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(NAR) VOL. 2 NO. 1/JANUARY-MARCH 1991

[ DOH ADMINISTRATIVE ORDER NO. 96, September 19, 1990 ]

GUIDELINES ON THE REGISTRATION OF FIXED-DOSE COMBINATION DRUG PRODUCTS



Pursuant to the provisions of R.A. 3720, also known as the Food, Drugs and Cosmetics Act, as amended by E.O. 175, the following guidelines are hereby issued relative to the registration of Fixed-Dose Combination Drug Products.

SECTION 1. Definition of Fixed Dose Combination Drug Products — Fixed Dose Combination Drug Products ( FDC’s) are pharmaceutical preparations containing two or more pharmacologically-active ingredients in a single formulation or dosage form.

SECTION 2.  Scope of These Guidelines — All products classified as FDC’s are covered by these guidelines. There are three categories of products included:

2.1 Currently registered products already recognized and identified by Bureau of Food and Drugs (BFAD) as FDC’s.

2.2 Currently registered products which may later be classified as FDC’s by BFAD.

2.3 Products with pending or for future initial registration under the category of FDC's.

All these categories of FDC’s are covered but the specific applicability will be defined below.

SECTION 3.  Safety, Efficacy, and Quality Criteria — The drug regulatory criteria of safety, efficacy, and quality shall be applied by the BFAD to the specific class of FDC’s using the following rules:

3.1 The FDC drug product must comply with the appropriate requirements of A.O. 67 s. 1989 on the registration of drug products.

3.2  The drug establishment seeking to register the FDC drug product should comply with the appropriate requirements of A.O. 56 s. 1989 on the registration of drug establishments.

3.3 In addition to the above, the FDC drug product in its final dosage form must be proven to adhere to all the following criteria:

a. The active and inactive ingredients should be pharmaceutically (i.e. chemically, physically) and pharmacologically compatible in combination.

b. The FDC taken as a whole should have clinical and therapeutic advantage over the individual active ingredients taken separately.  In this respect, acceptable clinical and therapeutic advantage involves more than additive effect, convenience, or better compliance.  It should include such advantages as complementary or synergistic pharmacological action or therapeutic effect, or reduction in adverse drug reaction.

c. It must not contain any ingredient whose proper administration or clinical use require special adjustments different from or in conflict with its other ingredients.

d. It must not contain active ingredients with abuse potential (those identified in List A of A.O. 63, s. 1989), with a narrow margin of safety, and/or requires special precautions in its use, and/or with bioequivalence problems (those identified in List B of A.O. 63, s. 1989), and which are banned or not yet registered in the Philippines.

3.4  FDC's that are listed in International Compendia, such as the United States Pharmacopeia, British Pharmacopeia, World Health Organization Compendia and other similar listings, and deemed essential by the Department of Health may be exempted from the criteria described in 3.3 above.

SECTION 4.  Applicability to FDC's with Pending or for Future Initial Registration

4.1 The new and initial registration of all FDC’s shall be governed by the above criteria upon effectivity of this Order.  At whatever stage of such registration, provided the registration certificate has not yet been issued, compliance with the above criteria (Section 3) shall be required prior to issuance of registration.

4.2 All registration applications of FDC’s shall henceforth be required to present the following:

a.  A detailed statement stipulating the therapeutic/clinical rationale for FDC.

b. Information on the pharmaceutical, pharmacological and therapeutic properties, and any adverse reaction(s).

c. Clinical documentation to support efficacy and safety.

d. Bioequivalence studies, where applicable, to be done on Filipino patients demonstrating no unfavorable effect on the bioavailability of any of its active ingredients.

SECTION 5. Applicability to Currently Registered FDC's — All currently registered FDC’s shall be required to comply with criteria stipulated in Section 3.  In order to effect the orderly and systematic application of these regulations, the following procedures shall be undertaken:

5.1 Identification of all FDC drug products currently registered and their classification into the following use groups and order of priority for BFAD Review:

Priority I

1.  Anti- infectives
2. Anti-asthmatics
3. Cough/cold remedies

Priority II

1. Anti-TB
2. Cardio-vascular preparations
3. Endocrine/ metabolics
4. Drugs acting on central nervous system

Priority III

1. Gastro-intestinal preparations
2. OB/ Gyne preparations
3.    Musculoskeletals
4. Urinary tract preparations
5. Vitamin-Minerals
6. Eye-Ear Preparations
7.  Dermatologicals
8. Others

The classification will be based on Philippine National Drug Formulary (PNDF) characterization of a product’s active ingredients and the manufacturer’s claims of the nature of drug action in its product registration as finally approved by BFAD.

5.2 For every group of FDC’s being reviewed, the BFAD director shall notify the drug establishments concerned that their registered product is being reviewed for compliance with the requirements of this Order.  All establishments with FDC’s of the same or similar ingredients shall be informed of the impending review.

5.3 Within one week of the receipt of BFAD's written Notice of Review, the Drug Establishment concerned shall notify BFAD in writing, stating, its intended response, which could be any of the following:

a. The establishment believes that it may not be able to meet the Section 3 requirements and prefers to cease production of the same in anticipation of cancellation of product registration, and expresses its readiness to do so.

b. The establishment believes it may be preferable to reformulate its FDC to insure that it meets Section 3 requirements and expresses its readiness to do so.

c. The establishment believes that its FDC can be proven to comply with the Section 3 requirements and expresses its readiness to do so.

5.4 Establishments shall be informed that whatever decision is taken on products similar to their own shall be applied to all similar products.  If a specific FDC is deemed to be not in conformity with Section 3 then all FDC's similar to that product will be so declared also.

5.5 All establishments are granted a maximum eighteen (18) months from date of BFAD Notice of Review to implement any one of the following courses of action, in relation to the BFAD Review:

a. Establishments that decide to cease production shall do so as soon as possible.  They shall be granted no more than eighteen (18) months to sell their remaining products.  BFAD shall cancel the registration and withdraw whatever products remain in the market at the end of 18 months.

b. Establishments that decide to reformulate shall be granted eighteen (18) months to do so.  The application for registration of the reformulated FDC shall be granted priority in processing through the special lane declared in BFAD M.C. No. 5, s. 1990.  During this period, the old product may be sold.  Within eighteen (18) months of the Notice of Review to the Company, the old formulation’s registration shall be cancelled upon issuance of the new registration of the re-formulated FDC.

c. Establishments that decide to present evidence of compliance with Section 3 shall be granted eighteen (18) months within which a decision by BFAD shall be made.  In the first six (6) months, the establishment shall be granted the opportunity to present all data, studies, and other information to show its product’s compliance with Section 3.  In the next six (6) months, BFAD shall evaluate these submissions with the company allowed supplementary submissions.  Then in the last six (6) months, a decision shall be rendered by BFAD.  If the FDC is deemed to have complied, then a new registration shall be so issued stating such compliance.  If the FDC is deemed not to have complied, then the current registration shall be cancelled and any products still in the market shall be drawn.

5.6 Only those products that have been registered under this Order shall be issued regular product registration certificates.  All other FDC’s, whether already under review or are yet to be reviewed, shall be issued provisional registrations when their current registration expires.

SECTION 6.   Effectivity — This order takes effect two weeks after its publications in two newspapers of general circulation.  This supercedes A.O. No. 133, s. 1985 and A.O. No. 7, s. 1986 relative to the same subject.

Adopted: 19 Sept. 1990

(SGD.) ALFREDO R.A. BENGZON, M.D.
Secretary
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