FDA/Regulatory
Drug Development: From Discovery to NDA
Introduction
The time it takes from starting a program to selling a product can vary but is usually estimated to be around 10 years and the total cost associated with bringing a drug to market is widely cited to be at least $850 million. These numbers outline high stakes and whether you are an investor or just new to the industry, it is crucial to understand the basic path from bench to bedside.
This review isn’t meant to be a discussion filled with nuance and detail (frankly, I don’t know a whole lot of the detail) but rather, a template / 20,000 foot overview of the industry and the steps required of a company thinking of marketing a product as medicine in the US.
Outline of Clinical Path
Drug Discovery
We’ll start the discussion at the point of having an idea. Company X has an idea. They conduct research and find a protein on the surface of cancer cells that they theorize aids in tumor growth. So, armed with a wad of cash (if only were this easy) they begin their quest to find some method of inactivating the protein. I’m hand waving here because this is where the magic happens but let’s assume that by using RNAi, monoclonal antibodies, small molecules or other newly discovered technologies, they succeed in finding a really good candidate to block this receptor and it has acceptable in vitro properties.
Preclinical Development
This is where the fun begins. The company begins testing the compound in animals for toxicity and for efficacy in models of disease. In most cases, animal models are a pretty poor representation of actual human affliction but this is a discussion for another day (if you’re interested, Derek Lowe @ In The Pipeline has sublime posts on this topic). After optimizing the ADME / pharmacokinetics properties and exhibiting efficacy in disease models and deciding the compound is good enough to be put in humans and into clinical trials.
Time in Stage: 0-4 years
Investigational New Drug Application (IND)
Before a drug is allowed into humans for testing, it must be cleared through the FDA in what is called an IND. The company submits an application with clinical trial design, investigator qualification and preclinical toxicology that demonstrates the case to the FDA for a phase I trial. In general, trials will specify the number of patients per treatment group, doses and the primary (the FDA approvable test for efficacy) and secondary endpoints (other tests that support the efficacy and safety).
Phase 1
A phase 1 trial is all about safety and are highly regulated. Usually, young, healthy individuals are paid to take the drug while the company monitors more parameters that you can possibly imagine, including ADME as mentioned above in addition to pharmacodynamics (how the drug interacts with the body). Don’t be fooled by success in phase 1 trials; in the vast majority of trials in this stage, the only thing you can deduce from a positive results is that the drug is safe in healthy individuals!
Time in Stage: 1-1.5 years
# Patients: 10-150
% Drugs successfully tested: ~67%
Phase 2
Phase II is the proof of concept phase, with some safety thrown in for good measure. In these trials the drug is finally given to patients that are diseased. Usually, a company tries a range of doses to optimize the efficacy/adverse event profile for the drug in phase 3.
As you might imagine, phase 2 trials are where people start paying attention and often, this is where people start losing a handle on the complexity of information. I can’t give you a case by case, “what to do if” guide, due to the sheer heterogeneity of clinical trials and indications but I can can give you two things to watch out for in general before you begin drawing conclusions. Check that the trial follows these two guidelines:
- The primary trial endpoint is FDA approvable (searchable FDA guidance docs here).
- The trial is double blind and placebo controlled (or at least have a control group).
Trials that conclude in an approvable endpoint are nice and easy, which is why I’ve included the point. In diabetes, for instance, the primary endpoint is change in glycosylated hemoglobin (HbA1c). Period. You don’t change A1c, you don’t get approved (at least at the time of this post). Many indications don’t have validated endpoints and it’s not so easy. Again, just keep your head up on this one.
As for trial design, it would be nice if every trial was double blind and have a control group. This just simply isn’t the case in all phase 2 trials. It’s not evil. The company (generally) isn’t trying to trick anyone. It’s just that trials that are open or have no placebo/comparator gold standard treatment are hard to interpret and what look like positive results could just be statistical noise. Again, just keep your head up.
Companies loudly trumped phase 2 success to drive stock price and the landscape is littered with failed phase 3 programs after showing efficacy (usually in an open or non-controlled trial) in phase 2. Lesson: there are no free passes in in drug development.
Time in Stage: 1- 2 years
# Patients: 10-300
% Drugs successfully tested: ~33%
Phase 3
Phase 3 trials are the Rose Bowl of drug development. They are why you play the game. The trials usually cost hundreds of millions of dollars and last over a year, maybe two or three. They are almost universally double blind and and have a control group (either placebo or standard treatment regime). Results in these trials are primarily what make or break a drug before the FDA.
Again, there is something to watch our for when a company presents it’s phase 3 data. First, hitting the primary endpoint is key. This should be the first thing the press release mentions and the release should have a huge portion of its text devoted to primary endpoint results. Sometimes, safety or other endpoints will be stated upfront and the primary results are tucked near the end; this should signal a huge red flag. While it is not unheard of for a program fail a primary endpoint and get approved, it is unusual (for a recent example, check out Promacta from GSK).
Time in Stage: 1- 4 years
# Patients: 500-2000
% Drugs successfully tested: ~70%
New Drug Application (NDA)
After phase 3 results are collected, assuming positive efficacy and safety, the company files a new drug application (NDA) with the FDA containing all the data making the case for approval.
The detailing of the NDA and approval process will conclude in another post.
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