Replies to post #285210 on Anavex Life Sciences Corp (AVXL)

[nidan7500]

tradeherpete

How long should it take for Dr. Missling to communicate to the FDA on the next steps to be taken?

And how long does the FDA have to respond?

IMO, a great deal of thought and planning must be applied to just what will AVXL ask the FDA to do? Is it a direct assessment of a specific trial/ indication data (summary of all relevant information) for one or multiple indications (AD/PDD/RSD...)? Looking for go/no go? Are we looking for MOA validation/verification?

Will the FDA need to analyze new devices/technology applications used during PDD trials? eg (actigraphy) ?

Keeping things focused w/a risk averse regulatory body is not easy. We will be required to present strong data from systems which have all been through and accepted BY FDA V&V processes. If not they could go on for many months just agreeing on how the trials and systems used were controlled and validated. Long story which takes time to get prepared for.

The decisions made will be carefully picked at by BP and others.

FDA are risk averse. Do your homework and understand exactly what your question is. Just exactly what are we asking for? Approval of a specific trial data via Old school, or basket Validation of MOA, or some combination new trial process results assessment-acceptance.

It would be great if the FDA were an open and supportive regulatory body who are easy to do business with and are able to walk and chew gum. These are the same people who have managed a regulatory process for which symptoms have been treated as final solutions. A Regulatory body who has recently stated they were "really not sure when AD starts", after decades of chasing a/the wrong solution.

In summary: Dr.M. must be very direct with exactly what he is asking for from the FDA. What do we want them to agree to? I have no information on how long FDA will require to respond.

[Doc328]

End of Phase 2 meetings are common and the Code of Federal Regulations discusses these:

Sec. 312.47 Meetings.
(a) General. Meetings between a sponsor and the agency are frequently useful in resolving questions and issues raised during the course of a clinical investigation. FDA encourages such meetings to the extent that they aid in the evaluation of the drug and in the solution of scientific problems concerning the drug, to the extent that FDA's resources permit. The general principle underlying the conduct of such meetings is that there should be free, full, and open communication about any scientific or medical question that may arise during the clinical investigation. These meetings shall be conducted and documented in accordance with part 10.

(b) "End-of-Phase 2" meetings and meetings held before submission of a marketing application. At specific times during the drug investigation process, meetings between FDA and a sponsor can be especially helpful in minimizing wasteful expenditures of time and money and thus in speeding the drug development and evaluation process. In particular, FDA has found that meetings at the end of Phase 2 of an investigation (end-of-Phase 2 meetings) are of considerable assistance in planning later studies and that meetings held near completion of Phase 3 and before submission of a marketing application ("pre-NDA" meetings) are helpful in developing methods of presentation and submission of data in the marketing application that facilitate review and allow timely FDA response.

(1) End-of-Phase 2 meetings - (i) Purpose. The purpose of an end-of-phase 2 meeting is to determine the safety of proceeding to Phase 3, to evaluate the Phase 3 plan and protocols and the adequacy of current studies and plans to assess pediatric safety and effectiveness, and to identify any additional information necessary to support a marketing application for the uses under investigation.

(ii) Eligibility for meeting. While the end-of-Phase 2 meeting is designed primarily for IND's involving new molecular entities or major new uses of marketed drugs, a sponsor of any IND may request and obtain an end-of-Phase 2 meeting.

(iii) Timing. To be most useful to the sponsor, end-of-Phase 2 meetings should be held before major commitments of effort and resources to specific Phase 3 tests are made. The scheduling of an end-of-Phase 2 meeting is not, however, intended to delay the transition of an investigation from Phase 2 to Phase 3.

(iv) Advance information. At least 1 month in advance of an end-of-Phase 2 meeting, the sponsor should submit background information on the sponsor's plan for Phase 3, including summaries of the Phase 1 and 2 investigations, the specific protocols for Phase 3 clinical studies, plans for any additional nonclinical studies, plans for pediatric studies, including a time line for protocol finalization, enrollment, completion, and data analysis, or information to support any planned request for waiver or deferral of pediatric studies, and, if available, tentative labeling for the drug. The recommended contents of such a submission are described more fully in FDA Staff Manual Guide 4850.7 that is publicly available under FDA's public information regulations in part 20.

(v) Conduct of meeting. Arrangements for an end-of-Phase 2 meeting are to be made with the division in FDA's Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research which is responsible for review of the IND. The meeting will be scheduled by FDA at a time convenient to both FDA and the sponsor. Both the sponsor and FDA may bring consultants to the meeting. The meeting should be directed primarily at establishing agreement between FDA and the sponsor of the overall plan for Phase 3 and the objectives and design of particular studies. The adequacy of the technical information to support Phase 3 studies and/or a marketing application may also be discussed. FDA will also provide its best judgment, at that time, of the pediatric studies that will be required for the drug product and whether their submission will be deferred until after approval. Agreements reached at the meeting on these matters will be recorded in minutes of the conference that will be taken by FDA in accordance with § 10.65 and provided to the sponsor. The minutes along with any other written material provided to the sponsor will serve as a permanent record of any agreements reached. Barring a significant scientific development that requires otherwise, studies conducted in accordance with the agreement shall be presumed to be sufficient in objective and design for the purpose of obtaining marketing approval for the drug.

The FDA also offers further guidance for formal meetings

Anavex will have a Type B (EOP) meeting. (end of phase)
Tables 1, 2 and A highlight timing issues:
Anavex must request a meeting. FDA has 14 days to respond yes/no
The meeting will be scheduled within 70 days of the request
--- Anavex must get the meeting informational package to the FDA by day 50 and another sentence said within 6 days of meeting request.
The FDA will have complete minutes for the sponsor by 30 days later.

The guidance also goes into detail about information Anavex should have available in the package (submitted shortly after meeting request). Points 14 and 15 are the most relevant for discussion.

14. A list of the final questions for discussion grouped by FDA discipline and with a brief summary for each question to explain the need or context for the question. Questions regarding combination products should be grouped together.

15. Data to support discussion organized by FDA discipline and question. Protocols, full study reports, or detailed data generally are not appropriate for meeting packages; the summarized material should describe the results of relevant studies and clinical trials with some degree of quantification, and any conclusion about clinical trials that resulted. The trial endpoints should be stated, as should whether endpoints were altered or analyses changed during the course of the trial.

For example, for an end-of-phase 2 meeting, this section of the meeting package should include the following: a description and the results of controlled trials conducted to determine dose-response information; adequately detailed descriptors of planned phase 3 trials identifying major trial features such as population, critical exclusions, trial design (e.g., randomization, blinding, and choice of control group, with an explanation of the basis for any noninferiority margin if a noninferiority trial is used), dose selection, and primary and secondary endpoints; and major analyses (including planned interim analyses and adaptive features, and major safety concerns).

From my understanding based on conversations in the past with an SVP Research, the most important thing to pin down with the FDA is the primary endpoint so that the sponsor and FDA are on the same page as to what constitutes a successful phase 3. Realized and potential Adverse events must also be completely discussed for the safety of participants (not a huge issue for Anavex273 compared say to immunosuppressant for MS).

The FDA does not design the study... the sponsor does. But they need to listen carefully to what the FDA says to help design features of the study. The company's statisticians will help decide population size once the primary endpoint is agreed upon. IMO, ADAS-Cog will be the primary endpoint for PDD because of precedence -- it was with Rivastigmine (success on primary and secondary endpoints) and donepezil (failed primary endpoint despite hitting almost all secondary endpoints)