We are all interested in having the promising new agents that we hear about in news stories emerge through clinical trials to become a proven, valuable anti-cancer agent in human patients that becomes commercially available.  But that process takes a very significant amount of both money and time.  One recent and rather famous book, The $800 Million Pill, described the drug development process and indicated that it cost several hundred million dollars to bring a new agent to market (hence the name).  In addition, the common estimates are that about 1 in 1000 agents gets from drug discover to te marketplace, that it takes 10-15 to go through that process, and that about 1 in 5 agents that is tested in humans is ultimately approved for clinical use.  So let’s review the highlights of the process, which is shown in a figure below:

  (click to enlarge)  You can see that there are many steps in the daunting process.

The figure, and a lot of the content of what I’m talking about, is covered at a very good website that is run by the Center for Drug Evaluation and Research, which is part of the US FDA. 

  The first step in the drug discovery and development process is preclinical testing, which is done through in vitro (test tube) testing and animal models.  This work gives the earliest evidence in support of an agent having the effect we’re looking for, such as killing cancer cells or leading to tumor shrinkage/death in animals.  Much of this work also focuses on establishing the safety profile of the drug, including details of how the drug is absorbed, metabolized and excreted.  Once this work can provide a reasonable sense of assurance that work in humans, a company can file an investigational new drug application, or IND.

   At that point, if trials are approved through institutional review boards, clinical trials can proceed.  From this point, there are some data showing that it’s about 5-8 years from the start of clinical testing to drug approval, and it varies by company, which are shown as anonymous letters in the figure below.  The likelihood of bringing a drug to market also varies by company, with a range of about 5% all the way up to 30%.

   Phase I trials are generally small trials of 15-30 patients that are designed to test the safety of a new drug or combination, usually escalating from a dose expected from animal trials to be well below the limits for safe administration.  These trials do not generally focus on a single tumor type, but rather recruit a broad sample of cancer patients.  From this careful assessment during gradual escalation of dose, the phase I trial defines a maximum tolerated dose, with the planned phase II dose usually just below that. 

These trials may also give a hint of the clinical value of a new drug.  Obviously, most cancer patients enroll on these trials in order to gain early access to a novel treatment, which may have a relatively small likelihood of proving beneficial, but we do certainly see patients who show responses to new drugs on phase I trials.  It’s great for them and provides a vote of confidence that we’re on the right track with an agent.  Drug companies will sometimes shape their future clinical development of a drug based on responses to phase I agents.  For instance, if a drug produces an objective response in a patient or two with lung cancer in early testing, they may be much more likely to focus larger future clinical trials on lung cancer. 

  From the identification of an appropriate dose from Phase I work, and also having potentially identified patient populations that may respond well to a new agent, we move on to phase II trials.  These are trials that are usually with fewer than 100 patients and often just a few dozen, may be conducted at a single center or at several, but that are focusing on identifying the utility of a particular drug at a particular dose and schedule in a fairly uniform patient population (such as second-line treatment of SCLC, or never-smokers with a lung adenocarcinoma who previously responded to an EGFR inhibitor and then progressed, etc.).

These trials aim to clarify the activity of an agent, looking at response rate and sometimes survival and/or time to progression, in order to determine whether the tested approach is active enough and safe enough to proceed to larger phase III trials.  They usually have a single arm, so enrolled patients are receiving a particular agent or regimen, but there has been a growing trend toward randomized phase II trials in which patients with the same eligibility characteristics (same type of cancer, stage, performance status, etc.) are randomized to agent or regimen 1 vs. agent/regimen 2, then “picking the winner” based on which approach appears more active. 

   Phase III clinical trials are large, generally with several hundred to more than a thousand patients, and these trials directly compare a new approach to the current standard of care.  These trials randomize patients to one approach or another, and they measure the success of one arm over another by important endpoints such as overall survival, symptom improvement/quality of life, etc.

  These trials usually take many months and sometimes even years to be completed, and they are generally conducted at many different centers around the country or even many countries, all enrolling patients with similar characteristics to answer the same question.  When the results become available, they are usually very important, especially if the new approach is superior to the old standard. 

  If a new agent is shown to be better than the prior approach we were using previously using, as shown by phase III trial research, a company will submit a new drug application, or NDA.  This is basically an enormously large document (>100,000 pages) that includes every scrap of information every produced about the drug, detailing production standards, safety, efficacy results, and proposed labeling.  Once approved, there is also post-marketing surveillance by the company, which is the reviewing of data from the larger clinical experience of that drug once it is approved, in case new safety issues emerge.

That’s a lot of information, perhaps more than you need, but in case you’re reading about various phases of trials, or want to get a sense of how close or far a new agent is from being a new available drug in our lung cancer armamentarium, this information will be here as a reference.