Expert advice for seeking emergency use
FDA guidance clarifies questions
For some patients, enrolling in a clinical trial is not an option. They may meet exclusion criteria, or the nearest trial center may be geographically inaccessible, despite having a disease or condition that could benefit from investigational treatment. In such cases, the patient’s physician can request expanded individual patient access from the Food and Drug Administration. In dire situations, the physician can seek emergency use.
Emergency use can be sought from the FDA when a patient is in life-threatening circumstances and no alternative treatment beyond the test drug exists. If emergency use is approved for one person or a small group, the use of the drug is still considered research.
In 2009, the FDA updated its expanded access regulations and added different categories of access. This includes individual patients (including emergency use), intermediate-size populations, and large populations under a treatment protocol or investigational new drug (IND) application.
"Part of what the FDA did in 2009 was make expanded access more available to treating physicians rather than just academic centers," says Mark Schreiner, MD, chair of the Committees for the Protection of Human Subjects at Children’s Hospital of Philadelphia (CHOP). "Smaller centers may not have an active trial — patients could be eligible, but it’s not open at their center." In June 2013, the agency released draft guidance in the form of questions and answers to clarify investigator and IRB questions concerning guideline implementation. (For more on the FDA’s guidance, see article on page 70.)
Seeking an emergency IND
The following steps and criteria must be met when an investigator is seeking an emergency-use IND, according to Schreiner and Barbara Engel, MD, vice chair of the Committees for the Protection of Human Subjects at CHOP:
• The patient is in a life-threatening health situation. This means that there is a high probability of death from the patient’s condition, or the patient may be come irreversibly debilitated.
• No acceptable alternative treatment exists.
• The probable risk to the patient from the test drug is not greater than the probable risk from the disease or condition. The safety of the drug hasn’t yet be approved by the FDA, but the probable side effects of the drug cannot be greater than the risk of leaving the condition untreated.
• The trial sponsor must agree to ship the test drug for emergency use. Some sponsors may require IRB approval, though many will accept a written statement that the IRB is aware of the emergency use.
• Obtain informed consent, or waiver. As the emergency use of the drug is still considered research, the investigator must obtain informed consent. In an emergency situation, consent can be waived if all four of the following are met:
-The patient is in a life-threatening situation.
-No acceptable alternative treatment exists.
-The patient is unable to communicate his or her consent.
-There is insufficient time to gain consent from the patient’s legal representative.
The waiver of consent should be reviewed and evaluated by a physician independent of the treatment within five working days.
• There is insufficient time to obtain IRB approval. The investigator must contact the IRB to see if a quorum can be convened for review. If treatment must begin immediately for a life-threatening condition and the IRB cannot convene in time, the FDA will not deny the request if IRB approval is the only obstacle. In these cases, a report must be submitted to the IRB within five days of receiving verbal approval from the FDA.
• Contact the FDA for an emergency-use IND.
"The FDA hotline is available 24/7 and can very rapidly approve these," Schreiner says. "The key is getting the sponsor approval."
There are many reasons why a sponsor company would not support an emergency use request, Schreiner says. A small company may have very limited resources and quantity of the drug, and limited funds with which to develop additional quantities. Expanded access could even delay or imperil getting final FDA approval of the drug. "These requests are for acutely ill people with high likelihood of dying and they [sponsors] have to report the effects [to the FDA]," he says. "When a company denies the request, there are individuals who are not getting treated, which is very sad. Everything that delays getting the drug approved, they deny hundreds of other people use of the drug. The shortest path to approval is the right way to go. A lot of companies will not issue treatment INDs in early phases."
If the sponsor does agree to ship the drug, the next step is determining whether the IRB has sufficient time to review. CHOP has an executive IRB that can meet on short notice, in as little as 24 or 48 hours. "We need to know when they need to treat the patient. It’s up to us to decide if we have enough time to review it and convene a meeting. If you have to start treatment immediately, the investigators are encouraged to exercise the option for prior review and approval, if there is sufficient time. If there is not enough time, we send them an email at their request and say that there is proof there is insufficient time. The only regulatory requirement is that they submit a five-day report," Schreiner says.
"But if we hear about it [the request] on a Friday and treatment has to start Sunday, that’s not enough time," Engel adds. "If it comes in with enough time, it goes through the same [approval] process — they submit a brief treatment protocol to the FDA, telling why they think it’s the best option and what the treatment plan will be."
When an emergency exemption from IRB approval is granted, the investigator must submit a report to the IRB of record within five working days. The reports should contain:
-drug/biologic name;
-IND number;
-reason for insufficient IRB approval time;
-patient information, including date of planned use, age/sex/diagnosis, summary drug use and risks/benefits;
-whether informed consent was obtained (and independent physician evaluation letter and exemption criteria statement if it is not);
-summary of the emergency use of the drug.
The investigator must also alert the CHOP pharmacy that the test drug is being shipped and provide a copy of the emergency IND from the FDA, the sponsor’s approval, and either the IRB’s approval or the notice of emergency exemption.
Types of requests
The CHOP IRB mainly sees emergency use requests for chemotherapy drugs and, occasionally, infectious disease treatments. "In the case of a virus treatment, you have to start as soon as you get the drug, as it is really urgent," Schreiner says. "For chemo, we really try to convene an executive IRB meeting so they can continue to report to us and have some oversight."
The IRB does occasionally deny requests. "Our IRB denied one [expanded access request], but it was a single-patient treatment and it was a first in human use and there was insufficient information that the risk was managed and reasonable, and no evidence of possible benefit," Schreiner says. "It was a situation where the company refused to allow the expanded access IND. It would have been an off-label use of the drug. It was a situation of having to review proposed safety and risks and benefits."
"We can be willing to review it before the IND is issued and approve it contingent to IND approval," Engel adds.
Conversely, treatment that does not show promise in a clinical trial can be approved for use in a single patient. "Another area we’ve seen is a case in oncology where a clinical trial basically didn’t show sufficient promise, but one patient responded positively and an IND allowed continued access," Schreiner says.
The FDA may also deny emergency use requests. Being at a certain stage of a disease or having comorbid conditions that could make use of the drug dangerous for the patient can lead to denial, or if access impedes clinical development of the drug. However, "I’ve never seen the FDA not approve if the sponsor has agreed to release the product," Schreiner says.
Draft guidance clarifies FDA regulations
Clarifies emergencies, length of treatment
In 2013, the FDA released draft guidance in the form of questions and answers to clarify its 2009 regulations on expanded access and emergency use. The nonbinding guidance gives the FDA’s suggestions for interpreting and implementing its regulations, and can be read at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM351261.pdf. The areas include:
• Emergency procedures. If a patient must be treated before a written submission can be made to the FDA, the agency can give verbal approval of emergency use. The physician or sponsor must submit an expanded access IND or protocol within 15 working days of approval.
• Approval for more than one use at the same facility. The FDA will allow more than one emergency use of the same drug at the same institution. When one emergency use is approved, the investigator is expected to go through IRB approval for subsequent uses. But if the second request is also an emergency, the FDA won’t deny the request on the grounds that IRB approval cannot be granted, and typical emergency procedures apply.
• Length of treatment. Emergency use is good for one course of treatment for the patient. "For some chemo agents, this could be five years," says Mark Schreiner, MD, chair of the Committees for the Protection of Human Subjects at Children’s Hospital of Philadelphia (CHOP). Under expanded access, the FDA has said it typically authorizes access for an extended duration for patients with chronic conditions.
