5. Investigator and Investigational Product

5.1 Does local regulation require PI/CI to be approved/registered by any health authority (e.g., RA/EC)?

Whilst we have not been able to formally identify that a PI/CI is required to be approved/registered by any regulatory authority, 21CFR312.53 (a) indicates the following: 

“(a) Selecting investigators. A sponsor shall select only investigators qualified by training and experience as appropriate experts to investigate the drug.” 

In the United States, medicine is a licensed profession regulated by the individual states. One of the most important functions of the nation’s state medical boards is issuing licenses to physicians. Through licensing, state medical boards ensure that all practicing physicians have appropriate education and training, and that they abide by recognized standards of professional conduct while serving their patients. Therefore, investigators must hold medical licenses for all the states where they will see study participants, investigators holding multiples licenses is normally the requirement for DCT studies to allow investigators to cover more than one state.

5.2 Does local regulation require any specific documents if PI/CI is based outside the country?

We have been unable to determine any specific regulations or guidance covering foreign-based principal investigators (please see Section 5.1 above), but to the best of our knowledge, a PI/CI cannot be based outside the U.S. for trials within the U.S.

5.3 Does local authority allow electronic ICF administration, including electronic signatures?

Yes, the FDA Guidance “Use of Electronic Informed Consent in Clinical Investigations – Questions and Answers Guidance for Institutional Review Boards, Investigators, and Sponsors” (December 2016). 

See also 21CFR11, which includes the statement: “Where electronic signatures and their associated electronic records meet the requirements of this part, the agency will consider the electronic signatures to be equivalent to full handwritten signatures, initials, and other general signings as required by agency regulations, unless specifically excepted by regulation(s) effective on or after August 20, 1997.” The general requirements for electronic signatures are set out in 21CFR11. 

5.4 Does local regulation require ICF to be administered as audio/visual and do these need to be recorded?

No, there is no absolute requirement from the FDA to do so, but the FDA has issued guidance - “Use of Electronic Informed Consent in Clinical Investigations – Questions and Answers Guidance for Institutional Review Boards, Investigators, and Sponsors” (December 2016) - which allows for audio/visual administration. See below some extracts: 

“Q7. What methods may be used to verify the identity of the subject who will be electronically signing an eIC for FDA-regulated clinical investigations? 

Compliance with the requirements in Part 11 is meant in part to prevent fraudulent use. Therefore, the regulations found in 21 CFR part 11 require that an organization verify the identity of an individual before it establishes, assigns, certifies, or otherwise sanctions an individual’s electronic signature or any element of such electronic signature (see 21 CFR 11.100(b)).

FDA regulations do not specify any particular method for verifying the identity of an individual and accept many different methods. For example, verifying someone’s identity can be done by using information from some form of official identification, such as a birth certificate, government-issued passport, or driver’s license. In addition, the use of security questions to confirm an individual’s identity can also be considered."

And:

“Q4. What steps may be taken to facilitate the subject’s understanding of the information being presented? 

To assist the subject in understanding the material, the eIC may use interactive electronic-based technology, which may include diagrams, images, graphics, videos, and narration. The eIC should be appropriate for the intended audience, taking into consideration the subject’s age, language, and comprehension level.

The eIC may contain various methods to help an investigator assess the subject’s understanding of the information being presented during the eIC process. For example, the eIC may include optional questions at any time during the eIC discussion that can be used to help educate the subject about the information presented, as well as assess the subject’s understanding of the informed consent materials. Such optional questions and other methods may be used as tools to gauge subject comprehension of key study elements and highlight areas where the subject might need further explanation and discussion before signing the informed consent to enter the study.”

5.5 Is there any specific information/requirement on data capture/management (e.g., privacy regulations, etc.)?

The FDA published the final guidance entitled “Digital Health Technologies [DHTs] for Remote Data Acquisition in Clinical Investigations. Guidance for Industry, Investigators, and Other Stakeholders” (December 2023). This guidance provides recommendations for ensuring that a DHT is fit-for-purpose and highlights the Privacy-Related Risks considerations when using Digital Health Technologies:

“Privacy-Related Risks 

Sponsors, investigators, and IRBs should be aware that unique privacy risks may arise when DHTs are used in a clinical investigation. The following should be considered, as applicable: 

• The risk of potential disclosure of personally identifiable information or participant locations via a breach of the DHT or associated data storage, such as a durable electronic data repository. 
• DHTs or other technologies may have end-user licensing agreements or terms of service that allow sharing of data with other parties, such as the manufacturer of a general-purpose computing platform used by a DHT. See section IV.F.3 of this guidance for considerations related to informing potential trial participants about who will have access to their trial data if they decide to participate. 
• To protect data privacy for trial participants, it may be appropriate for sponsors to proactively work with manufacturers to modify the end-user license agreement or terms of service for the purposes of the study, as applicable. 
• Sponsors should ensure that appropriate security safeguards are in place to secure data at rest and in transit to prevent access by intervening or malicious parties (e.g., cybersecurity threats). “

Section G-Provides FDA’s expectation for “Record Protection and Retention”:

“When using DHTs to record and transmit data during a clinical investigation, the relevant data captured from the DHT, including all relevant associated metadata, should be securely transferred to and retained in a durable electronic data repository as part of the record of the clinical investigation. FDA regulations include record retention requirements for clinical investigators and sponsors and provide for FDA inspection of certain records relating to a clinical investigation.” 

The FDA has also published draft guidance entitled “Electronic Systems,  Electronic Records and Electronic Signatures in Clinical Investigations Questions and Answers.  Guidance for Industry (March 2023) which provides useful context and additional clarifications.

5.6 If a clinical study involves the study product as OTC and this is provided via pharmacy/amazon, etc., are there any specific regulations for IP management that need to be followed?

It all depends how the OTC product is going to be used in the clinical trial.

If the OTC is going to be used as comparator under the IND, it will require the same labeling requirements as the investigational product (see FDA remarks on active-control design). 

In May 2023, the FDA released for public comment the DRAFT Guidance “Decentralized Clinical Trials for Drugs, Biological Products, and Devices”. Within this guidance, Section F- Investigational Products in a DCT, Section 1- Drug and Biologics, indicates the following:

An investigator must administer an IP only to participants under the investigator’s personal supervision or under the supervision of a sub-investigator responsible to the investigator. The nature of the IP should be considered when determining whether administration outside of a clinical trial site in a DCT is appropriate. IPs that involve complex administration procedures; have a high-risk safety profile, especially in the immediate post-administration period; or are in early stages of development such that the safety profile is not well defined may need in-person supervision by the investigator at a trial site. 

For IPs for which the safety profile is well-characterized and that do not involve specialized monitoring during the immediate period following administration, it may be appropriate for local HCPs or trial personnel working remotely to administer the IP at local health care facilities or participants’ homes. Hybrid DCTs may be designed for drugs that require supervised but infrequent (e.g., monthly) administration when administration can be done at trial sites with follow-up done remotely. 

Depending on the safety profile of the IP (e.g., a class of drug with a risk of hypersensitivity, abuse potential) and the type of trial (e.g., dose escalation trial), sponsors should estimate the urgency and complexity of care that may be needed based upon risks related to the IP and the participant’s underlying condition. Investigators should take steps to help ensure that participants have access to an appropriate level of local care. 

Drugs best suited for direct shipment to the participant’s home include those with long shelf lives and those with good stability profiles. Drugs that involve specialized handling, shipping, and storage conditions may not be suited for direct shipment to locations outside the trial site.

5.7 For a marketed study product/OTC, can a participant be compensated after confirmation of the purchased study product, or upfront prior to product acquisition? Does compensation in any way impact how the study is viewed (i.e., RWE vs. Interventional Study)?

In broad terms, the FDA would not object to a clinical subject’s commercial procurement of (and compensation for the cost of) a study product, subject to labeling and blinding concerns being suitably addressed.

In February 2024, the FDA released the Guidance for Industry “Charging for Investigational Drugs under an IND- Q&As”. This guidance provides information about the implementation of FDA’s regulations on charging for investigational drugs under an IND within a question and answers format, see below:

“Q10. If a sponsor’s own approved drug is used as concomitant therapy for an approved use during a clinical trial intended to evaluate another drug, is the sponsor required to obtain authorization to charge for the drug used as concomitant therapy?

No. In many clinical trials, approved drugs are used as concomitant therapy for subjects during the trials but are not part of the clinical trial evaluation. For example: 

• Patients may be required by a protocol to take certain approved drugs as concomitant therapy before or during the trial (e.g., patients may receive antihistamines for immune response concerns in a clinical trial to study a recombinant protein, in order to mitigate potential risks of participation in the trial; or all patients may receive concomitant therapy before randomization to either the investigational drug or placebo).
• Patients may be permitted by the protocol to continue taking certain approved drugs as concomitant therapy during the trial because such drugs are not likely to interact with the study drug or drugs or otherwise confound the results of the trial (e.g., pain medications for patients in a clinical trial to study a drug intended to treat cancer) or because discontinuing the drug might adversely affect the patient. 

In accordance with § 312.8(b)(1), a sponsor must obtain prior authorization from FDA to charge for its investigational drugs, including investigational uses of its approved drugs. However, FDA regulations do not require a sponsor to obtain prior authorization to charge for its own approved drug when that drug is used as concomitant therapy for an approved use and is not part of the clinical trial evaluation (i.e., the approved drug itself is not being evaluated for an investigational use).

Overall, sponsors will require FDA authorization to charge for some investigational products. However, for sponsor’s own approved drug when these are used as concomitant therapy for an approved used and have been purchased by the participant, it may be under the sponsor’s discretion to reimburse the cost. This type of information must be clearly indicated within the participant information sheet.

5.8 Is it permitted to pay participant stipends (i.e., is it permitted to pay the patients for their participation in the clinical trial)? If so, what is the average range?

Yes – the FDA has published an “Information Sheet. Payment and Reimbursement to Research Subjects Guidance for Institutional Review Boards and Clinical Investigators” (January 2018). 

No range is given for payments, but the sheet includes the following statement:

“FDA recognizes that payment for participation may raise difficult questions that should be addressed by the IRB. For example, how much money should research subjects receive, and for what should subjects receive payment, such as their time, inconvenience, discomfort, or some other consideration. In contrast to payment for participation, FDA does not consider reimbursement for travel expenses to and from the clinical trial site and associated costs such as airfare, parking, and lodging to raise issues regarding undue influence.  Other than reimbursement for reasonable travel and lodging expenses, IRBs should be sensitive to whether other aspects of proposed payment for participation could present an undue influence, thus interfering with the potential subjects’ ability to give voluntary informed consent. Payment for participation in research should be just and fair. The amount and schedule of all payments should be presented to the IRB at the time of initial review. The IRB should review both the amount of payment and the proposed method and timing of disbursement to assure that neither are coercive or present undue influence.”

5.9 Specific labeling requirements for clinical study product

21CFR312.6 sets out the following labeling requirements:

"(a) The immediate package of an investigational new drug intended for human use shall bear a label with the statement “Caution: New Drug - Limited by Federal (or United States) law to investigational use.” 

(b) The label or labeling of an investigational new drug shall not bear any statement that is false or misleading in any particular and shall not represent that the investigational new drug is safe or effective for the purposes for which it is being investigated." 

….

In addition, the FDA’s guidance document entitled “E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) (March 2018)” states that the IP must be coded and labeled in a manner that protects the blinding, if applicable. The IPs must also be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage.

5.10 What documents need to be submitted (including relevant fee if any), and to whom, if a permit is needed for an investigational/study product being shipped from outside the country? Are there any specific requirements for biologics?

21CFR312.110 - Import and export requirements: once the investigational new drug application (IND) is in effect, import of the investigational product is permitted into the U.S.

“Imports. An investigational new drug offered for import into the United States complies with the requirements of this part if it is subject to an IND that is in effect for it…. and: 

1. The consignee in the United States is the sponsor of the IND; 
2. The consignee is a qualified investigator named in the IND; or 
3. The consignee is the domestic agent of a foreign sponsor, is responsible for the control and distribution of the investigational drug, and the IND identifies the consignee and describes what actions, if any, the consignee will take with respect to the investigational drug.”

Please also refer to Section 4.2 of this guidebook.

There are no specific requirements for biologics that we have been able to determine.

5.11 What is the turn-around time to get an import permit?

There is no import permit required, that we have been able to determine. The IND acts as a waiver; an IP may be imported into the US if it is subject to an IND that is in effect for it and complies with one (1) of the following requirements (see 21CFR312.110):

• The IP consignee is the IND sponsor, or
• The consignee is a qualified investigator named in the IND, or
• The consignee is the domestic agent of a foreign sponsor, is responsible for the control and distribution of the IP, and the IND identifies the consignee and describes what actions, if any, the consignee will take with respect to the IP.

5.12 Does local authority allow the destruction of clinical supplies at an off-site location (e.g. third-party vendor in or outside the country) after study completion? Are certificates of destruction required?

FDA regulations outline sponsor and investigator responsibilities for storage conditions and accountability of investigational drug products, including disposition of unused investigational products (IPs). Under 21 CFR 312.59, the sponsor shall assure the return of all unused supplies of the investigational drug from each individual investigator. The regulation further provides that the sponsor may authorize alternative disposition of unused supplies of the investigational drug provided this alternative does not expose humans to risks from the drug. The sponsor shall maintain written records of any disposition of the drug in accordance with § 312.57.