Engineering Chapter 1: Various Stages of Innovative Drug Research and Development
The research (discovery) and development of innovative drugs is a matter of large investment, long cycle, and high risk. Data shows that the average discovery and development cost of a new (innovative) drug in the United States is $0.5-2 billion, with the highest cost reaching $5 billion, and the average cycle is more than 10 years. In China, the average research and development time for an innovative drug is 12 to 15 years, and the average capital investment is 1.5 billion to 2 billion yuan.
In general, new drugs need to go through multiple stages from discovery and development to launch. Here is a brief introduction to each stage, and more content will be added in the future chapters.
1. Drug Discovery and Preclinical Development
1a Drug Discovery (ranging from 2-10 years): This step is the search for new compounds that have the potential to treat a specific disease. Taking small molecule compound drugs as an example, it includes steps such as confirmation of drug targets, synthesis of compounds, screening of active compounds, main efficacy studies, in vivo and in vitro tests.
1b Preclinical development: This step is a series of animal experiments (ranging from 3-6 years) Including pharmacological research (pharmacodynamics, pharmacokinetics), toxicological research (acute toxicity, long-term toxicity, carcinogenesis, mutagenicity, reproductive toxicity)
1c Clinical trial application (IND): Prepare IND materials, submit IND, preliminary review by Center for Drug Evaluation and Research (CDER), safety review, and respond.
2 Clinical trials (3-7 years) - there are three phases:
Phase I clinical trials include 20-100 cases, health people or patients, mainly for safety evaluation.
Phase II clinical trials include 100-300 patients, mainly for effectiveness evaluation.
Phase III clinical trials include 300-5,000 patients, expanding the sample size for further evaluation.
Traditionally, the clinical research of new drugs is divided into Phase I/II/III. Later, Phase II was divided into IIa and IIb (largely due to oncology drug research), and then the concept of Phase 0 research appeared (also because of the development of oncology drugs).
Phase 0: The purpose is to preliminarily determine whether an investigational drug is effective with a limited sample size (usually no more than 20) and a limited time (the treatment period for each patient usually does not exceed a few weeks) on the premise of meeting certain statistical requirements, whether a certain dose is effective, whether it should continue to be developed, and whether some methods for judging efficacy are feasible.
From the perspective of purpose, the Phase 0 study is also a preliminary judgment on the effect of the drug, similar to Phase II (especially IIa), so the design of Phase 0 is similar to the single-arm study of IIa, but due to the small sample size, it must meet certain statistical requirements, so it also has its own characteristics, and the design may actually be more complicated.
Phase I: it usually explores dose finding, dose-ranging, pharmacokinetics (PK) and pharmacokinetics (PD), and the sample size is not large (generally no more than 20, or around 20). Especially in PD, crossover studies are usually used because crossover studies have their own characteristics and are suitable for such design purposes.
Phase II: it is for preliminary judgment of efficacy and safety (in fact, safety runs through the entire research and development process), so it is generally called a safety & activity study (SA study). There are many approaches. According to different clinical disease environments and past data, single-arm, parallel-controlled RCTs, etc. can be adopted. The endpoint is generally surrogate rather than clinical outcome. If divided into IIa and IIb, IIa is often a single-arm, and the sample size is generally not more than 100; IIb is often a parallel RCT.
Phase III: it is a rigorous confirmatory clinical study that verifies the effectiveness of a drug. Clinical studies are introduced at many conferences, often using such studies as a template and presenting them within the framework of hypothesis testing.
3 New Drug Approval (NDA) for small molecular drugs or Biologics License Applications (BLA) for biologics
3a The initial marketing approval process includes: preparing NDA materials, proposing NDA, preliminary review, formal acceptance, substantive review, then material review and on-site inspection, and finally obtaining the review results.
3b Post-marketing studies and post-marketing re-approval
Post-marketing research is the clinical monitoring period: Phase IV clinical trials, with more than 2,000 subjects, and social inspections must be conducted at the same time. Post-marketing re-approval (generally 4-10 years after marketing): Re-examine the effectiveness and safety in the NDA.
3c Expansion of indications: After relevant research and trials, it is found that the drug is also effective in other diseases, and then it is applied to the regulatory agency for approval to expand the indications (therapeutic scope) to new diseases.
The risk of failure in the research and development of new drugs, especially first-in-class ones, is extremely high. Most projects are stillborn and fail to enter the clinical stage. After that, 90% of new drugs will fail in the clinical stage. Even if they complete clinical studies, they will still face strict review.
