APPENDIX MATERIAL SUPPLIED FOR THE RECORD BY THE SUBCOMMITTEE ON MONOPOLY AND ANTICOMPETITIVE ACTIVITIES On July 5, 1977, I wrote to you concerning the communications between FDA employees and officials of the New York State legislature. We outlined the need for FDA to be extremely careful and particularly accurate if it intends to continue to suggest to the public that various versions of a particular drug are interchangeable. This matter was also discussed at the meeting that Dr. Laubach and I had with you and your colleagues on July 22. During the summer, additional communications by FDA representatives purporting to assure the ability of FDA to certify the equivalence of multi-source drugs have been brought to our attention. Such circumstances make the suggestions in our July 5 letter even more critical. I am enclosing a copy to reacquaint you with our concerns and recomendations. I suggest that these recommendations be brought to the attention of the Drug Monographs Division and other officials in the Bureau of Drugs who are involved in responding to inquiries on drug interchangeability. Many of the inquiries being made to FDA on this subject are directly connected to state legislative or regulatory issues. In this regard, it is appropriate to note Section 7322 of Title 5 of the United States Code dealing with proscriptions on Federal Executive Agency employees in influencing state political action. The intent of this code provision is to preclude as nearly as possible FDA and other Federal employees om directly or indirectly influencing state legislative or regulatory bodies in enacting new laws or regulations. FDA TRAC#7044-441 nufacturers of prescription pharmaceuticals. We have not yet received a response to our letter of July 5. We would appreciate your views on the thoughts expressed in it and this letter. Sincerely, C. Jargh Steel C. Joseph Stetler DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION ROCKVILLE MARYLAND 2012-2 January 26, 1977 Martin Golden State of Delaware Jesse S. Cooper Memorial Building Capital Square Dover, Delaware 19901 Dear Dr. Golden: This is in reply to your letter of inquiry concerning drugs listed in the HEW publication FDA 76-3009. Specifically you asked: 1) whether companies cited in the publication as holding an approved ANDA have submitted bioequivalence data; and 2) where bioavailability data is required of the originator, holder of a full NCA, whether this requirement is required for ANDA holders. You state in your letters that the Delaware Drug Advisory Committee is seeking advise in creating a list of interchangeable and noninterchangeable drug products. : As we have discussed over the phone the questions you have raised can neither be answered by "yes" or "no" as dealt with on a full NDA, ANDAbasis. In this connection the answer to the first question you pose is. "All firms holding approved ANDA's have not submitted bioequivalence data; however, all firms holding approved DA's have not done so either." The answer to question two is "where an NDA holder is required to demonstrate product bioavailability subsequent ANDA holders must usually also provide such information. Except there are instances where the NCA holder did not originally provide such information for his product, whereas the subsequent ARDA holders did. There are additional situations where neither the NDA or ANDA holders submitted such information.". In order to understand these answers the Committee needs to consider the following points: 1. The issue of drug bioavailability and bioequivalence was not widely .recognized as a possible concern in drug approval by the Agency, arug firms, and all but a few scientists until about 1970. Prior to that time, the field of biopharmaceutics was virtually unexplored because of the lack of methodology to detect the minute amounts of drug and drug metabolites in blood and urine. In developing its Biopnarmaceutic program with regard to generic drug products, the Agency has been faced with two major tasks. The first was to identify those drugs which 21-689 - 78 - 15 presented bioequivalence problems and impose a bioequivalence requirement on all products approved after that date. The second task was the need to "recycle" products previously approved prior to the introduction of the new bioequivalence requirement. On this basis both innovator (NDA'd) and generic (ANDA'd) type products will need to be recycled. 2. It is important to understand that while innovators of drugs approved prior to 1952 (the majority of currently marketed multiple-source drugs were approved by the Agency between 1938 and 1962) did carry out clinical trials to establish the safety and efficacy of their products. few firms at that time performed adecuate biopharmaceutic studies to de the in vivo performance of their product as would be required today. From the viewpoint of the Agency, if a particular active ingredient in a specified dosage form is amenable to a bioequivalence problem, until proven otherwise, the innovator himself cannot be presumed to be immune from the problem. While some drug firms are already initiating bioequivalence studies on their NDA'd products in anticipation of the Agency's new requirements this is not the usual case. 3. Furthermore, for several drugs, (e.g., warfarin sodium) firms were required to demonstrate clinical safety and efficacy under a full NDA, but not necessarily interchangeability between name brands. The new bioavailability/bioequivalence regulations finalized on Jan. 7, 1977 (see attached final regulation) will address these issues by requiring all firms including the innovator to establish proof of bioequivalence relative to specified standards. 4. Where bioequivalence is an issue, until such time that bioequivalence has been demonstrated for all manufacturers of a generic drug, the Agency cannot obviously assure the interchangeability of all producers of that drug. However, for these approved drugs the Agency can assure that all approved firms who market drugs in compliance with compendial and NDA specifications, meet the same high standards currenti imposed by the Agency including GMP's, manufacturing controls, etc. issue of drug quality and lot to lot reproducibility is of prime importance to the Agency. The 5. It is my recommendation that physicians and pharmacists should continue to prescribe generic drugs, but should not interchange brands when dealing with critical dose drugs, such as those that necessitate patient titration. Once a patient is titrated on a particular brand, innovator or otherwise the physician and pharmacist should continue to use the same brand in dealing with critical cose drugs. The obvious exception is any drug reviewed by the FDA for which a MAC is established by the Department of Health, Education and Welfare. 6. It is my concern that in dealing with critical dose drugs, such .nonbioequivalence factors or stress that might ensue in a patient upon switching brands cannot be ignored. For many drugs, e.g., phenytoin, quinidine, theophylline, etc. switching of brands and dosage forms is best accomplished by careful monitoring of drug blood levels. In conclusion, I would like to emphasize that the issue of "name brand" versus "generic brand" is in my opinion not germaine to the issue of drug interchangeability, but rather it is an issue of critical dose and patient titration that needs to be addressed. It is important that you understand that if FDA wishes to establish an additional or more stringent requirement to apply to previously approved drugs, it requires a regulatory proposal for public comment, evaluation of such comments, and publication of the resulting final order. The new January 7, 1977 regulations spell out these new procedures for bioequivalence problem drugs. Except where there is positive evidence that a product has significant inferior performance, the Agency cannot legally suggest favoritism between two products which meet ail current requirements for marketing. Along these same lines it is not possible to judge currently approved products according to prospective unofficial standards the Agency has not yet promulgated. One reason for this is the practical point that when the Agenc proposes its recommended requirement, i.e., future bioequivalence requireme it may necessitate a change in the original proposal based on the comments received by the Agency. While I realize that these comments do not simplify the drug interchangeabi issues for you, I hope that you understand the situation and the actions which the Agency is taking to resolve the problem. Sincerely yours, Bernaid E. Cabana Bernard E. Cabana, Ph.D. Biopharmaceutics/Drug Monographs Attachment |
