast Track, Accelerated Approval and Priority Review are approaches that are intended to make therapeutically important drugs available at an earlier time. They do not compromise the standards for the safety and effectiveness of the drugs that become available through this process. These revitalized FDA drug review approaches have yielded tangible results in bringing safe and effective drugs to patients with serious diseases more quickly. For example, since 1996, 68 drugs for cancer therapies have received priority review and approval. FDA reviewed Gleevec, a treatment for chronic myeloid leukemia, in four months. Shortened review times have also brought promising treatments to patients with HIV/AIDS more quickly. Kaletra for the treatment of HIV/AIDS was reviewed and approved in 3.5 months. Pegasys, a combination product for the treatment of Hepatitis C was approved for marketing in 4 months. The table below illustrates the improvement in FDA review times in the years between 1993 to 2003. The median time required to review a priority review drug was reduced from 13.9 months to 6.7 months. Fast Track, Accelerated Approval, and Priority Review have evolved over time. FDA has been vigilant in assuring that reducing the time necessary for drug development has not compromised the safety and effectiveness of drugs for patients with serious diseases.

Comparison of Approval Times for Priority and Standard Review Drugs Calendar Years 1993-2003 Priority Median Calendar FDA Number Number Year Review Approved Approved Time (months) 1993 1994 13 13 13.9 15.0 12 9 Standard Median FDA Review Time (months) 27.2 22.2

1995 1996 1997 1998 1999 2000 2001 2002 2003 -

9 18 9 16 19 9 7 7 9

6.0 7.7 6.4 6.2 6.3 6.0 6.0 13.8 6.7

19 35 30 14 16 18 17 10 12

15.9 14.6 14.4 12.3 14.0 15.4 15.7 12.5 13.8

FDA Fast Track Development Program
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The FDA Fast Track Development Program is a designation of the United States Food and Drug Administration (FDA) that accelerates the approval of investigational new drugs undergoing clinical trials. Such status is often given to agents that show promise in treating serious, life-threatening medical conditions for which no other drug either exists or works as well. 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. 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 FDA 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.

[edit] References


Reichert JM, Rochon SL, Zhang BD.A decade of the Fast Track programme. Nat Rev Drug Discov. 2008 Nov;7(11):885-6. Epub 2008 Oct 24 PMID: 18948998

News and Analysis
Nature Reviews Drug Discovery 7, 885-886 (November 2008) | doi:10.1038/nrd2733
FROM THE ANALYST'S COUCH:

A decade of the Fast Track

programme

Janice M. Reichert1, Stephanie L. Rochon1 & Bodi D. Zhang2

Leif Jorgensen, Round One (Hay). Available from http://www.scp.co.uk

The US Food and Drug Administration's (FDA's) Fast Track programme has existed for a decade. Created as Section 112 of the FDA Modernization Act of 1997, the programme is designed to facilitate the development and expedite the review of drugs and biologics that are intended to treat serious or lifethreatening conditions, and that demonstrate the potential to address unmet medical needs. Close, early communication between the FDA and sponsors to improve the efficiency of product development is emphasized. However, the programme's effectiveness has been questioned1. Sponsors are suspected of announcing Fast Track designations to facilitate an increase, albeit a temporary one, in company stock prices2, and the FDA has been criticized for its lack of transparency concerning the programme3. Not surprisingly, US Congress members are calling for enquiries. Other than tallies, the FDA does not provide information about Fast Track designated investigational candidates. However, sponsors often do. The Tufts Center for the Study of Drug Development (CSDD) has collected data on these candidates since 1998. The data set now comprises 344 therapeutic, vaccine and diagnostic agents that between them have been granted nearly 400 designations, representing approximately 70% of the Fast Track designations granted by the FDA between January 1998 and June 2008.

Data for 301 therapeutic candidates granted designations between 1998 and 2007 were analysed to assess 'fast track' effects on two benchmark metrics. In particular, two common presuppositions are that fast-tracked candidates could have decreased clinical phase lengths and higher success rates compared with those without designations. As described here, our analysis of the complex and limited data available suggests that such comparisons should be made cautiously. Analysis Candidate profile. The Fast Track therapeutic candidates were widely diverse. Innovative candidates that recently entered clinical study, approved products undergoing further study as treatments for additional indications, and unapproved candidates first studied in the clinic decades ago had all received Fast Track designations. Candidates were studied as treatments in five major therapeutic categories — anticancer (32%), anti-infective (22%), cardiovascular (11%), immunological (8%) and neurological (8%) — although none of these constituted a majority and 57 (19%) were for other indications. Small-molecule drugs and compounds of this nature, such as peptides, represented 69% of the molecules, with the remainder composed of protein therapeutics or other biologics. Rate of designations. The pace at which designations were granted increased dramatically between 2001 and 2003 (Fig. 1). A similar increase is apparent in the Center for Drug Evaluation and Research's (CDER's) reported number of applications received and designations granted in fiscal years 1998–2007. Because of the small number of protein therapeutics involved, the increase seems unrelated to the transfer of review responsibility for these

candidates from the Center for Biologics Evaluation and Research (CBER) to the CDER that occurred in June 2003. Figure 1 | Use of Fast Track (FT) designation, introduced in 1998, has increased significantly since 2002.

The data set included 301 Fast Track therapeutic candidates; 80 candidates with FT designations entered clinical study prior to 1993; year unknown for 5 candidates.
  

Full size figure and legend (49 KB) Figures and tables index Download high-resolution Power Point slide (88 KB)

Entry into clinical study. Dates of first entry into clinical study covered a broad range. Some drugs were first administered to humans in the 1960s and 1970s; at least 26% entered the clinic prior to 1993 (year known for 98%). At the outset of the programme, few candidates received designations early in development. Of the Fast Track candidates that first entered studies during 1998–2002, 13% were designated within 1 year and 42% received designations within 3 years after clinical entry. The corresponding values were 35% and 98%, respectively, for Fast Track candidates that first entered the clinic during 2003–2007. These results suggest that in the latter period sponsors began requesting designations for candidates earlier in the development process. However, few candidates that entered studies recently have been granted designations to date. The percentages will decrease as currently undesignated candidates become Fast Track therapeutics in the future.

Characteristics of Fast Track indications. Fast Track indications were often included as part of an overall development programme that involved clinical trials of additional indications and alternative drug formulation, delivery or dose. For example, docetaxel received a Fast Track approval for non-small-cell lung cancer 3 years after its approval for breast cancer, and well-studied drugs such as amphotericin, paclitaxel and vincristine were formulated differently as Fast Track candidates than previously approved versions of the products. Study of Fast Track indications lagged compared with study of candidates as treatments for other diseases (Fig. 2). Overall, Fast Track indications were more frequently terminated and less frequently approved compared with other indications for candidates designated in both the 1998–2002 and 2003–2007 periods. It should be noted that the majority of the candidates designated in 2003–2007 were still in clinical study. Taken together, these results suggest that Fast Track studies have a secondary role in development programmes. Figure 2 | Fast Track indications were more frequently terminated and less frequently approved than other indications.

1998–2002 and 2003–2007 are periods of Fast Track designation.
  

Full size figure and legend (49 KB) Figures and tables index Download high-resolution Power Point slide (88 KB)

Clinical phase length. The tendency for Fast Track studies to be embedded in overall development programmes that might be sponsored by different companies over potentially long periods of time made clinical phase length comparisons problematic. In theory, the clinical phase would start with the first study of the Fast Track indication and end with submission of the marketing application for the same indication. However, this method truncates the standard clinical phase by omitting Phase I, and ignores a confounding factor: knowledge gained from studies done prior to receipt of designations and those done for alternative indications might allow more efficient design and execution of studies done for Fast Track indications. Clinical phase lengths, ordinarily measured from the date of first clinical entry to the first marketing application submission, are notoriously variable over time4, thereby adding difficulty to the use of phase lengths to assess the Fast Track programme. Using the latter method, the average clinical phase was 66.5 months for new, Fast Track approved products that first entered clinical study after 1992. This value compares favourably with the average clinical phase length for new drugs, which has ranged from 64 to 97 months over the past two decades4 (Tufts CSDD, unpublished observations). The averages for Fast Track products in the two most frequently studied therapeutic categories, anticancer and anti-infective, were 73.4 and 59.7 months, respectively. Probability of success. Use of probability of success (POS) values for comparisons was also problematic. Fast Track designations were commonly granted after proof of concept had been demonstrated in clinical studies. So, Fast Track candidates were selected from a pool of investigational molecules

that had already undergone preliminary safety and efficacy evaluations. Phase I to Phase II and Phase II to Phase III transition probabilities were anomalously high (Fig. 3) compared with previously published values for drugs (approximately 60% and 40% for the Phase I to Phase II and Phase II to Phase III transitions, respectively)5. The FDA review-to-approval transition was also remarkably high for candidates granted designations during 2003– 2007 compared with the previously published value for drugs (approximately 75%)5. It is important to note that the POS values can be considered to be only rough estimates because the final fates of all candidates in each cohort are not yet known, and that the values have a probable upward bias. Judging from the FDA's Fast Track designation tallies, approximately 150 Fast Track candidates were not included in the data set. The CDER lists Fast Track approvals6, so it is likely that few, if any, approvals were missed. However, it is likely that at least some of the 'missing' candidates were discontinued. The POS values would have been lower if these had been included. Figure 3 | Phase transition probabilities were high in early development.

Clinical phase transition probabilities represent the likelihood that a candidate that begins a particular development phase will transition to the next phase. Phase transition probabilities were calculated as follows: the number of products that completed a given phase (e.g., Phase I) and entered the next phase (e.g., Phase II) was divided by the difference between the number of products that entered the phase and those that were still in the phase at the time of the calculation. Transitions occurring between phases of clinical studies conducted worldwide were included. FT, Fast Track.


Full size figure and legend (48 KB)

 

Figures and tables index Download high-resolution Power Point slide (87 KB)

Summary Overall, this analysis suggests that evaluation of the FDA's Fast Track programme requires a nuanced approach. The significance of designations cannot be determined by simplistic comparisons of clinical phase lengths or success rates for designated versus non-designated candidates because the available data introduces biases in these metrics. The programme's value lies with the output — products that treat serious or life-threatening conditions and address unmet medical needs that, without intervention from the FDA, might not be brought to the US market for these indications.

SOPP 8414: Fast Track Drug Development Programs: Designation and Review Programs
Version #1 Effective Date: November 16, 2001

1. Purpose 1. This document describes procedures and policies for handling fast track designation requests. It also provides procedures for handling of requests for submission of portions of applications (SoPA). 2. 2. Background

1. Section 112 of the Food and Drug Administration Modernization Act of 1997 (FDAMA) amended the Federal Food Drug and Cosmetic Act (FDCA) by adding section 506. Section 506 directs FDA to take actions appropriate to facilitating the development and expediting the review of applications for drugs that are intended to treat serious or life threatening conditions and that demonstrate the potential to address an unmet medical need for such a condition. The "Guidance for Industry: Fast Track Development Programs-Designation, Development and Application Review" was published on November 18, 1998, and is available on the CBER Guidelines web page. To obtain designation as a fast track drug development program, a sponsor must submit a request to FDA in their Investigational New Drug Application (IND). FDA has 60 calendar days from the date of receipt to review the request and determine whether it meets the criteria as defined in the statute and further explained in the Guidance, and respond in writing. Section 506(c) provides for review of incomplete marketing applications for a fast track product in certain circumstances. 2. 3. Policy 1. The decision whether to designate the drug development program as Fast Track will be based on the criteria contained in the guidance mentioned above. The clinical reviewer of the IND, with concurrence from the branch chief and/or division director, will have primary responsibility for the decision. Responsibility for coordination of the response will be through the Regulatory Project Manager (RPM) in the Application division. Section 506(c) of the FDCA provides that FDA may agree to submission of portions of a BLA application (SoPA) or efficacy supplement before the complete BLA is submitted. This provision only applies to a product and indication that has received Fast Track designation. FDAMA states that we will accept a SoPA only if the drug development program continues to meet the criteria for Fast Track designation (e.g., meets an unmet medical need) and preliminary evaluation of the efficacy data from the principal controlled trials supports a determination that the product may be effective. In addition, CBER will consider the availability of staffing resources to initiate early review of the portions and whether accepting a SoPA is anticipated to increase efficiency of review or lead to an earlier approval action. Reviewers should tell sponsors that their entire SoPA should be completed within 4 to 6 months after their first portion is submitted. Sponsors should be told that at the time they submit their CMC section, their facility should be ready for inspection so that the scheduling of an inspection can begin. 2. 4. Responsibilities and Procedures 1. Procedures for handling designation requests Pre-submission communications with sponsors With regard to general inquiries on fast track policies, sponsors should be directed to the WEB site or to OCTMA for a copy of the Guidance. If there are

remaining questions following their reading of the document they should discuss with the appropriate RPM. The RPM should inform interested sponsors to submit a fast track request as explained in the guidance document. This will generally be 5 to 15 pages in length, and contain summaries of preclinical or clinical data that support the contention that their product has potential to address an unmet medical need.
  

Potential for addressing an unmet medical need is supported by different types of data as drug development progresses. The level of detail required for documentation of the seriousness of the condition will depend upon generally accepted medical knowledge. The amount of information necessary to document an unmet medical need will depend on whether or not there are existing therapies for the condition.

At a sponsor's request, FDA will discuss details concerning a particular product and the fast track program at IND meetings and telecons if the sponsor includes this issue on the agenda, but FDA will not commit to decisions at such times. The actual decision will always be communicated in writing as a formal response to the designation request. Timeline for Review (calendar days) Day 0 CBER Document Control Center (DCC) receives request

Requests for fast track designation should be submitted as 3 copies with an appropriately labeled FDA Form 1571, as part of an Original IND Submission or an amendment to an existing IND. DCC will date stamp and route to the Application division for routine processing. Day 3 routing RPM conducts preliminary regulatory review and initiates

The RPM will indicate Fast Track on the IND ORIGINAL SUBMISSION FORM or the PRELIMINARY IND AMENDMENT SLIP for a request received with an original submission or amendment, respectively. The submission will be routed to the clinical reviewer and CBER Fast Track Coordinator. The submission is returned to DCC with a priority processing slip. DCC will update BIMS with the FR (Fast Track Designation Request) code and route to the designated reviewers. Day 3-5 RPM conducts regulatory review and notifies team (concurrent with DCC processing) As part of the administrative/regulatory review, the RPM will determine whether the request contains information addressing each of the criteria of fast track (serious disease, unmet medical need, and potential to address the unmet medical need). If the application is clearly deficient, following consultation with the appropriate Office specific supervisory official, the RPM will inform the sponsor

by telecon that the request is materially incomplete and will not be considered a request for fast track designation. The RPM will identify the deficiencies so that the sponsor will have the opportunity to correct them in a subsequent submission. If the request is materially complete, the RPM will notify all reviewers, clinical branch chief and division director, and the CBER Fast Track Coordinator of the arrival of the request by e-mail, along with target dates (e.g. day 40, 50) and the Fast Track check list attachment. The RPM will enter what the sponsor has identified as the condition for which the product is intended into the comment field of the amendment containing the request. If this is not clear in the submission, the indicated use will be entered. Day 5-40 Clinical review is completed Within 40 calendar days of receipt of the fast track request at CBER, the clinical reviewer should complete the review and submit a completed Fast Track check list (Appendix 7) or memo to the branch chief and/or division director for concurrence. The review should include "letter ready" comments. The decision will not be communicated by telephone. The RPM receives signed off comments from Division Director by day 40. Day 40-50 RPM drafts fast track letter Using wording provided by the clinical reviewer, the RPM drafts the decision letter and E-mails it to the appropriate reviewers and the fast track coordinator for concurrence and to resolve wording issues within 3 working days. Non response is considered concurrence. Day 50-60 Letter finalized The letter is signed off by the appropriate Office specific official and designated in BIMS as FS (Fast Track Designation Granted) or FD (Fast Track Designation Denied), and the conditions entered into the BIMS letter comment field. The amendment screen is updated by the RPM to the exact wording used in the letter for indication/drug development plan. Procedures for Submitting a SoPA Pre-submission conversations with sponsors RPM should advise sponsors considering a SoPA to:
 

include their proposal in the agenda for discussion at the pre-BLA meeting. present the preliminary analysis of data that supports a determination that the product is effective in the background package for the meeting.



include a proposal for the SoPA including a description of the sections and a timetable for submission of each section of the SoPA in the background package for the meeting.

RPMs should document any discussion of the SoPA in their pre-BLA meeting minutes. Submission procedures: Subsequently RPMs should advise sponsors to submit a written request for a SoPA after consideration of issues discussed at the pre-BLA meeting, and at least 2 months prior to the proposed submission date for the first portion of the SoPA. The request should:




be in triplicate with a Form 1571; the cover letter should clearly identify the amendment as a "Request for Submission of Portions of an Application." include a detailed schedule, a table of contents with brief description of the content of each portion, and a statement of when facilities will be ready for inspection.

CBER will respond in writing, granting or denying the SoPA request. Sponsors should be told that changes to the submission schedule prior to starting the SoPA must also be submitted in writing and accepted by CBER. Sponsors should be instructed that each portion of the SoPA should be in a form adequate to have been included in a traditional, complete BLA. Final reports, not draft documents, should be submitted. Generally, the review team will only agree to a SoPA if the portions are complete sections of a BLA, e.g. entire CMC section, toxicology section, clinical section, etc. Occasionally the review team may, at its discretion, agree to submission of portions that consist of a part of a section if they feel that such a subsection would constitute a reviewable unit and would be useful in facilitating the review process. Each portion, as well as the cumulative complete BLA, must be well organized to facilitate review. Handling of the SoPA Upon submission of the first portion of a SoPA, the RPM will ensure that a Submission Tracking Number (STN) is assigned in RMS-BLA with the Special Characteristics of "Fast Track Designation" and "SoPA Submission". ("Fast Track Designation" alone is used when the initial BLA submission for a designated program is a complete application.) A review committee is established, and the portion(s) routed for review. An acknowledgement letter is sent to the company at this time with their STN. No review schedule is entered in RMS-BLA for a SoPA until the final portion is submitted. Actual commencement of review will depend upon many factors including the submission schedule, workload, and other review priorities. Comments may be communicated to the sponsor in telecons, Information Request letters and Discipline Review letters. If application user fees and a Form 3397 do not

accompany the first portion, or if the applicant is in arrears on user fees, the first portion will be considered "Unacceptable for Filing". If the applicant deviates from the agreed upon schedule for the SoPA, CBER may consider the agreement to be void. The RPM will draft a letter informing the sponsor of the Center's decision. The letter will proceed through office specific sign off. The RMS-BLA tracking system should indicate "SoPA voided". Review will be restarted when the complete application is submitted. Each partial submission to the SoPA should be designated with the Special Characteristic of "SoPA Submission" in RMS-BLA until the application is complete. When the final portion of the SoPA is submitted, the applicant will indicate that the application is complete. Upon receipt of this notification, the RPM will ensure that the "Final SoPA Submission" Special Characteristic is assigned to the STN, the review schedule is established in RMS-BLA, and the review clock started. A filing review and decision will then be made within the usual timeframe. Generally, a BLA accepted as a SoPA will receive priority review status since the criteria for Fast Track at this stage of development are the same as those for priority review. There are cases where this would not be true, i.e., where another product has been approved since the first portion of the BLA was submitted that met the unmet medical need. In rare cases where multiple indications are submitted in a BLA and only some meet the Fast Track criteria, CBER may administratively unbundle the application and assign different review schedules as well as different Submission Tracking Numbers and possibly different review committees. 5. References 1. Appendix 1: Fast Track Granted Template Letter Appendix 2: Fast Track Denied Template Letter Appendix 3: SoPA Accepted Template Letter Appendix 4: SoPA Denied Template Letter (To be developed) Appendix 5: STN assignment letter (Under revision) Appendix 6: Database tracking elements Appendix 7: Checklist template - Review for Determining Fast Track Development Program Designation 2. 6. Effective Date 1. November 16, 2001

2. 7. History 1. Comment / Revision Bette Goldman, RN, MPH Approved By Robert Yetter, PhD Approval Date 11/16/2001 Version Number 1 Comment Original

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