Transcript 淺談藥物之臨床試驗

淺談藥物之臨床試驗
楊蕙瑛, M.S., RPh.
大綱
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藥物之發展與研究
何謂臨床試驗
歷史緣由
醫學研究的倫理準則
試驗醫師之責任與義務
Quiz
• How long will it
take?
• Probability?
• Profit? vs. Cost?
• Luck vs. Effort?
Statistics
• New Drugs Begin in the Laboratory , Discovering
and Bringing One New Drug to the public
• Typically Costs a Pharmaceutical or Biotechnology
Company Nearly $900 Million USD
• Takes an Average of 10 to 12 Years
• Out of Every 5,000 New Compounds Identified
during the Discovery Process
• Only 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 Research
• Clinical Research is Essential to New Drug
Discovery and Development.
• Through research, new drugs are tested for
– Effectiveness
– Safety
• Purpose: 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 Development
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Pre-Clinical Stage
(IND/CTX/CTA)
Phase I
第一期之臨床試驗
Phase II
第二期之臨床試驗
Phase IIIa 第三期之臨床試驗
(NDA/MAA)
Phase IIIb/IV 第四期之臨床試驗
Post-Marketing 藥品上市後之試驗
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 drug
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Pharmaceutical Composition (e.g. PK)
Safety
How the drug will be formulated & manufactured
How it will be administered to the first human subjects
Pre-Clinical Stage
• Preclinical Technology
– Laboratory tests document the effect of the
investigational drug
• in living organisms (in vivo) and
• in cells in the test tube (in vitro)
• Pharmacology/Toxicology
– Pharmacological 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)/Pharmaceutics
– The 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
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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, and
– Application for permission to begin
administration to healthy volunteers or
patients.
Applications
• Investigational New Drug (IND)-USA
• Clinical Trial Exception (CTX)-UK
• Clinical Trial Authorization (CTA) Australia
– are 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 Study
• These 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 body
– how 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) and
– An 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/IEC
• ICH GCP Guideline, Section 3.
•衛生署藥政處頒佈-藥品優良臨床試驗規範\
•第參章、人體試驗委員會\獨立倫理委員會
• An Independent Committee of Physicians,
Community Advocates and Others
• Ensures a Clinical Trial is Ethical and the
Rights of Study Participants are Protected
• An 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/IEC
• ICH GCP Guideline, Section 3.1.1
•第參章\第一節\責任
• Should Safeguard the Rights, Safety, and
Well-being of all trial subjects.
• Special Attention Should be Paid to Trials
that May Include Vulnerable Subjects.
•人體試驗委員會\獨立倫理委員會應確保受試者的
權利，安全以及福祉受到保護。對可能包括易受
傷害的受試者之試驗應特別留意-衛生署藥政處公告之
「藥品優良臨床試驗規範(九十一年八月)」
Composition of IRB/IEC
• ICH GCP Guideline, Section 3.2
•第參章\第二節\第八十五條\組成、功能及
運作
•人體試驗委員會\獨立倫理委員會應由合理
人數組成，其成員應具備審查及評估試驗之
科學、醫學層面及倫理之資格與經驗。
•人體試驗委員會\獨立倫理委員會應保留成
員及其資格之名單。
Composition of IRB/IEC (Cont.)
•建議人體試驗委員會\獨立倫理委員會組成
人員應包含：
（一）至少五位成員
（二）至少一位專業為非科學背景人士
（三）至少一位醫療機構\試驗機構外人士
•人體試驗委員會\獨立倫理委員會成員中唯
有非試驗主持人與試驗委託者身分者能夠參
與表決或提出試驗相關事宜之意見。
IRB審查須包括:
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計畫書是否符合優良臨床試驗規範？
試驗學理依據是否合理？
研究設計和統計是否適當？
受試者隱私的保護是否足夠？
主持人和研究地點是否合適？
是否為當地文化所能接受？
副作用和安全性是否可接受？
Phase II Study
Phase II Study
• Designed 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 隨機分配
• Randomly Divided into Groups
• One group: Receives the Investigational Drug
• Another 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 雙盲
• Neither Patients Nor Researchers Evaluating the Compound
Know who is Receiving the Investigational Drug or Placebo.
Phase III Study
Phase III Study
• Provide Expanded Testing of
Effectiveness/ Efficacy and Safety of an
Investigational Drug,
• They are usually:
– Randomized and Blinded Clinical Trials 隨機雙盲
– Multi-Center, Multi-Nation 多國多中心
– 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 Drug
• New 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 Process
– Conclusion of Successful Preclinical and Clinical Testing
– Substantial 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?
Yes
• After 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 are…
• Phase IIIb Study
• Phase IV Study
• Post-Marketing Study
– 上市後監測調查(Post-Marketing Surveillance
Study, PMS study)
– 為進一步了解病患長期的治療經驗，收集病患
資料之研究。
Phase IIIb Study
• Often Begin before Approval
• May 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 Study
• To 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)
Post-Marketing Study
• 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
Conclusion
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Safety/
Safety/
Tolerability Efficiency
Min./Max.
Dose
III
IV
Expanding
Efficiency/
Safety
Long-Term
Safety
Surveillanc
e
6~ 9 mth.
6 M ~ 3 yr. 1~4 yr.
20~100 人
數百人
數百至數千
人
Over 1yr.
數十至數千
人不等
Guidelines in Research Ethnics
醫學研究的倫理準則
Pre-Nuremberg Research Scandals
• 1796: 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 doctors’ trials for medical experiments
• Conducted among civilians and Allied
forces under the custody of the German
Reich
• Without subject consent
• Committed 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 (紐倫堡宣言)
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1948年公佈
Voluntary Participation/自願參與
Informed Consent/知情同意
Benefits Overweight Risks/
– Risks should not exceed benefits
利益超過風險
醫學研究的倫理準則
(Codes of Research Ethnics)
• Nuremberg Code for Human Experimentation
紐倫堡宣言 - 1948年發表
• Declaration of Helsinki 赫爾辛基宣言
– 1964年發表
– The 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
赫爾辛基宣言之精神
• 自主：受試者是在被充分告知相關訊息後，
自由決定要參加的。
• 有益：參加試驗的風險相對於可能有的好處，
是可以接受的。受試驗者參加試驗後，並不
會犧牲其權益，仍會受到已證明有效的最佳
照顧
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附註：中文有台北榮總江晨恩醫師翻譯，成大醫學院創院院長黃崑巖教授修訂版
Declaration of Helsinki * Principles
• Research 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 Guideline
• “International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for
Human Use”
• USA, EU and Japan (plus Australia, Canada, the Nordic
countries & WHO)
• The World Medical Association（WMA）世界醫學協會
• The Good Clinical Practice (GCP) guideline is Topic E6
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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)
藥品優良臨床試驗規範
本規範係依據八十五年十一月二十日衛生署
藥政處公告之「藥品優良臨床試驗規範(九
十一年八月)」，並參考國際醫藥法規協合
會之ICH E6 Guidance for Industry（E6
Good Clinical Practice: Consolidated
Guidance）所修訂的。
藥品優良臨床試驗規範 (GCP)
第壹章、名辭解釋
第貳章、基本方針
第參章、人體試驗委員會\獨立倫理委員會
第肆章、試驗主持人
第伍章、試驗委託者
第陸章、臨床試驗計畫書
第柒章、主持人手冊
第捌章、執行臨床試驗的必要文件
緒論
• 其為臨床試驗設計、執行、記錄與報告之倫
理與科學品質的國際標準。
• 遵守此標準可確保受試者的權利、安全與福
祉，使臨床試驗執行與赫爾辛基宣言的原則
相符，並可保證臨床試驗數據的可信度。
•凡供查驗登記用之藥品臨床試驗均應符合
本規範；凡供學術研究用之藥品臨床試驗及
其他有關人類安全與福祉之臨床研究亦應參
考本規範。
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 GCP
• Conduct 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
何謂 Qualified 的 Physicians 呢？
• ICH GCP Guideline, Section 4.1
• 藥品優良臨床試驗規範\第四章\第一節
\第一○二條:試驗主持人的資格與認定
藥品優良臨床試驗規範 (GCP)
第壹章、名辭解釋
第貳章、基本方針
第參章、人體試驗委員會\獨立倫理委員會
第肆章、試驗主持人
第伍章、試驗委託者
第陸章、臨床試驗計畫書
第柒章、主持人手冊
第捌章、執行臨床試驗的必要文件
試驗主持人的資格與認定
•試驗主持人合格與否應藉由教育、訓練課
程、和具備適當執行臨床試驗的經驗來判定。
除了需符合所有衛生主管機關規定的資格和
能力，並且需提供試驗委託者、人體試驗委
員會\獨立倫理委員會和衛生主管機關最新
的學經歷資料或其他相關文件，以證明其符
合試驗主持人的資格。
但………自97年5月18日起~~~~
責任?義務?
共十三節
一、試驗主持人的資格與認定
二、足夠的資源
三、受試者的醫療
四、與人體試驗委員會\獨立倫理委員會的聯繫
五、遵從試驗計畫書
六、研究用藥品
七、隨機分配過程及盲性解碼
八、受試者的受試者同意書
九、紀錄和報告
十、進度報告
十一、安全性通報
十二、試驗提早中止或撤銷
十三、試驗主持人\機構之總結報告
GCP Conduct Standards
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IRB & Regulatory Approval
Compliance with Protocol
Informed Consent
Confidentiality of Data
Medical Management of Adverse Events
Product Accountability
Qualification & Training
GCP Recording Standards
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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 Authorities
• Adverse Events/Serious Adverse Events
• Interim Reviews
• Progress Reports
• Final Reports
• Monitoring /Audit Reports
References
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http://www.fda.gov
http://www.acrpnet.org
http://www.europa.eu.int
http://www.wma.net/e/
http://www.ich.org/cache/compo/2
76-254-1.html
• www.jirb.org.tw
• www.doh.gov.tw