What is Clinical Hold and how do you deal with it?

A clinical hold is an order issued by a regulatory body to suspend or restrict a clinical study related to a particular drug product. The regulatory body may force a clinical hold due to many reason, such as  issues with the study, product, or researcher.

 A clinical hold is implemented for an Investigational New Drug - IND. It is a drug stage under clinical trials to investigate its efficacy & safety, and has not been officially allowed to market & used by patients.

In the event of a clinical hold, the party may respond to the clinical hold, which is evaluated by the regulatory body. Depending upon the response, the body may decide to lift the hold or not.

Clinical hold plays a critical role in drug development by allowing the investigator more time to remediate the issues found at that stage. It also helps to reduce the underlying risks by preventing the participants from harmful impacts of investigative drugs until rectified and reduced.

The agency may use the telephone or other rapid mode of communication to convey the order of  hold. The order will include studies under hold and the reason for such a decision.

Types of Clinical Hold

There are two types of clinical gold - Complete and Partial.

In complete clinical hold, the agency holds the entire clinical activity, and no part is allowed to be proceed in any of it's stage. It is when an agency finds discrepancies in the whole clinical studies not fit and  dangerous for human health.

In partial clinical hold, the agency holds part of the entire clinical study. The other parts of the clinical research are allowed to continue.  

Reasons for Clinical Hold

Let's discuss some common reasons behind pharmaceutical clinical hold

Safety risks to human participants

One basic reason for clinical hold is  risk to the human participants involved in the clinical studies. If the drug product poses significant dangers to human health or life, a regulatory agency imposes a clinical hold.  Because, researchers are ethically bound to protect the health of human participants  and is considered a failure of the Institutional Review Board - IRB.

For example, in a certain study, if more than a specific number of participants face fatal bleeding, the agency can clinically hold the research until proper mechanisms and appropriate corrective measures are performed and then approved.

Incompetence of the clinical investigator

The clinical investigator is a person under the guidance of which clinical studies are performed. It is their responsibility to execute the activity according to the agreed specifications.

If there is any deviation in the study at any stage, the clinical investigator is held responsible. Additionally,  non - compliance and misconduct by any participant is also considered incompetency of the clinical investigator

If a regulatory agency finds such deviation related to an investigator, it can impose a clinical hold.

In addition to the reasons mentioned above, other  are also possible, that can include but limited to the following.

● Failure to report adverse events

● Protocol violations, such as enrolling participants that do not meet the acceptance criteria

● Failure to carry out safety evaluations for the participants

● Failure to obtain adequate informed consent

● Deliberate manipulation or alteration during a research study indicating the safety of the drug under trial

● Failure to obtain IRB approval when a change in protocol is required.

The investigator brochure is misleading, erroneous, or materially incomplete.

An investigator brochure is the clinical and non-clinical data about the drug being investigated, and it aims to provide information to the investigator and other people involved with all critical  information about the drug, such as dose, dose frequency, administration method, and safety monitoring procedures.

The regulator can impose a clinical hold on a clinical study if it finds out that the investigator's brochure does not include all or correct information. The information contained is incomplete or erratic that can make clinical trials useless

Because error in the investigator's brochure would put the well-being of the human participants at risk of illness, and it also might get serious.

The IND application does not contain sufficient information needed to assess the risks to subjects of the proposed studies.

An Investigational New Drug -IND application to the US FDA,  before conducting clinical trials of an investigational drug is required for the sponsor or drug developers to submit. It includes critical information about the drug, such as preclinical data, CMC, and protocol.

An agency can impose a clinical hold if the developer fails to include all necessary information in the IND.

The information should include the proof indicating sufficient corrective measures have been placed to protect the human participants in the clinical trials.

The investigational Drug product has a risk of reproductive toxicity

Reproductive toxicity is a condition when any drug affects the reproductive health of both males and females. It  affects the ability of both to give birth to a child.

A regulatory body can issue a clinical hold for a drug under investigation if a specific group of humans is excluded from the study due to reproductive toxicity. Because eliminating such human groups indicates that the drug under investigation poses risks to the reproductive health of the participants.

What to do when a Clinical Hold is imposed?

When an IND receives a clinical hold, the sponsor or investigator is responsible to remove the clinical hold.  

The FDA guidance,  "Guidance for Industry Submitting and Reviewing Complete Responses to Clinical Holds." provides detailed guidelines to follow in order for the regulatory agency to further process the matter

Let's get a brief of what's inside these guidelines.

● When the decision to hold a study has been made and communicated to the investigator, the research cannot be continued until allowed by the agency.

● Within 30 days of the action, the agency sends the clinical hold letter, authorized & signed by the Division Director or Acting Division Director, describing the reasons for the clinical hold. The letter also includes the name of the responsible FDA contact.

● If the agency determines that it will not meet the 30-day review time, it will inform you and discuss the review date.

● The FDA, in its letter, also discusses non-hold issues, i.e., that are other than clinical hold, which is indicated in a separate section and clearly marked.

● When the sponsor addresses all issues indicated in the letters, the agency will respond within 30 days, that begin after the agency has received a complete response.

● The FDA will measure the Prescription Drug User Fee Act according to the secretary's letter to Congress based on the agency's response to the sponsor's complete response to clinical hold based on commercial INDs

● If the clinical hold were initiated prior to the issuance of this guidance, it would also be handled according to the issuance of this guidance.

● The response to the hold letter should not include other non-hold issues. I you want to respond to these issues, use a separate letter or communication.

● In the cover letter of the letter, indicate that you have included all of these issues raised by the agency, with bold letters at the top: "CLINICAL HOLD COMPLETE RESPONSE."

● It is the responsibility of the sponsor to ensure that the response letter reaches the agency in a timely manner by faxing a copy of the letter to the FDA contact responsible indicated in the clinical hold letter. Additionally, the response should be submitted in triplicate to the agency.

● If the FDA finds out that the response is incomplete, it will inform you as soon as possible, by phone or other rapid mode of communication, not later than 30 days after receiving your letter. In it, the agency will indicate the information required by the IND applicant.

● If the agency receives the complete response, it will review your application. After careful review,  it will respond to the applicant , which can indicate the following

○ Allowed to proceed under IND ( i.e. hold is completely lifted)

○ Allowed to proceed with restrictions, and the reason for this decision  (i.e. partial hold)

○ indicating that the hold is not lifted, and the reason for this decision

FDA Guidelines

Let's discuss some relevant FDA guidelines for clinical hold

312.42 Clinical holds and requests for modification.

The CFR 21 312.42 provides guidance about the clinical hold and how it can be managed. In it, the FDA addresses issues such as

● General definition

● Grounds for imposition of clinical hold

● Deficiency statement

● Clinical hold imposition

● Resuming Clinical activities

● Appeal

● Conversion of on-hold to inactive status

Guidance for Industry Submitting and Reviewing Complete Responses to Clinical Holds

In these guidelines, the FDA provides guidance about submitting responses to the clinical hold letter. It provides basic guidelines for the sponsors or IND applicants to follow steps, and it covers issues such as

● What happens in case of a clinical hold decision by the agency

● Measuring PDUFA goals on clinical hold

● Holds prior to issuance of this guideline

● Addressing non-hold issues

● Other related issues

● How to make timely delivery

● FDA disagreement

● Requirement of additional information

● What to expect when the agency receives a complete response