Can the FD&C conflict with the CFR?

Question

Page 77 of the textbook Vaccines states:

The Food, Drug and Cosmetic Act (Section 502[e][1][A][iii]) states that all inactive ingredients should be noted in labeling; it also states that this requirement is not necessary if trade secret information would be disclosed. The CFR additionally notes that an inactive ingredient should be listed in the labeling if the ingredient's presence is considered a safety factor (21 CFR 610.61[n]). In some cases, even in the absence of any evidence that a particular material might pose a safety factor, manufacturers have elected to disclose the presence of residual materials such as detergents, solvents, and chelating agents (see Table 6-2 for examples of manufacturing residuals).

Here is the relevant quote from the FD&C:

(iii) the established name of each inactive ingredient listed in alphabetical order on the outside container of the retail package and, if determined to be appropriate by the Secretary, on the immediate container, as prescribed in regulation promulgated by the Secretary, except that nothing in this subclause shall be deemed to require that any trade secret be divulged, and except that the requirements of this subclause with respect to alphabetical order shall apply only to nonprescription drugs that are not also cosmetics and that this subclause shall not apply to nonprescription drugs not intended for human use.

And from Title 21 of the Code of Federal Regulations:

The following items shall appear on the label affixed to each package containing a product:

• The preservative used and its concentration, or if no preservative is used and the absence of a preservative is a safety factor, the words "no preservative";

• The type and calculated amount of antibiotics added during manufacture;

• The inactive ingredients when a safety factor, or reference to an enclosed circular containing appropriate information;

• The adjuvant, if present;

• The source of the product when a factor in safe administration;

• The identity of each microorganism used in manufacture, and, where applicable, the production medium and the method of inactivation, or reference to an enclosed circular containing appropriate information;

FD&C allows keeping of trade secrets. CFR says the inactive ingredients must be disclosed when a safety factor. Let's say we have an inactive ingredient that is a trade secret that is also a safety factor.

1. Which law has precedence?

2. Why does the law that has precedence have precedence?

3. How is it determined if an inactive ingredient is a safety factor?

4. Does a trade secret ever have to be disclosed? When?

5. As far as you can tell, is this a "loophole" in the law?

Answer 1

Neither law has precedence - manufacturers have to obey both.

The FD&C says that they don't need to list ingredients which are trade secrets; the CFR says they must.

If they list the trade secrets they do not break either law. If they don't, they break the CFR. Conclusion: they must list the trade secret ingredients.

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If the FD&C said it was forbidden to list trade secret ingredients, but the CFR required it, manufacturers would still have to obey both laws - which would mean they couldn't sell anything where one of the ingredients was a trade secret.

Answer 2

The primary source of law is the various laws passed by Congress known as the FD&C Act and which is codified in the relevant part at 21 USC 352(e)(1)(A)(iii), which says

the established name of each inactive ingredient listed in alphabetical order on the outside container of the retail package and, if determined to be appropriate by the Secretary, on the immediate container, as prescribed in regulation promulgated by the Secretary, except that nothing in this subclause shall be deemed to require that any trade secret be divulged, and except that the requirements of this subclause with respect to alphabetical order shall apply only to nonprescription drugs that are not also cosmetics and that this subclause shall not apply to nonprescription drugs not intended for human use.

That law gives regulatory power to some part of the executive branch to enforce these statutes, currently the Department of Health and Human Services. Only Congress has the power to make new law, but the courts and executive branch have the power to interpret existing law. So Congress can delegate to the executive branch the power to make certain decisions as to what the law specifically means, within the confines of the acts passed by Congress.

A regulation (encoded in 21 CFR) legally cannot conflict with a statute. Anything that a regulation requires, requires statutory authority. That does not mean that the executive branch is incapable of writing a regulation that contradicts the statutes. If there is actually a conflict, then a person affected might sue the agency which promulgated the regulation, arguing that they exceeded their authority. There is a legal doctrine known as Chevron deference that requires the courts to defer to the agency's interpretation of an ambiguous or unclear statute.

In terms of impelling a manufacturer's practical decision, this favors minding the regulations over the statutes for two reasons. First, unless it is clear that the executive branch has exceeded its authority, the courts will defer to the executive branch. Second, enforcement actions are primarily carried out by the executive branch.

Suppose that the executive branch plainly stated that trade secrets must be divulged to comply with labeling laws. As you can see from the statute, Congress enacted a trade secret exception. If 21 CFR explicitly said otherwise then an affected person might have a basis for a lawsuit against DHHS. DHHS might argue that this means that there can be no trade secrets in food, drugs of cosmetics, but that would be a serious violation of the liberty and commercial interests of manufacturers, which are protected by the Constitution. This could then trigger an inquiry into whether Congress had intended to outlaw trade secrets in this domain, and whether they have the authority to do so.

However, the regulations do not say that (as far as I can tell: you'd have to hire an attorney who totally knows that title). I do not know if any manufacturer believes that they are compelled to divulge trade secrets, and if so, what was the basis for that belief. If they were directed to some part of CFR that literally said they must, then I would expect an eventual legal challenge, because there is no unclarity to the statutory exemption. That does not mean that a manufacturer will not voluntarily reveal a supposed trade secret for a business reason.

The FDA's role is to evaluate the evidence for safety and effectiveness, which it primarily does via a scientific review panel. The FDA does provide some scientific guidance, such as Safety Testing of Drug Metabolites, which "represents the current thinking of the Food and Drug Administration", and doe not establish legally enforceable responsibilities. They say to discuss an alternative approach, contact the FDA. It applies to small molecule nonbiologic drug products, so specific details regarding vaccines isn't covered, but this should give you an idea what concern a manufacturer should address in their testing. For instance,

Based on the nature of the chemical reactions involved, metabolites formed from Phase I reactions are more likely to be chemically reactive or pharmacologically active and, therefore, more likely to need safety evaluation ...

If at least one animal test species forms this drug metabolite at adequate exposure levels ...it can be assumed that the metabolite’s contribution to the overall toxicity assessment has been established...

Phase II conjugation reactions generally render a compound more water soluble and pharmacologically inactive, thereby eliminating the need for further evaluation. However, if the conjugate forms a toxic compound such as acylglucuronide, additional safety assessment may be needed

Potentially relevant to the specific question of 21 CFR 610.61[n], they state

Generally, metabolites identified only in human plasma or metabolites present at disproportionately higher levels in humans than in any of the animal test species should be considered for safety assessment. Human metabolites that can raise a safety concern are those formed at greater than 10 percent of total drug-related exposure at steady state. The choice of a level of greater than 10 percent for characterization of drug metabolites reflects consistency with FDA and Environmental Protection Agency guidances.

This is really just the tip of the scientific iceberg, but should give you some idea. They have a brief piece on vaccines here, a general FAQ, CDC's somewhat more informative account of the approval process for vaccines, and a FAQ-style discussion of some popular ingredients.

Basically, the reason why the law is unclear on what constitutes a safety concern is that it is a scientific question, and Congress delegated authority to make that determination to the FDA.

Answer 3

FD&C allows keeping of trade secrets. CFR says the inactive ingredients must be disclosed when a safety factor. Let's say we have an inactive ingredient that is a trade secret that is also a safety factor.

That is incorrect. In terms of medicines, it says the inactive ingredients must be listed, not that they must only be listed if they are a safety factor. The safety factor part you cite is referring to bold warnings on the box. All inactive ingredients get listed, though.

Which law has precedence?

Neither, trade secrets normally apply to things like beauty products or other things that are not pharmaceuticals. All ingredients in a pharmaceutical are listed.

How is it determined if an inactive ingredient is a safety factor?

Obviously, you can't definitively say if something would be safe for every single person in most cases, but they are looking at things that have been commonly reported as an irritant or harmful to a wide range of people.

Does a trade secret ever have to be disclosed? When?

No, a trade secret designation can't be forced to be disclosed, but they are very rare. In fact, there is only one thing that has been listed as a trade secret. https://www.fda.gov/cosmetics/cosmetics-labeling/trade-secret-ingredients

As far as you can tell, is this a "loophole" in the law?

No, they refer to two different things. Trade secrets are things that makers of beauty products want to conceal from competition and inactive ingredients are parts of medicine that are not the main ingredient that provides the medical attention the drug is intended for. They are not related.

Answer 4

To add a bit of detail from the FDA's own write-up on how they navigate the apparently conflicting requirements... they are clearly not fond of such requests for ingredient secrecy, but they may grant them in the sense of putting a more vague label on the product. That doesn't mean the applicant doesn't have to submit the exact nature of the substance to the FDA. The FDA may also not grant such a request, in which case the company has to choose between publicly disclosing the ingredient or forgoing authorization!

FDA requires cosmetics to have an “ingredient declaration,” a list of all the product’s ingredients. FDA requires this labeling under the Fair Packaging and Labeling Act (FPLA). This law is intended to make sure consumers have information they can use to compare the value of different products and make informed choices.

But according to the FPLA, regulations for this list of ingredients must not be used to force a company to disclose “trade secrets” (FPLA, section 1454(c)(3)).

For example, fragrance and flavor ingredients do not need to be listed individually on cosmetic labels, because they are the ingredients most likely to be “trade secrets.” Instead, they may be listed simply as “fragrance” or “flavor” (Title 21, Code of Federal Regulations (CFR), Part 701.3(a)).

To request “trade secret” status for any other ingredient, a cosmetic company needs to follow a process detailed in the cosmetic regulations.

First, be aware that it’s unlikely that FDA will grant your request. We’ve received only a handful of trade secret requests in the last 20 years and have granted such a request only once. But if you decide to proceed, here’s how: [...]

You will need to disclose to FDA the information we need to evaluate the factual and legal grounds justifying trade secrecy for the ingredient in question. There are two key elements to address:

• The extent to which the ingredient is known, both outside and inside your company, and what you have done to protect that information, as well as how easily it could be identified or duplicated.

• The value of the identity of the ingredient to you or to your competitors, if they became aware of it, as well as the effort and expense involved in developing the ingredient.

FDA will not disclose this information while it is under review. If we grant your request for confidentiality, the information you provide will not be subject to release under the Freedom of Information Act. If we deny your request, we will return the information to you without retaining copies.

In theory, a company might have a leg to stand on and argue that being forced to make this choice between authorization and keeping their secret is breaking the law, but it seems that FDA having a procedure for deciding the matter (which takes into account how secret the ingredient really is and how much the company stands to lose if it were publicly disclosed) insofar has precluded any [successful] lawsuits in this area. Also, the FDA is told the exact ingredient, so the FDA can evaluate it for safety even in the case when this info is later not made public in exact term.

As FPLA is pretty ancient (1966) its testing in court seemingly happened mostly around that time. I found a 1980 article that discusses the secrecy issue. Back then, there were far more requests. Between 1972 and 1978, there were some 1216 such requests for trade secrets status, the FDA granted 789 and denied 427. There were a few administrative appeals claiming the FDA decision [in this kind or matter] was "arbitrary and capricious".

Seemingly only one was of consequence: Zotos International, Inc. v. Kennedy [460 F. Supp. 268 DC] forced he FDA to modify its procedure for evaluating trade secret requests in 1978. This introduced the two-step procedure that is apparently still in use: the first bullet/step from the FDA's write-up further above is carried out first. The "tentative decision" is then communicated to the company which is given an opportunity to reply in 30 days. The relevant FDA Division then re-reviews the application in light of this additional material. Other than making the process a bit more back-and-forth, this didn't really change much otherwise. (The new procedure was upheld in Carson Products Co. v. Califano [549 F. 2d 453 CA-5, 1979].)