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Understanding US Food and Drug Administration (FDA) Approval Processes
The FDA approvals process is complex and time-consuming, taking an average of 12 and 7 years for drugs and devices, respectively.
US Food and Drug Administration approval processes comprise numerous steps to ensure the safety and efficacy of new drugs, therapies, and treatments. Navigating the process can be complex and time-consuming, and as a result, the FDA is proactively looking for methods to accelerate the pace of approval.
From preclinical testing to approval, research shows that the average approval process of new drugs and devices takes 12 and 7 years, respectively. While other studies place the average drug development cost at $2.8 billion, another study conducted in 2020 determined the average cost to be $1.3 billion. In the same study, the median cost of getting a new drug on the market was found to be $985 million.
FDA Application Types
The FDA has five common application types: New Drug Application (NDA), Abbreviated New Drug Application (ANDA), Over-the-Counter Drug (OTC), Biologics License Application (BLA), and Investigational New Drug (IND).
Name-Brand Drug/Vaccine/Biologics Approval Process
The name-brand approval process consists of five steps — discovery/concept, preclinical research, clinical research, FDA review, and FDA post-market safety monitoring.
The company must test the product on animals before humans to ensure safety.
After the product is tested, the company submits a New Drug Application. An NDA includes the following: the product’s test results, chemical manufacturing details of the product, results from the animal studies and human clinical trials, and complete product label including effective usages, possible risks or side effects, and detailed instructions.
Scientists and physicians within the FDA review all components of the submitted NDA and determine if the product’s benefits outweigh the known related risks/side effects. If it is determined that the benefits do outweigh the risks and that a quality product can be manufactured, the product will gain approval, meaning it can be legally marketed and distributed to the US market. The product will continue to be monitored by the FDA post-approval to ensure FDA compliance.
The FDA does not test the product before a decision is made; however, the approval process requires that the FDA inspects the product’s manufacturing facilities before gaining approval.
Generic Drug Approval Process
FDA approval is required for generic drugs; however, generics do not need to include animal or human data to establish safety the way brand-name products do for NDAs. Because of this, a different application, called the Abbreviated New Drug Application (ANDA), is required for the FDA approval of generic drugs.
The drugmaker is responsible for providing proof that the generic product ingredient is effective against the condition/illness being treated and is the same as that of the name-brand product. It also must show that the same amount of product enters the bloodstream in the same amount of time as the name-brand drug.
Over-the-Counter (OTC) Drug Approval Process
Approval for over-the-counter drugs can be done through an NDA or an OTC monograph.
The FDA defines an OTC monograph as a “rule book” for each therapeutic category establishing conditions, such as active ingredients, uses (indications), doses, labeling, and testing, under which an OTC drug is generally recognized as safe and effective (GRASE) and can be marketed without an NDA and FDA pre-market approval. Nonprescription drug products marketed under the OTC Drug Review are referred to as OTC monograph drugs.
Medical Device Approval Process
Medical devices follow a similar FDA approval process as name-brand drugs. Testing usually begins in a laboratory and progresses onto animal testing to address safety concerns. Then, the devices can be tested on humans to ensure safety and effectiveness.
An FDA decision can be made after the submitted data is reviewed. If approved, the device will be classified based on risk.
Class I devices are low-risk and non-surgically invasive devices such as bandages, handheld surgical instruments, and nonelectric wheelchairs.
Class II devices are moderate-to-high risk devices such as syringes, catheters, and contact lenses.
Class III devices are high-risk devices used for sustaining or supporting life or preventing impairment of human health such as pacemakers, fetal blood sampling monitors, and implants.
Patents
A new patent in the US is valid for 20 years after the application filing date. Before a patent expires, the generic drug company is federally allowed to synthesize a generic version of the patented product.
However, once the generic drug company submits an application, it must alert the patent holder if it decides to challenge the patent by claiming that the generic form doesn’t infringe on the name-brand patent or that the patent is invalid.
After the name-brand company has been notified, it has 45 days to take legal action against the generic drugmaker. If there are grounds for a legal argument, the approval will be delayed for 30 months unless the patent reaches expiration or is determined to be invalid or not infringed upon. If the generic drugmaker wins in court, the approval process will resume.
Reasons for Approval, Delay, and Denial
Drugs usually fail in late-stage development because they are deemed unsafe or ineffective or the supplied application data is inadequate, rendering the quality of the product indeterminable. A study in JACC: Basic to Translational Science found that approximately one in 1,000 potential drugs is progressed to human clinical trials after pre-clinical testing, and about 9 out of 10 new drugs fail in the human testing phase.
Sometimes, the drugmaker may have to conduct studies in a larger population or for a longer time span to obtain conclusive results. When approval is denied, the drugmaker will receive an FDA letter explaining the reasoning and offering an opportunity to address concerns. Then, the company is allowed to request a hearing, correct issues and submit changes, or withdraw the application altogether.
Manufacturing issues may interfere with the approval process since the FDA is responsible for inspecting manufacturing facilities during the application process. If the FDA observes an issue on-site, the company must correct it before approval can be granted.
Pay-for-Delay Agreements
Pay-for-delay agreements legally allow a name-brand drugmaker to financially compensate a generic drugmaker for delaying or even canceling the generic product release. Pay-for-delay patent settlements essentially restrict the generic drug market competition and keep name-brand drug prices high.
Rapid Approval Classifications
In 1992, the Prescription Drug User Fee Act (PDUFA) was passed in the US, producing two different time frames for approval: standard review and priority review. Normally, the FDA is allotted 10 months to review new drugs, whereas, under priority review, that time is shortened to 6 months.
The PDUFA permits the FDA to collect fees from drug manufacturers, and these user fees play an integral role in the expedition of the approval process.
According to the FDA, the PDUFA has allowed the FDA to bring access to new drugs as fast or faster than anywhere in the world. Since the PDUFA was passed, more than 1,000 drugs and biologics have come to market (i.e., HIV/AIDS antiretroviral drugs).
To give patients earlier access to critical new drugs, four rapid FDA approval designations exist — priority review, breakthrough therapy, accelerated approval, and fast track.
The designation of breakthrough therapy is intended to expedite the development and review of drugs used to treat severe, life-threatening conditions. Breakthrough therapy must have preliminary clinical data suggesting that the drug has significant treatment advantages over existing treatments on the market. In 2019, psilocybin-assisted therapy gained FDA designation as a breakthrough therapy for major depressive disorder and treatment-resistant depression.
Drugs that require many years to determine the health benefits in individuals may be ideal candidates for accelerated approval. The FDA granted Merck & Co. accelerated approval in 2021 for its drug Keytruda (pembrolizumab), which is used to target HER2-positive gastric cancer.
Drugs that treat severe diseases and fulfill an unmet medical need qualify for fast-track approval. As requested by Pfizer and BioNTech, the mRNA COVID-19 vaccine was fast-tracked in July 2020 to prevent death and serious illness during the global pandemic.
Potential Future Modifications to the Approval Process
Because many desired medications are held up in the lengthy FDA drug approval process, recent advances in technology focus on improving the speed of drug testing and supporting clinical trials.
Currently, the FDA is piloting artificial intelligence (AI) and machine learning (ML) technology to automate the early stages of review. Using algorithms and statistical models in AI will allow for outcome predictions with little to no explicit programming.
