Drug Development Process
The following graphic depicts the development process for a new drug, from test tube to new drug application review. Understanding the steps of the process, reviewing FDA guidance documents, and maintaining correspondence with the FDA via ongoing meetings, are all instrumental elements of the drug development process. This is also the development path for biologics that are used as drugs (i.e. erythropoietin, insulin, therapeutic antibodies). Biologics require an FDA approved Biologics License Application (BLA) for marketing authorization. Drugs require an FDA approved New Drug Application for marketing authorization. Discussions about drugs pertain to biologic drugs as well.
On average, it takes 10-15 years for an experimental drug to travel from the lab to U.S. patients. Only five in 5,000 compounds that enter preclinical testing make it to human testing. One of these five tested in people is approved . Furthermore, it costs a company approximately $802 million to get one new medicine from the laboratory to U.S. patients, according to a November 2001 report by the Tufts Center for the Study of Drug Development. Once a new compound has been identified in the laboratory, medicines are developed as follows:
Drug Development Activities
Preclinical Testing. A pharmaceutical company conducts laboratory and animal studies to show biological activity of the compound against the targeted disease, and the compound is evaluated for safety.
Investigational New Drug Application (IND). After completing preclinical testing, a company files an IND with the U.S. Food and Drug Administration (FDA) to begin to test the drug in people. The IND becomes effective if FDA does not disapprove it within 30 days. The IND shows results of previous experiments; how, where and by whom the new studies will be conducted; the chemical structure of the compound; how it is thought to work in the body; any toxic effects found in the animal studies; and how the compound is manufactured. All clinical trials must be reviewed and approved by the Institutional Review Board (IRB) where the trials will be conducted. Progress reports on clinical trials must be submitted at least annually to FDA and the IRB.
Clinical Trials, Phase I. These tests involve about 20 to 100 normal, healthy volunteers. The tests study a drug’s safety profile, including the safe dosage range. The studies also determine how a drug is absorbed, distributed, metabolized, and excreted as well as the duration of its action.
Clinical Trials, Phase II. In this phase, controlled trials of approximately 100 to 500 volunteer patients (people with the disease) assess a drug’s effectiveness.
Clinical Trials, Phase III. This phase usually involves 1,000 to 5,000 patients in clinics and hospitals. Physicians monitor patients closely to confirm efficacy and identify adverse events.
New Drug Application (NDA)/Biologic License Application (BLA). Following the completion of all three phases of clinical trials, a company analyzes all of the data and files an NDA or BLA with FDA if the data successfully demonstrate both safety and effectiveness. The applications contain all of the scientific information that the company has gathered. Applications typically run 100,000 pages or more. The average review time for the 28 new therapeutics approved by the FDA in 2005 was 12.5 months.
Approval. Once FDA approves an NDA or BLA, the new medicine becomes available for physicians to prescribe. A company must continue to submit periodic reports to FDA, including any cases of adverse reactions and appropriate quality-control records. For some medicines, FDA requires additional trials (Phase IV) to evaluate long-term effects.
FDA and Drug Development
The following bullets reflect key elements of FDA development guidance. The organization’s role in the process of working with sponsors on drug development is that of a guidance advisor.
Written guidance in the form of the following:
- Regulations, guidelines (incl. ICH), guidances
- Literature publications
- Regulatory letters
- (Statute, Congressional Reports)
Meetings in the following forms:
- Pre-IND (Investigational New Drug), EoP2 (End-of-Phase), EoP2a, EoP2, pre-NDA (New Drug Application), others as needed
- FDA Advisory Committee meetings
The FDA also provides guidance through podium presentations
What comprises FDA guidance
The following elements are key areas to which the FDA provides specific guidance, supported by an advisory role that should be taken advantage of by the sponsor, throughout the drug development process.
- Chemistry and manufacturing controls (CMC)
- Preclinical animal toxicology requirements
- Ethics of human clinical trials
- Documentary requirements for INDs, & NDAs
- Electronic records (21 CFR part 11)
- Trial design
Research by Margaret Rich