Exemptions for biologics (all vaccines) under PHSA 351, from FDCA 505 'new drug' provisions requiring substantial evidence of effectiveness.
Orientation for new readers; American Domestic Bioterrorism Program; Tools for dismantling kill box anti-law
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2022 Bailiwick News Volume 6 Jan. to Dec. (950 pages, 16.5 MB)
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Posting an email to a reader who is interested in untangling when and how some of the carve-outs exempting biological products — including all vaccines — from laws requiring ‘substantial evidence’ of effectiveness obtained through ‘adequate and well-controlled’ human studies for marketing and use of new drugs, came into being.
It’s part of my ongoing work on Part 5 of series.1
The text is rough, and I’m not providing links to most source documents, only because it takes time to assemble the links that I don’t want to spend right now. Better formatting of the same information will probably be published in Part 5.
Related:
Sept. 27, 2024 - Antibodies and surrogate endpoints: more pieces of the scientific and regulatory fraud puzzle. (Katherine Watt)
Oct. 16, 2024 - Anaphylaxis, allergens, immunogenicity, vaccines. 1980 GAO report to Sen. Abraham Ribicoff, Sen. Edward Kennedy and others, about allergenic products and vaccines. (Katherine Watt)
Email to reader:
Two other places to start (in addition to Tuskegee) are the 1937 Elixir tragedy (solvent used in antibiotic liquid caused 100+ deaths) and 1958/1959 thalidomide.
The Elixir incident is cited as a driver of the 1938 FDCA and the thalidomide incident is cited as a driver of the 1962 FDCA Kefauver-Harris amendments to FDCA 505 requiring non-biologic drug manufacturers to provide, in their marketing application materials, proof of safety and effectiveness of new non-biologic drugs.
Tuskegee is cited as the driver of the "informed consent" for human studies sections, which is related but more about the conduct of studies themselves, and less about product manufacturing and manufacturer submission of evidence in marketing application packages.
Because biologics and vaccine manufacturers have never had to collect or submit evidence from controlled human studies, rules about informed consent and conduct of human studies haven't ever applied to them….
In the original 1938 FDCA, the term new drugs is defined at FDCA 201 as
"any drug the composition of which is such that such drug is not generally recognized, among experts qualified by scientific training and experience to evaluate the safety of drugs, as safe for use..."
In 1962, Congress added effectiveness terms so that new drug was defined at FDCA 201 as
"any drug the composition of which is such that such drug is not generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, as safe and effective for use..."
The 1962 amendments also added in "effective" language in several parts of FDCA 505.
For example, FDCA 505(e) is about conditions under which a regulator can withdraw or suspend approval for a non-biological new drug. Without such suspension or withdrawal action, the application is deemed approved and the drug can be marketed.
Prior to 1962, the FDCA 505(e) section ended at 505(e)(2).
In 1962, a third condition under which approval could be suspended was added at 505(e)(3):
"on the basis of new information..that there is a lack of substantial evidence that the drug will have the effect it purports or is represented to have...in the labeling..."
The 1962 amendments added a definition for substantial evidence, at FDCA 505(d):
"the term substantial evidence means evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof."
To summarize, the finding of no substantial evidence of "effectiveness," as a basis for preventing new drugs from entering market or withdrawing new drugs from market, at least for drugs subject to FDCA (so not for PHSA biologics), was only added with the 1962 amendments, put in at 505(e)(3).
Setting aside, for now, the blanket or general legal exemptions that have existed from the beginning and still exist now for all PHSA 351 biologic products, from all provisions of FDCA 505 new drug rules, one specific carve-out the two-track system enabled, for PHSA biologic products, is that, because biologic product labels are not required to contain any information about the effect it is supposed to cause in the recipient, there is no statement of effect that could be assessed for whether the evidence that it will have such an effect is "adequate and well-controlled" or supports "fair and responsible conclusions" as to the validity of the claims.
Another legalized carveout for PHSA biologic products, appeared in implementing regulations (circa 1972) that said regulators could accept "partially controlled" "uncontrolled" and other implicitly insufficient, inadequate and not-well-controlled forms of evidence.
They also circumvented the FDCA effectiveness provisions usually by using some form of saying that human studies of biologicals, of the kind done for non-biologic drugs, are "not feasible" or "not ethical."
For example:
"Where adequate and well-controlled studies are not feasible, and acceptable alternative scientific methods of demonstrating effectiveness are available, the latter will be sufficient."- Aug. 18, 1972 FR.
Human safety and “efficacy” and effectiveness, could be derived, for “individual active components” of biological products, for “combinations of the individual active components” of biological products, and for “finished biological products” from:
Controlled studies.
Partially controlled or uncontrolled studies.
Documented case reports.
Pertinent marketing experiences that may influence a determination as to the safety of each individual active component.
Pertinent marketing experiences that may influence a determination as to the safety of combinations of the individual active components.
Pertinent marketing experiences that may influence a determination as to -the safety of the finished biological product.
Pertinent marketing experiences that may influence a determination on the efficacy of each individual active component.
Pertinent marketing experiences that may influence a determination as to the effectiveness of combinations of the individual active components.
Pertinent marketing experiences that may influence a determination as to the effectiveness of the finished biological product.
Pertinent medical and scientific literature.
There is useful discussion of the way that these terms created the gap for biologics to be used without controlled studies in the 1980 GAO report.
It's tricky reading, but the meat is in the back and forth between GAO inspectors and HEW officials.
GAO noted that Congress had considered applying the evidence standard to biologics, but the provisions were repeatedly stripped out of bills in the early 1960s. GAO noted that FDA hadn't provided detailed criteria about what kind of studies meet the standard for "acceptable alternative scientific methods." GAO suggested Congress pass legislation requiring controlled studies. GAO suggested FDA label products to notify doctors and patients that no good evidence of effectiveness had been collected or existed. GAO suggested a lot of things.
HEW replied by saying, paraphrased:
1) the Congressional laws are already good enough, we don't need more laws, and
2) we [manufacturers and regulators] can't do controlled studies because biologics can't be standardized and we can't figure out which parts of biological materials are the "active components" or the ones having the effect, or if any effect is caused. And we can't figure out how to account for the wide variability in response in humans from person to person, and from time to time within the same person. We can't figure out dosing. We can't figure out clinical endpoints. We don't really know anything about biologics, what's in them, or what they do. But we think that partially-controlled, uncontrolled studies, with case reports, with post-marketing (aka "real world") reports and with "pertinent medical and scientific literature” (aka Enders and other scientific misconduct papers) are good enough to keep making and using biologics.
1798-1972 US federal quarantine and biological product law series:
Aug. 5, 2024 - Part 1 - Federal communicable disease control, quarantine and biological product law, 1798 to 1972: orientation through founding of Marine Hospital Service (Lydia Hazel and Katherine Watt)
Aug. 12, 2024 - Part 2 - US federal quarantine and biological product law: Marine-Hospital Service (1798); National Quarantine Act (1878); Laboratory of Hygiene (1887) (Lydia Hazel and Katherine Watt)
Sept. 10, 2024 - Part 3 - 1901-1910: Federal government licensing of virus and toxin propagation establishments; criminalization of traffic in adulterated or misbranded drugs (Lydia Hazel and Katherine Watt)
Oct. 9, 2024 - Part 4 - 1911-1943: Continued non-existence of legal provisions directing federal agencies to establish and enforce biological product definitions and standards (Lydia Hazel and Katherine Watt)
