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PRESENTED BY:

Akhil Sood Puneet Puri Ravi Sahu Tanuj Kalra


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What is clinical research ICH-GCP guidelines Schedule Y CROs and case study

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Clinical research involves methodological and systematic study of drugs, devices ,biological ,vaccines used in the diagnosis, prevention or treatment of disease
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a. b. c. d.

Broad Aims of CR are:


Improve patient outcomes Improves quality of care Enhance efficiency of system Inform health policy

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Clinical trials translate results of basic scientific research into better ways to prevent, diagnose, or treat disease The more people take part, the faster we can: Answer critical research questions Find better treatments and ways to prevent disease

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DRUG DISCOVERY: There are following steps of research activities which begins the process and results in the development of new drugs
   

Target identification Target validation Lead identification Lead optimization

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Preclinical development IND application filed with FDA

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Clinical development
Phase 1 Phase 2 Phase 3

NDA filed with FDA




Phase 4(PMS)

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Phase 1: 15-30 people What dosage is safe? How should treatment be given? How does treatment affect the body? Phase 2 (Therapeutic exploratory trials ): more than 100 people Does treatment do what it is supposed to? How does treatment affect the body? Phase 3 (Therapeutic confirmatory trials) : From 100 to thousands of people Compare new treatment with current standard Phase 4: From hundreds to thousands of people Usually takes place after drug is approved Used to further evaluate long-term safety and effectiveness of new treatment

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Eligibility criteria: Can range from general (age, sex, type of cancer) to specific (prior treatment, tumor characteristics, blood cell counts, organ function); eligibility criteria also vary with trial phase Endpoint: Measurable outcome that indicates an interventions effectiveness

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Randomization:

A method used to prevent bias in research; a computer or a table of random numbers generates treatment assignments, and participants have an equal chance to be assigned to one of two or more groups (e.g., the control group or the investigational group)

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Stratification:
Categorizing subjects into subgroups by specific characteristics

For example, male and female patients may respond differently to treatment, so a trial may record the subject sex. Such a trial would usually ensure that similar proportion of male and female subjects were in each treatment group. Subjects could be stratified by demographic information (such as sex, body weight or location) or by clinical criteria such as previous or simultaneous medication.

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Single-blind Describes experiments where information that could introduce bias or otherwise skew the result is withheld from the participants, but the experimenter will be in full possession of the facts Double-blind Describes experiments where information that could introduce bias or otherwise skew the result is withheld from the participants as well as investigator. Open-label trial or open trial It is a type of clinical trial in which both the researchers and participants know which treatment is being administered

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International Conference on Harmonization What is ICH Evolution of ICH Need to harmonize ICH Goals ICH structure Good Clinical Practice Definition Objective Organization of GCP

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ICH = International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use A joint initiative involving both regulators and research-based industry representatives of the EU, Japan and the USA in scientific and technical discussions of the testing procedures required to assess and ensure the safety, quality and efficacy of medicines.

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Rising costs of healthcare , R&D . Minimum delay in making safe and effective new treatments available to patients. Rapid increase in laws, regulations and guidelines for reporting and evaluating data on safety, quality and efficacy of new medicinal products. Different regulatory systems with divergent technical requirements made it necessary for industry to duplicate time consuming and expensive test procedures for different markets.

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To promote international harmonization. To remove redundancy/duplication in development and review process

For new medicinal products, single set of data should demonstrate : Efficacy (E1-E12), GCP(E6) Quality (Q1-Q6) Safety (S1-S7 & M3) Multidisciplinary (M1,M2,M4)


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USA :

The trigger was sulfanilamide tragedy (1930).

JAPAN: Government regulations requiring all medicinal products to be registered for sale (1950). EUROPE :The trigger was the thalidomide tragedy (1960)

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Three countries : USA, EU, Japan with six founding member parties  EU: European Union  EFPIA: European Federation of Pharmaceutical Industries Association  MHLW: Ministry of Health, Labor and Welfare, Japan  JPMA: Japan Pharmaceutical Manufacturers Association.  FDA: US , Food and Drug Administration  PhRMA: Pharmaceutical Research and Manufacturers of America .

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An international ethical and scientific quality standard for designing, conducting, recording and reporting clinical trials that involve the participation of human subjects. Provides public assurance that rights, safety and well being of trial subjects are protected. Consistent with the principles that have their origin in Declaration of Helsinki and clinical trial data are credible.

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To promote a unified standard for the EU, Japan and the US to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.

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GCP is applicable to : Prophylactic, diagnostic and therapeutic trials. Drugs devices and procedures. Epidemiological studies.

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SIX sections: Section 1: Principles of ICH-GCP Section 2: IRB/IEC Section 3: Investigator Section 4: Sponsor Section 5: Essential Documents Section 6: Investigators Brochure & ICF

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Clinical trials should be conducted in accordance with ethical principles that have their origin in DoH and that are consistent with GCP and other regulatory requirements. Before a trial is initiated foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. The rights, safety and well-being of the trial subjects should prevail over the interests of science and society. The available non-clinical and clinical information on an IP should be adequate to support the trial.

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Clinical trials should be scientifically sound, described in clear detailed protocol. A trial should be conducted in compliance with protocol that has received prior IRB/IEC approval. The medical care given to and medical decisions made on behalf of subjects should always be the responsibility of a qualified physician /dentist. Each individual involved in conducting a trial should be qualified by education, training and experience. Freely given informed consent should be obtained from every subject prior to clinical trial participation.

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All clinical trial information should be recorded, handled and stored in a way that allows its accurate reporting , interpretation and verification. The confidentiality of records that could identify subjects should be protected. IP should be manufactured, handled and stored in accordance with applicable GMP. Systems with procedures that assure the quality of every aspect of the trial should be implemented

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Institutional Review Board exist to safeguard the rights, safety and well being of all trial subjects. ICH-GCP Guideline for IRBs outlines the following:
   

Responsibilities. Composition, Function and Operations. Procedures Records

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An investigator is defined as the person responsible for the conduct of the clinical trial at the trial site. For the investigator the guideline outlines the following:
     

Investigators qualifications and agreements. Adequate Resources to conduct a trial. Medical care of the trial subjects. Communications with IRB/IEC. Compliance with the protocol. Handling of Investigational Products.

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Randomization Procedures and Un blinding. Informed Consent of the trial subjects. Responsibilities for records and reports. Need for progress reports. Responsibilities for safety reporting. Premature Termination or Suspension of the trial. Final report(s) by the Investigator.

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An individual, company, institution or organization that takes responsibility for the initiation, management and/or financing of a clinical trial. Responsible for large number of issues including but not limited to:
     

Quality Assurance and Quality Control. Contract Research Organization. Medical Expertise Trial Design. Trial Management, Data Handling and Record Keeping. Investigator Selection.

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Allocation of Duties and Functions. Compensation to subjects and investigators Financing. Notification and submission to Regulatory Authority(ies). Confirmation of Review by IRB/IEC. Information on Investigational Product(s). Manufacturing, Packaging, Labeling and Coding Investigational Product(s). Supplying and Handling Investigational Products. Record Access. Safety Information.

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Adverse Drug Reaction Reporting. Monitoring Audits Noncompliance Premature termination or suspension of trial. Clinical Trial/Study Report. Multicenter trials

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Documents that individually and collectively permit evaluation of the conduct of a trial and quality of the data produced. Significance: Serve to demonstrate compliance of the investigator, sponsor and monitor with the standards of GCP. Successful management of the trial. Documents audited by the sponsors independent audit function and inspected by the regulatory authorities.

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Grouped into three sections according to the stage of the trial Before the clinical phase of the trial commences During the Clinical conduct of the trial. After completion or termination of the trial.

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A compilation of clinical and nonclinical data on the investigational product that are relevant to the study of the product in human subjects. Purpose is to provide information to the investigator and others to facilitate: understanding of the rationale. compliance with the protocol. IB should include: Title page Confidentiality statement

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CONTD.. Table of contents Summary Introduction Physical, Chemical and Pharmacological Properties and formulations. Nonclinical Studies Effects in Humans Summary of the data and guidance for the investigator.

o o o o

o o o

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Schedule -Y

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What is drug and cosmetic Act 1940. What is schedule -Y what it covers, and associated Rules. Rules of D & act 1940 in schedule -Y Different terminology, under schedule-Y Application for permission under form 44

The Drugs & Cosmetics Act, 1940 regulates the import, manufacture, distribution and sale of drugs in India.

Requirements and guidelines for permission to import and/or manufacture of new drugs for sale or to undertake clinical Trails.

122 A 122B 122D 122DA

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SAE/SADR Adverse-Event (AE) Adverse drug reaction (ADR)

Application for grant of permission to import or manufacture a New Drug or to undertake clinical trialI/We.... of .., hereby apply for grant of permission for import and / or clinical trial or for approval to manufacture of a new drugor fixed dose combination or subsequent permission of already approved new drug. The necessary information / data is given below :

Particulars of New Drug :1.Name of the drug : 2.Dosage Form 3.Composition of the formulation 4.Test specifications : Active ingredients : Inactive ingredients : 5.Pharmacological classification of the drug : 6.Indications for which proposed to be used 7.Manufacturer of the raw material :

2.Data submitted along with the application Permission to market new drug 1.Chemical and Pharmaceutical information 2.Animal Pharmacology 3.Animal Toxicology 4.Human / Clinical Pharmacology 5.Exploratory Clinical Trials 6.Confirmatory Clinical Trials 7.Bioavailability / dissolution and stability data

8.Regulatory status in other countries 9.Marketing information : (a) Proposed product monograph (b) Drafts of labels and cartons 10.Application for test license:

A contract research organization, also called a clinical research organization, (CRO) is a service organization that provides support to the pharmaceutical and biotechnology industries in the form of outsourced pharmaceutical research services (for both drugs and medical devices).

The ICH-GCP definition of a Contract Research Organization (CRO) is: "A person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or more of a sponsor's trial-related duties and functions."

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They manage clinical trials on a routine basis Have staff that likely speaks the language of the clinical site staff Most have database management services that are validated (saving time to the company and expense) Have their own internal sops Offer service to a variety of geographical areas Serve as a translator for correspondence items, and are familiar with the local member state regulations Offer guidance and assistance with development of CRF and other aspects of registering the study.

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Cadila Pharmaceuticals Limited Chembiotek Research International Clinigene Clininvent Research Pvt. Ltd ClinTec International Clintrac International D & O CRO Dr Reddy's Laboratories Limited Eli Lilly and Company (India) Pvt. Ltd Limited Pharma-Olam International Pharmanet GlaxoSmithKline GVK Biosciences Pvt Ltd iGATE Clinical Research International Intas Pharmaceuticals INTOX Private Jubilant Clinsys Johnson & Johnson, India Kendle India

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Lambda Therapeutic Research Ltd Lotus Labs Pvt. Ltd. Lupin Limited Magene Life Sciences Manipal Acunova Matrix Laboratories Ltd. Metropolis Clinical Laboratories Merck Limited Novartis Novo Nordisk India Private Ltd Ocimum Biosolutions Omnicare Clinical Research Panacea Biotech Pfizer

Current Scenario
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India, in particular, is expected to play a crucial role according to McKinsey, due to the growing prevalence of lifestyle disorders similar to those in developed countries.

Statistics reveal that the prevalence of diabetes in India will rise from 2.8 percent in 2005 to 3.7 percent in 2015, cardiac disorders from 3.3 to 4.9 percent, obesity from 1.3 to 2.7 percent, and the hypertensive population to hit five crore over the next decade.

Changing Disease Patterns


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Patient Population

Cardiovascular diseases Degenerative neurological diseases Diabetes Cancer Psychiatric illnesses Gastro Intestinal Disorders Infectious Diseases Tropical diseases

8 million Epileptics 40 million Asthmatics ~34 million Diabetics 8-10 million HIV +ve 3 million Cancer patients > 2 million Cardiac deaths 1.5 million Alzheimer patients 15% Hypertensive 1% Schizophrenia patients

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Annual Revenues USD 120 M with 40% growth in past year 240 international studies recruiting subjects = 1.2% of the total studies worldwide 66% of international clinical trials are Phase III 207 sites FDA registered 40,000 subjects participated in clinical trials to date (<0.02% of population)

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Large pool of patients Amendments with TRIPS(shift from process to product patent), ICH, GCP, WTO, WHO, etc. Incentives for patients Amended drug laws that made the processes for global studies, easier Less import duties PPP encouragement US FDA compliances Data exclusivity Low cost for trials

A significant portion of R&D budgets are used for the outsourcing services offered by the CRO industry, approximately $15 billion in 2007. This figure is expected to grow at 15% over the next seven years. As outsourced services in developing countries such as China and India move up the value chain to cover phase 1/2 trials, the total contracts value has gone up to $20 billion by 2010. Further, certain therapeutic areas within pharmaceutical development are slated for an even greater growth curve, namely the oncology class, expected to see continued growth of upwards of 21% over the next few years due to the large target market, strong unmet medical need, and overwhelming number of drugs currently in development (667 for cancer vs. 252 for CNS disorders, 206 for cardiovascular disorders, and 186 for infections). There are over 1,100 companies in the world. It is a very fragmented industry with the top 10 controlling 56.1% of the market in 2008

Challenges
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Regulatory issues (import duty, drug laws, long start up times, data exclusivity, etc.) Educational challenges (info about GCP, ICH, FDA, WHO) Ethical concerns (IRB, SOPs)

1. SLE (Kendle) 2. Prozac (Eli Lilly) 3. Diarrhoea (Placebos- Kendle)

Thank you
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