This guidance covers the use of investigational drugs, drugs approved by the U.S. Food and Drug Administration (FDA) that are being researched for new indications or in new populations, and Schedule IV drugs that may be regulated by the Drug Enforcement Agency (DEA) as well as or instead of the FDA.
In cases of drugs that are regulated by the DEA, there may be additional requirements included in the license that go above and beyond what is described in HRPP guidance.
Both state and federal regulations regarding the distribution, dispensing and administration of drugs are applicable to research studies involving drugs and medications. Federal law establishes the requirements with which all facilities and individuals must comply. However, similar to most other states, Rhode Island state law legislates and promulgates more restrictive requirements that establish the minimum standard of practice with which compliance is required. Any licensed practitioner, including those involved in research studies and/or PIs who handle drugs either by distribution, dispensing or administration, must comply with these minimum standards.
Federal and Rhode Island state laws that are applicable to activities related to drug procurement, distribution and dispensing include, but are not limited to the following.
In accordance with federal and state regulations, study investigators must establish procedures for drug management that include all of the following elements:
Any authorized licensed person or entity — physician, nurse practitioner or pharmacy — may order study drugs from the manufacturer or wholesaler. If study personnel are responsible for ordering the drug, best practice is to arrange for the drug to be drop shipped to the contracted pharmacy. Alternatively, study personnel may transport the study drug to the pharmacy or the pharmacy may utilize a courier to pick up the drug from the study site.
To maintain proper chain of custody, transfer documentation should include the following information:
If the pharmacy is procuring the study drug, the invoice must be for the study drug exclusively, and must indicate the IRB protocol number and institution/PI conducting the study. Copies of the signed transfer document must be maintained by the PI and the pharmacy.
The pharmacy and investigator must ensure that the following information is available from the manufacturer or wholesaler:
A complete current copy of the research protocol should be supplied to the pharmacy.
Storage requirements for drugs are referenced in the U.S. Pharmacopeia. Individuals responsible for handling drugs are required to maintain environmental controls during the transport and storage of the drugs. Study drugs that are to be shipped off site for a protocol must be packaged in containers that maintain the proper storage conditions during transport. Chain of custody and maintenance of proper storage conditions during transport should be documented. Study drugs should be stored in a limited-access location. Proper storage conditions should address the temperature, light, moisture, ventilation and sanitation needs of the product. Documentation of systematic recording of key environmental conditions should be maintained during the entire storage timeframe.
If the drug is a controlled substance, the item must be stored in a securely locked, substantially constructed cabinet to which access is limited to individuals with dispensing or administration responsibilities. Any facility that stores controlled substances on site must obtain a federal DEA registration and Rhode Island Controlled Substance Registration. PIs planning to obtain controlled substances for their research for the first time are encouraged to contact HRPP staff for further guidance and assistance related to DEA registration and licensing.
The PI is responsible for establishing and implementing procedures for the control of drugs. A copy of the IRB-approved research protocol, study procedure manual and all amendments should be maintained at the institution and/or pharmacy. The research study is also responsible for creating and maintaining an adequate drug information/reference sheet. This sheet should be prepared for all study staff and pharmacy staff with responsibility for study drug dispensing and should contain the following, at minimum:
The PI must maintain a system of a detailed inventory record for all study drugs including those transferred and/or received by the study, dispensed to participants, stored at the study site, provided/administered to participants and wasted or disposed of. Inventories and all other records may be stored electronically. Pharmacies participating in the dispensing process must ensure that all documentation will be provided to the study PI at the conclusion of the study and at any other time upon request.
If administration is to occur at the study site, the PI must maintain a log of participant-specific drugs received from the pharmacy and a separate log for administration of the drug to the study subject. Storage and security of investigational drugs must comply with Drug Security and Storage guidelines.
Only an authorized practitioner (physician, physician assistant or nurse practitioner) may prescribe the study drug. Pursuant to state laws, the prescription must include the following elements:
The study drug will be dispensed by a licensed pharmacist. (Medication obtained directly from the manufacturer or wholesaler in prepackaged unit of use containers may be administered on site by a licensed practitioner or his/her delegate, without the pharmacist intermediary.) A delegate may be another person associated with the study who has received appropriate in-study training and guidance from the licensed practitioner.
Prior to dispensing, it is expected that the pharmacy will have been provided with the study protocol, drug information, a valid and complete physician’s order/prescription for each study participant and a list of all medications that the participant is taking, so that the pharmacist may check for drug-drug interactions.
Study drugs must be labeled by the pharmacy, consistent with RI Board of Pharmacy Regulations, as follows:
Pharmacists may fill the prescription with required labeling and deliver the filled prescription to the Brown study site for direct administration by authorized individuals.
The pharmacy must maintain a log for all medications delivered to the study site that includes the following:
A copy of the log must be provided to the study site with the drug. The log must be signed by the PI, physician or delegate who has received the drug and be maintained at the study site and at the pharmacy.
Administration of study drugs directly to patients at the study site must be done by duly licensed individuals or a designated delegate. A physician, physician assistant, nurse practitioner, nurse or authorized delegate must administer the drug from appropriately labeled containers provided by the pharmacy, or unit of use containers labeled by the manufacturer. An administration log for each research protocol must be maintained at the study site. The log must contain the study participant’s name, drug administered, quantity administered, date and name of person who administered the drug.
Study drugs and supplies returned by subjects may not be re-dispensed to other study subjects and must be discarded/disposed of in the manner described in the approved IRB protocol. Containers returned by subjects are to be stored separately from study supplies that have not been dispensed.
Controlled drugs and medications must be managed in accordance with all DEA procedures either for reverse distribution or witnessed destruction. The proper disposal process for the specific drugs and medications used in the research shall be coordinated with the responsible DEA Licensee and documented in your IRB protocol. Disposal of excess and/or unused controlled drugs and medications that are returned to the study site must be done in accordance with Title 21 CFR Section 1300.
Whether the DEA licensee or other study personnel arranges for witnessed destruction or utilizes a reverse distributor, the destruction or transfer must always be documented by the responsible registrant using a Form DEA-41.
If the drugs and medications cannot be reverse distributed or witness destroyed due to the type of experimental process or the final condition of the drugs (e.g., contamination, dilution, spills, etc.), the DEA requires them to be rendered "nonretrievable" at the initial point of waste generation (e.g., by chemical oxidation, thermal treatment, chemical dissociation, etc.).
If you anticipate generating waste containing controlled drugs or medications that cannot be managed through the standard DEA procedures, contact an Environmental Compliance staff member in Brown Environmental Health and Safety (EHS) for assistance determining appropriate methods of rendering materials nonretrievable. The agreed-upon methodology should be included in your IRB protocol. This type of treatment for rendering drugs and medications nonretrievable must also be documented by the registered researcher using a Form DEA-41.
Once the drug is made nonretrievable by the DEA licensee, the resulting waste must be managed through the existing Brown University routine hazardous waste disposal procedures.
When noncontrolled drugs and medications have been obtained through a pharmacy, that same pharmacy may have a procedure in place for accepting the return of the unused supply of drugs and medications for appropriate disposal. If this is the case, the typical procedure is that the pharmacy will receive the returns and arrange for pick-up by a reverse distributor. If this is the procedure to be used, this information must be included in your IRB protocol.
If a pharmacy return system, as described above, is not in place, noncontrolled drugs and medications may require disposal as either hazardous waste or regulated medical waste depending on the drug being used. Contact an EHS Environmental Compliance staff member for assistance determining the proper waste disposal procedures for your noncontrolled drug. The agreed upon waste disposal procedure should be included in your IRB protocol.
Some noncontrolled drugs may meet the definition of a hazardous waste (e.g., nicotine patches, chemotherapeutics, etc.) and must be managed through existing Brown hazardous waste disposal procedures. For assistance with hazardous waste determinations contact Brown Environmental Compliance.
If drugs do not meet the definition of a hazardous waste and do not pose a risk to human health or the environment, then they may be disposed of with the Regulated Medical Waste (otherwise known as the Red Bag Lined Box, or RBLB). Contact Brown’s EHS Biological Safety Officer to request an RBLB pickup or supply delivery.
During a randomized and blinded research study, a situation may arise that requires breaking the blinding code to reveal the identity of the study drug when in the best interest of the study participant. A protocol for this situation must be established by the PI and described in the IRB protocol, addressing the following points:
In general, the code should only be broken in the case of an adverse event in which it is necessary for the PI to know which treatment the patient is receiving before the participant can be treated. The code may also have to be broken if someone not in the study uses the investigational drug (e.g., accidental ingestion by a child) to determine treatment.
The IRB must be notified if the blind is broken and any sponsor notification requirements must also be followed. In the case of emergency treatment, or if a patient’s treating practitioner questions the pharmacy regarding the identification of the study drug, the pharmacy may break the blinding code. If this occurs, the pharmacy shall notify the PI as soon as possible. As referenced above, the PI will provide the pharmacy with a list of medications the subject is taking.
Pharmacies utilize a computer software program that provides a system for screening for drug interactions. If a significant drug interaction is detected, the pharmacy will notify the PI prior to dispensing the product.