New Drug Development & Approval Process

New Drug Development & Approval Process

1. Definition & overview of the new-drug pipeline

• A new drug is, in the regulatory sense, a chemical or biological agent that becomes a "legal drug" only when approved by a national regulatory agency — the US FDA, the European Medicines Agency (EMA), or in India the Central Licencing Authority (CLA)/CDSCO (G&G 14e Ch.1, p.3).
• NDCT-2019 statutory definition of "new drug" (India) — a drug is "new" if it is: (i) not used in India to any significant extent and not yet approved as safe & efficacious by the CLA for its claims; OR (ii) an approved drug now proposed with modified/new claims (new indication, route, dosage, dosage form); OR (iii) a fixed-dose combination of separately-approved drugs combined for the first time in a fixed ratio; OR (iv) a modified/sustained-release form or novel drug delivery system; OR (v) a vaccine, r-DNA product, living modified organism, monoclonal antibody, cell/stem-cell-derived product, gene-therapeutic product or xenograft (NDCT-2019 r.2(1)(w), p.5) [CDSCO].
  • "New drug" status persists for 4 years from the date of CLA permission for ordinary drugs; categories (iv) modified-release/NDDS and (v) biologicals are always deemed new drugs (NDCT-2019 r.2(1)(w) Explanation, p.5) [CDSCO].
• A new chemical entity (NCE) / new molecular entity (NME) is a novel molecule not previously tested in humans; NDCT-2019 defines NCE as a substance never approved as a drug by any regulator and proposed to be developed as a new drug "for the first time by establishing its safety and efficacy" (NDCT-2019 r.2(1)(v), pp.4–5) [CDSCO]. (KDT/Padmaja 8e Ch.5, p.69–70)
• The pipeline is arduous, highly technical and enormously expensive — only about 1% of compounds that enter full testing become licensed medicines; the cost of an NCE from synthesis to market is estimated at >$1.6 billion (Bennett & Brown Ch.3, pp.28–31); G&G cites $1–4 billion per NME (G&G 14e Ch.1 Table 1-1, p.14) and a development timeline that may exceed 15 years including up to 10 years of clinical study (Bennett & Brown Ch.3, p.30 footnote).
• Brunton frames it as drug invention rather than drug discovery — today only a fraction of new drugs come from nature; most are "totally new compounds, painstakingly optimized against many criteria through an interplay of design and experimentation" (G&G 14e Ch.1, p.4).
• The four key decision points of making a new medicine (Bennett & Brown Ch.3, p.28): 1. Selecting the molecular target the drug should act on (probably the single key decision). 2. Choosing the right chemical as the drug candidate ("all the promise and all the faults become fixed at this point"). 3. Designing the right clinical experiment to show the medicine does what is intended. 4. Showing how the medicine improves health and benefits health-care systems.
• Medicinal therapeutics rests on the two pillars of pharmacology (Bennett & Brown Ch.3, p.28):
  • Selectivity — "We must learn to aim with chemical substances" (Paul Ehrlich).
  • Dose — "The dose alone decides that something is no poison" (Paracelsus).
• Sequence of new-drug development (Bennett & Brown Ch.3, p.28–29):
  • Idea/hypothesis → design & synthesis of substances → preclinical studies (tissues/whole animal) → clinical studies in humans → grant of an official licence → post-licensing (marketing) studies.

Pipeline at a glance (the canonical stages this topic covers):

• Discovery / lead identification → lead optimisation → clinical candidate selection → preclinical (pharmacodynamics, pharmacokinetics, toxicology) → IND (US) / CT-permission (India) → Phase I → Phase II → Phase III clinical trials → NDA/BLA (US) / new-drug import-or-manufacture permission (India) marketing approval → Phase IV post-marketing surveillance.