2.3 D RUG P ATENTS
3.1.2 Drug Development
Drug development is a process which the goal is rather clear, to bring the drug through clinical development and into the markets. The whole process involves three aspects, technical, investigative and managerial issues.
The technical aspects involves mainly the development of production, quality, formulation and delivery of the drug candidates. The investigative aspect involves the safety and efficacy clinical development. Together, the technical and investigational issues explore the three main issues that USFDA
scrutinizes, safety, quality and efficacy of a drug. The last, managerial aspects involves the coordination of all development activities and control the go or no-go decision at every step at the development stage.
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Drug Development stage is categorized into three main phases,
preclinical development, clinical development and regulatory approval. All phases are discussed below.
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Pre-Clinical Development
Before clinical studies, safety assessment of a drug candidate is necessary. A preliminary toxicology profile has already been studied
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Supra note 34.
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Supra note 38, at 203-204.
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Supra note 34.
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previously in the drug discovery stage, during which a short period of toxicity study and some in vitro studies are employed. These preliminary studies require no good laboratory practice (GLP) and could provide clues for further toxicology studies.
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If a pharmaceutical company is seeking approval to enter human clinical trials, it must conduct comprehensive toxicology studies under GLP regulation. Such safety assessment studies are also called pre-clinical studies.54 55
In pre-clinical phase, safety is assessed in both pharmacology and toxicology studies. These studies in the United States are currently in compliance with International Conference on Harmonization (ICH) guidelines. In pharmacology studies, PK and PD are evaluated. PK is the study of ADME while PD is the study of dose response effects.
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Toxicology studies focus mainly on the chronic toxicity of repeated administration. It provides long term effect on animal as well as dose range information. Other toxicity profiles are also evaluated at appropriate times corresponding to clinical phase of the studies, including genotoxicity, carcinogenicity, reproductive toxicology, mutagenicity and special toxicity tests. Both pharmacological and toxicological studies are mostly performed by in vivo animal tests in order to provide references for human clinical studies.
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Together, the pre-clinical studies could provide references for doses and dosing regimens in clinical trials. Once the toxicology profiles of the drug candidates are explored and proven promising, the results will be submitted to USFDA for an IND review which will be reviewed in Section 3.2.
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Supra note 38, at 212.
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Supra note 38, at 211.
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Supra note 36, at 137-139.
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Supra note 38, at 213-216.
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Id.
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Clinical Development
According to the ICH, the definition of a clinical trial is any
investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects on an investigational product, and/or to identify any adverse reactions to an investigational product, and/or to study absorption, distribution, metabolism, and excretion of an investigational product with the object of ascertaining its safety and/or efficacy.
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In general, clinical development can be divided into at least three stages, clinical trial phase I, clinical trial phase II and clinical trial phase III. In most cases, there is post-market clinical studies known as phase IV trial. Each phase has a primary aim. Phase I clinical trials assess mainly the safety profile of a drug in healthy human subjects, usually accompanied with PK and tolerability assessment. Phase II trials study the efficacy and safety in a small group of patients and explore the appropriate dose range. Phase III trials explore the efficacy and safety in a large population. Phase IV trial evaluate the safety and efficacy of a drug after the drug is on the market.
Each phases are further discussed below.
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Clinical Trial-Phase I
A typical Phase I study takes around a year and 10 million USD to develop.
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Usually, around 100 healthy subjects are enrolled in the study. In some cases, patients in critical conditions may be recruited in this phase if58
ICH Guidelines, Section 7.11.
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Supra note 38, at 240.
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Supra note 36, at 181-186.
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Supra note 36, at 182.
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the benefits outweigh risks after cautious evaluation.
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In this phase, safety, tolerability and PK of a drug in an intended
formulation is evaluated.
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Trial design includes single ascending dose (SAD) and multiple ascending repeated dose (MAD) studies.64
The primaryobjective of the SAD and MAD studies is to provide initial safety and tolerability information of a drug. Secondary objective, including PK, is also evaluated in most cases. If patients are included, initial efficacy data may be collected.
Information collected in this phase, including dosing, maximum tolerable dose, PK profile, adverse events and PD profile, are crucial and determinative in designing the next phase, Phase II clinical trial.
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Clinical Trial-Phase II
A typical Phase II clinical trial takes around one to two years and 20 million USD to complete. About 50 to 500 patients are enrolled in the study.
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In this phase, safety and efficacy of the drug is again studied. However, unlike in Phase I which testing is focused on safety, Phase II safety and efficacy studies are indication oriented.
Phase II studies are used to explore the safety, efficacy, dose-response relationships, dose selection and dosing regimens. Tolerability and adverse side effects are also evaluated in patients. Phase II results are necessary for
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Supra note 60.
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Supra note 38, at 240-244.
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Id.
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Id.
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Supra note 36, at 183.
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Phase III trial designs.
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Clinical Trial-Phase III
A typical Phase III clinical trial takes around three to five years and 50 to 100 million USD to complete. Patient numbers may range from several hundreds to thousands.
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In this phase, trials are designed to resemble to how the drug mighty be used after approved. The primary aim of this phase is to study the drug's effectiveness in statistical aspects. In order to reach statistical significance under a pre-determined power, hundreds or thousands patients might be needed.
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Trials are usually conducted in several different centers and hospitals so that the results might also provide population-specific information. In addition, two Phase III trials are usually required.71
The results of trials determines the dosage, dosing regimens and target patients.If the results of the trials are positive, a new drug application will be prepared to submit to the USFDA to see marketing approval. Once the drug is approved and hits the market, a Phase IV study is triggered.
Clinical Trial-Phase IV
In Phase IV study, treated patients are monitored for their adverse side effects. This post market surveillance is set to protect patients from risks unidentified in all previous development. Serious adverse side effects shall be reported to USFDA. If necessary, USFDA may decide to recall the drug or
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Supra note 38, at 241.
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Supra note 36, at 182-183.
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Supra note 36, at 183.
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Supra note 36, at 183.
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Id.
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change labels.