The FDA as we know it today was born out of a 1937 tragedy in which 107 people died after taking the marketed “elixir” drug sulfanilamide, which prompted the government to enact more strict codes for food and drugs that could be legally sold in the United States [4]. Since then, the FDA approval process has continued to evolve in response to changes in drug technology, particularly in the realm of cancer therapy. Currently, there are three mandatory clinical trial phases through which a drug must go to be marketed in the United States, as well as a Phase 0 and a Phase IV which are sometimes required (Fig. 1). Given the lengthy, somewhat complex nature of clinical trials, as well as the wealth of cancer-treating nanoparticles spanning multiple phases, knowledge of the FDA approval process can provide a helpful context for evaluating the progress of a given treatment.

Before a therapy can reach clinical trials, it must be discovered, created, and tested both in vitro and in vivo. This period of invention and development is referred to as the “preclinical” phase and on average takes 6.5 years [5]. The ultimate goal of the preclinical period is to receive approval for an Investigational New Drug (IND) Application from the FDA. A successful IND lists the drug’s manufacturing information, clinical protocols, investigator information, and must also show a wealth of animal data suggesting positive pharmacological effects and tolerable toxicity [4]. In short, the transition from preclinical work to clinical trials requires a novel therapeutic that shows sufficient promise to be effective and safe in treating human disease. However, due to the diversity of nano-platforms, as well as the low number of nanoparticle therapeutics that have made it all the way to clinical approval, determining what constitutes a “promising” nanoparticle drug can be difficult; to this end, the National Cancer Institute developed the Nanotechnology Characterization Laboratory (NCL) in 2004 to address the standards for preclinical nanoparticle data [5, 6]. Researchers may apply via the NCL website (http://​ncl.​cancer.​gov) to have their preclinical nanomaterials and devices extensively characterized in an “assay cascade,” that is, a battery of tests to determine physical properties, toxicology, pharmacology, efficacy, and many other parameters. The NCL has the infrastructure to perform this crucial preclinical testing on a large scale, allowing researchers to characterize their nanotechnology far more rigorously than they could alone. Moreover, this process can provide an accurate prediction of whether or not a technology will likely face significant efficacy or safety issues when it reaches clinical trials.

While many therapeutics will move directly from a successful IND to Phase I trials, some will first go through Phase 0 trials. Phase 0 trials, also developed by the National Cancer Institute, generally involve microdosing (dosing at sub therapeutic levels) of the drug in order to obtain relevant pharmacokinetic data; this process was developed largely as a means of streamlining the FDA approval process by serving as an early benchmark of the translatability of an IND [7]. As with the NCL, Phase 0 trials provide more clarity in the matter of which therapeutics are ready to take the leap from preclinical studies to the arduous FDA clinical trials.

The bulk of the FDA approval process, both in terms of time and capital, lies in Phases I–III. Phase I evaluates the safety of the new drug as its primary endpoint. Generally, 20–100 volunteers are enrolled, and the drug dose administered is gradually increased in order to observe patient response. These volunteers are usually healthy, though exceptions can be made for especially life-threatening illnesses [4]. Phase I generally lasts anywhere from 6 to 18 months, and about 2/3 of all INDs will progress to Phase II [5]. Phase II trials look at the efficacy of the drug. 100–300 patients are typically enrolled and the effective dose method of delivery, optimal dosing interval, and further safety concerns are all evaluated [4]. Phase II can last anywhere from 6 months to 2 years, and is typically where the majority of drugs fail, given that it is the first stage to really evaluate the effectiveness of the new drug in humans [5]. Indeed, since 2003 only about 3 in 10 drugs have made it through Phase II testing [8]. If a drug is deemed effective and suitably safe after Phase II, it then moves on to Phase III. Phase III is the largest (and most expensive) of all the phases, with 1000–5000 patients from all over the United States often enrolled in randomized, placebo-controlled experiments [5]. This phase can take up to 10 years to complete, and roughly 10 % of the drugs that make it through Phase II will still fail in Phase III [4]. While less common than failure in Phases I and II, failure in Phase III can be caused due to safety or efficacy shortcomings that only manifest themselves in a large-scale pool of patients, or could simply be a result of the sponsoring institution running out of capital to fund the trial [9]. Success in Phase III depends largely on a drug’s efficacy or safety relative to a “gold standard” (i.e., it has to have some advantage over a market treatment currently used) [5].

If a treatment makes it through Phase III testing, the sponsor can file for a New Drug Application. The FDA will take 6–12 months to review this application; at the end of the review process, they can approve the drug if the Phase III data suggests increased efficacy relative to the gold standard, reject the drug if they believe it to have insufficient safety or to not represent a significant improvement over current treatments, or ask for more data on the drug [4]. An approved NDA means that the new drug can be marketed in the US, after which many drugs will undergo Phase IV trials. Phase IV studies take numerous forms, such as gathering data from consumers and double-blind tests in hospitals that are more similar to Phases II and III testing; these trials are largely concerned with drug safety, especially in populations such as children, which are rarely a part of premarket studies [10]. On the whole, it is estimated that the approval rate for all new oncology drugs entering clinical trials is somewhere around 5 % [7], with oncology drugs having a historically lower than average rate of making it through Phase III [8]. Moreover, an average drug requires somewhere around $1 billion total cost to make it through clinical trials [11].

The nanoparticle cancer therapies currently undergoing clinical trials primarily fall into the following three classes of therapeutic mechanisms: chemotherapeutics, short interfering RNA, and imaging agents.

There are currently many FDA clinical trials involving nanoparticle therapies for cancer, along with a few examples of nanoparticles that have gained FDA approval. The different nanotechnologies that have successfully translated from the lab to clinical trials will be discussed in the following categories: liposomes, polymeric nanoparticles, protein-bound chemotherapeutics, polymer-bound chemotherapeutics, and inorganic nanoparticles.