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Drug Safety and Tissue-Based

In February, FDA released a draft guidance with the long title of: “Investigating and Reporting Adverse Reactions Related to Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) Regulated Solely under Section 361 of the Public Health Service Act and 21 CFR Part 1271.

This is a guidance that FDA issued to assist companies that make human cell, tissue and cellular and tissue-based products (HCT/Ps) in complying with the safety reporting in 21CFR1271 for clinical trials. The safety regulations are short and are found in 21CFR1271.350.

These regulations are separate from those for drugs, devices and other biological products and cover products which don’t fall in these other categories.

Nevertheless, this document, or this blog, is worth a quick review even for those in the PV world who do not handle such products. Why? Because these rules are similar but newer than the drug/biologic/device rules but may give us an idea of how safety handling is evolving in FDA’s eyes. We may be seeing here the “wave of the future” of drug, biologic and device safety reporting. So they are worth reviewing to see where we may be heading.

The CFR section covering these products is complex and covers many aspects of HCT/Ps including registration of the products, donor eligibility and “Good Tissue Practices.” The reader is referred to this document and the CFR for full details. We will focus here on the safety aspects that the draft guidance discusses. There are significant differences from the regulations for drugs.

Adverse Reaction (AR)

An “adverse reaction” is defined as a noxious and unintended response to any HCT/P for which there is a reasonable possibility that the HCT/P caused the response. This is different from drug regulation definition of an AR.

The closest equivalent we have in the drug regulations for clinical trials is: “Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, “reasonable possibility” means there is evidence to suggest a causal relationship between the drug and the adverse event. Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug.”

Comment: Note the difference in wording. The HCT/P is presented more as a “noxious and unintended response”. Compare this to a drug adverse event: “any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related”. See 21CFR312.32. Interestingly, the word medical does not appear in the HCT/P definition. A nuance of difference.

“Unlikely” is considered “possibly related”

A very interesting point that differs from many people’s interpretation of drug AEs/ARs is noted regarding “unlikely” events for HCT/Ps: A reportable AR may have many causes and this “would include situations in which the relationship between the response and the HCT/P is “unlikely” but nevertheless reasonably possible.” That is, “Unlikely” is interpreted as possible or reasonably possible. Many in the drug world take “unlikely” to be “unrelated”. This is a critical distinction in the drug world as many people would consider “Unlikely” to be “Unrelated” and thus a serious AE that is unlabeled would not be an expedited (7 or 15 day) report. Here, in the HCT/P world it would be expedited.

Investigate and Report

Certain ARs must be investigated “as soon as practical”. The ARs that should be investigated are those that involve a communicable disease and are fatal, life threatening, result in permanent impairment of a body function or permanent damage to body structure or necessitate medical or surgical intervention including hospitalization.

The establishment that made the product available for distribution must report these ARs to FDA within 15 calendar days of receipt. Follow-ups also follow the 15 day rule. If no follow up information is obtainable, there must be a follow-up report to FDA describing the steps taken to get additional information and why it could not be gotten.

As part of the guidance, FDA lists key data to obtain in the investigation:

They note that “diligent efforts” should be made though this is not defined. Of course, all efforts – successful or not – should be noted in writing.

The information on the donor eligibility determination should also be reviewed and verification that screening and testing were done in accordance with the regulations should also be done.

Information on the recovery (where possible) of the product should be included.

Information on the “processing” of the HCT/P should be done including testing for microorganisms, sterilization etc. See the guidance for full details.

Information on the storage information, environmental controls and monitoring information should also be cone including temperature and humidity controls, ventilation, work surfaces, sinks and drains etc.

Microbiology information including the types of organisms, whether the some ones found associated with the HCT/P were found in the environment etc.

Comment: This is very specific. FDA does not really give this level of specific information on what should be obtained in follow up for drug AEs.


A “record of complaints” for the product must be kept. This is, in effect, the database.

Comment: Since safety reports to the FDA must be reported on MedWatch forms (3500A) and, likely at some point in the future, electronically, one of the standard electronic safety databases should be used. A spreadsheet is probably not enough to produce MedWatch reports and track complex data, notifications to other institutions etc.

Labeling and Signaling

FDA also wants the reviewer to look at the product labeling to see if it is appropriate and whether changes are needed. It should be reviewed as part of the investigation to see if other similar or relevant complaints have been received. The word “signaling is not used but it is implied.

Sharing Information

FDA recommends the HCT/P equivalent of investigator notification. FDA states: “We recommend that the shared information include any pertinent information that you have collected from your investigation of an adverse reaction and note that these procedures can be designed so that patient confidentiality is not compromised. Sharing this information should assist other establishments in taking appropriate action(s). We also recommend that you seek information regarding any complaints that the other establishments who have recovered or performed manufacturing steps on HCT/Ps from the same donor may have received related to those HCT/Ps.” This is a complex statement and means proactive requests in the notification are to be made in order to seek out similar problems. This is well beyond what is required for investigator notification in clinical trials.

Complex Situations

FDA addresses the situation where the HCT/P is not regulated as an HCT/P but rather as a drug, device or biologic. In this case, FDA refers the reader to the appropriate safety reporting in the drug, device and biologic sections of the CFR. That is, these are handled as drugs, devices or biologics and not HCT/Ps.

Submission is done on a MedWatch (3500A) form to CBER.

What does FDA do after it receives the report?

FDA refers the reader to the CBER SOP on HCT/Ps. This is worth the read if you are involved in this field.

The rest of the guidance covers, field by field, how to fill in the MedWatch form.


This is a clear and well written draft guidance which covers the handling of certain HCT/P reports. Comments from the public can be submitted to the address noted on the first page of the guidance.

What lessons can we draw from this for the future? I would suggest the following:

So to conclude, this document represents FDA’s current thinking on ARs to HCT/Ps. Does it also represent the path FDA will eventually take for drugs, biologics and other products? We shall see.



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