Quality can be defined as conformance to one’s requirement. The perception of quality is quite dynamic and varies in conformance from person to person according to their requirements. But in clinical research, the definition of quality is pretty standard as globally the conformance is to GCP, regulatory, protocol and SOP requirements. Research involving human participants call for supreme quality management. This is especially true in early phase clinical trials (CT) because they are exploratory, first-in-man (FIM) studies that are conducted most often, but not always, in healthy volunteers and are critical to the development of a potential new drug. The Indian regulatory does not permit phase- I trials for drug substances discovered outside India, unless the disease has specific relevance to Indian population.
The core functions of quality controls are to ensure patient protection and to validate integrity of the data. Phase- I trials give vital information on the safety of the drug in healthy volunteers. This phase is also instrumental in determining the maximum tolerated dose of a particular drug in patients and possibilities of any adverse reactions.
Responsibility
Sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written standard operating procedures (SOP) to ensure that trials are conducted and data are generated, documented, and reported in compliance with protocol, Good Clinical Practice (GCP), and applicable regulatory requirement(s).The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled is quality control. Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly.
Quality Control system:
Quality Control (QC) system can be divided into in-process QC checks and raw data QC check. A typical QC operation comprise of a Plan–Do–Check–Act (P–D–C–A) cycle for every trial. It is important to plan the QC activities as per scheduled activities.
In process checks includes the review of live ongoing activities like:
- Recruitment and screening of trial subjects
- Management of the investigational medicinal product (IMP)
- Informed consent process
- Dosing and study events like blood, urine sample collection, clinical examination, distribution of meal, measurement of vital signs, electrocardiogram (ECG), etc. and collection of data
- Analysis of samples by the clinical safety laboratory
- Analysis of pharmacokinetic (PK) samples by the bioanalytical laboratory
- Follow-up and adverse events resolution, reporting of serious adverse events (SAEs)
- Bioanalytical processes for study sample analysis
- Data management and database lock
- Statistical analysis and report writing
While the raw data checks includes the review of documents like:
- Study design, protocol writing and preparation of the informed consent document (ICD), case report form (CRF), trial specific SOP/ WI (working instructions)
- Approval documents of trial by ethics committee and competent authority
- Duty delegation and protocol training of the study personnel
- Inclusion-exclusion criteria of trial subjects
- Compilation of the trial master file (TMF) before, during and after the clinical trial as per ICH-GCP, chapter- E, Essential documents for the conduct of a clinical trial.
In a clinical trial, the principal investigator (PI) is the one responsible for the entire conduct of a trial, but because the PI alone cannot carry out all the activities, s/he has a team delegated with specific task and duty while the responsibility still lies with the PI. PI’s team comprises of sub-investigator, physicians, nurses, phlebotomist, project managers, project administrators, trial coordinator and other assisting staff. The management at any clinical facility puts in place, quality control and quality assurance team to oversee the implementation of all the procedures, which have been laid down in protocol, SOPs, WI, GCP and applicable regulatory guideline. And any deviations from these set of procedures has to be documented in form of a deviation indicating the detailed description , reason for deviation, impact on the outcome of the trial and preventive action. Good documentation plays a vital role in an audit trail. QC oversees the implementation and adherence to all these requirements and cites missing links, if any. QC can be addressed as ‘Watch-Dog’ in Clinical Research Area even though it can be clinical as well as non-clinical. In this article we will restrict to Clinical part only.
Quality Control of a Phase 1 Clinical Trial:
Shown below is the phase 1 CT approval process in India
Some of the most vital points in carrying out a phase 1 trial in India are as follows and QC by validating implementation will ensure the compliance to the requirements.
Regulatory requirement: No clinical trial for a new drug, whether for clinical investigation or any clinical experiment by any institution, shall be conducted except under, and in accordance with, the permission, in writing, of the licensing authority. Mentioning every detail of regulatory will go beyond the scope of this article so for citation, presently the draft guidance available on Central Drugs Standard Control Organization (CDSCO) website are “Guidance for Industry on approval of Clinical Trial and New Drugs”and “Guidance for Industry for Submission of Clinical Trial Application for Evaluating Safety and Efficacy, Requirements for permission of New Drugs Approval, Post approval changes in biological products: Quality safety and Efficacy Documents, Preparation of the Quality Information for Drug, Submission for New Drug Approval: Biotechnological/ Biological Products”.
Documents required for phase I trial application are covering letter, a copy of final/draft protocol with sponsor’s signature, Form - 44 along with treasury challan for Rs 50,000, a copy of undertaking of principal investigator along with the curriculum vitae, letter of site approval from Drugs Controller General of India (DCGI) for conducting studies, list of investigators, investigator’s brochure, CRF usually in English, ICD in English and local language, data from phase I and drug regulatory approval of the country of origin for doing phase I along with pre-clinical data, authorization letter from sponsor, stability data and dissolution data of the test formulation also needed at the time of submission (not mandatory), certificate of analysis, data/ information as per the checklist for clinical trials.
The types of phase 1 trials include FIM studies, food-gender-age effect studies, drug interaction studies, phase 1 QT studies, pharmacokinetic and pharmacodynamics studies. The protocol of a phase 1 trial should be thoroughly quality checked for the rationale, trial design, trial procedures and pre-clinical toxicology information about the IMP. Any protocol amendments need to be Independent Ethics Committee (IEC) and regulatory (when applicable) approved.
Contracts and agreements should be in place between investigator/institution and sponsor, investigator/institution and contract research organization (CRO), sponsor and CRO (where required) before the conduct of a trial.
The phase 1 facility should be equipped with special care unit with emergency equipments like ECG machines, resuscitation equipments, central monitors for continuous monitoring and emergency medicines for any unforeseen adverse events and should be in the proximity of a primary care hospital. The facility should have well- defined area for dosing the subjects, pharmacy, safety lab, subjects’ ward area, clinical examination, phlebotomy area, subject’s entertainment area, catering area, refrigerators & deep freezer, synchronized clock, emergency call buttons for subjects to seek help, alarm systems for out of range alert.
The facility should have qualified investigators by qualification and training, physicians, nurses, project managers, quality control staff, quality assurance staff, lab technicians, support staff who are trained and well versed with the trial protocol, should be clear about their delegated activities with proper documentation in a duty delegation log signed by PI.
The facility should be able to recruit study participants as per requirement of the protocol like elderly, young adult male, female, children, and patients. The facility should have a database for registering these kinds of participants and screening as per the trial requirement with set of written standard procedures.
Before starting any phase 1 trial, the investigator must obtain written approval of an independent ethics committee (IEC)-an independent body, consisting of healthcare professionals and non-medical members, whose responsibility is to protect the rights, safety and well- being of human subjects involved in a clinical trial and to provide public assurance of that protection.
The facility should have/outsourced a pathology laboratory which is an accredited lab with documented standard procedures for analysis of blood, serum, urine or any other body fluid as mentioned in the protocol.
The facility should have designated pharmacy with ‘authorized access only’ with IMP storage area, with continuous temperature and humidity monitoring, light sensitive area and an SOP in place for the receipt, handling, storing, dispensing, disposing or retaining or retrieval of the IMP with relevant documentation and a registered pharmacist.
The facility should have adequate resources in terms of man, material and method in order to take up any phase 1 trial.
Informed consent process as per GCP should explain about all the trial related activities, should be non-coercive, should explain about the trial for research purpose only, confidentiality, insurance, compensation and indemnity to the trial subjects. Recently DCGI has issued compensation guidelines.
Pharmacovigilance is investigator’s and sponsor’s shared responsibility. Any SAE whether related or unrelated to the IMP, investigator should report to the sponsor and IEC within 24 hours and a detailed report can follow within seven working days and to the DCGI in 14 calendar days. DCGI has issued Draft Guidance for Industry on Reporting Serious Adverse Events in Clinical Trials.
Document management-All the essential documents should be filed in the TMF before, during and after the conduct of a trial. Every document should be reviewed for correctness and accuracy, stored in a restricted controlled area and archived after the completion of the study. Archiving should be as per GCP standards so as to enable easy retrieval of files when required for an audit.
Biostatistics and report writing- Data management and biostatistics may be done in house or outsourced by a qualified person comprising of data entry and data cleaning, statistical analysis and writing a report on the basis of the data generated during the conduct of the trial. The report should be an exact interpretation of the data which should also be quality checked.
Conclusion
Benefits of quality perseverance system are customer satisfaction and repeat business and referral so profitability, optimizing the time of drug development preventing unnecessary delay. Quality system gives reassurance to genuine drug research as today’s IMP
will be tomorrow’s medicine, so only the safe and efficacious drug should reach the consumer.
The author is Consultant in Clinical Research, U.S.A.