DSI Newsletter: Phases of Clinical Development

DSI Newsletters, Issue 56:
Phases of Clinical Development

The U.S. system of New Drug Approvals (NDA) is perhaps the most rigorous in the world. This flow chart gives the success rate of promising new pharmaceutical compounds (drugs) and the length of time each step takes, on the average to complete.

**Clinical Trials**
	Preclinical Testing	File IND at FDA	Phase I	Phase II	Phase III	File NDA at FDA	FDA		Phase IV
Years	3.5		1	2	3		2.5	12 Total	Additional Post marketing testing required by FDA
Test Population	Laboratory and animal studies		20 to 80 healthy volunteers	100 to 300 patient volunteers	1000 to 3000 patient volunteers		Review process / Approval
Purpose	Assess safety and biological activity		Determine safety and dosage	Evaluate effectiveness, look for side effects	Verify effectiveness, monitor adverse reactions from long-term use		Review process / Approval
Success Rate	5,000 Compounds Evaluated		5 Compounds Enter Trials in the IND Process				1 Drug Approved

It takes about 12 years and $800M on the average for an experimental drug/compound to travel all the way from the bench in the lab to your medicine chest. Only Five in 5,000 of the compounds that enter the preclinical discovery testing phase make it to human testing via the IND Drug Study discovery process. And then, only one of these five compounds tested in the IND study process eventually earns FDA approval and becomes available on the market to be purchased in drug stores. New medicines are developed in Phases as follows:
Preclinical Testing: A pharmaceutical company conducts laboratory and animal studies to show biological activity of the compound against the targeted disease, and the compound is evaluated for safety. These tests take approximately three and one-half years to complete. If the animal dies, so does the experimental future drug!
Investigational New Drug Application (IND: After completing preclinical testing, the company files an IND with FDA to begin to test the drug in people research subject volunteers). The IND becomes effective if FDA does not disapprove it within 30 days of the application. The IND shows results of previous experiments, how, where and by whom the new studies will be conducted; the chemical structure of the compound; how it is thought to work in the body; any toxic effects found in the animal studies; and how the compound is manufactured. In addition, the IND must be reviewed and approved by the IRB (Institutional Review Board) where the studies will be conducted, and progress reports on clinical trials must be submitted at least annually to FDA.
Clinical Trials, Phase I: These tests take about a year and involve about 100 normal, healthy volunteers; typically medical students and BDB attendees. The tests study a drug's safety profile, including the safe dosage range. The studies also determine how a drug is absorbed, distributed, metabolized and excreted, and the duration of its action.
Clinical Trials, Phase II: In this phase, controlled studies of approximately 500 volunteer patients (people with the disease) assess the drug's effectiveness and take about two years. This would be the first time, for example, a diabetic patient would be used to study a potential new diabetes treatment.
Clinical Trials, Phase III: This phase lasts about three years and usually involves thousands of patients in clinics and hospitals. Physicians monitor patients closely to determine efficacy and identify adverse reactions to ensure safety.
New Drug Application (NDA): Following the completion of all three phases of clinical trials, the Sponsor/Drug Company analyzes all of the data and files an NDA with FDA if the data successfully demonstrate safety and effectiveness. The NDA must contain all of the scientific information that the company has gathered. NDAs typically run 100,000 pages or more. Hopefully someday they will be filled electronically. By law, FDA is allowed six months to review an NDA. In almost all cases, the period between the first submission of an NDA and final FDA approval exceeds that limit; the average NDA review time for new molecular entities is about 2.5 years.
Approval: Once FDA approves the NDA, the new medicine becomes available for physicians to prescribe. The company must continue to submit periodic reports to FDA, including any cases of adverse reactions and appropriate quality-control records. For some medicines, FDA requires additional studies (Phase IV) to evaluate long-term effects.
Discovering and developing safe and effective new medicines is a long, difficult and expensive process. The research-based pharmaceutical industry will invest billions in research and development each year, and that investment has been doubling every five years. The Sponsor Drug Companies isolate a drug target or receptor and then find 5000 or so compounds to study to affect these target receptors. Typically only five of these will be good enough to enter the IND drug study process and then only one of them will make it all the way through to FDA approval. But then, the Sponsor Drug Company needs to negotiate how many years of patent protection before the drug goes generic and how to educate physicians to start using this new treatment. All the while, phase 4 studies are continuing along with Med Watch reports which could lead to this nacient pharmaceutical drug dying an expensive premature death. It is the money from brand name drugs that funds this expensive lottery of testing 5000 drugs to get one for a limited period of time with questionable profitability. But, it is the one block buster drug that really feeds the system. Advances in pharmaceutical medicine are directly attributed to the Sponsor Drug companies gambling on the drug's future.

Sincerely:

Joseph Saponaro, MD, DABIM, FACP, CPI, CCI, CCTI, CCRC, CCRP
Expert Medical Witness, ExpertMD
PI (Principal Investigator), DSI (Drug Study Institute)
Board Certified Internist, JPMC (Jupiter Preventive Medicine Center)
DABIM (Diplomat American Board of Internal Medicine)
FACP (Fellow American College of Physicians)
CPI (Certified Physician Investigator) by the AAPP (American Academy of Pharmaceutical Physicians)
CCTI (Certified Clinical Trial Investigator) by the ACRP (Association of Clinical Research Professionals)
CCI (Certified Clinical Investigator) by the DIA (Drug Information Association)
CCRC (Certified Clinical Research Coordinator) by the ACRP (Association of Clinical Research Professionals)
CCRP (Certified Clinical Research Professional) by SoCRA (Society of Clinical Research Associates)
Member, SIMPD (Society for Innovative Medical Practice Design)
Member, ACPM (American College Preventive Medicine)
Ethics Committee Member, Jupiter Medical Center
IRB Member, Jupiter Medical Center
Founder, CertifiedResearchers.com

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