Proposed changes in schedule Y – A step forward
The proposed changes in schedule Y are a major step forward in the direction of GCP compliant trials and will provide the much-needed regulatory support, says Dr Arun D Bhatt
Schedule Y, the current valid regulatory process, for clinical trial (CT) permission and new drug development, which came into force in 1988, was essentially a provision supporting a predominantly generic pharma industry. Some of the provisions eg. phase lag were obstructing integration of India in global clinical development. Besides, the schedule did not provide for any quality standard eg.; Good Clinical Practice (GCP) for clinical trials.
Some of multinational and big Indian pharma companies have been carrying out clinical trials conforming to international GCP standards trials since 1995. CDSCO released the Indian GCP guidelines in Dec 2001. However, as there was no regulatory requirement for GCP compliance, most companies did not invest in GCP CTs. This has delayed the development of GCP culture and affected quality of clinical trials. There was, thus, a need to harmonise Indian regulations in line with global requirements of good quality clinical development. The proposed changes in schedule Y are an outcome of this need.
The title of new draft schedule Y reflects the direction of the change. The title encompasses the ‘‘Regulations and Guidelines for permission for development (pre-clinical and/ or clinical), import and manufacture of New Drugs for Marketing in India’’ The overall focus of the document is on pre-clinical requirements.
Clinical trial process: Responsibilities of Ethics Committee (EC), Investigator and Sponsor Formats for critical documents: This article summarises the proposed changes in clinical development arena.
As compared to current Schedule Y, which has narrow and restrictive definitions of clinical trial phases, the new draft provides pragmatic definitions for phase I to IV. The definitions and guidelines for clinical trial phases are broad and rational and the earlier restrictions on number patients and centres in early phases have been removed allowing the sponsor freedom to decide these in relation to protocol requirements. The phase lag requirements have given way to acceptance of concurrent phase II-III as part of global CTs. However, phase I for a new foreign drug will not be permitted India.
A notable feature is flexibility in data requirements for new drugs for life threatening/ serious conditions or disease of relevance to India. There is also a new classification of Fixed Dose Combinations for clinical studies.
One of the issues for global CTs was dual permission – from DCGI office and DGFT-for export of trial samples to central laboratory abroad. Now the sponsor is likely to obtain this permission through DCGI office. There is a special focus on certain vulnerable populations eg. paediatrics, gaeriatrics, pregnancy. The sponsor may be asked to generate CT data as part of investigational new drug application, if the indication is relevant to any of these special populations.
Ethics Committee and Informed Consent: One of the lacunae in compliance to GCP was composition and functioning of EC. Revised schedule Y devotes significant attention to roles and responsibilities of EC. It also describes composition of EC as per the ICMR guidelines and provides formats for approval letter of EC.
The revised schedule Y stipulates that EC approval of protocol/ informed consent form (ICF) is essential and the EC approval should be notified to DCGI prior to initiation of clinical trial. It also allows trials sites without EC to accept the approval granted to protocol by EC of another site or Independent EC, provided the approving EC is willing to accept their responsibilities for site without EC.
By including Independent EC, this provision also provides for regulatory recognition of independent ECs. EC for paediatric trials has to include members knowledgeable about paediatric, ethical, clinical and psychosocial issues. The general requirements of ICF and special situations (illiterate or those unable to give consent) are described. There will be a new requirement for mature minors and adolescents to sign an assent form.
There are also appendices detailing a checklist for informed consent documents and the format for informed consent form. The format, besides the patient’s signature at the end of form, also requires his initials on all the five consent clauses.
Guidelines for investigator: The investigator should have appropriate qualifications and experience and access to relevant investigational and treatment facilities and will be responsible for conduct of trial according to protocol and GCP. Besides, he has to sign an undertaking, which demands several commitments. Some of the commitments are: – Ensure that study will not begin until EC/ DCGI have given approval
Agree to adhere to protocol and provide personal supervision
Ensure requirements of IC and EC review
Agree to report of Adverse Drug Event to sponsor
Agree to maintenance of records and availability for audits/ sponsor inspection/ EC and DCGI
Ensure that all associates, colleagues and employees are suitably qualified and experienced and aware of their obligations
Consent to cooperation in audits
Ensure report to EC promptly about changes and unanticipated problems
Agree to confidentiality of data and patients
Accept compliance with all other obligations of clinical investigators
Responsibility of sponsor: The sponsor will be responsible for implementing and maintaining quality assurance to ensure compliance to GCP guidelines of CDSCO. The sponsor will have to submit status report at prescribed periodicity and also inform DCGI reasons for premature termination to be communicated. The period for reporting Serious Adverse Events is now defined. Serious adverse event has to be communicated promptly (within 14 calendar days) to DCGI and other investigators.
Checklists and formats: There are several appendices, which cover some critical data requirements, formats and checklists. These are:
Data for submission along with clinical trial application
Undertaking by investigator
Ethics committee and Format of EC approval
Checklist of contents and format for ICF
Structure and content of report
Fixed Dose Combinations
Study conditions for drug storage
Content of Protocol.
Overall perspective: The changes in clinical trial definition and acceptance of multi-national concurrent phase II-III will rationalise regulatory guidelines for integration of India in global clinical development.
The focus on Ethics committee composition and function will go a long way in bringing uniformity in EC function and improving GCP compliance. The additional five signatures on the ICF will be a torture for both the patient and the investigator. The compliance undertaking by the investigator is unlikely to find favour with the investigators. It is likely to lead to conflict between the sponsor and investigator and may dampen enthusiasm of a good investigator.
As there are differences between Indian GCP and ICH-GCP guidelines, the audit of an Indian trial will be a challenging task for the foreign sponsor’s auditors and the Indian subsidiary.
GCP is considered a shared responsibility between sponsor, investigator, regulatory Authority and Ethics Committee. Until now, there was no regulatory enforcement of GCP compliance. In absence of regulatory support, the onus of GCP compliance, to a large extent, fell on the sponsors with some support from the investigators.
The proposed changes in Schedule Y are a major step forward in direction of GCP compliant trials and will provide the much-needed regulatory support!
Dr Arun D Bhatt is the member faculty of Pharmaceutical Medicine (Royal College UK) president of ClinInvent Research India Pvt Ltd.