The goal of early therapeutics development research is to reach a critical decision on continuing investment into pivotal large studies—the product decision. This

* Retired

Note: See Appendices on pp. 439-449 for Routine Clinical Analyte Test Results.

decision point should be after most predictable failures when the probability of successful marketing is high. About 90% of new molecules chosen for development fail before marketing or are soon withdrawn from market. After the first dose in a human the failure rate is 78%. To reduce the failure rate to 10%, how many chemical tests, toxicology protocols, and patient studies must be performed?

Data from the Center for the Study on Drug Development, the Centre for Medicines Research, industry benchmarking surveys, and Eli Lilly and Company suggest that late failures of truly innovative and medically important therapies occur with:

Unpredictable toxicity in animals, such as carcinogenicity despite negative tests for genotoxicity

Unpredictable infrequent severe clinical reactions, such as aplastic anemia or agranulocytosis, with no animal or clinical premonitory signs

Unexpected early marketing of equivalent, better or cheaper competitive treatments

Avoidable errors in the planing of manufacture, marketing, pricing, reimbursement, or pharmacoeconomic proofs of cost-effectiveness

If all the avoidable and predictable failures are eliminated, the probability of global marketing should be nearly 90% for most drugs after careful comprehensive studies of about 100 patients who have the target illness and are given appropriate doses of the new molecule for periods of up to 3 months. Enough should then be known to write a comprehensive product label and to complete sufficient studies of the markets, disease epidemiology, and competition to allow a very well-informed, high-quality product decision.

For many decades we have followed a rubber-stamp paradigm of completing in a lockstep series:

Chemistry studies: analytical standards, analytical assays for feed and biological samples, bulk synthesis routes, formulations, formulation stability, metabolism, impurity identification, kinetics, metabolite identification and synthesis

Animal studies: efficacy in too many animal models; in-vitro and ex-vivo toxicology; in-vivo acute, subacute, and chronic toxicology; metabolism and kinetics in many species

Phase I clinical studies: often in healthy homogeneous volunteers examining kinetics and symptoms, signs, and laboratory tests suggesting adverse events

Phase II efficacy and safety studies: in relatively healthy homogeneous patients with a single target disease and no concomitant confounding factors

Such studies are often done in series, with toxicology demanding completion of the chemistry before they will set doses, clinicians demanding final reports of the toxicologists, and each group of prima donnas focusing only on their own navels. This wastes chemists, animals, and patients as well as time, money, and expertise.

If studies are restricted to homogeneous subjects, it may provide no basis for predicting product performance in a heterogeneous marketplace, and it is exactly this error that has caused many of the postmarketing product withdrawals.

Everyone should realize the goal is not submitting a New Drug Application (NDA), gaining market approval, obtaining an appropriate price, or initial launch—it is sustained dominance of the global market.

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