Investigational product documentation
An investigational product is the medicine or placebo that a clinical trial tests or uses as a reference. ICH E6(R3) sets out who is responsible for it, how it should be accounted for, handled, stored and labelled, how its blinding should be kept and broken, and how it may reach the participant's location.
What counts as an investigational product
ICH E6(R3) defines an investigational product as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial. This includes a product with a marketing authorisation when it is used or assembled (formulated or packaged) differently from the approved form, when it is used for an unapproved indication, or when it is used to gain further information about an approved use. Investigational products should be considered synonymous with drugs, medicines, medicinal products, vaccines and biological products.
ICH E6(R3) defines a comparator as an investigational or authorised medicinal product (that is, an active control), a placebo or standard of care used as a reference in a clinical trial.
Who is responsible for the product
Responsibility for managing the investigational product, including its accountability, handling, dispensing, administration and return, rests with the investigator or institution. The sponsor may facilitate aspects of that management, for example by providing forms and technical solutions such as computerised systems, and by arranging distribution of the product to participants. Where the investigator or institution delegates some or all of these activities to a pharmacist or another individual in accordance with local regulatory requirements, that individual should be under the investigator's or institution's oversight.
Where activities have been delegated, or the sponsor has facilitated aspects of them, the level of the investigator's oversight depends on factors that include the characteristics of the product, the route and complexity of administration, the level of existing knowledge about the product's safety, and its marketing status. Annex 2 of ICH E6(R3) says the investigator should maintain appropriate oversight of the activities related to product management and ensure that appropriate documentation is maintained, and it names the trial design among the factors on which the level of that oversight depends, alongside the characteristics of the product, the route and complexity of administration, the level of existing knowledge about its safety, and its marketing status. The activities under the investigator's oversight should include, but are not limited to, the participants' receipt, use and return or alternative disposition of the product, where appropriate, and the commencement, continuation, dose and dose adjustments of the allocated product as the protocol specifies. An appropriate designee of the participant may undertake the receipt and the return or alternative disposition.
The sponsor is responsible for supplying the investigators and institutions with the product, and where appropriate it may supply the participants, in accordance with applicable regulatory requirements. The product should be supplied after the required approval or favourable opinion has been obtained from the ethics committee and the regulatory authority for the trial. The sponsor should ensure timely provision of the product to investigators or, where appropriate and in accordance with applicable requirements, to participants, so that the trial is not interrupted and participants' treatment continues. Various approaches to shipping and dispensing may be taken, considering, for example, the product's characteristics, the route and complexity of administration and the level of existing knowledge about its safety profile. Product management should be arranged and conducted in accordance with applicable regulatory requirements, with safeguards in place to ensure product integrity, product use per protocol and participant safety.
Accountability records
The investigator or institution, or a pharmacist or other appropriate individual, should maintain records of the product's delivery, the inventory, the use by each participant, including documentation that participants were provided the doses the protocol specifies, and the return to the sponsor and destruction or alternative disposition of unused product. These records should include dates, quantities, batch or serial numbers, expiration dates where applicable, and the unique code numbers assigned to the products and to the participants. For authorised medicinal products, alternative approaches may be considered in accordance with local regulatory requirements.
Depending on applicable requirements, documentation and processes the institution or healthcare centre already uses may be sufficient for managing the product. For example, existing standard pharmacy practices for product accountability, and the records of storage conditions a pharmacy keeps routinely, may be appropriate.
The sponsor should:
- maintain records of the identity, shipment, receipt, return and destruction or alternative disposition of the product
- maintain a process for retrieving the product and documenting the retrieval, for example for a deficient product recall, for return and destruction or alternative disposition after the trial, or for reclaiming expired product
- maintain a process for the disposition of unused product and for documenting that disposition
- take steps to ensure the product is stable over the period of use and used only within its current shelf life
- keep sufficient quantities of the product used in the trials to reconfirm specifications should that become necessary, and maintain records of batch sample analyses and characteristics
Samples of the product should be retained until the analyses of the trial data are complete or for as long as applicable requirements demand, whichever is longer. Where an authorised medicinal product is used as the investigational product unmodified from its authorised state, the sponsor may not need to keep samples, in accordance with local requirements, and the manufacturer typically keeps them.
Handling, storage, manufacture and labelling
The sponsor should ensure that instructions on handling and storing the product are available to the investigator, institution or participants. Those procedures should consider adequate and safe receipt, handling, storage and dispensing, the retrieval of unused product from participants, and the return of unused product to the sponsor, or its alternative disposition if the sponsor authorises it and applicable requirements permit.
The sponsor should determine acceptable storage temperatures, storage conditions such as protection from light, and shelf life for the product, as well as appropriate reconstitution fluids and procedures and any devices for administering it. It should inform all involved parties, such as monitors, investigators, pharmacists and storage managers, of these determinations. The product should be packaged to prevent contamination and unacceptable deterioration during transport and storage.
The product should be stored as the sponsor specifies and in accordance with applicable regulatory requirements, and the investigator should ensure it is used only in accordance with the approved protocol. Where applicable, the investigator or a person the investigator or institution designates should explain its correct use to each participant and check, at intervals appropriate for the trial, that each participant is following the instructions properly.
The sponsor should ensure that the product, including active controls and placebo where applicable, is characterised as appropriate to its stage of development, manufactured in accordance with any applicable good manufacturing practice, and coded and labelled in a manner that protects the blinding where applicable. The labelling should also comply with applicable regulatory requirements.
If significant formulation changes are made to the product, including active controls and placebo where applicable, during clinical development, the results of any additional studies of the formulated product needed to assess whether the changes would significantly alter its pharmacokinetic profile, such as studies of stability, dissolution rate or bioavailability, should be available before the new formulation is used in clinical trials.
Blinding and unblinding
In blinded trials, the sponsor should implement:
- a process to blind individuals, including sponsor staff, participants, investigators and site staff as appropriate, to the product's identity and assignment, and a process to prevent and detect inappropriate unblinding
- a procedure and mechanism that lets the investigator identify the product rapidly in a medical emergency where unblinding is considered necessary, while protecting the treatment assignment of the other participants
- a mechanism that protects the blinding of the trial where a participant's treatment assignment is unblinded for safety reporting to regulatory authorities or the ethics committee, where appropriate
The investigator should follow the trial's randomisation procedures, if any, and in an investigator-blinded trial should ensure that the treatment randomisation code is broken only in accordance with the protocol. To protect participant safety in an emergency, the investigator should be prepared and capable from the start of the trial to unblind without undue delay or hindrance. The investigator should promptly document and explain to the sponsor any premature unblinding, such as accidental unblinding, emergency unblinding to protect a participant, or unblinding due to a serious adverse event.
Supply to the participant's location
The product may be shipped to the participant's location or supplied to or dispensed at a location closer to the participant, such as a local pharmacy or a local healthcare centre. It may be administered at the participant's location by site staff, the participant, a caregiver or a healthcare professional. Annex 2 of ICH E6(R3) says the product may be dispensed or supplied to the participant or to an appropriate designee, such as a caregiver, a home nurse or a local pharmacist, for administration at the participant's location, such as their home or a local healthcare centre, by appropriate parties, such as site staff, the participant, a home nurse or a local pharmacist.
The investigator or institution may arrange to send the product to the participant, following the sponsor's documented instructions where applicable and in compliance with applicable regulatory requirements. When the product is shipped to a participant, the following should be considered:
- the process for protecting the privacy and maintaining the confidentiality of the participant and their disease status
- that the product is being received by the intended recipient, that is, the participant or an appropriate designee such as a caregiver
- the process for the receipt, storage, handling, administration, return, destruction or alternative disposition and accountability of the product
- the process by which blinding is protected, where applicable
- the availability of participant support tools, such as online tutorials, information brochures, visual aids and contact details for support, such as technical support
Where applicable regulatory requirements permit, the sponsor may arrange to send the product to the participant. In that case:
- the investigator or institution retains responsibility for the safe and appropriate use of the product for participants under their care
- the investigator should be aware of the shipping arrangements and remain informed of the product's receipt and use and of any participant-reported issues and their resolution
- the roles and responsibilities of the sponsor and the investigator should be clearly documented
- there should be clear communication and predefined procedures between the sponsor, the investigator and any service provider involved in the shipping
The sponsor should assess its approach to product management during protocol development. The assessment should consider, for example, the product's stability and any need for specialised storage conditions, the preparation needed for administration such as complex reconstitution or administration, and the route of administration. It should also consider the trial population, what is known of the product's safety profile, the need for in-person clinical observation immediately after administration, the measures needed to protect blinding where applicable, and the need for emergency plans related to administering the product, such as a requirement for rescue medication. A shipment the sponsor arranges should be carried out in accordance with the protocol, and the sponsor should ensure it is initiated after the investigator has authorised it. The sponsor may deploy systems, such as interactive response technology or digital health technologies, and help the investigator establish processes, such as home nurse visits, to ensure that the allocated product was delivered and administered appropriately.