This document outlines a working agreement between the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER). It assigns to the Centers jurisdiction for regulation of Drug and Biological products and combinations of Drugs and Biological products, and describes those product characteristics or medical indications that will require a collaborative review effort by the two Centers. The document also contains agreements on mechanisms for dispute resolution, and on the logistic aspects of collaborative reviews, including the use of advisory committees.
This agreement arose from the need to allocate responsibility for regulation of various new products, some of which do not easily fit into the traditional jurisdictional responsibilities of the two Centers, and from the desire to use available resources and expertise efficiently. This document is intended to provide a clear basis for the Centers' program planning and for guidance to applicants. Submissions should be made directly to the lead Center identified in this document.
For further information contact either:
Bruce Burlington M.D., Deputy Director Scientific and Medical Affairs
Center for Drugs Evaluation and Research
Parklawn Building, Room 13B28, HFD501
5600 Fishers Lane
Rockville, MD, 20857
Janet Woodcock, M.D., Acting Deputy Director
Center for Biologics Evaluation and Research
Building 29, Room 129, HFB-2
8800 Rockville Pike
Rockville, MD, 20892
I. EFFECTIVE DATE
This agreement takes effect on October 31, 1991.
II. GENERAL DESCRlPTlON
CDER is the lead Center for regulation of human drugs that are regulated by FDA under the authority of the Federal Food Drug and Cosmetic (FD&C) Act. Drug products are defined in section 201(g) of the FD&C Act. CBER is the lead center for regulating biological products. Biological products are regulated under authority of, and defined in, Section 351 of the Public Health Services (PHS) Act and in 21 CFR 600.3. Products that are biological products are also either drugs or medical devices as defined in the FD&C Act. This agreement supersedes all prior agreements.
III. CENTER JURlSDlCTION OVER PRODUCT CLASSES.
Under this agreement, Center jurisdiction over products is allocated by product class. A product class is defined as a distinct category of agents recognizable by physical characteristics, source materials or pharmacologic properties. Examples of product classes include antibiotics, vaccines, hormones, and human blood derivatives.
In certain cases, for scientific or administrative reasons, the designated lead Center, with the concurrence of the other Center, may transfer the responsibility for a specific product to the other Center. Such transferred products will ordinarily be regulated by the same mechanism (NDA or BLA) as the other products in the class to which they belong. This agreement continues the previous agreement under which CBER has had full responsibility for regulation of certain products used in conjunction with blood banking that are regulated as drugs under the authority of the FD&C Act.
Assignment of a product to a Center means that the Center is responsible for administering regulation of the product and for evaluation of product quality, i.e., manufacture, quality control and specifications. In certain cases (see Section IV, Medical Review Assignments), a major part of the pharmacological/toxicological, biopharmaceutic, and medical review may be conducted by the Center that is not assigned responsibility for the product. It is understood that assignment of product responsibility to one Center does not preclude consultation with the other Center on productrelated issues. In all cases, the Center with product responsibility will have final responsibility for actions taken on the application.
Product Responsibility Assignments:
A. CDER is responsible for the following classes of drug and antibiotic products:
- Naturallyoccurring substances purified from mineral or plant source materials (excluding vaccines or allergenics);
- products that are produced from nonhuman animal or solid human tissue sources (excluding animalderived procoagulant products or antisera, venoms, red blood cell replacement products, vaccines, allergenic products, products composed of living cells, and certain other products listed under B. below)
- antibiotics as defined by Section 507(a) of the FD&C Act, regardless of the method of manufacture:
- certain agreedupon classes of substances constitutively produced by fungi or bacteria including:
a. disaccharidase inhibitors
b. HMGCoA reductase inhibitors;
- chemicallysynthesized molecules (excluding vaccines and allergenics) including:
a. products produced by chemical synthesis that are intended to be analogies of cytokines, thrombolytics, or other biologic, or that function by binding to the receptors for biological products,
b. chemicallysynthesized mononucleotide or polynucleotide products, including products complementary to RNA or DNA sequences; and
- hormone products, regardless of method of manufacturing, e.g., insulin, human growth hormone, pituitary hormones.
B. CBER is responsible for the following classes of products:
- Biological products subject to licensure:
a. vaccines, regardless of method of manufacture including those vaccines which at the effective date of this agreement are being studied under active INDs administered by CDER (For the purpose of this agreement, a vaccine is defined as an agent administered for the purpose of eliciting an antigenspecific cellular or humoral immune response);
b. in vivo diagnostic allergenic products, in vivo diagnostic tests for DTH, and allergens regardless of the method of manufacture intended for therapeutic use as "hyposensitization" agents;
c. human blood or human bloodderived products including placental blood-derived products, animalderived procoagulant products and animal or cell culturederived hemoglobinbased products intended to act as red blood cell substitutes;
d. immunoglobulin products, whether monoclonal or polyclonal, produced in humans, animals or in cell culture;
e. products composed of or intended to contain intact cells or intact microorganisms including bacteria, fungi, viruses or virus pseudotypes, or viral vectors;
f. protein, peptide or carbohydrate products produced by cell culture excepting antibiotics, hormones, products listed in A.3. above, and products previously derived from human or animal tissue and regulated as approved drugs;
g. protein products produced in animal body fluids by genetic alteration of the animal, i.e., transgenic animals; and
h. animal venoms or constituents of venoms.
- Other product classes:
a. Syntheticallyproduced allergenic products that are intended to specifically alter the immune response to a specific antigen or allergen; and
b. certain drugs used in conjunction with blood banking and/or transfusion.
- All products that are subject to approved or pending NDAs or BLAs as of the effective date of this agreement will be left under that regulatory mechanism and under the jurisdiction of the center that currently administers the NDA or PLA.
- New products that use the same active ingredient(s) as the above approved products will be assigned to the same lead Center and regulated by the same mechanism (BLA or NDA) as the approved products. Questions about the similarity of active ingredients will be settled by the CBERCDER jurisdiction committee.
D. Combination products:
Products that are combinations of one or more drug and one or more biologic products will be assigned based on the products primary mode of action. This mechanism assigns administration and precinct quality responsibility: the medical, pharmacological and other reviews will be conducted as described in Sections IV. and V. below.
- Assigned to CBER:
a. Combination products that consist of a biological product from a product class subject to licensure (including biological products that have been chemically modified) combined with a radioactive component.
b. Combination products that consist of a biological product component used as a mode of localization and a toxin component that is not itself a drug product (e.g., ricin A toxin) used as an effector.
c. Combination products that consist of drug component and a biological component where the drug product enhances the efficacy or ameliorates the toxicity of the biological product.
- Assigned to CDER:
a. Combination products that consist of a biological product component used as a mode of localization or used to affect the distribution of the product, combined with a nonradioactive drug component used as an effector.
b. Combination products that consist of a biological component and a drug component where the biological component enhances the efficacy or ameliorates the toxicity of the drug product.
IV. MEDICAL REVIEW ASSIGNMENTS
This agreement provides for apportioning medical review between the Centers, based on existing programs and foci of clinical expertise. This arrangement will facilitate efficient utilization of existing resources and rational program planning. CBER has program areas and medical expertise predominantly in the fields of allergy, clinical immunology and rheumatology, infectious diseases, hematology, and coagulation and oncology. CDER has programs in a wider variety of clinical areas, including a number of those where CBER also has ongoing programs.
This agreement outlines three categories of medical indications. The first group includes clinical indications for which CBER will ordinarily take the lead in medical review. For these areas, CBER agrees to maintain programs and medical expertise. The second group outlines the areas for which CDER will ordinarily take the lead in medical review and will maintain programs and expertise. A third category is those medical areas for which both Centers expect to maintain programs and expertise. Products with clinical indications in this category will ordinarily have the medical review performed by the same Center assigned responsibility for product quality review and application administration.
The assignment of review responsibility to one Center does not preclude review involvement of the other Center. In those clinical indications for which clinical review may occur in either Center, the Centers agree to ensure consistency in standards for clinical evaluation and outcome measures by cooperating in the development of pertinent policy, guidelines and regulations and by continuing to hold working meetings at the staff level to discuss clinical issues. Periodic intercenter coordination meetings on products intended for treatment of AIDS, and cancer will continue and will include specific planning of the coordinated review of pending applications.
Medical and other reviewers from a second Center who are participating in a collaborative review will be expected to fully participate in the review processes of the Center with responsibility for administration of the application (see Section VI, Collaborative Review Process). It is understood that the primary Center will have final signatory authority on all actions; however the collaborating reviewers are expected to develop specific recommendations based on their review of the data, on their interaction with other experts reviewing the application, and on input from their supervisors.
In certain cases (e.g. allergy and dermatology, or clinical immunology and GI), the clinical indication may be a hybrid between several areas. In these cases a medical review team consisting of appropriate experts from both Centers may be formed.
Either Center may decline to participate in a requested collaborative review if expertise or resources are not available.
The following are the medical review responsibilities:
A. Clinical data which will ordinarily be reviewed by CBER medical staff.
Products intended for or acting by a mechanism of:
- replacing the 02 carrying function of red blood cells;
- directly and specifically activating the proliferation of hematopoietic cells;
- replacing plasma coagulation factors;
- achieving a passive immune response;
- diagnosing allergy or delayed type hypersensitivity by in vivo testing; and
- inducing an antigenspecific active immune response or tolerant state (i.e., vaccines and allergenics) but excepting vaccines intended to induce a contraceptive state.
B. Clinical data which will ordinarily be reviewed by CDER medical staff.
Products intended for diagnostic or therapeutic use in:
- hormonal disorders,
- obstetrics, gynecology and contraception,
- metabolic disorders,
- dermatological disorders,
- ophthalmological disorders.
- neurological or psychiatric disorders,
- surgical indications including use in anesthesia,
- dental practice,
- pulmonary disorders,
- gastrointestinal disorders,
- cardiovascular disorders, and
- renal disorders.
C. Clinical data which may be appropriately reviewed by medical staff in either Center, in accordance with Center product jurisdiction assignment.
Products intended for:
- diagnosis, prevention or treatment of infectious diseases,
- diagnosis, prevention or treatment of neoplastic disorders,
- diagnosis, prevention or treatment of rheumatological disorders,
- diagnosis, prevention or treatment of immunodeficiency disorders,
- diagnosis, prevention or treatment of hematological disorders other than those mentioned in A.), or
- nonantigenspecific diagnosis, prevention or treatment of allergic disorders.
V. RESPONSIBILITY FOR OTHER REVIEWS
A. Pharmacology/Toxicology Review
- When one Center is performing medical review of a product assigned to the other, responsibility for the pharmacology and toxicological review will ordinarily be shared between the two Centers. Prior to initiating a PLA or NDA review, a formal agreement delineating responsibilities for pharmacology/toxicology review will be made.
- The Centers will ensure consistency in standards for pharmacological/toxicological product evaluation by continuing to cooperate in the development of pertinent policy, guidelines and regulations and by continuing to hold working meetings at the staff level to discuss issues.
B. Additional Aspects of Product Quality Review
- The Center assigned responsibility for product quality is responsible for obtaining or performing any necessary facility inspections, reviews of such inspectional findings, and product test results.
- Where relevant expertise in product quality aspects is not available in the Center with product jurisdiction and is present in the other Center, collaborative review will be sought and provided.
In cases where a product regulated by CDER is derived from human source material, including cell culture, it is agreed that CDER will request and CBER will provide consultation on testing for adventitious agents and related issues. To provide consistency, in cases involving animal source material, each Center agrees to consult with the other when issues refuted to policy development arise.
VI. COLLABORATIVE REVIEW PROCESS
Collaborative review is defined as a review process where the responsibility for medical review is assigned to a different Center than the responsibility for regulatory administrative actions and review of product quality. Collaborative review is distinct from consultation in that consultants provide opinions to primary reviewers whereas collaborative reviewers are responsible for developing a definitive review in a particular area. Such a review is a permanent part of the administrative record. It is nonetheless subject to appropriate supervisory review from the official delegated responsibility for final agency action on an application.
A. IND Review.
When an lND is filed in CDER for a clinical use requiring CBER review input, the CDER Division Director will send a request specifying the review assistance sought, accompanied by one copy of the application to the Director, DBIND, CBER, with informational copies of the request to the Director of the relevant CDER Office and the Director, CBER. The Director, DBIND, will, according to CBER procedures, obtain any necessary input from other CBER divisions.
Similarly, when an IND is filed in CBER for a clinical use for which CDER has review responsibility, the Director, DBIND, CBER will send a request for clinical review and one copy of the IND to the relevant CDER Division with an informational copy of the request to the Director of the relevant CDER office.
Reviewers from the collaborating Center will be expected to participate fully in all aspects of review during the IND process. The organizational component with IND responsibility for administrative and product quality review; i.e., either DBIND or the CDER NDE review Division, will be responsible for coordination of document flow, arranging all meetings and correspondence with the sponsor.
B. NDA/PLA Review.
- Requests for intercenter clinical review will be submitted from the Center with administrative responsibility for the application, to the office of the other Center Director.
- Each Center will have in place administrative procedures for formal assessment of review staff to the NDA or PLA with concurrence in the assignment of the individuals' immediate supervisor(s) and Division Director.
- Each Center will develop short written procedures regarding the contribution required for intercenter or collaborative review, including the types of reviews required and the appropriate extent of documentation. Where CDER has administrative responsibility, reviews by CBER staff will be documented in writing and returned through the appropriate division and office director, for incorporation into the administrative record. Where CBER has administrative responsibility, reviews by CDER staff will be written full reviews through the division (and, if applicable, office) director. The reviewer will meet with the PLA committee and will coordinate the review through that committee with the product quality review in CBER.
- A designated supervisor, usually the CBER PLA committee chair or CDER Division Director, with responsibility for ensuring the review of the application in the responsible Center, will negotiate an agreement with the supervisor(s) of the collaborating reviewer(s) with regard to the contribution (i.e., time and work product) expected and also will provide ongoing feedback, as required, with regard to timeliness, setting of priorities, and quality of work. At each designated performance review date, and after completion of an action on the application, this designated supervisor will be responsible for submitting a written evaluation of the collaborating reviewer(s) to their permanent supervisor.
- The Center with administrative responsibility will be responsible for final decision making. It is the responsibility of collaborating reviewers to form and document their best scientific and regulatory assessment and recommendations regarding assigned reviews. It is the responsibility of the delegated official in the Center with administrative responsibility to take final action regarding the application. In the case of differences in judgment, when the designated official in the center with administrative responsibility intends to override the opinion of the collaborating reviewer(s), there shall be a memorandum to the administrative record documenting the reasons for overriding the opinion of the clinical reviewer, which will be copied to and discussed with the collaborating reviewers and the collaborating reviewers' Center Director (or delegate) before final action is taken.
C. Advisory Committee Review
It is recognized that many of the new products subject to collaborative review will generate complex scientific and medical regulatory issues and that the Centers will need to utilize all available advice during the regulatory decisionmaking process. Therefore, every attempt will be made to involve pertinent advisory committees from either or both Centers for products under collaborative review.
VII. INTERCENTER JURISDICTIONAL COMMITTEE
An intercenter jurisdictional committee is now formed. It is composed of one representative and one alternate from each Center. The committee members will meet on an ad hoc basis, will discuss all jurisdictional questions, and will be expected to handle the majority of requests for jurisdiction assignments. Where this committee cannot agree upon jurisdictional assignment, or where the sponsor requests review of assignment at the agency level, the product jurisdiction procedures will be used.
Carl C. Peck, M.D.
Center for Drug Evaluation and Research
Gerald V. Quinnan, Jr., M.D.
Center for Biologics Evaluation and Research
David A. Kessler, M.D.
Commissioner of Food and Drugs