Drug Development: The Short Story
3. Clinical Development

Once the company receives approval from the FDA to study an NCE in humans, several parallel events take place which are organized in phases. While there is general agreement about what constitutes each phase, there is no standard definition. The clinical studies section is organized as follows:

• Phase I - Establishes safety in humans. The patient population is a limited (20 - 40) group of healthy volunteers. The studies are used to determine toxicity, dosages (formulations and amounts), blood levels, excretion profiles, and pharmacokinetic profiles.
  
  
• Phase II - Establishes that the NCE is effective in treating the disease in limited patient populations (2A, about 100 subjects) and medium populations (2B, about 300 subjects). Phase II is generally when adverse effects of a potential drug are observed. The studies are used to determine toxicity, compatibility with other medications, bioavailability/bioequivalence of different formulations and a variety of other effects.
  
  
• Phase III - During this phase, a variety of patients with varying degrees of the disease are studied. Multicenter, controlled trials on thousands of patients are run to complete the establishment of safety, efficacy and dosage for the compound.
  
  
• Phase IV - Post marketing surveillance is used to monitor the drugs efficiency in treating large populations, locate any reports of adverse effects, and assess the relative efficacy of the drug. All reports about a drug which appear in public are maintained by the company which markets the drug.

In addition to the clinical trials, development of a new drug also requires a number of supporting activities:

• Completion of manufacturing protocols
• Toxicology studies in animals to assure long-term safety
• Dosage formulation and stability
• Metabolism studies to assure that the drug does not accumulate or is not converted into a toxic substance

When all of these activities have been completed, the company prepares an NDA submission. Data from all of the clinical studies and the manufacturing efforts is collected and formatted into the appropriate reports. This collection of documents (which can occupy a large moving van), includes not only the interim and final study reports for all human and animal studies, but also all of the "raw data" that was used to produce the reports and details of the manufacturing processes that will be used to make the final drug.

The formal review process for a company's NDA submission is initiated on the date that the FDA receives the submission. Some, but not all, of the activities that occur during the review are highlighted below.

• Chemists review the synthesis route for the drug, manufacturing controls and packaging as they relate to the stability of the product, and whether the proposed labeling accurately reflects the effects of the drug.
  
  
• Pharmacologists evaluate results reported for short- and long-term studies in animals. In human studies, they analyze the rate and extent to which the drug's active ingredient is made available to the body, and the way it is distributed, metabolized and eliminated. Their analyses determine whether the data supports the labeling for the recommended dosing regimen.
  
  
• Physicians examine clinical data to check adverse and therapeutic effects of the drug.
  
  
• Statisticians evaluate the designs for each controlled study, the validity of statistical analyses, and the conclusions of safety and effectiveness based on the study data.

While the law requires that the FDA respond to an NDA submission within 180 days, several questions can arise during review which may require additional studies. Thus the amount of time which is required to assemble, submit and receive final approval can span several years.