From Phase 1 to FDA Approval: Following a Drug Through the Development Pipeline (2023)

New drugs are celebrated for the lives they can improve, but it’s a long and arduous journey for those developing them and most treatments don’t make it to FDA approval.

From Phase 1 to FDA Approval: Following a Drug Through the Development Pipeline (1)

From Phase 1 to FDA Approval: Following a Drug Through the Development Pipeline (2)

The room full of researchers and doctors erupted in applause around Peter Chin as positive results from the phase 3 trial of ocrelizumab were announced. After over a decade of hard, uncertain work on the multiple sclerosis drug, the team celebrated their success. “Some people were crying and others were cheering,” he recalled, “because you realize when you see those results that you contributed to something that may make a difference in people’s lives.”

(Video) FDA Approval Pathways 101

Ocrelizumab went on to become the first therapy for primary progressive multiple sclerosis ever approved by the US Food and Drug Administration a couple years after this celebration. However, that achievement followed nearly 2 decades of preclinical research, clinical trials, and regulatory review, the arduous path that all new drugs and biologics must take before they reach the physicians who prescribe them.

Early Clinical Trials Exploring Possibilities

Before the US Food and Drug Administration (FDA) approves products, they undergo an extensive three-phase clinical trial process. During phase 1 and 2, drugs are tested on small to medium sized groups of patients to examine toxicology and pharmacodynamics and to test for efficacy and safety. Then, phase 3 trials administer the drug to an even larger group of patients to confirm efficacy and compare results with other treatments. Not all drugs are successful, however, with many failing because of safety or efficacy concerns. Finally, sponsors submit the results in a lengthy and thorough application to the FDA and wait for approval or denial.“Drug development is a really challenging endeavor and the vast majority of investigational medicines don’t make it to approval,” Peter Chin, MD, MSHS, Group Medical Director for Neuroscience at Genentech told MD Magazine. Nonetheless, year after year, pharmaceutical companies submit the Investigational New Drug applications (INDs) that are required before clinical testing may begin.

Chin, a neurologist whose work has focused on multiple sclerosis (MS) for more than a decade, was involved in the development of ocrelizumab (Ocrevus, Genentech) from the beginning of its clinical trials. “I worked on the original IND, or initial new drug application, and had a hand in the design of the phase 2 study in relapsing remitting MS,” he said.

For certain physicians in this field of work, the curiosity begins early on in their careers. Sheena Aurora, MD, a medical fellow and migraine launch leader for Eli Lilly and Company became interested in migraine research as a second-year neurology resident. “I started working in clinical research when I was in my residency,” Aurora told MD Magazine. “In fact, I moved from India to the US because I really was interested in research and in India there weren’t any research opportunities.”

A phase 1 trial of galcanezumab (Eli Lilly and Company), a drug that Aurora works on, included 160 healthy participants. Phase 1 trials are typically focused on evaluating toxicity and determining how the drug is metabolized and excreted. These trials usually include about 20-80 participants who are healthy volunteers, though those numbers do vary.

Like many early trials, the phase 1 galcanezumab study focused on the pharmacokinetics and pharmacodynamics of the drug, laying the groundwork for later trials. Later on in the process Aurora helped design the phase 2 proof of concept trial that led to Lilly’s years-long series of trials of the drug for migraine and headache prevention.

The Growing Expectations for Phase 3 Clinical Trials

According to the FDA, approximately 70% of drugs proceed from phase 1 trials, while just 33% successfully move from phase 2 into phase 3 studies. Understandably, the researchers who dedicate years to working on these efforts are thrilled when progress is made. “I feel like it’s a child as it’s evolving from phase 2 to completion of phase 3 and then through the process of regulatory submission,” said Aurora.Even with drugs that have successfully passed through phase 1 and 2 trials, uncertainty looms in phase 3. Chin recalled the challenge of designing the phase 3 Oratorio trial of ocrelizumab for primary progressive MS (PPMS) and the numerous hurdles he faced just in planning the study. No other company had successfully conducted a phase 3 trial for PPMS, and very few, he pointed out, had even made an attempt.

(Video) The Drug Development Process

“There were a lot of unknowns that we had to overcome and some of the challenges in designing clinical trials include having the right outcome measures, understanding how they behave, the statistical analysis of the primary endpoint, selecting the right patient population, and also the operation conduct of the study,” said Chin. “All of these things had to be put together. There really is no guarantee that you’re going to be successful.”

A key characteristic of phase 3 trials is their length, especially those studying progressive diseases like multiple sclerosis. The Oratorio trial began in early 2011 and lasted through the fall of 2015. “During that whole time there’s no way to know if the investigational medicine is effective or not — we found out at the very end,” Chin said.

Typically, these pivotal trials also include much larger groups of participants, from about 1000 to 3000. However, in studies for less common conditions those numbers may be smaller. The Oratorio trial, for example, included 732 patients with primary progressive MS and the phase 3 trials of galcanezumab for migraine prevention, EVOLVE-1 and -2, included 862 and 922 patients, respectively. Conversely, the now-approved asthma drug, benralizumab, was tested in 1306 patients during the CALIMA phase 3 trial.

No matter the number of patients or the length of the trial, the wait doesn’t end with the last administered dose or recorded piece of data. Trials of this size and scope are followed by lengthy data analysis. Teams of statisticians and programmers clean and process the massive database in a systematic approach, which is pre-specified in the study design to avoid bias.

Trials and Tribulation

When the data analyses are finally complete, the research team comes together to hear the results. For some, like the ocrelizumab team, these gatherings are a wonderful celebration. “It was just a really gratifying moment,” said Chin, recalling the joyful crying and cheering that filled the room that day. However, not all studies end with such celebration.When there is preliminary evidence of possible success in multiple indications, pharmaceutical companies might consider testing the drug in several studies for other conditions or groups of patients. Following the trial of galcanezumab for migraine prevention, Eli Lilly initiated 2 additional phase 3 studies evaluating the drug’s performance in episodic and chronic cluster headache. In this case, the trial of episodic cluster headache met its primary endpoint, but the chronic cluster headache trial did not.

“Obviously, it’s disappointing,” Aurora said. “You wonder about it. Is it the biology that is different? Why didn’t it separate from placebo? That’s where the scientist in me comes out and says ‘Let’s look at the science.’”

In another case, benralizumab received FDA approval for treatment of severe eosinophilic asthma in 2017, but the more recent GALATHEA trial of benralizumab for chronic obstructive pulmonary disease reported negative topline results.

(Video) An Overview of the Drug Development Process

In a competitive arena, negative results can be a major setback for pharmaceutical companies as well as the patients they ultimately hope to serve. However, researchers emphasize the value of negative results that put the research one step closer to a treatment that will improve patients’ lives.

FDA Application and Approval Process

“I’m a big fan of not only publishing positive data, but also contributing to science with negative data because we can learn so much about the disease and mechanism by publishing our negative studies as well,” Aurora said.Another process awaits the drugs that show promise during preclinical lab studies and continue to succeed throughout the phases of clinical testing — thorough vetting by the FDA, specifically the Center for Drug Evaluation and Research (CDER). “An enormous amount of work occurs involving hundreds of people and interactions with approval agencies,” Chin explained.

Since 1938, a new drug application (NDA) has been submitted to the FDA for every new drug approved in the US. These thorough applications include safety and efficacy data from all stages of preclinical and clinical trials, proposed labeling, information on potential drug abuse, patent information, data from any studies conducted internationally, information on institutional review board compliance, as well as directions for use.

Chin remembered that the ocrelizumab application contained millions of pages of data pulling from studies along each step of the process. “There’s an army of people that actually have to complete that process for a program that’s as large as the ocrelizumab program,” he said. “But it’s well worth it because there’s a good chance that at that point, with positive data from phase 3 trials, the drug may be approved and have a good chance of potentially transforming people’s lives.”

The FDA has had a two-tiered evaluation process in place since the Prescription Drug User Fee Act (PDUFA) was passed in 1992. The Standard Review takes about 10 months, while drugs granted Priority Review are fast-tracked to a 6-month time-frame.

Priority Review may be granted to drugs that display evidence of effectiveness in treatment, prevention or diagnosis of a condition, that eliminate or reduce a drug reaction, that improve patient compliance leading to improvement in serious outcomes, or that show safety and efficacy in a new subpopulation. Ocrelizumab, with its potential to significantly reduce disability progression in patients with PPMS and relapsing remitting MS, was granted Priority Review in addition to the Breakthrough Therapy designation it had already obtained.

Following the acceptance of an NDA submission, an FDA review team of medical doctors, chemists, statisticians, microbiologists, pharmacologists, and others works to determine whether data show that the drug’s benefits outweigh its risks. Additionally, for some cases the FDA includes an advisory committee to provide independent assessment of the application.

(Video) FDA Approval: Drug Development (Part I)

"Some considerations would be if it's a drug that has significant questions, if it's the first in its class, or the first for a given indication," said Mark Goldberger, MD, a former director of one of CDER's drug review offices. "Generally, FDA takes the advice of advisory committees, but not always," he says. "Their role is just that — to advise."

After months of deliberation and input from the team of expert reviewers, the FDA issues either an approval or complete response letter. Drugs may be delayed or denied due to safety issues, a failure to sufficiently prove efficacy, or problems with the drug manufacturing process, which is also inspected by FDA officials.

Once again, however, Chin and the team working on ocrelizumab had reason to celebrate. The FDA’s approval of ocrelizumab on March 28, 2017 made waves as it became the first drug approved for the treatment of primary progressive multiple sclerosis.

Chin’s pride while recalling that day was unmistakable. “I’m having a hard time finding the words to describe this feeling. Joy and gratification are the two words that come to mind,” he said. “There’s also a sense of achievement on behalf of people, knowing that now, the drug that you worked on and that so many other people worked on over such a long period of time, is actually going to make a difference in some people’s lives and hopefully many people’s lives for a long time to come.”

Passing the Baton

In 2017 the CDER approved 46 novel drugs, over twice the number approved in 2016. So far this year, the agency has approved 15 new drugs. Many more are in review, including galcanezumab for the prevention of migraine, which will likely face a decision by the end of 2018.For her mother and all the patients with debilitating migraine whose lives will be impacted by a long-term migraine prevention treatment, Aurora is looking forward to that decision. “I’m really excited about ushering in this new era for migraine prevention, because there haven’t been any drugs to work on migraine prevention forever,” said Aurora.

In the end, whether end points are met and applications are approved or not, clinical researchers know they are in this process for the long haul as they continually work to develop treatments and improve our collective knowledge of how drugs can help clinicians treat their patients.

“Clinical research is somewhat of an infinite relay race,” Chin said. “You always learn from the last leg, whether it’s positive or negative, and the baton is passed to the next sponsor of a new clinical trial to take what was learned from the last one and design a better trial in the hopes of being successful or being more successful.”

(Video) Drug Discovery Phases = Introduction to Drug Development | Drug Discovery | Drug Development


What is Phase 1 of FDA approval? ›

During Phase 1 studies, researchers test a new drug in normal volunteers (healthy people). In most cases, 20 to 80 healthy volunteers or people with the disease/condition participate in Phase 1.

Which of the FDA approval phases occurs after FDA approval? ›

Once FDA approves a drug, the post-marketing monitoring stage begins.

What are the three phases of the drug development pipeline? ›

The complexity in drug development has increased manifolds over the past 40 years, requiring preclinical phase of drug development, investigational new drug (IND) application, and complete clinical testing before marketing approval from the FDA.

How long does it take from Phase 1 to FDA approval? ›

Priority Review: During Priority Review, the FDA takes action on a new drug application within six months, compared to 10 months under standard review.

How long does it take to get approved for Phase 1? ›

On average, it takes 10.5 years for a Phase I program to progress to regulatory approval.

How long after FDA approval is a drug available? ›

The FDA will then take 6-10 months to review all of the data submitted and either accept or deny the NDA. Once a medication is approved, the FDA requires the manufacturer to continue to monitor safety of its drug.

What are the 3 phases of FDA approval? ›

Phases of Clinical Trials
  • Phase 1 Clinical Trial. The purpose of Phase 1 is to ensure that the treatment is safe in humans and to determine how and where it distributes within the body. ...
  • Phase 2 Clinical Trial. ...
  • Phase 3 Clinical Trial. ...
  • Monitoring Post-FDA Approval.
Sep 2, 2021

How does the FDA approval process work? ›

A team of CDER physicians, statisticians, chemists, pharmacologists, and other scientists reviews the company's data and proposed labeling. If this independent and unbiased review establishes that a drug's health benefits outweigh its known risks, the drug is approved for sale.

What are the 4 stages of drug development process? ›

Drug development can be divided into four phases: discovery, preclinical studies, clinical development and market approval. The image below provides an overview of the process, including an estimated timeline for each step.

How many phases are there to the FDA approval process? ›

Drug Review Steps Simplified

Phase 1 studies (typically involve 20 to 80 people). Phase 2 studies (typically involve a few dozen to about 300 people). Phase 3 studies (typically involve several hundred to about 3,000 people). The pre-NDA period, just before a new drug application (NDA) is submitted.

In which phase of trial is it not necessary to take approval from FDA? ›

Phase 0 clinical trials, developed in response to the United States Food and Drug Administration (FDA)'s recent exploratory Investigational New Drug (IND) guidance, are intended to expedite the clinical evaluation of new molecular entities.

How often do Phase 1 trials fail? ›

It takes 10 to 15 years and around US$1 billion to develop one successful drug. Despite these significant investments in time and money, 90% of drug candidates in clinical trials fail.

How long does it take from Phase 2 to FDA approval? ›

They found that, on average, it took 10.5 years for a drug to get from Phase I to regulatory approval. Looking at individual stages of the process, the averages were 2.3 years for Phase I, 3.6 years for Phase II, 3.3 years for Phase III, and 1.3 years between Phase III and regulatory approval.

How long does it take from Phase 2 to approval? ›

Phase II typically takes about 2 years. Phase III Clinical Trials: These are the definitive, large randomized trials that are submitted to the FDA in order to obtain approval of a drug. This phase examines the effectiveness as well as the safety (adverse events) of the new drug.

Which FDA approval process takes the longest? ›

The FDA approval process can take between one week and eight months, depending on whether you self-register, submit a 510(k) application or submit a Premarket Approval (PMA) application.

How long is the drug development process? ›

There is no typical length of time it takes for a drug to be tested and approved. It might take 10 to 15 years or more to complete all 3 phases of clinical trials before the licensing stage. But this time span varies a lot. There are many factors that affect how long it takes for a drug to be licensed.

What is the quickest FDA approval? ›

Fast Track designation must be requested by the drug company. The request can be initiated at any time during the drug development process. FDA will review the request and make a decision within sixty days based on whether the drug fills an unmet medical need in a serious condition.

What is the difference between Phase 1 and Phase 3 clinical trials? ›

Phase 1 trials are the earliest phase trials and phase 3 are later phase trials. Some trials have an earlier stage called phase 0, and there are some phase 4 trials done after a drug has been licensed. Some trials are randomised. This means the people taking part are put into one of the treatment groups at random.

What is Phase 1 vs Phase 2 clinical trial? ›

Phase I trials test if a new treatment is safe and look for the best way to give the treatment. Doctors also look for signs that cancer responds to the new treatment. Phase II trials test if one type of cancer responds to the new treatment. Phase III trials test if a new treatment is better than a standard treatment.

Which of the following are considered as Phase 1 trial? ›

A phase I clinical trial tests the safety, side effects, best dose, and timing of a new treatment. It may also test the best way to give a new treatment (for example, by mouth, infusion into a vein, or injection) and how the treatment affects the body.

What are the 4 phases of FDA approval? ›

Information For
  • Step 1: Discovery and Development.
  • Step 2: Preclinical Research.
  • Step 3: Clinical Research.
  • Step 4: FDA Drug Review.
  • Step 5: FDA Post-Market Drug Safety Monitoring.
Jan 4, 2018

What is the difference between a Phase 1 and Phase 1b study? ›

Phase 1a will involve dose escalation to determine the maximum tolerated dose (MTD). The MTD will be determined on the basis of the results from the safety evaluation. Phase 1b will involve cohort expansion at one or more dose levels to determine the recommended Phase 2 dose.

How many drugs pass Phase 1? ›

A Phase I trial takes several months to complete. About 70 percent of experimental drugs pass this initial phase of testing.


1. Drug Development - Ataxia Drug Discovery Pipeline
(National Ataxia Foundation)
2. The Road from Clinical Development to a Drug
3. Translational Science in Drug Development: Surrogate Endpoints, Biomarkers, and More - Day 1
(Duke Margolis)
4. The Four Phases of Clinical Trials | Diversity in Clinical Trials | AKF
5. The Drug Discovery Process
6. Section 1. Lecture 2 - Drug Development Overview
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