From Laboratories to saving lives - Pfizer does it all

Clinical Trials : Corner Stones of Research and Innovation

All new treatments are carefully studied in laboratories, before they are tested in patients. Initially, a drug is considered because it changes cells or parts of cells in a way that suggests it will destroy the disease or help the body deal with the side effects of the treatment. Then, the new treatment is tested in animals to learn what it does in the body. But this early research cannot predict exactly how a new treatment will work in people or define all the side effects that might occur.

Clinical trials are designed to help us find out how to give a new treatment safely and effectively to people. All patient who participate in a clinical trial provide information on the effectiveness and risks of the new treatment. Advances in medicine and science are the result of new ideas and approaches developed through research. New treatments must prove to be safe and effective in scientific studies with a certain number of patients before they can be made available to all patients.

Treatments now being used (standard treatments) are the base for building new, hopefully better, treatments. Many standard treatments were first shown to be effective in clinical trials. Clinical trials show researchers which therapies are more effective than others. This is the best way to identify an effective new treatment. New therapies are designed to take advantage of what has worked in the past and to improve on this base.

Pre-clinical Testing

The sponsor of the clinical trial needs to gather data regarding safety of a new drug in small-scale clinical studies before it is studied in humans. Animal studies provide data regarding the absorption, distribution, metabolism and excretion of a new drug. Data regarding the short-term toxicity of the drug in animals is also obtained. Short-term studies in animals can range from 2 weeks to 3 months depending on the proposed action of the new drug.

The sponsor then files the IND (Investigational New Drug) application. The main purpose of the IND application is to provide documentation that it is indeed reasonable to conduct human trials with the drug.

Phase I
These studies are designed to determine the metabolic and pharmacological actions of the drug in humans, the safety of the drug associated with increasing doses, and, some evidence on efficacy. The total number of subjects included in Phase 1 studies is in the range of 50-100.

Phase 2
These studies are carried out to evaluate efficacy and short-term safety of the drug in selected populations. A dose range for the drug is established. Optimal dose of the drug is also established. Phase 2 studies involve several hundred people.

Phase 3
These trials are conducted in several hundred to several thousand people. The objective of these trials is to confirm efficacy of the study drug and to establish its safety profile.

Regulatory review
The data gathered during the animal studies and human clinical trials of an Investigational New Drug (IND) become part of the NDA (New Drug Application). The FDA (Food and Drug Administration) sends an action letter that provides an approval, approvable or non-approvable decision and a justification for that recommendation.

Phase 4
Once the drug is marketed, a large number of subjects are exposed to it. Therefore, new adverse events may be found. Post-marketing surveillance studies are carried out in order to detect previously unknown adverse events and risk factors.

Phase 4 studies are additional safety and efficacy analyses focusing on formulations, dosages, durations, drug interactions and/or new patient groups.

Prior to conducting a clinical trial the following are needed :

• Protocol
• CRF (Case Report Form)
• Informed consent form
• Investigator’s brochure
• Regulatory approvals (Phase I, II, III)
• Ethics Committee approvals
• Documentation formats for monitoring

The actual clinical trial involves the following personnel
Clinical/ Biometrics/Study site personnel

• Investigator/s (at the site where subjects are actually given the study drug)
• Site coordinator
• Clinician (responsible for the trial from the sponsor’s end)
• Project manager
• Clinical Research associate
• Data Manager
• Programmer
• Statistician
• Medical writer

For clinical trials using paper CRF’s the scanning/indexing personnel scan the data into an imaging system and data entry personnel enter the data in the project database.

The data passes through the following steps before it is compiled in the form of a clinical study report.

• Data transcribed onto paper case report forms/ electronic data capture systems at the site.
• Scanning/Indexing into imaging system (for paper CRF’s)
• Data entered in the databases
• Electronic checks run for data errors
• Clarification of errors through Data Clarification forms sent to the site.
• Resolution of Data clarification forms and database updated
• The “clean” data is then forwarded to the programmer and statistician
• Data is analyzed and represented in formats as per FDA requirements
• The clinical study report is written
• Data for the clinical trial is submitted to the FDA or relevant regulatory authorities

Future of clinical trials in India

Many factors have fuelled the growth of Clinical Research in India.

• There is a positive change in the business environment in India. There has been a move to bring in regulations regarding data protection and data exclusivity.
• Infrastructure required for conducting clinical research is available. This includes connectivity with remote locations. It is possible to conduct meetings/ training through audio-visual media.
• Since cost of drug research and development is high, pharmaceutical companies worldwide are attempting to lessen the time and cost required to bring a new drug to the patient. A large number of Contract Research Organizations have established operations in India, further influencing the clinical research culture.
• There is increased awareness regarding ICH–GCP (The International Conference on Harmonisation-Good Clinical Practice) guidelines for conduct of clinical research.
• The availability of a large pool of scientifically trained, English speaking personnel.

Pfizer has contributed to the development of clinical research and Biometrics in India, being the first multinational to establish clinical research operations in India. One of its initiatives has been the Academy for Clinical Excellence (ACE), first organization in India that is dedicated to training and education in clinical research.

References :

• http://www.fda.gov/cder/about/default.htm
• Clinical Pharmacology. D.R.Laurence, P.N.Bennett 8th edition, 1997
• http://iis1.india.pfizer.com/Functional_Areas/ Medical_Research/clinical_trial/mrd_clinical_trials.asp