During Health and Human Services (HHS) public health emergencies, our health organizations take special measures to facilitate solutions to the crisis. These measures often include assigning special advisory committees and setting aside specific funds for the research, development, and implementation of assay development, that is the development of new drugs. HHS additionally fund treatment and measures to return to normalcy. The FDA specifically deals with fast-tracking diagnostics and therapies in order to cut some of the red tape normally associated with regulatory development, from inception to consumer.
Red tape, though typically a negative term, isn’t always a bad thing. In the case of drug development particularly, it is found in the traditional FDA approval pathway for a medication and includes a rigorous process of non-clinical bioavailability and toxicology (animal model), pharmacokinetic testing (levels of drug in the blood of healthy subjects), and trials utilizing the drug in patients with the indication you are trying to treat.
Every step of drug development must meet specific documentation requirements for adverse events (AE’s) and focus more on the safety of the therapy than even its efficacy. We must first Do No Harm. Efficacy is the drug’s ability to do exactly as the investigator claims in their trial protocol, and meet specified endpoints such as a particular blood level or a specified resolution of symptoms or abnormal physiological or biochemical states as defined in a claim. The approval is granted when the FDA determines that the product is safe and effective for its designated use. This process typically takes many years with the final review period by FDA alone taking up to a year.
Emergency Use Authorizations (EUAs) are measures that the FDA takes in order to get the potential treatment out to the public at a much faster rate. In unusually urgent circumstances, an EUA is granted if the benefit of the potential drug or treatment’s use appears to outweigh any known or anticipated risk. This is not the same as an FDA approval and should not be conflated as such. It merely allows an unapproved medication or diagnostic to be used with the intention of saving lives.
The data still must be reviewed by the FDA; however, certain measures are waived to expedite the process, such as:
· Site inspections of clinical or manufacturing facilities
· Reducing data requirements
· Suspending certain safety requirements before administering the study medication
· Not requiring rigorous tech. transfers when changing manufacturing facilities
In my experience with EUA’s, study trials typically fail to stratify patients with regard to age or disease severity, not allowing apples to apples comparisons whereby muddying the data. Additionally, it is typical for the blind to be broken, and endpoints to be altered midway to massage data in order to meet minimum efficacy requirements, such as occurred with the EUA for the Covid-19 drug, Remdesivir. There were changes in the trial used to gain EUA, the duration of the study was changed after initial data made it evident that it would not meet the stated endpoint, so a new endpoint was created, and the study extended from 15 days to 29 days. This allowed a statistical alteration to increase odds of obtaining a p-value. Typically the blind is broken due to its “emergency” nature and this also can make it difficult to distinguish between side effects from the drug and disease symptoms. Typically, EUA’s can lead to full approval after enough patients are studied and enough time has elapsed; however, not all drugs with EUA’s are truly efficacious, despite FDA review in an emergency.
Risk analysis isn’t the easiest thing to determine when granting an EUA and because of this challenge, we run the risk of authorizing a therapeutic that shouldn’t be used. Anticipated safety is decided in absence of long-term data and is approached when there is no other safe, efficacious alternative for treatment during that emergency. Ongoing surveillance of adverse events occurs throughout its use and health professionals are required by law to report all related AE’s to a surveillance system.
In the case of covid-19 vaccines, the database is called the Vaccine Adverse Event Reporting System (VAERS). This information can be helpful in discerning long-term safety of the emergency therapeutic; however, not all AE’s are reported to the VAERS system usually due to false attribution of adverse event or loss to follow up of vaccinated patients. Part of the challenge in reporting accurately is the subjectivity in determining correlation. Other challenges in cases of mass vaccination at public facilities, occur when the event manifests well after the subject has left the facility and lacks the ability to attribute cause. VAERS can be helpful in identifying trends but numbers must be taken with a grain of salt.
Condensing many years of study for a new therapeutic into only a few months can elicit deleterious consequences. Rarely do subjects come out unscathed. We must be careful not to treat the unknowing population like a clinical trial without informed consent. This is a fine line in medical ethics that should never be crossed as it is in direct violation of the Declaration of Helsinki and the Nuremburg Code.