Abstract
Recently, the 117th Congress passed S.5002, a bill to allow for alternatives to animal testing for purposes of drug and biological product applications.
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This bill, entitled “FDA Modernization Act 2.0,” was signed by President Biden on December 30, 2022. In this bill, Section 505 of the Federal Food, Drug and Cosmetic Act (the law that created the Food and Drug Administration [FDA]) was modified to strike “preclinical testing (including testing on animals)” from the language and insert “nonclinical tests” and additionally strike “animal” from other sections and insert the same “nonclinical tests.” A nonclinical test is defined in the modified bill as, …a test conducted in vitro, in silico, or in chemico, or a non-human in vivo test that occurs before or during the clinical trial phase of the investigation of the safety and effectiveness of a drug, and may include animal tests, or non-animal or human biology-based test methods, such as cell-based assays, microphysiological systems, or bioprinted or computer models.
Although this language does not preclude or prevent the use of animals in safety or testing of new drugs and biosimilars, it does allow for the omission/substitution of animal testing with a variety of current and new technologies designed to be cheaper or faster than rigorous animal testing. For biosimilars, this change in the language is celebrated since biosimilars are already demonstrated to be clinically identical to their FDA approved biological reference products. And, although the FDA already supports the approval of biosimilars through an abbreviated pathway, 2 this additional modification of the requirements will continue to expedite the delivery of safe biosimilars to patients.
However, this legislative change does enable new small molecules to be submitted to, and potentially, pass through FDA approvals, without rigorous in vivo testing as part of the federally mandated requirements. This has the potential to radically endanger a healthy human cohort that first takes a new chemcial entity (NCE) that follows this suggested guideline.
The original Pure Food and Drugs Act enacted in 1906 prohibited the sale of misbranded or adulterated drugs in interstate commerce 3 but did not include two important steps. The manufacturers were not required to submit any information to governing agencies before sales, and in the event of fraud (i.e., ineffective or deleterious effects), it left the burden of proof on the intent to defraud or mislabel a product to the government.
This was until 1933 when 107 people died from poisoning by taking an Elixir sulfanilamide (a sulfonamide antibiotic) dissolved in ethylene glycol, otherwise known as a component in antifreeze. Ethylene glycol is poisonous to humans and mammals, but no safety testing or toxicological data existed at that time. Congress updated its 1906 version of the FDA law to its 1938 status, requiring new drugs to be both tested and their data reported to the FDA before it enters the market.
The new language taken to its logical extension would directly impact the drug development process by allowing for the replacement, substitution, or wholesale deletion of proven empirical evidence-based in vivo data from the development pipeline for a new drug. These data are then replaced by what? An in vitro cell-based assay (usually artificial) created to give a specific pharmacological read out (as the law highlights)?
There are ample data to show severe and unexpected in vitro/in vivo disconnects for a given compound or drug, and whole divisions of Big Pharma are dedicated to the understanding of these disconnects and how to properly predict drug dose, exposure, and metabolites, and to scale these findings to humans before that drug is ever being dosed in a patient. This is to ensure that a healthy volunteer in Phase I remains as such and the efficacy of the drug can be monitored in subsequent studies without endangering the patient.
The law also cites that “microphysiological systems, or bioprinted” systems are suitable replacements for animal testing. The argument could be made that human-based microphysiological systems and/or cultivated human tissues could be used as replacements for animal studies soon. However, these areas of study are nascent and the robust data cohorts to empirically prove that these systems accurately measure drug toxicology, drug effects on physiology, and predict responses to drugs for a vast array of human physiological endpoints do not exist. More importantly, the Congress, through the various funding agencies, does not adequately support the development and study of these systems on scale to rapidly generate the missing data in a reasonable timeframe.
The implications of the new updated language in the law are clear. Some data packages for new drugs, while still requiring evaluation and approval by the FDA, may be missing these critical safety testing results. Researchers and drug hunters will need to avoid the temptation of “no data is better than negative data” with respect to safety studies and the pressure to eliminate costs associated with animal testing. Indeed, the financial pressure to minimize animal testing already exists. Moreover, researchers and drug hunters have always worked to minimize the use of animals in testing for their humane treatment, while weighing this against the safe use of medicines in humans. The removal of federal mandates was promised to “reboot a broken drug development paradigm…” but at what cost?
Certainly, any doctor prescribing medicines to patients will want the guarantee that the drug is safe and effective in humans. But if that statement is not validated and proved true by first demonstrating safety and efficacy in animals, then how? With the legislation enacted, drug development teams should stick to what they know is true, in vivo testing using a safety species (or multiple species) has been critical to the development of safe drugs using evidence-based approaches. And although the complete understanding of a new drug's safety and toxicological profile in humans can never be known before its first-in-human dose, drug development teams have accurately predicted exposure, therapeutic indices, identified biomarkers, and predicted therapeutic endpoints resulting in new drugs for decades.