Research
What a combination product has to report
When one product is a drug and a device at the same time, two harm-reporting regimes point at it. Federal rules stack them, set a five-day clock between the companies involved, and stretch one deadline in a way worth knowing.
The problem this subpart solves
Drug harm reports and device harm reports run on different rules, different forms and different clocks. A product that is both raises an obvious question: which set applies.
Subpart B of 21 CFR part 4 answers it. It "identifies postmarketing safety reporting requirements for combination product applicants and constituent part applicants."
Its limits are set in the same section. It does not apply to investigational products, to products without marketing authorization, or "to persons other than combination product applicants and constituent part applicants."
And it adds rather than replaces. It "supplements and does not supersede other provisions of this chapter," naming parts 314, 600, 606, 803 and 806.
Two kinds of company, and why it matters
Section 4.101 distinguishes a combination product applicant from a constituent part applicant, and the distinction drives everything that follows.
A combination product applicant holds the application for the whole product. A constituent part applicant is the applicant "for a constituent part of a combination product the constituent parts of which are marketed under applications held by different applicants."
That second case is the interesting one. It describes a product assembled from pieces owned by different companies, each holding its own authorization.
Section 4.102 then draws the consequence. Reporting requirements "applicable to you" reach only your constituent part if you are a constituent part applicant, and reach "your combination product as a whole" if you are the combination product applicant.
The base layer: report under whatever you were authorized under
Paragraph (b) of section 4.102 is the floor, and it is simple.
A product or device constituent part authorized under a device application follows "the requirements for postmarketing safety reporting described in parts 803 and 806."
A product or drug constituent part authorized under a new drug application or an abbreviated one follows the requirements "described in part 314."
A product or biological constituent part authorized under a biologics license application follows those "described in parts 600 and 606."
So far this is ordinary. The application type you hold determines the reporting rules you follow.
The second layer: report the other side too
Paragraph (c) applies only to the combination product applicant, and it is where the stacking happens.
If the product contains a device constituent part, the applicant must also submit five-day reports, malfunction reports, and correction or removal reports. It must keep records for corrections and removals that are not required to be reported.
If it contains a drug constituent part, the applicant must also submit field alert reports and fifteen-day reports.
If it contains a biological product constituent part, the applicant must also submit biological product deviation reports and fifteen-day reports.
There is a sensible anti-duplication rule alongside. A report already filed under one paragraph does not have to be filed again under the other for the same event. It must carry the required information, go in by the same route, and meet the applicable deadline.
The deadline that changes length
Buried in paragraph (c) is a detail that is easy to skim past and worth stopping on.
A fifteen-day report about a drug constituent part "must be submitted within 30 calendar days instead of 15 calendar days if your combination product received marketing authorization under a device application."
The same substitution appears for the biological product branch: a fifteen-day report there also becomes 30 calendar days where the product was authorized as a device.
So the name of a report and its actual deadline can differ, depending on which application the whole product came in under. A document called a fifteen-day report is not always due in fifteen days.
The five-day duty between companies
Section 4.103 is the section that makes the split-ownership case work, and it is the shortest clock in the subpart.
The trigger is information about an event involving a death or serious injury, or an adverse experience, associated with use of the combination product. On receiving it, an applicant "must provide the information to the other constituent part applicant(s) for the combination product no later than 5 calendar days of your receipt of the information."
And the handoff has to be evidenced. Records must include a copy of the information provided, "The date the information was received by you," the date it was passed on, and the name and address of the applicant it went to.
That is a paper trail with four fields. It exists because one company can learn something the other needs to file its own report on time.
Where reports go, and how long records live
Section 4.104 handles routing. A constituent part applicant submits under the regulations applicable to its own application type.
A combination product applicant submits "in the manner specified in the regulation applicable to the type of report." Two named exceptions redirect certain reports, depending on whether the product came in under a drug, biologics or device application.
Section 4.105 handles retention, and it resolves the conflict the obvious way. A combination product applicant must keep records "in accordance with the longest time period required for records under the regulations applicable to your product."
The same longest-period rule governs the records of the five-day handoff under section 4.103.
There is also a reserve power in section 4.102(d). Where a combination product was authorized under a device application, FDA may require additional postmarketing safety information in writing, stating the reason for the request, the due date, and the events it relates to.
What this does and does not tell a buyer
The honest answer is that it tells a buyer about a structure rather than about a product.
It explains why harm data for a delivery-device product can be split across more than one reporting system, which makes any single public database an incomplete picture on its own.
It explains why two companies can both be answerable for the same event, and why one of them may learn of it second.
What it does not do is reach anything compounded, unapproved or sold without marketing authorization. Section 4.100 puts those outside the subpart by its own terms, and most of this market sits there.
The regulations this subpart points at, in parts 314, 600, 606, 803 and 806, were not read for this page. Only what part 4 itself says about them is described here. Nothing above names a seller, assesses anyone's compliance, or is legal advice.
Key takeaways
- Subpart B of part 4 stacks drug and device harm-reporting duties onto a single combination product.
- The base layer follows whichever application the product was authorized under.
- A combination product applicant also files the report types belonging to every constituent part it contains.
- A fifteen-day report becomes a 30-calendar-day report where the product was authorized as a device.
- Where different companies own the pieces, information about a death, serious injury or adverse experience must be shared within 5 calendar days.
- The subpart reaches only products with marketing authorization, which leaves compounded preparations outside it.
Frequently asked questions
Why would one product be under two reporting systems?
Because it contains constituent parts of two kinds. Section 4.102(b) says an applicant follows the reporting rules matching the application its product was authorized under. Paragraph (c) then adds a second layer for combination product applicants. Device constituent parts bring five-day, malfunction and correction or removal reports. Drug constituent parts bring field alert and fifteen-day reports, and biological constituent parts bring deviation and fifteen-day reports.
Does a fifteen-day report always take fifteen days?
No. Section 4.102(c) provides that a fifteen-day report for a drug constituent part must be submitted within 30 calendar days instead of 15 if the combination product received marketing authorization under a device application. The same substitution applies to the fifteen-day report on the biological product branch. The name of the report and its deadline can come apart.
What happens when two different companies own the pieces?
Section 4.103 creates a duty between them. The trigger is information about a death or serious injury, or an adverse experience, associated with use of the combination product. An applicant must pass it to the other constituent part applicants no later than 5 calendar days after receiving it. Records of the handoff must include a copy of the information, the date it was received, the date it was forwarded, and the name and address of the recipient.
How long do the records have to be kept?
For the longest applicable period. Section 4.105 provides that a combination product applicant keeps records for the longest time period required under the regulations applicable to its product. A constituent part applicant keeps the section 4.103 handoff records for the longest period required under the reporting regulations applicable to it.
Does any of this reach a compounded peptide?
Not on the face of the subpart. Section 4.100 states that it does not apply to investigational combination products, to combination products that have not received marketing authorization, or to persons other than combination product applicants and constituent part applicants. A compounded preparation is not marketed under such an application, so this machinery is not what governs it.
Sources
Each document below is named as it names itself, with the date printed on that document rather than the day it was read.
- Title 21 Code of Federal Regulations section 4.100, What is the scope of this subpart? — Electronic Code of Federal Regulations, Office of the Federal Register, December 2016
- Title 21 Code of Federal Regulations section 4.101, How does the FDA define key terms and phrases in this subpart? — Electronic Code of Federal Regulations, Office of the Federal Register, December 2016
- Title 21 Code of Federal Regulations section 4.102, What reports must you submit to FDA for your combination product or constituent part? — Electronic Code of Federal Regulations, Office of the Federal Register, December 2016
- Title 21 Code of Federal Regulations section 4.103, What information must you share with other constituent part applicants for the combination product? — Electronic Code of Federal Regulations, Office of the Federal Register, December 2016
- Title 21 Code of Federal Regulations section 4.105, What are the postmarketing safety reporting recordkeeping requirements for your combination product or constituent part? — Electronic Code of Federal Regulations, Office of the Federal Register, December 2016