Compiled by Denise Dengel, Board of Directors, National MPS Society, Committee on Federal Legislation
The National MPS Society has provided this document to clearly define key terms contained in the accompanying position statement with “industry accepted definitions.”
“a laboratory or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful endpoint that is a direct measure of how a patient feels, functions, or survives and that is expected to predict the effect of the therapy.”
Although some surrogate endpoints are recognized as well establishes and have long been a basis for approval (e.g., blood pressure as a predictor for heart attack or tumor size/amount as a predictor for mortality), the accelerated approval rule allows reliance in specific circumstances on a “surrogate endpoint that, while ‘reasonably likely’ to predict clinical benefit, is not so well-established as the surrogates ordinarily used as bases of approval in the past” (57 FR 58942 at 58944, December 11, 1992).
Physiologic or pharmacodynamic measurements that can reliably predict the course of the disease or the impact of treatment on the course of the disease.
In certain cases the biomarker “of choice” for a certain product and indication will be the same thing as the surrogate marker “of choice”.
1st Cycle Review
Approval (or non-approval) of an application (BLA or NDA) at the end of the first PDUFA user fee deadline.
When an application (BLA or NDA) is made to the FDA for approval of a product the FDA have a PDUFA goal (timeline) in which to reply to the applicant. E.g. for Aldurazyme which was Fast Track & priority review this timeline was 6 months. 1st cycle review means that the FDA replies with an approval (or non approval) letter at the end of this 1st timeline and not reply with more questions which would prompt the applicant to have to answer the questions and another cycle of PDUFA timelines are initiated.
An application that is submitted to FDA (BLA or NDA) is assessed as priority or standard review. The difference is the timeline for which the FDA then review applications ? 6 months for priority & 12 months for standard. Fast Track products are intended to treat serious or life threatening conditions and demonstrate the potential to address unmet medical needs and are therefore given priority review.
Clinical Verification Study
When a product is given accelerated approval based on a surrogate endpoint it is a requirement for the applicant to further study the product to verify and describe the clinical benefit of the product. This clinical benefit study is what is referred to as the clinical verification study and is normally conducted in the post-approval setting.
Pre IND Meetings
“Pre-IND” meetings between the Sponsor and the Agency are intended to discuss the planned filing of an Investigational New Drug application (IND) and thus the initiation of clinical studies of a new product. The agenda for the meetings is flexible to meet the specific needs of the Sponsor, which are often determined by the type of product and indication. Common subjects are what pre-clinical studies are required prior to the filing of the IND and the proposed design of the first clinical trial. This meeting is recommended but not required and is most often held over the telephone.
Submission of a license application to FDA in “pieces over a defined period of time. The option of submitting a rolling BLA (or NDA for CDER products) is a theoretical option for products with “fast track” designation. The program is intended to speed the review of the license application by allowing Agency reviewers to initiate the review of certain information while the sponsor completes other sections.
The proposal for the submission of a rolling BLA must be reviewed and agreed upon with FDA prior to commencement of the submission. To date FDA has determined that the best way for this system to work is to make the “pieces” reasonable and logical–hence it is most often interpreted to submit the major sections (“preclinical,” “clinical,” and “CMC”) within approximately 3 months of each other.