““To Market, To Market” or To Market, To Market” or “From Test to Chest “From Test to Chest

(Medicine Chest, that is)”(Medicine Chest, that is)”

A high-level overview of the A high-level overview of the clinical trial process in the clinical trial process in the

development of brand development of brand pharmaceutical drugspharmaceutical drugs

Presented by Michael OPresented by Michael O’’HeaHea

Hmmm…Hmmm…

Did you ever wonder how a brand Did you ever wonder how a brand pharmaceutical drug that youpharmaceutical drug that you ’’ve been ve been prescribed for a condition got into the prescribed for a condition got into the

marketplace for sale and consumption by marketplace for sale and consumption by consumers? Did you ever ask yourself consumers? Did you ever ask yourself

““How do I know the drug will work for me, How do I know the drug will work for me, and how do I know if itand how do I know if it’’s safe?s safe?””

The answer lies in the clinical trial.The answer lies in the clinical trial.

So why conduct a Clinical Trial?So why conduct a Clinical Trial?

““Clinical trials are conducted to collect data Clinical trials are conducted to collect data regarding the safety and efficacy of new drug regarding the safety and efficacy of new drug

development…development…””

How did they develop and why are they used?How did they develop and why are they used?

A Brief History of the FDAA Brief History of the FDA 1906 – the US Food and Drugs Act was created, 1906 – the US Food and Drugs Act was created,

which prohibited interstate commerce in which prohibited interstate commerce in ““misbranded and adulterated foods, drinks and misbranded and adulterated foods, drinks and drugs.drugs.””

1937 – Sulfanilamide Elixir Catastrophe 1937 – Sulfanilamide Elixir Catastrophe 1938 – Congress passed the Food, Drug & 1938 – Congress passed the Food, Drug &

Cosmetic Act.Cosmetic Act. Required new drugs to be shown safe before Required new drugs to be shown safe before

marketingmarketing 1962 – Kefauver-Harris Drug Amendment, aka 1962 – Kefauver-Harris Drug Amendment, aka

““Drug Efficacy AmendmentDrug Efficacy Amendment”” was passed in was passed in response to the Thalidomide tragedy in Europe. response to the Thalidomide tragedy in Europe.

Kefauver-Harris AmendmentKefauver-Harris Amendment

The amendment introduced a The amendment introduced a ““proof of proof of efficacy requirement,efficacy requirement,”” which was not in which was not in prior amendments.prior amendments.

Strengthened the FDAStrengthened the FDA’’s control of s control of experimentation on humans, and also experimentation on humans, and also changed the process of how new drugs changed the process of how new drugs are developed and regulated thus…are developed and regulated thus…

The birth of the Gold Standard, i.e. the The birth of the Gold Standard, i.e. the Randomized Clinical Trial.Randomized Clinical Trial.

Gold Standard for Clinical TrialsGold Standard for Clinical Trials

Well-controlled (pursuant to 21 CFR 314)Well-controlled (pursuant to 21 CFR 314) RandomizedRandomized Single-blindSingle-blind Double-blind (preferred)Double-blind (preferred) Placebo-controlledPlacebo-controlled

Phases of a Clinical TrialPhases of a Clinical Trial

Phase IPhase I Phase IIPhase II Phase IIIPhase III Phase IVPhase IV

and sometimes…Phase 0.and sometimes…Phase 0.

How long does it take to develop a How long does it take to develop a new drug?new drug?

11-15 years (idea to marketing).11-15 years (idea to marketing). Prior to 1995, the patent life of a drug was Prior to 1995, the patent life of a drug was

17 years, but the Uruguay Rounds 17 years, but the Uruguay Rounds Agreement in 1995 increased it to 20 Agreement in 1995 increased it to 20 years. years.

So, what gets the ball rolling?So, what gets the ball rolling?

Drug screening is conducted by scientists Drug screening is conducted by scientists to identify candidates for possible to identify candidates for possible development.development.

Candidate is identified. Candidate is identified. Animal testing is conducted, which is Animal testing is conducted, which is

called called ““preclinicalpreclinical”” or or ““nonclinicalnonclinical”” phase. phase. This testing can go on for two or more years This testing can go on for two or more years

and typically goes on during the clinical trial in and typically goes on during the clinical trial in humans.humans.

What is the animal most What is the animal most frequently used in nonclinical frequently used in nonclinical

testing and why?testing and why?MiceMiceCostCost

Other test animals include:Other test animals include:RatsRatsDogsDogsMonkeysMonkeys

Problems with animal testingProblems with animal testing

Is not a perfect indicator of whether or not Is not a perfect indicator of whether or not a drug was will be useful for human a drug was will be useful for human treatment.treatment.

Examples – chocolate and dogs, guinea Examples – chocolate and dogs, guinea pigs and penicillin, Thalidomide/rat pups, pigs and penicillin, Thalidomide/rat pups, TGN1412 debacle.TGN1412 debacle.

Gives some general indications of what Gives some general indications of what the sponsor should look for.the sponsor should look for.

More ethical than using prisoners.More ethical than using prisoners.

QuestionQuestion

When does the patent clock start ticking for When does the patent clock start ticking for the test drug?the test drug?

AnswerAnswer

Once the investigational compound is Once the investigational compound is patented.patented.

QuestionQuestion

How much does it cost to bring a How much does it cost to bring a pharmaceutical drug from the test phase pharmaceutical drug from the test phase

to market?to market?

AnswerAnswer

It depends on the source. It depends on the source.

Historically, the industry has espoused that Historically, the industry has espoused that from testing phase to marketing, a from testing phase to marketing, a

pharmaceutical company will spend $1B. pharmaceutical company will spend $1B. Others say it can go up to $4B-$5B.Others say it can go up to $4B-$5B.

WhatWhat’s needed before a clinical trial ’s needed before a clinical trial can start?can start?

FDA approval for the sponsorFDA approval for the sponsor ’’s IND s IND (Investigational New Drug)(Investigational New Drug) The sponsor must submit:The sponsor must submit:

Preclinical or Preclinical or ““nonclinical studiesnonclinical studies”” Proposed Study Protocol for Phase IProposed Study Protocol for Phase I Approval by an Ethical Review BoardApproval by an Ethical Review Board InvestigatorsInvestigators’’ Brochure Brochure

Phase 0Phase 0

Also known as Also known as ““first in man studies.first in man studies.”” Single sub therapeutic doses of the study drug Single sub therapeutic doses of the study drug

are given to a small number of human test are given to a small number of human test subjects (around 10-20), usually about 1/100subjects (around 10-20), usually about 1/100 thth the dose planned for the actual clinical trial. the dose planned for the actual clinical trial.

Became more prevalent in the mid-2000s.Became more prevalent in the mid-2000s. The concept is to see if the test drug is hitting its The concept is to see if the test drug is hitting its

intended molecular target – mechanism of intended molecular target – mechanism of action.action.

Phase 0 (continued)Phase 0 (continued)

The micro doses take place before the The micro doses take place before the safety of the drug in humans has been safety of the drug in humans has been demonstrated.demonstrated.

Evaluate pharmacodynamics (i.e. what the Evaluate pharmacodynamics (i.e. what the drug does to the body) and drug does to the body) and pharmacokinetics (what the body does to pharmacokinetics (what the body does to the drug – Absorption, Distribution, the drug – Absorption, Distribution, Excretion – Excretion – ““ADEADE””).).

QuestionQuestion

What percentage of drugs submitted to the What percentage of drugs submitted to the FDA are ultimately approved for FDA are ultimately approved for

marketing?marketing?

AnswerAnswer

10-20%10-20%

Phase IPhase I Human test subject must meet Human test subject must meet

inclusion/exclusion criteria and sign an Informed inclusion/exclusion criteria and sign an Informed Consent Form. Phase I involves healthy Consent Form. Phase I involves healthy volunteers without the condition being studied.volunteers without the condition being studied.

Primary objective is screening for safety Primary objective is screening for safety (PK/PD).(PK/PD).

The number of test subjects usually is anywhere The number of test subjects usually is anywhere from 20-80 (some say 100).from 20-80 (some say 100).

Other objectives are to determine safe dosage Other objectives are to determine safe dosage ranges, and identify side effects. (Example – ranges, and identify side effects. (Example – Akros).Akros).

Example of a Study TitleExample of a Study Title

A Phase I, Randomized, Single-blind, A Phase I, Randomized, Single-blind, Placebo-controlled Study to Evaluate the Placebo-controlled Study to Evaluate the Safety, Tolerability, and Pharmacokinetics Safety, Tolerability, and Pharmacokinetics

of of Study Drug XXX Study Drug XXX Administered Twice Administered Twice Daily for Seven Days.Daily for Seven Days.

QuestionQuestion

Do you think women can and should, Do you think women can and should, participate as human test subjects in participate as human test subjects in

clinical trials?clinical trials?

Historically, women were not Historically, women were not allowed to participate as human allowed to participate as human test subjects in clinical trials. test subjects in clinical trials. The sponsors argued that men The sponsors argued that men are cheaper and easier to study are cheaper and easier to study

because men donbecause men don’t have ’t have menstrual cycles, so they will be menstrual cycles, so they will be metabolically consistent month metabolically consistent month

to month. to month.

Until 1988, clinical trials were Until 1988, clinical trials were almost exclusively conducted on almost exclusively conducted on

men, even though women men, even though women consume 80% of consume 80% of

pharmaceuticals in the United pharmaceuticals in the United States, and there are States, and there are

physiologic gender differences.physiologic gender differences.

Why?Why?

Liability due to the possibility of birth Liability due to the possibility of birth defects (remember the Thalidomide defects (remember the Thalidomide tragedy).tragedy).

Cultural bias that our society should Cultural bias that our society should protect women and children.protect women and children.

Phase IIPhase II

Proof of concept – the sponsor (typically the Proof of concept – the sponsor (typically the manufacturer) is studying the disease state you manufacturer) is studying the disease state you wish to put on the label, and the sponsor is wish to put on the label, and the sponsor is looking for a signal of efficacy.looking for a signal of efficacy.

Further evaluation of safety.Further evaluation of safety. Can be randomized and controlled (placebo).Can be randomized and controlled (placebo). Usually involves 100-300 test subjects (can be Usually involves 100-300 test subjects (can be

healthy volunteers and people with the healthy volunteers and people with the condition). Can be divided into Phase IIA/IIB.condition). Can be divided into Phase IIA/IIB.

Can last several months to a couple of years.Can last several months to a couple of years.

QuestionQuestion

““Statistics show _______ out of 20 drugs in Statistics show _______ out of 20 drugs in development will never see the light of development will never see the light of day.day.””

AnswerAnswer

19!!19!!

Phase IIIPhase III

Typically involves several hundred to several Typically involves several hundred to several thousand test subjects.thousand test subjects.

Are randomized, controlled, multi-center trials Are randomized, controlled, multi-center trials with subjects who have the condition being with subjects who have the condition being tested.tested.

Goal is to confirm the test drugGoal is to confirm the test drug ’’s effectiveness, s effectiveness, monitor side effects, and to evaluate label monitor side effects, and to evaluate label design (i.e. what the label will say), continued design (i.e. what the label will say), continued safety and efficacy.safety and efficacy.

Can last several years. Tick tock re: patent.Can last several years. Tick tock re: patent.

Phase IIIPhase III’s done. Now what?’s done. Now what?

Sponsor collects all data and submits a New Sponsor collects all data and submits a New Drug Application (Drug Application (““NDANDA””) to the FDA) to the FDA’’s Center for s Center for Drug Evaluation and Research (Drug Evaluation and Research (““CDERCDER””), ), requesting authority to market the test drug.requesting authority to market the test drug.

Can take anywhere from 6 to 24 months to Can take anywhere from 6 to 24 months to obtain approval, which is not a guarantee. obtain approval, which is not a guarantee.

If the FDA approves the drug, an approval letter If the FDA approves the drug, an approval letter is issued, and the drug can then be marketed. is issued, and the drug can then be marketed. Tick tock re: patent.Tick tock re: patent.

Phase IVPhase IV

Typically called Typically called ““Post marketing Surveillance.Post marketing Surveillance.”” Several objectivesSeveral objectives

Monitor long-term effectiveness on consumers (both Monitor long-term effectiveness on consumers (both good and bad);good and bad);

Compare the newly approved drug with other drugs Compare the newly approved drug with other drugs already on the market;already on the market;

Determine cost-effectiveness of a drug therapy Determine cost-effectiveness of a drug therapy relative to other new therapies.relative to other new therapies.

Additional treatment risks, benefits, possible other Additional treatment risks, benefits, possible other areas for treatment/new indications? areas for treatment/new indications?

WhoWho’s responsible for safety ’s responsible for safety reporting to the FDA?reporting to the FDA?

SponsorsSponsors ManufacturersManufacturers Packers / Distributors, i.e. the supply chainPackers / Distributors, i.e. the supply chain The pharmacistThe pharmacist

QuestionQuestion

In which phase do you think most clinical In which phase do you think most clinical trials for brand pharmaceuticals fail?trials for brand pharmaceuticals fail?

Answer:Answer:Phase IIPhase II

Only about 18% of studies proceed to Only about 18% of studies proceed to Phase III.Phase III.

Can drug testing lead to Can drug testing lead to unexpected, marketable products?unexpected, marketable products?

Absolutely!Absolutely!

Examples:Examples:ViagraViagraPropeciaPropecia

Food for thought!Food for thought!

FDA approval does not mean that medications are FDA approval does not mean that medications are risk free! Risk/Benefit ratio.risk free! Risk/Benefit ratio.

2007 – Congressman Waxman (CA) wanted to 2007 – Congressman Waxman (CA) wanted to pass a law requiring no television ads for drugs pass a law requiring no television ads for drugs on the market for less than three years. He lost.on the market for less than three years. He lost.

The Wellness Letter (UC Berkley) has espoused a The Wellness Letter (UC Berkley) has espoused a three year rule on newly approved drugs, unless three year rule on newly approved drugs, unless

there are no other options for treatment. there are no other options for treatment.

Take-awaysTake-aways

Clinical trials are not panaceas, but theyClinical trials are not panaceas, but they ’’re the re the best that we have. best that we have.

FDA balances the needs of the public and FDA balances the needs of the public and business sectors. business sectors.

If you have a clinical trial liability claim, you If you have a clinical trial liability claim, you should ask for what?should ask for what? A copy of the approved Study Protocol;A copy of the approved Study Protocol; A copy of the approved Informed Consent Form;A copy of the approved Informed Consent Form; A copy of the IB that the sponsors provide to the A copy of the IB that the sponsors provide to the

clinical investigators.clinical investigators.

ResourcesResources

centerwatch.comcenterwatch.com money.msn.commoney.msn.com wikipedia.orgwikipedia.org www.fda.govwww.fda.gov ““Innovative Product Development Course,Innovative Product Development Course,””

Drexel University College of Medicine, Drexel University College of Medicine, Spring Semester, 2012.Spring Semester, 2012.