Expanded Access Trials, IITs and Safety Risks
It’s worth taking a new look at expanded access/compassionate use trials and investigator initiated trials in light of FDA’s revised guidance issued in October 2017 and the FDA’s new policy of encouraging such use under Commissioner Gottlieb. The actual regulations on expanded access are in: 21CFR312.300 to 21CFR312.320.
There are three mechanisms permitted for expanded access:
- Expanded access for individual patients, including for emergency use (21 CFR 312.310)
- Expanded access for intermediate-size patient populations (generally smaller than those typical of a treatment IND or treatment protocol — a treatment protocol is submitted as a protocol to an existing IND by the sponsor of the existing IND)9 (21 CFR 312.315)
- Expanded access for widespread treatment use through a treatment IND or treatment protocol (designed for use in larger patient populations) (21 CFR 312.320)
Larger Trials (#2 & #3 above)
For most companies and sponsors involved in expanded access, the second and third are essentially clinical trials with standard protocols. The sponsor/company in most cases will handle this as a regular study and will include a safety section in the protocol. They will receive all SAEs, process them and enter them into their safety database. In many cases the sponsor will handle the regulatory submissions of SUSARs and other safety data. This is not my focus here. In other words, these are usually “regular” sponsor trials. See here.
Individual Investigators (#1 above)
An area where there can be more problems and complications involves individual investigators doing compassionate use or expanded access. Sometimes the investigator approaches the sponsor to do a trial; sometimes the sponsor seeks out investigators to do such a trial.
FDA has published on its website some very specific instructions for sponsors and individual investigators to help them get through the IND process. It is complicated and summarized here:
The physician who wishes to do compassionate use or an expanded access trial may do it either by opening up his/her own IND with permission from the company supplying the study drug or he/she may do it within the company’s already existing IND. The FDA much prefers that the trial be done within the company IND and not create many new investigator INDs. Nonetheless investigator INDs are allowed.
When a physician wants to request an IND to use an unapproved drug for a single patient, the first step is to obtain permission from the manufacturer. Without the consent of the manufacturer, the unapproved product will not be available to the patient. After the manufacturer agrees to provide the product, the recommended procedure is to submit the following information to the appropriate review division:
- Request for a single patient IND for Compassionate or Emergency Use should be stated at the top of the correspondence.
- Brief Clinical History of the patient including the diagnosis, the disease status, prior therapy, response to prior therapy and the rationale for requesting the proposed treatment.
- Proposed Treatment Plan including the dose, route, planned duration, monitoring procedures and modifications (e.g. dose reduction or treatment delay) for toxicity. Reference a published protocol or journal article if appropriate.
- Drug Supply Reference Statement which would name the supplier or manufacturer and a statement that a Letter of Authorization to cross reference an appropriate IND of the supplier or Drug Master File (DMF) of the manufacturer is included. The treating physician must contact the supplier or manufacturer for such a statement.
- Informed Consent Statement that states that informed consent and approval of an appropriate Institutional Review Board (IRB) will be obtained prior to initiating treatment. There are some IRBs that have specific procedures for approving emergency requests.
- Investigator Qualification Statement that specifies the training, experience, and licensure of the treating physician. The first two pages of a Curriculum Vitae typically contain this information and are usually sufficient.
- Form FDA 3926 can be used by physicians when submitting requests for individual patient expanded access to investigational drugs, including in emergencies. This form is designed specifically for single patient IND requests.
- FDA Form 1571 and 1572 are no longer required for individual patient expanded access to investigational drugs and biologics. Form FDA 1571 and 1572 are still required for other expanded access submissions (e.g., intermediate access or treatment INDs) and for IND submissions by commercial sponsors or drug manufacturers.
- Contact telephone number and facsimile number. If the request is approved, an IND number will be issued by the FDA and the treating physician will be contacted by phone or fax with a letter to follow. The IND is considered active upon issuance of the number. The IND sponsor (treating physician) will then contact the drug supplier and provide the IND number. The supplier may then ship the drug directly to the treating physician.
Comments on PV, Safety and Risk
There are two areas of concern here. The first is who handles the routine and non-routine PV and drug safety requirements. The second is protecting the drug (and the sponsor/company).
FDA states in multiple places that individual investigators holding an IND are responsible for all the IND regulatory requirements that all IND holders must perform.
The pharmacovigilance (collecting SAEs and NSAEs), databasing them, evaluating them, analyzing them, determining which are SUSARs, and thus reportable to FDA, must be done by the IND holder or it must be delegated to someone else via a written agreement or contract.
The issue here is that sometimes the individual investigators are not experienced in doing clinical trials and the sponsor (or CRO) will have to walk them through all the details of setting up the trial, writing an informed consent, getting IRB approval, etc. The individual investigator may also have no experience in evaluating SAEs regarding causality and expectedness (in the Investigator Brochure). This may lead to problematic issues with submissions to FDA. In addition, notification of other investigators doing sponsor-initiated “regular” trials as well as other investigator initiated trials may also need to be notified about SUSARs. This is almost always done by the sponsor (or CRO).
To Do List
- The sponsor/company should protect itself, since it is cross-referencing its own IND or actually having the investigator do the trial under its own IND, by putting in place a detailed written agreement/ contract clearly specifying what the investigator does and what the company does in regard to all PV requirements. It should note who handles and reports SUSARs, DSURs, signaling, evaluation of non-serious AEs, investigator notification, reporting to ex-US health authorities etc. No matter who is responsible for the above tasks, the sponsor should receive all SAEs/SUSARs in more or less real time and specify in the agreement whether they can review and comment or not before submission. The sponsor should be able to stop the study if the investigator performs poorly or fails to do his/her IND responsibilities.
- The sponsor/company should decide what level of oversight they will maintain. Although the company usually does not do formal monitoring , it is in their interest to track and to “assist” the investigator if he/she has problems or issues in doing Good PV Practices and providing quality data.
- The company should ensure that its own internal SOPs and procedural documents cover expanded use programs and investigator initiated trials.
Risk to the Product Under Study
The second area in regard to safety concerns protecting the product from problems that might occur with inexperienced investigators.
There is always risk to patients and the product when clinical trials are done. The drug may fail in its efficacy endpoints, it may produce more or unexpected and new SAEs, warnings, precautions, contraindications. This is not the area of concern but is, of course, the risk in doing any clinical trial.
Problems occur if the investigator does not do a good job. For example, if patient selection criteria are not strictly adhered to or if the patients are not followed according to the protocol etc. safety problems may result. This may then produce deaths and SAEs that might not have occurred if the protocol were followed correctly and high risk patients were excluded. If the company is not monitoring the individual investigators at some level, they may perform badly for a longer length of time than if the company tracked the investigator’s handling of each patient more closely.
Thus, it is possible that the drug product will be “harmed.” This is especially true if patients are more ill than the protocol permits, if there are additional concomitant diseases or medications being used that are forbidden etc.
To Do List
- The company should vet and chose its investigators for expanded use very carefully especially since the company is supplying the drug supplies and a contract and “paper trail” exists even if the investigator holds the IND.
- These trials often now occur with very ill patients and with advanced therapeutics and biologics with complex safety and pharmacologic profiles which may produce greater risks than with “simpler” drugs and products. The company should think these studies through very carefully.
- The company should maintain some level of oversight. If possible every enrolled patient should be known and reviewed by the company. This may not be full scale clinical trial monitoring but it should at least track all patients and SAEs. If the number of patients involved is small, this should be quite feasible.
- Review before submission all SUSARs and non-SUSAR SAEs. Enter the cases in the safety database if feasible. Use these cases for signaling.
- The drug safety/PV group should pay close attention to these trials. It is no surprise that the DS/PV groups generally don’t like expanded access or IITs. Nonetheless, the business and management do like to do these trials and there may indeed be real medical and business reasons to do such trials. Note, however that the regulations allow the sponsor to refuse to do such trials.
This is a complex and expanding area. More and more of these trials will be done. The rules will change over time and will vary in different countries. Stay alert.