The Technology Readiness Level (TRL) scale was developed during the 1970s and 1980s. The National Aeronautics and Space Administration (NASA) introduced the scale as a discipline-independent program figure of merit (FOM) to allow more effective assessment and communication regarding the maturity of new technologies. Later, it was generalized to apply to any project, not only aeronautical or space projects, from its original idea until its deployment. Yet, there is increased use of the Technology Readiness Levels (TRL) scale as a planning tool for innovation management. As with every tool, the TRL scale has its strengths as well as its clear limitations. Although it is a standardized scale, different definitions may be found depending on the technology being assessed.
Here we are trying to understand the basics of the TRL scale as applied to the pharmaceutical drug discovery process. For Hardware & Systems technologies, please see this post. In future posts, we will do the same with Software, Pharmaceutical Developments, and Medical Devices compared to applied technology (NASA TRL scale).
From basic research activities to preclinical studies: TRL 1–4.
At the first stage, scientific findings are reviewed and assessed as a foundation for characterizing new technologies. Researchers are generating scientific and bioengineering knowledge bases, and scientific awareness (TRL 1).
The main focus is on the problem itself, as the intense intellectual work is to compile and generate research ideas, hypotheses, and experimental designs in scientific «paper studies.» This normally ends with developing new and improved protocols or research plans (activity-guided and/or high-throughput screening protocols, in-silico docking principles…). As the problem is deeply studied, hypotheses are formed and preliminary studies are set to define parameters and identify candidate concepts and/or therapeutic drugs (TRL 2).
It is time to start testing the hypothesis and collecting data to explore alternative concepts and identify and evaluate technologies supporting drug development. As initial screening hits are identified and the initial synthesis of candidates gets underway, limited in-vitro and in-vivo research models are carried out to set the initial proof of concept. Identification of hits (candidates), sites, and mechanisms of action (MoA), along with initial characterization of hits in preclinical studies, are carried out at the TRL 3 stage.
The next level starts with the first preclinical studies, using animal models to identify and assess potential safety and toxicity problems, adverse events, and side effects. At this level, exploratory studies of hits/leads are performed to establish formulation; routes of administration; method of synthesis; physical and chemical properties; metabolic fate and excretion/elimination; and dose ranging. The results of formulation studies, laboratory tests, and pharmacokinetic studies are used to demonstrate proof of concept and the safety of candidate drug formulations (TRL 4).
Investigational New Drug (IND) application corresponds to TRL 5.
Pharmaceutical leads are selected during the intense period of non-clinical and preclinical research studies involving parametric data collection and analysis in well-defined systems. Pilot lots of the drug candidate are produced for further development and provide the basis for a manufacturing process amenable to current Good Manufacturing Practice (cGMP)-compliant pilot lot production. At this level, GLP safety and toxicity studies in animal model systems are used to evaluate the pharmacokinetics and pharmacodynamics of candidate drugs. Available results are compiled in the draft technical data package, which contains data from animal pharmacology and toxicology studies, proposed manufacturing information, and clinical protocols for Phase 1 clinical testing. Now we are reaching a decision point at which it is determined whether sufficient data on the candidate drug exist in the draft technical data package to justify proceeding with preparation of an Investigational New Drug (IND) application.
Clinical trials fall within TRL 6–8.
Before starting clinical trials, a pre-IND meeting is held with the European Medicines Agency (EMA) and/or the United States Food and Drug Administration (FDA-CDER) to check the general adequacy of information and data to support submission of the IND application. After approval of the IND application, Phase 1 clinical trials are conducted to demonstrate the safety of the candidate in a small number of humans under carefully controlled and intensely monitored clinical conditions. At this level, production technologies are demonstrated through production-scale cGMP plant qualification. As pharmacokinetic and pharmacodynamic data meet clinical safety requirements to support the design of well-controlled, scientifically valid Phase 2 studies, we move through TRL 6.
Phase 2 clinical trials are conducted to demonstrate initial efficacy (preliminary evidence) and capture further safety, toxicity, and immunogenicity data. The product’s final dose, dose range, schedule, and route of administration are established from clinical data. By the end of Phase 2 clinical trials, a pre-Phase 3 meeting is held to discuss the results of Phase 1 and Phase 2 trials, clinical endpoints and/or surrogate efficacy markers, and test plans. Protocols or test plans provide a record of agreements and a basis for the sponsor to proceed with a Phase 3 clinical study or surrogate test plan. Then an updated IND application, amended with a new clinical protocol to support Phase 3 clinical trials or a surrogate test plan, is submitted (TRL 7).
The safety and effectiveness of the candidate drug are tested in Phase 3 clinical trials or surrogate tests. Trials are conducted to evaluate the overall risk-benefit of administering the candidate product and to provide an adequate basis for drug labeling. Process validation is completed and followed by lot consistency and reproducibility studies. A New Drug Application (NDA) is prepared and submitted to the EMA/FDA. With the issuance of an Approval Letter, after FDA/EMA review, we reach TRL 8.
Product launch and monitoring in the market: TRL 9.
At TRL 9, the new pharmaceutical drug can be distributed and marketed. Post-marketing surveillance studies (non-clinical or clinical) may be required and are designed. Phase 4 studies, such as safety surveillance, studies to support use in special populations, and clinical trials, are performed.