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From pipeline to prescription: New drug approval process

Optometry Times JournalMay digital edition 2021
Volume 13
Issue 5

FDA review pathway looks to balance innovation with data review

In an era driven by innovation, new medical therapies and expanding indications of existing treatments are at the forefront of providing the opportunity for improved patient outcomes. This is the case whether discussing the management of ocular disease, the multispecialty care required for the treatment of hospitalized individuals due to COVID- 19 and its complications, or disease prevention through vaccine development.

When we think about health policy related to pharmaceutical agents, drug pricing reform often takes center stage—and for good reason. However, the interest that has developed in not only newly approved drugs, but also in the process and science behind new medical breakthroughs leading to their availability, makes it worthwhile to clarify the processes and policies that have encouraged a wave of innovation.

The balance of innovation acceleration and resulting improved access to therapies with the continued need for the careful, methodical review of data form the basis to expand and develop policies and regulations. This balance guides new drug development in the United States under the purview of the FDA.

So, let’s talk process: How does a molecule developed in a laboratory end up as an innovative therapeutic agent that we prescribe to our patients? What is the role of the FDA in the process? Do all drugs go through an identical clinical trial and evaluation process? And why are some drugs approved more quickly than others? From bench to Rx pad

The pathway that leads to the marketing of a new drug is often a long, arduous, and expensive scientific venture. For every 5000 molecules screened, 5 make it to clinical trials, and usually only 1 becomes an approved new drug.1

It begins with basic science discoveries of pathophysiology of the disease process, which identifies targets for therapy. This preclinical phase of drug development has a high rate of failure and involves the identification, synthesis, and purification of a molecule and the determination of potential safety and efficacy. The practical application of basic science through translational research leads to drug candidates that undergo initial toxicology studies in nonhuman animals.2,3 Positive results in the preclinical phase lead manufacturers to filing an investigational new drug application with the FDA, which is a prerequisite to testing any product in humans.2-4

Clinical trials typically involve testing drugs in up to 3 phases over approximately 6 years.3 Small phase 1 trials evaluate the drug for toxicity in a group of healthy volunteers, phase 2 trials are designed to study the range of safe drug dosage in individuals with the condition, and phase 3 trials—the large, randomized, controlled clinical trials that we are most familiar with—include large groups of individuals and are used to establish efficacy of a drug.2-4

The studies that form the basis for the new drug application (NDA) or the biologics license application (BLA) that the FDA evaluates for affirmation of efficacy and safety are called pivotal trials, and these studies may be in phase 2 or 3.2,3 Study design can vary depending on the drug and indication and may include comparison with a placebo or with a well-known product (eg, timolol 0.5% ophthalmic solution) and may use surrogate markers as end points in place of clinical outcomes.

In evaluating drugs that treat chronic conditions, using a surrogate end point, such as reduction in intraocular pressure, in place of a clinical end point, such as visual field damage, greatly reduces the time required for the study period. However, there is no guarantee that improvement in a surrogate marker will directly translate to improvement in long-term patient outcomes.3,4

Once a pharmaceutical manufacturer believes that it has evidence to demonstrate safety and efficacy of a drug, it will submit an NDA or BLA to the FDA for consideration.4 Although the role of the FDA in the timeline of a drug’s life span may not begin for many years after a molecule is discovered, the framework that drugs are developed and evaluated within and incentives for development are guided through policy and regulations implemented by Congress and within the domain of the FDA.4

The goal of the FDA is person-centric: to ensure that human drugs in the United States are effective and reasonably safe.4 The FDA employs experts in science, medicine, and public health who are tasked with the evaluation of an NDA or BLA.3

There is no trick to the FDA approval of a drug— approval follows a logical pathway based on well-controlled clinical trials that are required to demonstrate safety and efficacy of a drug. There is an understanding of the balance of safety and efficacy in any new product. For example, if pivotal trial results show significantly increased efficacy of a novel drug compared with a known product, evaluators may allow for a reasonable increase in adverse effects.5

Regulation and efficiency are concepts that are traditionally at odds, but the modern FDA has aimed to balance both interests. Long review times of nearly 3 years in the 1980s and 1990s have been improved to the current average of 8 to 10 months because of the expansion of user fees.3,6

The Prescription Drug User Fee Act (PDUFA) was developed to streamline the review process of NDAs and BLAs, primarily by increasing the budget to allow for increased FDA personnel.3,5 As part of the PDUFA agreement, review deadlines are set by the FDA to accept or reject applications by 10 months following submission for typical applications or by 6 months for applications eligible for priority review.3,6 Drugs that may qualify for priority review must meet significant therapeutic advancement criteria compared with available treatments.3,5

As a result of the implementation of PDUFA, the FDA is one of the most efficient drug regulatory agencies in the world and often completes evaluation of data for therapies earlier than in Canada or Europe.3 The shift to a system of improved efficiency in which 45% of the FDA’s budget is funded through user fees means that a significant proportion of FDA staff salaries are funded by industry, which raises the concern of industry influence.7

Although PDUFA has reduced drug approval timelines, the assessment of safety in quickly approved drugs has been called into question. However, large evaluations of post-approval safety events have found no association between shortened review times and increased drug safety–related events.4,5

Following approval of a drug, the manufacturer continues to monitor adverse effects and clinical benefits, which may be formally evaluated through a phase 4 clinical trial.3 Adverse events identified in a clinical setting by physicians or patients are to be reported through the FDA’s Adverse Event Reporting System. Underreporting is a serious concern, and as a result a system called the Sentinel Initiative was developed to ensure the ability to evaluate data from a large number of individuals using electronic records, insurance registries, and insurance claims.3

Road to new treatments

Of interest are expedited pathways to drug development in the United States. In addition to priority review designation, 4 pathways allow for increased flexibility in developing new drugs that may be used in combination, which may allow for approval based on smaller or fewer trials that may not be randomized, controlled, or blinded; or based on traditional outcome measures.3,4

The Orphan Drug Act (1983) allows maximum flexibility to the design of pivotal trials, including single-arm studies and use of surrogate end points for drugs that treat rare conditions (fewer than 200,000 individuals affected in the United States), for example biallelic RPE65 mutation. To promote drug development for rare conditions, manufacturers are also eligible for the Orphan Drug Act tax credit which covers 25% of research and development costs and access to grants and additional market exclusivity.3,4

Fast-track designation (1988) was developed at the height of the AIDS crisis and may be granted to drugs that fill an unmet clinical need. Drugs that may qualify include those for conditions with no currently approved treatment, such as geographic atrophy. Drugs that receive this designation may be approved without phase 3 clinical trials. Additionally, continuous communication with FDA officials through the drug development process helps to ensure that concerns are quickly resolved or averted, which can significantly speed the development process.3,4

Accelerated approval (1992) may be granted to drugs based on evaluation of surrogate end points in clinical trials that are “reasonably likely to produce patient benefit” in drugs that fill an unmet clinical need for the treatment of serious conditions, which can shorten the length of pivotal trials.3,4 granted to drugs designed to treat serious conditions when preclinical data indicate significant improvement over current treatments. These drugs are eligible for the same features as fast-track designation, including early and frequent communication with the FDA, but have a more formalized list of actions that the FDA may take, resulting in decreased time to approval.3,4

The 21st Century Cares Act was passed by Congress in 2016 to accelerate drug discovery, development, and delivery of new treatments for patients in new ways, including allowing for the modernization of clinical trial design and incorporation of real-world or observational evidence into the FDA’s decision-making process. It emphasizes the use of the above pathways to expedite drug development and includes 2 new expedited development programs for biologics and devices.8

Pandemic impacts

The pandemic has resulted in never-before-seen collaborations among American agencies, worldwide health authorities, academia, and philanthropic organizations to expedite the development and evaluation of treatment and prevention strategies for COVID-19.9

The lag time in clinical testing often related to funding, data acquisition and evaluation, and human resources has been trimmed to a minimum, while the rigorous scientific process required for new drug development continues.9

A range of short- and long-term impacts of the pandemic on clinical trial progress have been and will continue to be seen. Effects have ranged from pausing trial participant enrollment and study visits, hindering individuals’ access to potentially lifesaving treatment by limiting entrance to clinical trials, to delaying or canceling new projects.

For investigators, especially early-stage investigators, changes to original timelines put funding in jeopardy, threatening new scientific progress. In ongoing trials, fewer consistent follow- up visits and resulting smaller sample sizes and reduced statistical power can make it more difficult to determine the benefits of a particular therapy—or its adverse effects.10

Bottom line

At a glance, the pathway of drug development can seem convoluted at best and opaque at worst. Understanding the process and regulations that permit the FDA to ensure that the benefits of a drug outweigh the known risks prior to entering the marketplace can help optometrists make informed treatment decisions.

Continued developments to regulatory framework aim to ensure the most innovative, transformational drugs have a pathway to approval and still meet safety and efficacy requirements with the goal of increasing availability and access to potentially game-changing therapies.


1. Kraljevic S, Stambrook PJ, Pavelic K. Accelerating drug discovery. EMBO Rep. 2004;5(9):837-842. doi:10.1038/ sj.embor.7400236

2. Mohs RC, Greig NH. Drug discovery and development: role of basic biological research. Alzheimers Dement (N Y). 2017;3(4):651-657. doi:10.1016/j.trci.2017.10.005

3. Darrow JJ, Avorn J, Kesselheim AS. FDA approval and regulation of pharmaceuticals, 1983-2018. JAMA. 2020;323(2):164-176. doi:10.1001/jama.2019.20288

4. Kesselheim AS, Darrow JJ. FDA designations for therapeutics and their impact on drug development and regulatory review outcomes. Clin Pharmacol Ther. 2015;97(1)29-36. doi:10.1002/cpt.1

5. Grabowski H, Wang YR. Do faster food and drug administration drug review adversely affect patient safety? an analysis of the 1992 Prescription User Fee Act. J Law Econ. 2008;51(2):377-406. doi:10.1086/589934

6. Carpenter MA, Novack GD. FDA review times for new drugs in ophthalmology. Ocul Surf. 2020;18(4):963-966. doi:10.1016/j.jtos.2020.08.003

7. Fact sheet: FDA at a glance. US Food and Drug Administration. November 2020. Accessed November 6, 2020. https://www.fda.gov/about-fda/fda-basics/fact-sheetfda- glance

8. Kesselheim AS, Avorn J. New “21st century cures” legislation: speed and ease vs science. JAMA. 2017;317(6):581-582. doi:10.1001/jama.2016.20640

9. Corey L, Mascola JR, Fauci AS, Collins FS. A strategic approach to COVID-19 vaccine R&D. Science. 2020;368(6494):948-950. doi:10.1126/science.abc5312

10. Servick K, Cho A, Couzin-Frankel J, Guglielmi G. Coronavirus disruptions reverberate through research. Science. 2020;367(6484):1289-1290. doi:10.1126/ science.367.6484.1289

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