Quality Assurance in Clinical Trial

 

Patil SM, Sapkale GN, Kumbhar PB and Maske AP*

ASPM’s. K. T.Patil Collage of Pharmacy Osmanabad- 413 501(MS) INDIA.

 

ABSTRACT:

Clinical research is a systemic study of the drug biologic or device on human subject.

Any investigation in human s meant to determine the clinical, pharmacological pharmacokinetic, pharmacodynamic, and or risk/benefits properties of a drug device or biologic. There are four phases in clinical trials. Need of quality assurance in clinical trial is for building quality in upfront assuring quality through the process. As in clinical trial we are dealing with a human life and every thing is for patient safety. When drug development reaches the stage where the drug product are produced for clinical trials in human, then compliance with the cGMP regulation is required. The drug product must be produced in a qualified facility, using laboratory and other equipments that have been validated. Operating under a State of Control produces drug products for which there is adequate level of assurance Quality, Strength, Identity and Purity The manufacturer is responsible for the quality of the Pharmaceutical product at batch release by applying GMP During manufacturing, packaging, QC testing. The product should be stable throughout the shelf-life Quality assurance for the product should be Monitoring environmental conditions under which products are manufactured/stored, air and water systems to prevent contamination, Monitoring of personnel QA at Clinical Site to Supervise, Maintain Records, Adhere to Protocol, Learn investigator procedures, Report Adverse effect, Retain Records and Train Staff.

 

KEY WORDS: Clinical research, Quality assurance, pharmacodynamic, cGMP

 

INTRODUCTION:

Clinical Research is a systematic Study of a drug, biologic, or device on human subjects or Any investigation in humans meant to determine the clinical, pharmacological, pharmacokinetic, pharmacodynamic, and/or risk/benefit properties of a drug, device, or biologic. Mainly there are four phase in clinical research Phase I: are tested in healthy human subjects, closely monitored to gather information about the safety profile of the drug. ADME Studies carried out in this phase. Phase II: Trials to evaluate the effectiveness of the drug for a particular indication in a specific patient population with the disease or condition under investigation, and to determine the dosages and dosing regimens, which may be, used in future large-scale trials. The objective of this phase to provide evidence of the safety of the drug in the intended subject population, determine the common short term side effects and risks associated with drug. Phase III: Large-scale studies conducted in support of a future marketing application. Conducted versus a comparator/placebo and data from several hundreds to thousands of subjects in multiple countries collected for that therapeutic indication. Phase IV: These are post-marketing studies often carried out after the drug approval cycle to identify the incidence of adverse reaction,pharmacovigilence.5

 

There are various merits for conducting clinical trials in India, which are huge patient base with large diversity of diseases. There is a large population showing large genetic variation. As India is having high enrolment rates with excellent patient compliance / retention. State of the art hospital facilities Reliable, well trained, motivated investigators. Increasingly accommodating regulatory environment.
Need for QA in a Changing Clinical Trial:
For more studies; more sites; greater volume at each sites. Expansion and fluidity of clinical investigator pool, Release of regulatory guidelines, Increased focus on patient safety and safeguarding human rights, New technologies (electronic record-keeping, IVRS).More participation by “vulnerable” subjects, Building quality in upfront, Assuring quality throughout and everything is for Patient Safety.1

 

Quality: The total set of characteristics of product or service that affect its ability to satisfy a customer stated or implied needs. To Control the quality operating under State of Control produces drug products for which there is adequate level of assurance Quality, Strength, Identity and Purity. Quality Systems: The organizational structure, responsibilities and resources for Implementing quality management. 4 Quality Assurance: The systematic and independent examination of all trial related activities for the compliance with GMP and GCP guidelines.

 

Need of Effective Quality Systems:

To assure the patients safety, To safeguard the human rights and protection of public health. To make products that are safe, pure and effective and be in regulatory compliance.

 

Quality Systems: All Phases of Clinical Trials: When drug development reaches the stage where the drug products are produced for Clinical trials in humans, then compliance with the cGMP regulations is required. The drug Product must be produced in a qualified facility, using laboratory and other equipments have been qualified, and processes have been validated. Investigational drug products have always been subject to the agency’s cGMP inspectional activities. 2

 

Conducting Global Clinical Trials in India:

Broad regulatory reforms, a seizable and growing pharmaceutical market, combined

With highly attractive professional and patient populations, make India a compelling new   region for conducting global clinical trials. India’s business and regulatory climates have undergone a dramatic change through passage of a patent bill, regulations updated to  harmonize with U.S and international standards, and plans for a more FDA-like regulatory body. 6

 
Government’s facilitating initiatives:
Schedule Y introduced and updated,Forms and Fees prescribed,Review of submission – average 3 months,National Pharmacovigilance Program Ethics Committee approvals concurrent,Import License for clinical trial drug supplies from DCGI ,Export License for blood and blood products from DGFT after clinical trial approval,

 

Exemption from registration requirements for clinical trial supplies, Export of clinical trial related biological specimens allowed, based on protocol approval. Exemption from Service tax. 1

 

Current status of Clinical Trials in India:

Total Number of Clinical Trials: 536 i.e. Phase - I: 10,PhaseI/II: 1,Ph-II: 105,Ph-III: 350,Ph IV: 55 . Quality can achieve by Good Laboratory Practices, Good Clinical Practice. Good manufacturing Practices, Effective record keeping, Design, installation, operational and process qualification ,Self-inspection and self-regulation, Good Distribution Practices,

Quality Systems:- Control Management: - Define the mechanism of Control, Facilitates

cGMP, Develops Standards that facilitate Control, Quality Management: Identity,    Quality. Purity. Strength4 Quality Systems: What to Control: - Validations, Qualifications, Maintenance Cleaning, Cross- contamination, Mix up, Stability, Specifications, SOPs, Test Methods, Product, Premises and Equipments, Labelling. 7

 

 

Quality Systems: - Auditing and self inspections, Training, Deviations and change control, Documentation and record keeping, Risk management, Validations, Qualifications and maintenance of premises, equipment utilities, and services, Calibration, preventative maintenance, Supplier certification, including knowledge of supply.

 

Audits: To evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the applicable regulatory  requirements. Existence of cGMP and GCP.To verify that procedures an are in Place and followed. To ensure Clinical trials/systems conducted in accordance with the Sponsor’s Written procedures. Audit ensures processing, manufacturing and handling of Investigational medicinal product as per cGMP guidelines.

Evaluation of processes and systems in order to maintain product purity, strength, identity and Quality

 

Different Types of Audits:

Study Based, Facility /System, Process based, Contractors and Suppliers, Final Report/Raw Data, Management of Change Control and Deviations. Management of Change Control and Deviations To ensure that changes made in formulations, manufacturing, packaging, QA procedures, and QA specifications and deviations from the predefined processes do not change the safety, strength, efficacy or purity of the product., Equipments, SOPs Manufacturing Instructions Specifications: Labels, Labelling/packaging instructions Environmental conditions any other aspect that may affect the state of control. 4

 

Training:

Quality systems assures extensive training prior to initiation of clinical trials as well as Production  of clinical supplies. Quality Systems assures the complete education, training to the personnel involved in any GMP task. Assures the cGMP training and job-specific training. Continued training with sufficient frequency

 

Qualifications and Validations:

Qualification: Action of proving that any premises, system, and items of equipment work Correctly and actually lead to expected results.Validation: Action of proving (in accordance with principles of GMP) that any procedure, process, material, activity, or system actually leads to expected results. 1

 

Role of Quality Unit:

Reviews Production and QC records, Investigates deviations, Approves or rejects Components and products, Approves or rejects procedures and specifications. Ensure that all applicable Quality systems are in place and followed Properly.

 

 
 

Sr. No

Regulatory body

Approval

Time

1

Drugs Controller General of India (DCGI)

Regulatory approval for study conduct in India

10 weeks - mean

Ethics Committees

2

Ethics committee

The various study sites

4 - 6 weeks (in parallel) 10 weeks – mean Ethics Committees

3

Drugs Controller General of India (DCGI)

Test license to import trial supplies

2 weeks

4

Total (parallel processing)

N.A.

12 weeks

5

Directorate General of Foreign Trade (DGFT)

Permission to export blood samples outside India

2 – 4 weeks

6

Genetic Engineering Approval Committee (GEAC)

Approvals for studies using r-DNA products

12 to 14 weeks.

 
Table No.1 TYPICAL TIMELINES FOR REGULATORY APPROVAL

 

Key Regulatory Controllers in India:

A) Drugs and Cosmetics Act and Rules.

B) Schedule -Y: Requirements and Guidelines for permission to import /manufacture of new drug for sale or to undertake Clinical Trial (Amended in Year 2005).

C) Schedule - M:Indian drug regulation which describes about the Good Manufacturing Practices (cGMP) and requirements of premises, plant and equipments. ‏

 

Regulatory Authorities: 2

DCGI (Drug Controller General of India)‏, State FDA (Food and Drug Administration).

 

Key Regulatory Controllers in Europe:

EMEA: European Medicinal Evaluation Agency, MHRA: Medicinal and Healthcare Regulatory Agency, UK, European Directives, Orange Guide (Annexure 13) .

 

Key Regulatory Controllers in US:

Title 45 of the U.S. Code of Federal Regulations, part 46 (45: CFR 46) Policy for protection of human research subjects, Applies if the study is for U.S. FDA filings, Assurance/Ethics Committee requirements, Informed Consent, Protection of pregnant women/ foetuses/neonates, Protection of prisoners, Protection of children.

 

Websites of Regulatory Bodies:

http://cdsco.nic.in/, http://www.mhra.gov.uk,  http://www.fda.gov/,  http://www.ich.org

Quality Must Be Designed Into A Product, Quality is not an add-on: it begins with research and development, Product quality criteria must be established, Detailed specifications provide quantitative parameters for measurement, Written procedures document how quality is attained and maintained, Continuous monitoring (sampling, testing) to confirm quality is being built-into product. 4

 
Quality of the product:

The manufacturer is responsible for the quality of the pharmaceutical product at batch release by applying GMP during manufacturing, packaging, QC testing. The product should be stable throughout the shelf life if in the original packaging, when correctly distributed, stored and handled.Comprehensive system for ensuring products are consistently produced and controlled according to quality standards. 3 Designed to minimize risks involved in any pharmaceutical production that cannot be eliminated through testing of final product alone. Contamination of products (microbial, particulate or other). Incorrect labels on containers (Substandard Drug). Insufficient Control on Systems.

 

Quality Assurance for Product Quality:

Monitoring environmental conditions under which products are manufactured/stored. Monitoring of air and water systems to prevent contamination. Monitoring  personnel. Feedback and follow-up.

 
Quality Assurance: Requirements:

Must be independent of financial pressures and directly reporting to head of the company/Organization. Must ensure that quality policies are followed. Must have final authority for product acceptance, rejection and release. Responsible for day-to-day operations and for long term goal settings. 9

 

Good Clinical Practices (GCP):

A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that:The Data and Reported Results are credible, accurate, and authentic = Quality Data The Rights, Integrity

 
QA at Clinical Site:

Supervise, Maintain Records, Adhere to Protocol, Learn investigator procedures,Report Adverse Events, Retain Records and Train Staff, Conduct “ethical” clinical Research; protect the “needs of” and “risks to” patients, Generate “quality data”, Follow  “GCP responsibilities”, Seek out more education in“GCPs”, Develop strong  Partnerships between investigator and study coordinator, GCP Connections: Quality Control and Quality Assurance9

 

Quality Control (QC):

Daily, ongoing, “real time” activities, Usually 100 %.

Examples: QC is performed on 100% of CRFs (Case Report Form) prior to entry into the databaseA second staff member verifies that informed consent forms are signed before enrolling subjects. 8

 

Quality Assurance (QA):

A periodic, planned, objective review of research related activities to ensure compliance with the protocol, GCP and other regulatory requirements, Retrospective (audit).

GCP: Quality Areas, Sops, data handling, Investigator, Monitoring, Auditing, Protocol.

 

 

Table No.2 TOP 10 PHARMA COMPANIES IN INDIA

Rank

Name of the company

Sales in Rs. (Crores)

1

Ranbaxy Laboratories

4199

2

Dr.Reddy’s Laboratories

4162

3

Cipla

3764

4

Sun Pharma

2463

5

Lupin Laboratories

2216

6

Aurbindo Pharma

2080

7

GSK

1773

8

Cadila

1613

9

Sanofi Aventis

984

10

Ipca Laboratories

980

CONCLUSION:

From the above review quality assurance is main role in clinical trail for patient safety. QA are systematic and independent examination of all trial related activities for the compliance with GMP and GCP guidelines. Need of Effective Quality assurance systems to safeguard the human rights and protection of public health, to make products that are safe, pure and effective. The drug product must be produced in a qualified facility, using laboratory and other equipments that have been qualified, and processes have been validated. QA at clinical site to supervise, maintain records, adhere to protocol, learn investigator procedures, report adverse events, retain records and train staff, conduct “ethical” clinical research; protect the “needs of” and “risks to” patients. 7

 

REFERENCES: -

1)       Elisabeth P. compliance corporate Sanafi research, gentilly codex, France,1992, 2,189-196.

2)       Chillarege.Software testing best practices, IBM research technical report, 1999,26.

3)       Chase D, and Letzel H.. System audit of contract research organizations in Germany lat.J.pharma med. 2001,15,191-196.

4)       Gierend M, Clinical trail, 2009,6,373-377.

5)       Washington DC. U.S.Depatment of healthand human services, code of federal regulation, 2002,42, 493.

6)       I.J. Townshend and. Bissel AF.Sampling for Clinical Report Auditing," Statistician 1987,36, 531–539.

7)       ICH/GCP Consolidated Guidelines, E6.

8)       Lisa Henderson; Applied Clinical Trials, 2009,1.

9)       MRC Guidelines for Good Clinical Practice in Clinical Trials, 20 Park Crescent, London, W1N 4AL, United Kingdom, 1998.

 

Received on 09.09.2009

Accepted on 11.11.2009     

© A&V Publication all right reserved

Research J. Pharmacology and Pharmacodynamics 2(1): Jan. –Feb. 2010: 01-04