Managing Drug Shortages During Clinical Trials
CTEP-sponsored clinical trials may be affected by shortages of non-IND agents including commercial cancer drugs, supportive medications, or resources such as sterile IV fluids.
CTEP does not have a supply of agents to supplement the supply at local institutions nor does it have an inside track on information that a shortage is about to start or when it will end. A very useful resource is pharmacy staff at the local level. When a shortage develops, the first people who know about it will be the pharmacy staff who attempt to order an agent that is in short supply.
The American Society of Health-Systems Pharmacists (ASHP) website provides the most current information on drug shortages. The FDA's Drug Shortages Web Page provides a searchable database of ongoing and historical shortages and a list of extended use dates to assist with shortages.
When to Contact CTEP Regarding a Drug Shortage
When any shortage of a commercial agent(s) may affect an ongoing clinical trial, the organization leading an affected trial (Lead Protocol Organization or LPO) should contact the appropriate CTEP physician to discuss necessary modifications or delays in study therapy for enrolled participants at affected sites.
For Phase 1 and/or Phase 2 trials under a CTEP an investigational new drug (IND) application: The LPO should contact the appropriate physician in the Investigational Drug Branch (IDB) who monitors the trial if it appears sites are likely to experience a shortage of the commercial agent in order to discuss management of study patients before instituting any directives on delays or changes in therapy or submitting a protocol amendment. The CTEP Protocol and Information Office (PIO) should also be copied on this correspondence.
For Phase 3 trials under CTEP IND: The LPO should contact the appropriate physician in the Clinical Investigations Branch (CIB) who oversees the disease portfolio for that trial to discuss potential changes or delays in study therapy or potential study amendments. The CIB physician will also ensure that the IDB physician who monitors the trial is involved in all these discussions. The CTEP PIO should also be copied on this correspondence.
For CTEP-sponsored trials not under a CTEP IND: The LPO should inform the appropriate physician in CIB of any management plan instituted for enrolled subjects who do not have access to the commercial agent in short supply. The CTEP PIO should also be copied on this correspondence.
Guidance for Management of Participants Already Enrolled On Study
The following general principles should be used in determining how to adjust protocol regimens for participants already enrolled on study, outside of a protocol amendment, if the commercial agent is not available at a local site because of a temporary drug shortage.
If the LPO for a specific clinical trial believes or has been informed that some participating local sites will not have access to a commercial agent for on-study patients, the LPO should develop an appropriate management plan for the treatment of these patients so that they will all be treated in the same manner. LPOs must make reasoned and good faith judgments regarding appropriate delays and/or modifications in treatment(s) for the study patients. They should also provide specific instructions to all local investigators about delays and delivery of any modified treatment(s) for on-study patients until the commercial agent is available and treatment can be resumed per protocol specifications. In addition, LPO should provide instructions to participating sites on procedures for specifying/tracking delays and modifications in treatment regimen(s) due to the shortage in order to be able to analyze study data appropriately per the study’s statistical analysis plan and handle protocol deviations at time of audit.
This general approach regarding management plans for appropriate delays and/or modifications in therapy for participants already enrolled in the research without prior IRB approval is permissible under the Department of Health and Human Services (HHS) regulations at 45 CFR 46.103(b)(4)(iii) since the modifications are being made in order to eliminate immediate apparent hazards to these patients/study subjects-in this case, providing appropriate instructions for delays and/or modifications in study treatment because an essential component of standard therapy (i.e., the commercial agent) is not available. The medical and research records of the study patients should reflect that the patient was informed of any delays and/or modifications in protocol therapy related to the shortage of the agent and the associated risks.
In addition, in accordance with HHS regulations, a local investigator must promptly inform the Institutional Review Board(IRB) of record of this unanticipated problem and of the management plan for the trial that the local investigator is participating in, as outlined by the study LPO conducting the trial. In accordance with local policy, the IRB may determine whether participants already enrolled should be re-consented or sign a consent form addendum. Investigators at local sites experiencing a shortage that affects patients on a particular trial should report this to the LPO leading the trial. The LPO should then report this (if it occurs) to the NCI CIRB along with the management plan being used to address the shortage of the commercial agent for the affected trial(s).
Guidance for Enrollment of New Participants
When a LPO becomes aware of a shortage of a commercial agent affecting a CTEP-sponsored clinical treatment trial that they are conducting, the LPO must advise local sites participating in the trial to check with their local pharmacists about the available supply of the commercial agent at the local site before starting to evaluate new participants for entry on a CTEP-sponsored clinical trial that involves the agent. If a sufficient supply of the commercial agent is not available to cover therapy in the respective clinical trial at a local site for the anticipated length of the shortage, the local investigators should not consent new patients for enrollment on the study. The expected duration of the shortage should be based on a reasonable assessment by the LPO given what is being reported by manufacturers regarding the specific shortage. Sites should be advised that their local pharmacists might be able to obtain supplies of the commercial agent from other institutional pharmacies that have adequate supplies. A formal protocol amendment would be required before new participants could be consented and enrolled on study using an alternative/modified treatment regimen.