- Docket Number:
- Issued by:
Guidance Issuing OfficeCenter for Veterinary Medicine
Revised October 1983
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
CENTER FOR VETERINARY MEDICINE
Regulation 514.1 (b)(8)(v) of 21 CFR states the requirements for efficacy of drug combinations as:
"Each ingredient designated as active in any new animal drug combination must make a contribution to the effect in the manner claimed or suggested in the labeling, and, if in the absence of express labeling claims of advantages for the combination such a product purports to be better than either component alone, it must be established that the new animal drug has that purported effectiveness."
This guideline is the Bureau of Veterinary Medicine's interpretation of this regulation. Specifically, prior to approval of a drug combination, the sponsor is to submit information and data to demonstrate that the combination of drugs provides a benefit that cannot be obtained by the use of each of the drugs individually (i.e., each drug has made a contribution).
When 3 or more drugs are used in the same combination, the resulting benefit from the use of the full combination must be a benefit that cannot be obtained from combinations involving a lesser number of drug components than the number contained in the full combination (e.g., a 3-way combination must be better than all possible 2-way combinations of the same 3 drugs).
This demonstration of benefit is satisfied when the sponsor has proven that each active drug ingredient has made a meaningful contribution to the overall effect (safety and/or efficacy) of the combination.
Demonstration of effectiveness of drug combinations is subject to the following qualifications and restrictions:
The effects of actions of each drug in the combination should be as good as or superior to its actions when used alone. Exceptions to this non-interference requirement will be considered only when the benefits of the combination outweigh any reduction in potency of effectiveness incurred by an individual drug component as a result of being included in the combination. If appropriate, any decrease in efficacy should be clearly indicated on the label.
When drug claims or drug actions are not the same, the sponsor is to provide information and data to demonstrate the existence of a readily identifiable set of animals that require or will benefit from such concurrent drug usage.
The level of each drug used in the combination has to be sufficient to produce the claimed effect and each drug is to be administered according to its proper regimen. The level of drug should not exceed its level for optimum effectiveness in the particular combination. Optimum effectiveness is defined as that single level of drug (administered at its proper regimen), beyond which any further incremental increase in drug level produces no meaningful improvement in desired efficacy, or if further drug doses provide increased efficacy the benefit is outweighed by increased risks in terms of human and/or animal safety.
The amount and kind of titration data required on each individual drug used in the combination, collected in studies with the combination, will depend on:
(a) The quality of the titration data available on the individual components in the combination;
(b) Whether a fixed point or range approval is requested on the individual components in the combination; and
(c) The amount of data and information available on the type and extent of possible interactions between the actions of the individual components in the combination.
If however, the combination contains one or more new animal drugs with production claims (e.g., growth promotion, feed efficiency, increased milk or egg production), it is not necessary to provide titration data for the production drug(s) from studies done with the combination, provided the drugs have been previously approved for use at a particular dosage level or within a given range.
Ranges in dose levels for therapeutic or prophylactic drugs contained in combinations will be allowed only when adequate directions can be written so that the user knows when different levels of the drug should be used. The conditions requiring the use of the various drug levels are to be clearly identifiable so that changing the drug level will not change the desired efficacy.
Ranges for production drugs that are included in combinations will be allowed when it has been demonstrated that, over the entire range of drug use, an increased dose results in an increased response. It is not necessary to establish, through studies done with the combinations, the effective ranges for the production drugs if two conditions are met. First, the ranges for these drugs must have been previously approved. Second, the sponsors must demonstrate that in combination each production drug contributes to the claimed effect at a level selected by the sponsor that is within the approved range. Note, however, that in any event the sponsors will be required to conduct studies with the combination using the highest levels in the ranges, to assess effects on animal safety. If these requirements are satisfied, the full ranges that had been established for the individual production drugs will be allowed for the combination use.
In all cases the combination must be more effective than no treatment (or placebo) for all the claims associated with the combination.
DESI Reviewed Drug Combinations
Drug combinations found to be effective by the Drug Efficacy Study Implementation program (DESI) are not subject to this guideline.
Combination Claims and Treatment Comparisons
Most of the various situations that are encountered when evaluating drug combinations are listed below along with the necessary comparisons to demonstrate efficacy:
a) If claims are different for each drug ingredient. i.e.,
drug A has claim Y
drug B has claim X.
then it needs to be demonstrated that the combination is superior to drug B alone for claim Y and superior to drug A alone for claim X. i.e.,
(A+B)> B for claim Y
(A+B)> A for claim X.
Example: If drug A for strep organisms and drug B for staph organisms, then the combination of (A+B) is to be better than B alone for strep and better than A alone for staph.
b) (i) If the claim is the same for each drug ingredient. i.e.,
drug A has claim X
drug B has claim X
then it needs to be demonstrated that the combination is superior to each of the component drugs alone for that claim, i.e.,
(A+B)> for claim X
(A+B)> for claim X.
Example: If drug A is for increased rate of weight gain and drug B is for increased rate of weight gain, then the combination of (A+B) is to be better than A alone and B alone for increased rate of weight gain.
(ii) If more than one claim is the same for each drug component. i.e.,
drug A has claim X and Y
drug B has claim X and Y,
then it needs to be demonstrated that the combination is superior to each component drug for at least one of the claims. i.e.,
A+B > A for at least one claim
A+B > B for at least one claim.
Example: If drug A is for staph and strep organisms and drug B is for staph and strep organisms, then the combination of (A+B) is to be better than A alone for either strep or staph and better than B alone for either strep or staph.
c) (i) If one of the claims overlaps while a second claim does not, i.e.,
drug A has claim X
drug B has claim X and Y.
then it needs to be demonstrated that the combination is superior to drug B for claim X and superior to drug A for the non-overlapping claim Y, i.e.,
(A+B)> B for claim X
(A+B)> A for claim Y.
Example: If drug A is for increased rate of weight gain and drug B is for increased rate of weight gain and improved efficiency, then the combination of (A+B) is to be better than B alone for increased rate of weight gain and better than A for improved feed efficiency.
(ii) If there is an overlapping claim and each drug component has its own unique claim, i.e.,
drug A has claim X and Y
drug B has claim Y and Z.
then it needs to be demonstrated that the combination is superior to drug A for claim Z and superior to drug B for claim X, i.e..
(A+B)> A for claim Z
(A+B)> B for claim X.
Example: If drug A is for strep and staph organisms and drug A is for strep and coliform organisms, then the combination of (A+B) is better than A for coliform and better than B for staph.
d) If the combination is intended to decrease the toxicity of individual active ingredients, i.e.,
drug A is toxic at X mg/ka
drug B reduces the toxicity of drug A
then it needs to be demonstrated that the combination reduces the toxicity of drug A and is superior to drug B for the claims of drug A.
(A+B)< A In toxicity
(A+B)< B for the claims of A.
Example: If drug A is for anesthesia and drug B reduces the toxic effects of drug A, then the combination (A+B) is to result in lesser toxic effects than drug A alone and is to be better than drug B for anesthesia.
e) If the claim for the combination is different from the claims for each of the individual drugs, i.e.,
drug A has claim Y
drug B has claim X
the combination (A+B) has claim Z.
then it needs to be demonstrated that the combination is superior to drug A and drug B for claim Z, i.e.,
(A+B)> A for claim Z
(A+B)> B for claim Z.
Example: If drug A is for strep and drug B is for staph, and the combination is for E. coli, then the combination of (A+B) is to be better than A or B alone for E. coli.
This guideline is intended to cover the majority of situations encountered in dealing with drug combinations. On rare occasions a combination may be proposed which is not specifically covered by this guideline. However, a careful application of the underlying concepts presented above should be sufficient to handle these situations, provided one keeps in mind the prime consideration for justification of any combination - the full combination is to provide a benefit that cannot be obtained from lesser combinations involving only a fraction of the drug components contained in the full combination.
You can submit online or written comments on any guidance at any time (see 21 CFR 10.115(g)(5))
If unable to submit comments online, please mail written comments to:
Food and Drug Administration
5630 Fishers Lane, Rm 1061
Rockville, MD 20852
All written comments should be identified with this document's docket number: FDA-2021-D-0627.