Develop Investigational Drug Management Standards to Withstand Regulatory Scrutiny
While the FDA strictly enforces the handling of investigational drugs, the COVID-19 pandemic is shining a spotlight on the accountability issues involved. Agency regulations are only two paragraphs long, giving investigators and sponsors little guidance on the specifics of the drug management process. In the absence of clear instruction from the FDA and other regulators, the clinical trials industry has begun to develop its own standards.
Complicating the issue of investigational drug accountability is the current pandemic. Trials that remain open during the COVID-19 crisis still will need to keep track of drugs, even if staff and monitors are unable to check supplies manually on site.
Sponsors must determine if it is possible to track the drug remotely through existing electronic records or if supply checks can be put off until sites reopen, says Kathryn King, Aptinyx senior vice president of clinical development. Sponsors that choose to institute remote monitoring should be aware of the additional burden that may place on site staff when they aren’t in the office or are focused on other things like patient care, King adds.
FDA regulations in 21 CFR 312.62 regarding management of investigational drugs in one short paragraph address record-keeping on disposition of the drug and handling of unused supplies after the trial ends. A second paragraph, 312.69, sets out requirements for secure storage of controlled substances. The agency does not weigh in on such specifics as receipt, identification, storage and handling, preparation, and dispensing of the drug.
The American Society of Health-System Pharmacists’ (ASHP) guidelines for management of investigational drug products offer a standardized approach that can be adopted by clinical researchers. The guidelines cover investigational drug receipt, accountability, storage, handling, preparation, dispensing and final disposition of unused product. The guidelines also address compliance with regulations and requirements from the FDA and the International Council for Harmonization (ICH) on good clinical practice.
The ASHP guidelines emphasize the importance of having a clinical pharmacist on staff. Pharmacists, the society says, have the necessary expertise to fully understand the special handling requirements of investigational drug products, including the importance of proper documentation at all stages of drug flow through the clinical trial.
“Failure to accurately document investigational product accountability can undermine the validity of clinical study data, which could spur sponsors to halt a site’s participation in current or future studies and result in a loss of local patients’ access to clinical studies,” ASHP warns.
The clinical research pharmacy should be included in the pre-IRB review for new clinical protocols, the guidelines state. During this review, the clinical research pharmacy should determine the safety and feasibility of conducting the clinical research study at the institution with respect to its policies, pharmacy services and fees.
ASHP also notes the importance of having an investigational drug-handling manual to guide everyone who is involved with managing drugs. Created with input from the clinical research pharmacy, the manual should include, among other items:
- A description of the investigational drug product, including dosage forms, strength and packaging;
- Information about investigational drug and ancillary supply sourcing provided by the sponsor or sourced locally by a clinical research pharmacy;
- A list of concomitant medications, including adjunctive therapies or pre-medications;
- Instructions for storage conditions, such as temperature and humidity;
- Warnings about special handling precautions, such as exposure to light, temperature variations and hazardous handling precautions;
- Procedures for handling participant investigational drug product returns; and
- Instructions for interactive response technology, such as interactive voice (IVRS) or web response systems (IWRS), if applicable.
The Institute for Safe Medication Practices (ISPM) also recommends that sponsors develop and provide clinical sites with study-specific pharmacy manuals. Clinical sites should create a reference sheet summarizing the most important protocol information relevant to investigational drug management and accountability. A process should be established to update and maintain these sheets as protocols are amended, including a system for version control.
Sponsors, in consultation with regulators, should select and approve a standardized identifier for the investigational drug prior to clinical trials, ISPM says. This identifier should be unique and distinctive from other investigational drugs and the protocol number. They also should perform a risk assessment on the drug’s name, labeling and packaging to identify any potential risks that might result in medication errors. A similar evaluation should be part of the IRB process for each individual clinical site.
Processes, protocols and manuals should be developed with regulatory compliance in mind and the understanding of how the FDA will inspect drug management records. When looking at dispensing and administration records, FDA field investigators want to see assurance that the investigational drug was provided only to patients enrolled in the clinical trials. And for returns, they will check return logs against administration logs to confirm that correct doses were dispensed. The FDA also will expect explanations for any damaged or lost investigational product.
Similarly, investigational drug destruction must be completely documented. The documentation must detail all products that were actually destroyed, as well as how that was accomplished.
Failure to maintain accurate, complete and current records related to investigational product storage, use and disposition is frequently cited in Form 483s and warning letters from the FDA. For example, warning letters have been issued to clinical trial sponsors due to lack of documentation about distribution, return of product from study subjects and final disposition of the drug. Other common citations include failure to ship investigational products only to qualified investigators participating in a given clinical trial (e.g., shipping directly to patient homes).
Something as simple as the lack of a central, controlled storage location could lead to a warning letter. For example, one investigator received a warning letter because the product was stored in various locations with uncontrolled access, meaning that non-trial staff could gain access to it. Warning letters to investigators have also cited failure to label a drug as investigational, as required under federal regulation.
Investigators under FDA inspection are not required to divulge subject names unless the records of individual subjects require a more detailed review or, according to the agency, “there is reason to believe that the records do not represent actual case studies or do not represent actual results obtained.”
Read the ASHP guidelines here: https://bit.ly/2u3B2ZL.