DRUG DEVELOPMENT. How do drugs become available for prescription?

Transcription

1

2

3 DRUG DEVELOPMENT How do drugs become available for prescription?

4 OUTLINE Birth Idea, Chemistry, Pharmacology. Obtaining a patent. Passing regulatory hurdles (IND and NOC) Pre-clinical trials and data. Clinical trials (Phase 1, 2, and 3). Phase 4: Post-marketing trials, Adverse Drug Reaction reporting. Assessing benefits and harms

5 BIRTH OF A DRUG As a pre-med student your father, a biologist, dies of cancer. On his death-bed he gives you a jar of a white chemical and a stack of papers. He says the chemical has potent metabolic effects in mice and may prove useful as a drug.

6 BIRTH OF A DRUG You become a summer student in the lab of an endocrinologist. The endocrinologist is seldom in the lab. The lab is studying dietary effects in an obese diabetic mouse model. You take the opportunity to test your Dad s chemical in this model.

7 BIRTH OF A DRUG The chemical reduces glucose in the mice without increasing insulin. It is effective in microgram amounts and the mice appear to tolerate it well. You complete 2 week experiments with different doses and the results are highly consistent.

8 INFANCY OF A DRUG You take the data to your uncle who just happens to be a patent lawyer. He is willing to patent your chemical in all countries with a potential market. The patents are in place on Sept.1996 and last 20 years. You now feel confident in informing your supervisor.

9 INFANCY OF A DRUG As your last duty before starting medical school, you present the data to your supervisor. Fortunately she is very interested in pursuing the chemical further. The endocrinologist confirms your work and approaches a large drug company, Novartis.

10 INFANCY OF A DRUG (1YEAR) Novartis is interested and after long careful negotiations you strike a deal. Novartis agrees to do the preclinical and clinical development of the drug in return for the patent. They pay all the patent costs and give you $100,000 now. You insist on and achieve a 1% royalty for all future sales of the drug.

11 PRE-CLINICAL STUDIES IN ANIMALS (2 YEARS) Efficacy studies animal models of diabetes (at least 2 additional species). Safety studies acute and subacute toxicity studies in at least 3 species. Chemistry, biopharmaceutics etc. Dossier submitted to regulatory body for IND (investigational new drug) approval.

12 EARLY PHASE TRIALS (0.5 YEARS) Phase 1 drug administered to 15 young healthy male volunteers in hospital setting. Dose ranging from very low to higher than anticipated effective dose. Monitor for pharmacokinetics and toxicity parameters. At highest doses hypoglycemia is noted.

13 PHASE II TRIALS (1.5 YEARS) RCTs in 150 patients with Type 2 diabetes mellitus (2 months). Dose ranging compared to placebo (effective dose range mg). Results confirm the findings in animals: decrease glucose and no effect on insulin. Only significant adverse effects: 3 patients hypoglycemia, 2 patients elevated AST and ALT, 1 patient with drug rash.

14 PHASE III TRIALS (3 YEARS) Long-term (2 yr) toxicity studies in animals completed. Only potential problem is hepatotoxicity at highest doses. Larger RCTs at 100 to 400 mg doses in patients with Type 2 diabetes (age 40 to 70 years) to 2000 diabetic patients (3 and 6 month pivotal RCTs), some patients treated and followed for up to 2 years. Less than 1% of patients have reversibly elevated liver enzymes.

15 RE-SUBMISSION TO FDA AND TPD, HEALTH CANADA (1.5 YEARS) Apply for fast track approval accepted. What do you think about that?

16 RE-SUBMISSION TO FDA AND TPD, HEALTH CANADA (1.5 YEARS) Only evidence of benefit is that it lowers glucose compared to placebo in Type 2 Diabetic patients. What do you think about that?

17 RE-SUBMISSION TO FDA AND TPD, HEALTH CANADA (1.5 YEARS) Assessment for safety is very limited from a relatively small number of middle aged uncomplicated patients. Possible concerns: reversible elevations in liver enzymes, small increases in low density lipoprotein cholesterol and weight. What do you think about that?

18 RE-SUBMISSION TO FDA AND TPD, HEALTH CANADA (1.5 YEARS) Not required to be as good as or better than currently available drugs for Type 2 Diabetes. What do you think about that?

19 NOTICE OF COMPLIANCE (NOC) Chemical and tablet formulation has met the criteria. NOC allows physicians to prescribe drug as they see fit. NOC allows the company to advertise and market the drug to physicians for the approved indication (to lower glucose in Type 2 Diabetics). Do you have any concerns about this?

20 MARKETING A DRUG In United States price is completely up to the drug company (no regulation). In Canada maximum price is set by Patented Medicines Price Review Board (PMPRB), based on average price in 7 major markets. Average time from conception (patent) to NOC is 10 years (market exclusivity for 10 years). Company must apply to the provinces to get government funding approval. DiaCure is launched April, You have 10.5 years of patent remaining.

21 PHASE IV (FIRST YEAR) Marketed as specifically reversing insulin resistance. Concept is well accepted by physicians. Also launched in USA and Europe. Sales in first year--$500 million worldwide. A few cases of severe hepatotoxicity are reported with the drug. How much money would you receive?

22 PHASE IV (SECOND AND THIRD YEAR) Sales peak at $1 billion per year and remain stable. Short-term trials show reduction of glucose in combination with sulfonylureas and acarbose. No long-term trials initiated to assess the effect on morbidity and mortality.

23 PHASE IV (SECOND AND THIRD YEAR) More spontaneous reported cases of hepatotoxicity leading to death or liver transplantation.

24 PHASE IV (4 TH YEAR) 90 cases of liver failure and 63 deaths in the USA. Law suits against the company are accumulating. Novartis CEO asks you to attend an urgent board meeting.

25 BOARD MEETING CONSIDERATIONS Only proven efficacy is on surrogate marker (glucose). Adverse publicity is already hurting sales, and projections don t look good. Worldwide company safety data reveals more cases of liver damage than are known to the regulatory authorities. Projected legal costs are hundreds of millions of dollars.

26 CONCLUSION Drug is withdrawn from the market worldwide on July 1 st, Time from birth to death just under 14 years. Hopefully you have invested your money wisely.

27 QUESTIONS? What is the generic and Trade name of this drug? Try searching the TI website.

28