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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?

  • What more do you want? I don't mean it in a mean way. I just feel we answered the question and was wondering what you want clarified. – Putvi May 13 '19 at 15:19
  • @Putvi That's alright. Could you suggest how it is determined if something is a safety factor? The law doesn't seem very clear (to me) on this and I am confused about it. – Barry Harrison May 13 '19 at 17:18
  • Its not a 100% specific black and white thing. It is just their interpretation of what would be so harmful to a large portion of the patients that it needs a warning on the front of the box. Like if tomorrow most people were suddenly allergic to something it would fit. – Putvi May 13 '19 at 17:20
  • @Putvi So the FDA decides? If so, how? If it's not black and white, then won't there be loopholes? – Barry Harrison May 13 '19 at 17:21
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    I'm happy if you are. – Putvi May 13 '19 at 17:43
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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.


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.

  • But the federal government can only create regulations to implement legislation. The FD&C Act does not appear to give the government the authority to require trade secrets be divulged; is there another law that does? If not, then the regulation might be illegal. – Nate Eldredge May 10 '19 at 16:41
  • Thanks for answering! Are you suggesting that manufacturers will always disclose all vaccine ingredients so as to comply with both laws? – Barry Harrison May 10 '19 at 17:35
  • @Nate Well, if the regulation is illegal, then obviously nobody has to obey it. – Martin Bonner supports Monica May 10 '19 at 20:04
  • @Barry I have only responded to the law as you have delegating it, but if you have described it accurately, then: yes. – Martin Bonner supports Monica May 10 '19 at 20:05
  • @MartinBonner Got it, thanks. – Barry Harrison May 10 '19 at 20:18
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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.

  • Thanks for answering! Upvoted. So your short answer is that manufacturers will divulge trade secrets per the CFR? – Barry Harrison May 8 '19 at 15:25
  • No, although maybe: see the edit at the end of my answer. – user6726 May 8 '19 at 15:39
  • "...this favors minding the regulations over the statutes for two reasons..." If I am reading it correctly. FD&C is the statute and CFR is the regulation? I guess what you mean is: Manufacturers will not divulge trade secrets? – Barry Harrison May 8 '19 at 15:50
  • The quote is the general principle, in case there is reasonable uncertainty. But here there is no unclarity: CFR does not require disclosure and the statute directly contradicts any implication that disclosure is required. The primary tendency is to obey regulatory agencies, but in the specific instance, the regulator has not commanded anything, and therefore manufacturers will not be compelled to divulge secrets (and will probably not do so). – user6726 May 8 '19 at 16:04
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    @BarryHarrison, yes only trade secrets (if you are referring to inactive ingredients). – user6726 May 9 '19 at 0:55
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+100

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.

  • Thanks for answering! Could you cite the relevant portion of the law for "In terms of medicines, it says the inactive ingredients must be listed?" Thanks again. – Barry Harrison May 8 '19 at 16:06
  • It's literally the law you listed in your other question. "(n) The inactive ingredients when a safety factor, or reference to an enclosed circular containing appropriate information;" – Putvi May 8 '19 at 16:07
  • I know. If you include it in the answer, other people (not including me) will understand it better. – Barry Harrison May 8 '19 at 16:07
  • Barry, it was meant for you! Jk – Putvi May 8 '19 at 16:09
  • Also, I think it says listed "when a safety factor" which means it doesn't always have to be listed. Is this correct? – Barry Harrison May 8 '19 at 16:09

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