, M.S., RPh.

QuizHow long will it take?Probability? Profit? vs. Cost?Luck vs. Effort?

StatisticsNew Drugs Begin in the Laboratory , Discovering and Bringing One New Drug to the public Typically Costs a Pharmaceutical or Biotechnology Company Nearly $900 Million USDTakes an Average of 10 to 12 YearsOut of Every 5,000 New Compounds Identified during the Discovery ProcessOnly 5 are Considered Safe for Testing in Human Volunteers after Preclinical Evaluations. After 3 to 6 Years of Further Clinical Testing in Patients, Only 1 of these Compounds is Ultimately Approved as a Marketed Drug for Treatment.

About Clinical ResearchClinical Research is Essential to New Drug Discovery and Development. Through research, new drugs are tested for Effectiveness SafetyPurpose: Be designed to ensure that only those pharmaceutical products that are both safe and effective are brought to market.

About Clinical Research (Cont.)

Before a patient learns that a new drug is available for their condition, many patients have taken the drug on an investigational basis. Patients who participate in clinical research help in the development of new treatments which help people to live longer and feel better.

About Clinical Research (Cont.)The final phases of clinical research, involving patients with chronic or acute illness, follow years of research in the laboratory as well as testing of the drug in people who have no illnesses.

Only after all phases of research are complete can the Food and Drug Administration approve drugs for use by the general public.

About Drug Discovery and DevelopmentPre-Clinical Stage(IND/CTX/CTA)Phase I Phase II Phase IIIa (NDA/MAA)Phase IIIb/IV Post-Marketing

In General..Clinical testing is usually described as consisting of Phase I, Phase II and Phase III clinical studies. In each successive phase, increasing numbers of patients are tested.

What is Required before an Investigational Drug can be Tested in Human Volunteers? In Preclinical Stage of Drug Development An investigational drug (ID) must be tested extensively in the laboratory to ensure it will be safe to administer to humans. Testing can take from 1 to 5 years Must provide information about the drugPharmaceutical Composition (e.g. PK)SafetyHow the drug will be formulated & manufacturedHow it will be administered to the first human subjects

Pre-Clinical StagePreclinical TechnologyLaboratory tests document the effect of the investigational drugin living organisms (in vivo) and in cells in the test tube (in vitro)Pharmacology/ToxicologyPharmacological testing determines effects of the candidate drug on the body. Toxicology studies are conducted to identify potential risks to humans.

Pre-Clinical Stage (Cont.)Chemistry Manufacturing and Controls (CMC)/PharmaceuticsThe results of preclinical testing are used by experts in pharmaceutical methods to determine how to best formulate the drug for its intended clinical use.e.g. A drug intended to act on the sinuses may be formulated as a time-release capsule or as a nasal spray. Regulatory agencies require testing that documents the characteristics Chemical Composition Purity Quality Potency: the drug's active ingredient and of the formulated drug

Pre-Clinical Stage (Cont.)Results of all testing must be provided to the FDA in USA and/or other appropriate regulatory agencies (e.g. EMEA in Europe) in order to obtain permission prior to begin clinical testing in humans. Regulatory agencies review the specific tests and documentation that are required to proceed to the next stages of development.

How are ID Tested in Humans?Testing of an investigational new drug (IND) Begins with submission of information about the drug, andApplication for permission to begin administration to healthy volunteers or patients.

ApplicationsInvestigational New Drug (IND)-USAClinical Trial Exception (CTX)-UKClinical Trial Authorization (CTA) - Australiaare examples of requests submitted to appropriate regulatory authorities for permission to conduct investigational research. These researches can include testing of A new dosage form, or New use of a drug already approved to be marketed

Phase I Study

Phase I StudyThese are the first studies conducted in humans. Designed to verify safety and tolerability of the candidate drug in humans and typically take 6 to 9 months. A small number of subjects, usually from 20 to 100 healthy volunteers, take the investigational drug for short periods of time.Testing includes observation and careful documentation of how the drug acts in the bodyhow it is absorbed, distributed, metabolized and excreted

Before Start Running.Should Obtain Permission from Appropriate Regulatory Authorities (e.g. FDA of USA; DOH of Taiwan) andAn institutional or independent review board (IRB) or ethical review/advisory board (ERB)Must approve the protocol for testing as well as the informed consent documents (ICFs) that volunteers sign prior to participating in a clinical study.

Why?Many laws and safeguards are in place to protect the rights and safety of patients who volunteer for clinical research. Clinical research trials are carefully designed to protect and monitor patients who receive investigational drugs. Before the first participant enrolls, every trial is reviewed/approved by DOH of TWN (FDA in USA) and IRB.

Purpose of IRB/IECICH GCP Guideline, Section 3.-\\ An Independent Committee of Physicians, Community Advocates and Others Ensures a Clinical Trial is Ethical and the Rights of Study Participants are ProtectedAn Important Part of IRB Approval is:to review the informed consent for the trial to ensure that it lists all information that a patient needs to make a decision about participating.

Responsibilities of IRB/IECICH GCP Guideline, Section 3.1.1\\Should Safeguard the Rights, Safety, and Well-being of all trial subjects. Special Attention Should be Paid to Trials that May Include Vulnerable Subjects.\-()

Composition of IRB/IECICH GCP Guideline, Section 3.2\\\ \ \

Composition of IRB/IEC (Cont.)\\\

IRB:

Phase II Study

Phase II StudyDesigned to determine effectiveness and further study the safety of the candidate drug in humans. Depending upon the type of investigational drug and the condition it treats, this phase of development generally takes from 6 months up to 3 years. Testing is conducted with up to several hundred patients suffering from the condition the investigational drug is designed to treat. This testing determines safety and effectiveness of the drug in treating the condition and establishes the minimum and maximum effective dose.

Phase II Study (Cont.)Most Phase II Clinical Trials are:Randomized Randomly Divided into Groups One group: Receives the Investigational DrugAnother Group: Gets a Placebo Containing no Medication, and Sometimes a Third Group that Receives a Current Standard Treatment to which the New Investigational Drug will be Compared. Double-Blinded Neither Patients Nor Researchers Evaluating the Compound Know who is Receiving the Investigational Drug or Placebo.

Phase III Study

Phase III StudyProvide Expanded Testing of Effectiveness/ Efficacy and Safety of an Investigational Drug, They are usually:Randomized and Blinded Clinical Trials Multi-Center, Multi-Nation Requires 1 to 4 years of testing, depending upon the type of drug candidate and the condition it treats Several hundred to thousands of volunteer patients suffering from the condition the investigational drug treats.

Applications to Market a New DrugNew Drug Application (NDA): in the U.S.Marketing Authorization Application (MAA) : in the U.K.Applications Need to Present:Document Safety and Efficacy of the Investigational Drug and Contain All the Information Collected during the Drug Development ProcessConclusion of Successful Preclinical and Clinical TestingSubstantial Evidence that the Drug will have the Effect it is Represented to have when People Use it or under the Conditions for which it is Prescribed, Recommended or Suggested in the Labeling (in-Label Use). Obtaining Approval (e.g. by FDA in USA) to Market a New Drug frequently takes between 6 months and 2 years

Does Testing Continue After A New Drug is Approved?

YesAfter the FDA (or other Regulatory Agency for Drugs Marketed outside the U.S.) Approves a New Drug, Pharmaceutical Companies may Conduct Additional Studies.

Late-Stage Drug Development Studies of Approved, Marketed Drugs may Continue for Several Months to Several Years.

They arePhase IIIb StudyPhase IV StudyPost-Marketing Study(Post-Marketing Surveillance Study, PMS study)

Phase IIIb StudyOften Begin before ApprovalMay Supplement or Complete Earlier Trials by Providing Additional Safety Data, or May Test the Approved Drug for Additional Conditions for which it may Prove Useful.

Phase IV StudyTo Expand Testing of a Proven Drug to Broader Patient Populations To Compare the Long-Term Effectiveness and/or Cost of the Drug to other Marketed Drugs available to Treat the Same Condition.Post-Marketing Surveillance (PMS)

To Test a Marketed Drug in New Age Groups or Different Patient Types. Some Studies Focus on Previously Unknown Side Effects or Related Risk Factors. As with All Stages of Drug Development Testing, the Purpose is to Ensure the Safety and Effectiveness of Marketed Drugs

Post-Marketing Study

Conclusion

IIIIIIIVSafety/ TolerabilitySafety/ Efficiency Min./Max. DoseExpandingEfficiency/SafetyLong-Term SafetySurveillance6~ 9 mth.6 M ~ 3 yr.1~4 yr.Over 1yr.20~100

Guidelines in Research Ethnics

Pre-Nuremberg Research Scandals1796: Edward Jenner (discovered smallpox vaccine) -injected healthy eight-year-old James Phillips first with cowpox then three months later with smallpox 1845-1849:J. Marion Sims, "father of gynecology--performed multiple experimental surgeries on enslaved African women without the benefit of anesthesia.--After suffering unimaginable pain, many lost their lives to infection.

Pre-Nuremberg Research Scandals (cont.)1900:Walter Reed--injected 22 Spanish immigrant workers in Cuba with the agent for yellow fever paying them $100 if they survive and $200 if they contract the disease. 1906:Dr. Richard Strong, Harvard professor of tropical medicine--experimented with cholera on prisoners in the Philippines killing thirteen.

Nuremberg War Crimes- Nov 20, 1945 Nazi doctorstrials for medical experimentsConducted among civilians and Allied forces under the custody of the German ReichWithout subject consentCommitted murders, brutalities, cruelties, tortures, atrocities and other inhuman acts

Principles of Research Ethics --Nuremberg Code 1947 Informed Consent

Requirement of Prior Animal Experiment

Anticipated Scientific Findings to Result from the Experiment

Only Qualified Scientist

Avoidance of Physical and Mental Suffering

No Death or Disabling Injury

Nuremberg Code ()1948Voluntary Participation/Informed Consent/Benefits Overweight Risks/Risks should not exceed benefits

(Codes of Research Ethnics)Nuremberg Code for Human Experimentation - 1948Declaration of Helsinki 1964The Nuremberg Code had little or no influence on the actual conduct of research.The medical and research community realized that the Code did not provide adequate guidance for most of the research activities carried out by medical doctors

Declaration of Helsinki * PrinciplesResearch must Conform to Scientific Principles

Protocol and Independent Ethics Committees

Supervision and Conduct of Trial by Suitably Qualified Persons

Objectives and Possible Benefits Balanced against Risk to Subjects

Privacy Respected and Minimal Physical and Mental Impact on the Subject

Informed Consent * (1996, 2000, 2002 and 2004)

Ethical Research Requires Scientific Validity and Careful Thought and Planning to Protect Human Subjects

ICH GCP GuidelineInternational Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human UseUSA, EU and Japan (plus Australia, Canada, the Nordic countries & WHO)The World Medical AssociationWMAThe Good Clinical Practice (GCP) guideline is Topic E6Adopted:17 January, 1997 in the EU (guideline, as CPMP / ICH /135/95)1 April, 1997 in Japan (law)9 May, 1997 in the USA (guideline, in the Federal register)

()ICH E6 Guidance for IndustryE6 Good Clinical Practice: Consolidated Guidance

(GCP) \

Good Clinical Practice (GCP) An International Ethical and Scientific Quality Standard for Designing, Conducting, Recording, and Reporting Trials that Involve the Participation of Human Subjects Public assurance that the Rights, Safety, and Well-being of trial subjects are protected well-Results in Credible Data Consistent with the Declaration of Helsinki

Principles of ICH GCPConduct Trials according to GCP

Weigh Risks vs. Benefits

Protect the Subjects

Have Adequate Information to Justify Trial

Write a Sound Protocol

Receive IRB/IEC Approval

Use Qualified Physicians

Principles of ICH GCP (cont.)Use Qualified Support Staff

Obtain Informed Consent

Record Information Appropriately

Protect Confidentiality

Handle Investigational Products Appropriately

Implement Quality Systems

Qualified Physicians ICH GCP Guideline, Section 4.1\\ \:

(GCP) \

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GCP Conduct Standards IRB & Regulatory Approval Compliance with Protocol Informed Consent Confidentiality of Data Medical Management of Adverse Events Product Accountability Qualification & Training

GCP Recording Standards CRF Completion Data Handling Security Maintenance Audit Requirements by Sponsor/FDA/DOH/IRBs Investigational Product Accountability Management of Study Files/Essential Documents

GCP Reporting Standards To Sponsor/IRB/Regulatory AuthoritiesAdverse Events/Serious Adverse EventsInterim ReviewsProgress ReportsFinal ReportsMonitoring /Audit Reports

Referenceshttp://www.fda.govhttp://www.acrpnet.orghttp://www.europa.eu.inthttp://www.wma.net/e/http://www.ich.org/cache/compo/276-254-1.htmlwww.jirb.org.twwww.doh.gov.tw

*Pattern expired Local vs. global*The European Agency for the Evaluation of Medicinal Products (EMEA) **COX-2

COX-2VioxxVioxx18Vioxx18

Cox-2 Vioxx Merck 2004 9 Vioxx

*NSAIDs vs. COX-2 inhibitor* - 2003euthanize 140851500 16 ** **FDA debarment list