Anavex Life Sciences Corp (AVXL)

[Doc328]

You need to start all 450 patients within a specified time frame (60 day time period?), otherwise you’ll be waiting a longer time to get meaningful data/results from the same time period.

Pogue,
That’s not how it work. Patients are enrolled in a rolling fashion at different rates at the different sites. There seems to be a lot of confusion around this subject so here goes:

Steps in initiating and running phase 2 and 3 studies:

1. Before a study starts, the sponsor (Anavex) writes the investigator’s brochure and the protocol – these are typically 60-100 pages long. The IB describes everything known about the drug (chemistry, pharmacokinetics/dynamics, metabolites, safety issues, phase 1 results, other phase 2 results, etc. The protocol describes the drug and previous studies in less details, describes the inclusion and exclusion criteria in exquisite detail, describes what is performed at each visit (in text visit by visit and in a handy chart for reference), details of proposed statistical evaluation (yes this is prespecified in every study that will one day be evaluated by a regulatory agency), references, etc. This process takes time with feedback from key individuals (study PI, other MD/PhD level, statisticians). However, it can be initiated well before a study starts and updated before beginning and many parts are cut and paste from previous documents.
2. The sponsor (Anavex) negotiates with and hires a CRO (Leon in Spain, not sure in Australia or US) to help conduct the study. They are contracted to help at multiple steps before and after the study starts.
3. The study gets regulatory and ethical authority to proceed. Once this step is achieved they can say ‘We have approval to initiate’ and release a PR (as Anavex did in April with PDD)
4. Sites are selected --- many have already been pre-selected to save time. The CRO and sponsor may both offer up a list and these sites are contacted about interest as follows (a) email asking about interest with loosest of inc/exc criteria, objectives, timeline to help gauge interest. There will be a disclosure agreement that must be signed by the appropriate party (I can sign for myself but in academics may need another to sign) in order to get the protocol (b) Protocol is sent for review. If the site is still interested they will express this. (c) Site selection interview by CRO – usually by phone but may be a visit if site has limited study experience in the field. The purpose is to make sure site has appropriate patient population and staff and facilities to conduct the trial (d) Site is told that they have been selected.
5. Site initiation: A selected site (a) agrees upon a budget (this takes me one or two backs and forths but academic sites may have someone central to do this). This step may be easier in Australia where it looks like they have a national budget template. (b) Site signs a clinical trial agreement (once again may require a larger process at some sites than others). (c) After a and b, the site prepares the ethical review applications (IRB in US; HREC in AU). Academic sites may have to use their IRB, we can use a central IRB so this step is faster. (d) The site may now have their site initiation visit (some studies may allow this step to be by phone). (e) After this point a site is ACTIVE and ready to enroll. (f) Investigator meetings may occur at any point during this process.
6. Recruitment: Most studies have preselected some patients and more pre-selection occurs as the study proceeds. Preselected patients meet basic inc/exc criteria such as age, stage, etc. Patients are contacted or re-contacted with some details of the study by doctor, nurse or research staff. If interested and basic inc/exc criteria still valid, a screening visit can be scheduled. We often email/mail a copy of the informed consent form (ICF) at this point so patient/family have opportunity to read before this appointment.
7. Screening visits: Details of the studies are further discussed. Patient (and/or family as needed) sign the ICF. At this point the patient receives a unique identifier (i.e. 11001 for first patient in the 2a) and is considered by most to be enrolled. Screening blood tests, EKG, scales, etc all done. Some patients will flunk out at this point (i.e. an AD patient with 18 on the MMSE) and others will flunk out for safety (labs, EKG, etc) or medical reasons (suicidal, recent cancer, uncontrolled diabetes). Depending on studies additional tests may need to be ordered (PET scan for AD trial if not already done; eDiary training for parents in second Rett study). If patient or family can’t do the eDiary correctly for a couple weeks they may be excluded (no use doing a study on a patient who will not follow protocol). If PET scan not consistent with AD, they will fail the screen.
8. Approval to proceed. After the screening visit, lab results, PET results etc come back in. The PI must sign off that patient has passed. Many (most) studies will have an MD at the CRO review and get clarifications (i.e recent hypothyroid diagnosis, Is patient stable on dose x 3 months?) and they have the final word.
9. Patient has now passed screened and is RANDOMIZED. They are ready to be dosed. At this point patient is included in all ITT analysis. If they drop out before the dosing visit they are not included in mITT analysis. Depending on the study this can be done the same day as the First dose visit
10. First dose and baseline scales visit. The first dose may be done at the clinic. For AD, they will do ADAS-Cog, ADCS-ADL and CDR-SB according to Dr. Hampel. For PDD they do CDR-attention and MDS-UPDRS scales according to the registry.
11. Patient returns for other visits (can vary tremendously study to study) with labs, exams, scales, etc per protocol
12. Patient has end of study (EOS) visit with final studies.
13. Depending on the study, they may roll over to open label extension. Some studies also do a final safety visit for those who did not rollover into OLE a month or so later (will not slow down analysis of primary endpoint).
14. Once last patient is randomized the study enrollment is complete. Study completion can easily be calculated at this point (+ 14 weeks for PDD; +48 weeks for AD)
15. Last patient completes the EOS visit. The study is now complete
16. Data is analyzed, presented etc.

These steps are not unique to Anavex / A273. Every other company also has the same timeline and challenges. To get 450 patients for AD, they will likely screen more than 500-600 patients. Several months have already passed since approval to proceed. I can’t tell whether or not he first patient has been dosed.

A one year recruitment is possible but many sites won’t even be up until 2019Q1 so 15-18 months is more probable for recruitment and then 48 weeks till last patient has EOS visit and 2-3 months for analysis. I’m thinking 2020Q3 is optimistic earliest possible and 2021Q1 is more likely for study results to be PR’d with primary endpoint release. Of course, if they do analysis after ½ the patients have EOS or other milestone and add more sites and keep n=450 the timeline could be a few months faster. But, if they add more sites and increase n, the timeline could be slower.