Category: Study Start up

FDA 1572 Form – Commitments

I have to admit I inherently know what is meant by the 1572 Investigator Commitments, but it has been some time since I read them, line by line. I did so recently during an inspection. There is a lot the PI agrees to do, let’s review them:

-I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, rights, or welfare of subjects.
-I agree to personally conduct or supervise the described investigation(s).
-I agree to inform any patients, or any persons used as controls, that the drugs are being used for investigational purposes and I will ensure that the requirements relating to obtaining informed consent in 21 CFR Part 50 and institutional review board (IRB) review and approval in 21 CFR Part 56 are met.
-I agree to report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with 21 CFR 312.64. I have read and understand the information in the investigator’s brochure, including the potential risks and side effects of the drug.
-I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above commitments.
-I agree to maintain adequate and accurate records in accordance with 21 CFR 312.62 and to make those records available for inspection in accordance with 21 CFR 312.68.
-I will ensure that an IRB that complies with the requirements of 21 CFR Part 56 will be responsible for the initial and continuing review and approval of the clinical investigation. I also agree to promptly report to the IRB all changes in the research activity and all unanticipated problems involving risks to human subjects or others. Additionally, I will not make any changes in the research without
IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.
-I agree to comply with all other requirements regarding the obligations of clinical investigators and all other pertinent requirements in 21 CFR Part 312

What does all this mean?
As the sponsor, we have an obligation to the PI, to provide all the necessary documents to ensure the PI understands the expectations: protocol, IB, ICFs and any additional documents for full disclosure.

The PI agrees to follow the protocol, comply with ICH GCP, conduct the work personally or directly supervise the study activities, report any issues as required, and ensure there is ethics committee oversight, for the safety of clinical trial subjects.

This means there is a partnership and a contract that has been entered into. Sponsors will provide full disclosure as well as the PI and conduct the study as indicated in the protocol.

Have you reviewed and read these commitments? Have you had any challenges with PIs following through on these? How do they respond if you remind them of these, if there is a reason to think there may be non-compliance.

Let me know if this has helped you, I’d love to hear from you!

Reference: http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM074728.pdf

A new study….. now what – QIU form……

5. QIU- Qualified Investigator Undertaking form- Canadian sites
http://www.hc-sc.gc.ca/dhp-mps/prodnatur/applications/clini/form/qual_invest_under_form-eng.php

It is really important not only to have the form completed but also ensure it is done correctly. Question for you, have you actually read the document that you are sending to the PI and having them sign?

Do you know what the PI is signing? Does the PI know what they are signing?

“QIU Statement: In respect of the identified clinical trial, I certify, as the qualified investigator for this site that:

• I am a physician or dentist and a member in good standing of a professional medical or dental association as defined in Part C Division 5 of the Food and Drug Regulations;
• I will supervise the medical care and medical decisions respecting this clinical trial at this site;
• I will conduct this clinical trial in accordance with Good Clinical Practices; and
• I will immediately on discontinuance of the clinical trial by the sponsor, in its entirety or at a clinical trial site, inform both the clinical trial subjects and the Research Ethics Board for this site of the discontinuance, provide them with the reasons for the discontinuance, and advise them in writing of any potential risks to the health of clinical trial subjects or other persons.”

Having read these points, they agree to follow the protocol, follow GCP, and oversee the conduct of the clinical trial.

This is very imortant! We will talk about PI oversight again in another blog post. Over the years, it is incredible what we see as PI oversight. It deserves its own post.

Here for the QIU, it is important to hold the PI accountable and responsible for the agreement they have made to the sponsor, Health Canada and the clinical trial subjects and lastly the Research Ethics Board.

Why would we do this? If not done, the data collected may be called into question. You don’t want your site to be the one where they compare the aggregate data with and without that sites data, for a breach of this agreement.

Next post will discuss the FDA1572 form

A new study…… now what? cont’d………

2. If working with a central IRB, ensure that any documents specific to the REB are known and completed. These may include an Investigator/Siteform- providing site and PI details, a checklist for patients to sign, a place for initials on the footer of each page are a few examples.
3. The same applies for the submission letter to either central or local ethics board. The more detailed, comprehensive and complete the submission letter is, it will reduce the need for revisions and reduce start up delays.

2. Investigators brochure. These are typically used when the molecule in study has not been approved by the local health authority in the specific country. It contains all the essential animal data and any updates to date current available clinical trial data with adverse event profiles beginning to be generated. If the molecule has been in study in humans for a period of time, there may be clinical data included with a ‘cut-off’ date. That date corresponds to all clinical data is being used up to and including that date and contained in the brochure. Investigators are encouraged to review these data to become familiar with the side effect profile of the study drug and othe key information aboutvthe molecule. Should the ethics committee have some questions, the PI may address them in the context of his experience in the therapeutic area in conjunction with the product knowledge. It is always A good idea to have the sponsors scientific team assist where possible as well.

In supplement to the IB, based on when the study begins, it may be necessary to provide the team a listing and disk containing the safety reports generated since the cut-off date in the IB. At the time of submission to the ethics committee, it is important to ensure the site has all the necessary information available at the time of start up

3. Product monograph. This document is used when the product used as study drug is approved on the market in the specific country, and it is studied per the local indication. The safety reference document at the sponsor would be called the ‘Core data sheet’. It contains the specific product details, adverse event profile and the indication for use, and administration details.
4. Final informed consent
Sponsors will routinely provide a template consent form. It is highly recommended that it be reviewed against the protocol to ensure it is accurate, reflecting all expected visits and assessments study subjects need to complete. We are all human, and mistakes happen. Ensure the ICF contains all the necessary elements required based on ICH-GCP guidelines. On another post I will discuss the required ICF elements. The ICF will need to be customized to the site specifics. If a local, IRB site, the study coordination may do this. If a central IRB site, the central IRB may customize the consent by site.

Submit the ICF as approved by the sponsor. This is an important element. If the sponsor has reviewed the ICF, they will help to limit any potential delays for missing elements and additional back and forth after IRB approval. Ensure the ICF version date / version identifier is added to the submission letter. When any changes are made, be sure to update the footer version with each change-this helps with version control.

5. QIU- Qualified Investigator Undertaking form- Canadian sites
http://www.hc-sc.gc.ca/dhp-mps/prodnatur/applications/clini/form/qual_invest_under_form-eng.php

Please review this statement to ensur you and the PI understand the responsibilities.

QIU Statement: In respect of the identified clinical trial, I certify, as the qualified investigator for this site that:
• I am a physician or dentist and a member in good standing of a professional medical or dental association as defined in Part C Division 5 of the Food and Drug Regulations;
• I will supervise the medical care and medical decisions respecting this clinical trial at this site;
• I will conduct this clinical trial in accordance with Good Clinical Practices; and
• I will immediately on discontinuance of the clinical trial by the sponsor, in its entirety or at a clinical trial site, inform both the clinical trial subjects and the Research Ethics Board for this site of the discontinuance, provide them with the reasons for the discontinuance, and advise them in writing of any potential risks to the health of clinical trial subjects or other persons.

6. FDA-1572 form

I would encourage you to read the back to really understand, and reacquaint yourselves with the “commitments” being signed and agreed to. I think typically we do these so often with sites, we have actually lost touch with what it means to sign that document.

http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM074728.pdf

Further specifics on each document will be posted.

Please let me know your thoughts on this post. I look forward to hearing from you!

A new study…..now what?

You are the new CRA or study team member and have just received the go ahead for a protocol at a site in start up. Now what? Great question.

The following are the minimal documents you need to ensure you and your site have to begin work:

1. Final Protocol

2. Investigators brochure for the investigational drug.

3. Or, product monograph for an on-label study

4. Final informed consent

5. QIU- Qualified Investigator Undertaking form- Canadian sites

6. FDA-1572 form

7. REBA form – Research Ethics Board attestation form – if the ethics committee does not have the statement on their approval letter directly

8. Check for any patient facing documents- advertising, print, radio and Web based as well as social media based advertisement

9. Check for any paper or web/device based disease based rating scales for completion

10. Confirm if any central vendors need to approve site staff or qualify site staff for protocol specific activities, ie. Raters, radiology facilities, laboratories etc.

Now that all the documents are available, we will review each one (over a few posts) to ensure all that is needed for ethics submission and approval is done correctly.

In another post we will review all the documents & forms needed for sponsors to activate the site.

For the ethics committee submission, whether local ethics or a central ethics, the following process should be followed.  Regardless of which type of committee is used, ensure you have reviewed the ethics  committee process documents to confirm the submission conforms to their expectation.  Remember, keep a copy of their process document to ensure subsequent processes we will discuss are followed and adhered to.

When submitting to ethics, you can follow these guidelines.

1. The letter of submission will need to contain very clear details of all documents submitted for review.  The letter would need to include,

 the protocol number and title, including the version date and or number letter.

 The IB or PM for the study dug used will need to include the product name, and version date for the product and all safety documents from the data cut off as indicated in the IB.

 Submit all safety letters, SUSARs, by MSN or other tracking indicators

 All patient facing advertising , detailed by name and version number

 All patient facing disease based rating scales, detailed by name and version number

 For Canada, if a public website is to be used, ensure it conforms to the Health Canada regulations ( no sponsor, no drug name can be used, it can only provide general disease details for the indication ‘ an investigational or study drug’ is being studied and a central call in number can be added ) prior to posting and live and patient facing

 Final sponsor approved ICF template, specific to the site, with version date or number

2. If working with a central IRB, ensure that any documents specific to the REB are known and completed.  These may include, but not be limited to, an Investigator/Site form- providing site and PI details, a checklist for patients to sign, a place for initials on the footer of each page are a few examples.

More to come!