ANDA PROVISIONS 2. The definition of the term "therapeutic alternative" has been deleted from the June 2 draft, but the bill still includes the concept (page 3, lines 24-27; page 4, lines 1-3) and the associated petition procedure for combination drugs (page 6, line 24; page 7, line 9). The petition procedure would permit prospective applicants to seek permission to file for ANDA approval of combination drugs that have not been previously approved. These new combinations would be required to include at least one ingredient that is the same as an ingredient in a listed (previously approved) ézug. Because ANDA approval would appear to be authorized for a combination of active ingredients that had not been previously approved, the petition procedure and its associated therapeutic alternative" concept are plainly inconsistent with the medical and scientific rationale that supports FDA's current ANDA procedure. In addition, the petition procedure appears to be inconsistent with FDA's combination policy, 21 CFR 300.50, which generally requires a showing through appropriate studies comparing the combination with its individual active ingredients that each ingredient contributes to the safety or effectiveness of the combination drug. A number of provisions in the June 2 draft would appear to restrict FDA to consideration only of the safety and effectiveness of the different active ingredient in the new combination rather than to the new combination as a whole: O ANDAS for new combinations would be required tc - o The petition procedure (page 6, line 24 - page 7, o Approval of an ANDA authorized through the petition procedure may be denied if the ANDA fails to contain information required by the Secretary respecting the active ingredient in the new drug which is not the same as in a previously approved drug (page 9, les 6-IT). o Approval of an ANDA authorized through a petition may be denied if the application fails to show that the new drug can be expected to have the same therapeutic effect as the listed drug (page 9, lines 12-24). Under FDA's current policy, approval of combination drugs that have not been previously approved would require data showing that the new drug (not just one of its ingredients) will have its intended effect. Consistent with the agency's current policy, the abbreviated procedure should be limited to drugs with the same active ingredients. Combinations of drugs with active ingredients different from previously approved drugs should be the subject cf investigations to establish whether they are safe and effective. For these reasons, the petition procedure, that would authorize ANDA approval for combination drugs that have not been previously approved should be removed from the bill. The statutory ANDA procedure should be limited to duplicate versions of previously approved drugs under previously approved conditions of use. The 3. Page 6, line 24. If a petition procedure consistent with FDA's current policy for ANDA approval and the approval requirements for new combination drugs were to be incorporated in the bill, it should eliminate consideration of ANDAS for drugs with different "active ingrediens." procedure should be limited to minor differences in route of administration, dosage form, or strength. Under FDA's current ANDA policy, different "active ingredients" as therapeutic alternatives are not permitted. There may be circumstances in which route of administration, dosage form or strength may differ slightly from those for a previously approved drug product. However, it should be stressed that even minor changes would not routinely be subject to implementation through ANDAs without clinical data. 4. Page 10, lines 6-14. The June 2 draft provides for denial of ANDA approval if the information submitted in the application or other information available to the Secretary shows that the inactive ingredients of the drug are unsafe or the composition of the drug is unsafe due to the type or quantity of inactive ingredients or the manner in which the inactive ingredients are included in the new druç. We had suggested such a revision, but our suggested revision also included, as a ground of denial, the failure of the information submitted to provide sufficient information to establish the safety of the inactive components or the composition. of the new drug for its intended uses. Because it is the applicant's obligation to provide the information needed to support ANDA approval, the provision should be revised to provide for denial of ANDA approval if the information submitted is insufficient to show the safety of the inactive ingredients or composition of the product for its intended use. The following revision is suggested: (H) information submitted in the application 5. Page 11, lines 1-5. The June 2 draft continues to provide that the 180 day period for ANDA approval or disapproval runs from the initial receipt of the application. Consistent with the statutory provision for full NDAS, the period should run from the filing of the application, rather than the time of submission. There should be no implication that FDA may not refuse for filing an ANDA that is facially deficient nor should the agency be required to develop different procedures to deal with such problems than those already established for full NDAS. The provision should be revised to read as follows: (4)(A) Within 180 days of the filing c the Secretary and the applicant, the Secretary 6. Page 11, line 6 et. seg. The June 2 draft continues to condition the effective date of ANDA approval on the patent information filed for pioneer drugs and on the patent status of pioneer drugs. FDA would continue to be required to consider whether an ANDA is the "first application which contains" a certification, to hold application approvals pending applications for preliminary injunction to district courts, to hold the approval of applications pending a request for a reexamination of patentability to the Patent Office, and to hold the approval of subsequent applications until the first application involved in a patent dispute has been marketed for 180 days. As pointed out previously, the provisions which key. the effective date of ANDA approval to the patent status of the pioneer product would impose burdensome requirements upon. the agency. Although the requirements are not intended to require judgmental determinations by the agency with respect to patent status, the complexity of the recordkeeping. requirements and effective date of ANDA approval provisions will be burdensome and will be inconsistent with the kind of recordkeeping for which the agency is currently responsible. From a practical viewpoint, moreover, a successful litigant in a patent suit would learn of a court decision before FDA could be officially notified and could attempt to pressure the agency to issue an approval prior to the official notification. As also pointed out previously, the patent status of the pioneer product would be adequately protected through a notice provision like that already incorporated the revised bill. See page 5, lines 10-22 (ANDA applicant required to notify patent owner of application which applicant believes does not infringe a valid patent). Notification of the pioneer firm by the applicant, which would precede ANDA approval in every case by six months cr more, would enable the pioneer manufacturer to protect its patent rights through judicial remedies and would not require FDA to divert its limited resources to issues that are peripheral to its primary public health protection responsibilities. - The complex effective date provisions, which would impose burdensome requirements on FDA, obviously are intended to prevent duplicate product marketing before issues concerning the pioneer's patent status are resolved. Those provisions should be replaced by a provision which prohibits the duplicate applicant from marketing the duplicate product -- even if it has received ANDA approval - until the patent issues are resolved. Since the patent issues will already be involved in litigation before the courts, a statutory prohibition on marketing could be easily enforced as part of the litigation. Note that the patent term extension provisions already authorize a court to establish by order the effective date of approval for a duplicate product involved in a patent infringement suit (page 44, line 25 et. seg.). Under such an approach, FDA would be relieved of complex administrative responsibilities and it would be permitted -- as it is now to act on ANDAS without regard to patent controversies. - 7. Page 20, lines 2-6. The June 2 draft continues to provide for the amendment of section 505(e) to authorize the withdrawal of pioneer NDA approval if the patent information for the pioneer product was not filed "within 30 days after the receipt of written notice from the Secretary specifying the failure to file such information." The agency continues to be concerned that the provision may impose additional burdens on the agency if it contemplates that FDA would be expected to take affirmative action to require pioneer manufacturers to supply information to the agency concerning the patent status of their products. 8. Page 23, line 9 et. seq. The June 2 draf: continues to establish effective dates for the approval of paper NDAS based on the applicant's certification cf the patent status of the pioneer drug product. Although paper NDAS may be less attractive to generic manufacturers if a post-1962 ANDA procedure were available, the new provisions would impose additional burdens on the agency that could be resolved by a less burdensome procedure, discussed above, which would require notification by the paper NDA applicant to the pioneer NDA holder and a statutory prohibition on market introduction pending the resolution of the pioneer product's patent status. Patent Extension Provisions 9. Page 34, line 17. to require the applicant to The June 2 draft continues submit to the Commissioner of |