Institution Bulletin vol 5, issue 3
In May 2015, the FDA issued a draft guidance document for investigators who plan to conduct their own medical research (Draft Guidance: Investigational New Drug Applications Prepared and Submitted by Sponsor-Investigators). The draft guidance describes this type of researcher as a sponsor-investigator, that is, an individual who acts as sponsor and researcher of the same study. The proposed policy explains how a sponsor-investigator can request the FDA’s authorization to research drugs or biological products in humans through the investigational new drug (“IND”) application process. Some types of medical research are exempt from the IND requirement; the FDA provides guidance on those categories of research here.
A study that needs an IND also requires an IRB review, and information from the IND can and should support an IRB submission. This draft FDA guidance notes some key areas in which IND applications and IRB submissions can intersect. For more information and guidance on how to submit sponsor-investigator studies to an IRB, you can visit Quorum Review’s webpage for Investigator Generated Studies.
The draft guidance opens with a reminder of why the FDA reviews these research proposals. There are two primary purposes:
- To protect the rights and safety of subjects in the study; and
- To assess whether the trial is designed to adequately test the drug’s effectiveness and safety.
The FDA anticipates that nearly all sponsor-investigators studies will involve treatments that the FDA already has approved for at least one purpose; treatments that a sponsor is already researching under another IND; or (less frequently) treatments that have been approved in other countries but not the United States. The information required for the IND is essentially the same in all cases, although the source of that information may differ depending on whether the drug or biologic is commercially available.
Drug information, the IND, and the Sponsor–Investigator
An IND application needs to include safety information about any drugs that will be in the study. The FDA draft guidance notes two typical sources of this information:
- If the drug or treatment is already approved, then the information is available through existing public resources such product labeling and FDA announcements;
- If the drug or treatment is not already approved and being investigated under another IND, the FDA suggests using what it identifies as a cross-reference letter. In this case, the sponsor of the other investigation provides the safety and efficacy information that appears under that study’s IND.
IRB Submission: An IRB requires all known safety and efficacy information for any drugs or biologics in a study. IRB’s typically accept an Investigator’s Brochure for unapproved drugs, or the product label for an approved treatment.
Submission Waiting Period
After completing and submitting an IND application, the sponsor-investigator must wait 30 days for a response. No response allows the researcher to continue. The FDA will review all of the information in that period, and if it identifies any concerns it must respond within that time if it wishes to delay initiation of the research.
IRB Submission: The IRB typically will request the date of the IND application, and possibly the control number that the FDA provides. A sponsor-investigator does not need to wait for the 30-day period to pass before submitting to an IRB. Many IRBs, including Quorum Review, will review research any time after an IND application has been submitted, and then will issue approval documents once the sponsor-investigator provides notice that the 30-day period has passed without FDA comment.
FDA Forms 1571 and 1572
Key documents for the IND application are the FDA’s forms 1571 and 1572. In a sponsor-investigator study, the researcher is responsible for submitting both. The 1571 addresses the sponsor aspects of the study – such as all of the product and protocol information – while the 1572 addresses the investigator portion of the research. The 30-day countdown begins ticking once the sponsor-investigator has submitted those forms and the necessary supporting documents.
IRB Submission: On the 1571 the sponsor-investigator includes the IRB(s) for the study. During an IRB submission, Quorum Review will ask when the IND application was filed. Some IRBs require a copy of the investigator’s 1572, but Quorum Review does not. We collect the information and assurances we need through our electronic submission process.
The FDA does not require an informed consent document with the IND application, but the draft guidance encourages sponsor-investigators to include one.
IRB submission: An IRB must review the informed consent document and any other information about the sponsor-investigator’s consent process. The IRB also must review any recruitment materials or other study materials the study participants will see.
Chemistry, Manufacturing and Control (CMC) Information
The FDA requires detailed information about formulation and quality of any investigational products. This level of detail is necessary for the FDA, but not an IRB. For an IRB submission, the IND application and the passing of the 30-day waiting period typically is sufficient.
Pharmacology and Toxicology Information
The FDA requires information about dosing, as planned for the trial, and essential observations from any animal studies or other human trials. For an IRB submission, the material that appears in the product labeling or an Investigator’s Brochure usually suffices.
The FDA’s IND Review Process:
The FDA can stop research at any time with a clinical hold on the IND. The FDA considers any actions to delay research during its initial 30 day IND review period as a clinical hold.
IRB Notification: The IRB needs to be informed of any clinical holds from the FDA. The IRB also has the authority to stop research in case of anything that could endanger participants’ safety.
The FDA requires notification of any changes to the IND. The sponsor-investigator does not need to wait for approval or response from the FDA, but may request comment. The IRB must review and approve protocol changes before the changes are implemented.
Some significant changes may necessitate a new IND application rather than amending a current one. A new IND application also would require a new IRB review.
IRB Submission: The IRB must review and approve protocol changes. (Quorum Review differentiates between administrative changes and changes that may affect the participants’ consent form)
Overview of other Sponsor-Investigator Responsibilities
The draft guidance reviews generally what else the sponsor-investigator must do to complete a study under an IND.
- IRB Review and Approval
- Good Clinical Practices: See the FDA’s guidance for maintaining GCP
- Records keeping: According to the FDA, poor record-keeping is a frequent reason for clinical holds
- IND Safety Reports: Adverse reporting is required, and the sponsor-investigator is responsible for it
- Proper Research Monitoring: A sponsor-investigator faces a wider range of reporting duties than as an investigator in a larger study under a separate sponsor
- Annual Reporting: A sponsor-investigator must provide IND updates within two months of the IND’s anniversary date; the report should include overall progress, a summary of adverse events, a summary of all IND safety reports, any subject withdrawals because of adverse events, new information, and an investigation plan for the coming year
The IND Endgame: Withdrawal, Termination, or Inactivation
If for some reason the study cannot be completed, the sponsor-investigator usually can stop IND research and withdraw an IND at any time. Otherwise, the sponsor-investigator should inform the FDA when the study is completed.
The FDA may terminate an IND if the IND itself proves inadequate, or if research is not conducted properly.
Sponsor-investigators can inactivate an IND if no one enters the trial after two years, or if the research remains on clinical hold for a year. An advantage of inactivation over withdrawal is that the sponsor-investigator may be able to resume research by reactivating the IND. The sponsor-investigator can do this with a formal request and a protocol amendment. As with a new IND application, a request to reactivate an IND has a 30-day waiting period.
IRB Role: The sponsor-investigator must coordinate the ending of a study with the IRB. Routine completion can be reported and acknowledged, but the IRB must approve any unexpected stop that could affect participants in the study. The IRB needs to see and agree with all plans for informing participants and taking them out of the study safely.
The FDA’s draft guidance on IND applications for sponsor-investigators does not set any new policies, but it does provide a useful overview of the application process. A sponsor-investigator’s interaction with an IRB frequently intersects with the requirements of IND-based reporting. Quorum Review IRB reviews sponsor-investigator studies as Investigator Generated Studies, and you can find forms and guidance materials at the links below. All of Quorum Review’s policies are consistent with the draft guidance and we would be happy to help you with your sponsor-investigator study.
Guidance on IND Exemption (September 2013)
Guidance on Form 3674 and other stuff
Guidance on Safety Reporting: Safety Reporting Requirements for INDs and BA/BE Studies
Other FDA Guidance