Q. We have received DCGI and EC approval for a protocol and the patient recruitment is about to start in a week. But there has been a protocol amendment in which one of the exclusion criteria has been removed. This is likely to enhance to patient recruitment. Can the site recruit patients as per the selection criteria of the approved protocol and later after getting DCGI/EC approval of the amended protocol recruit patients as per the amendment? Is this acceptable?
● Sravan

You have 2 options 1) wait for approval of amendment or 2) include patients with current protocol and later include as per the approved amended protocol. If you follow the 2nd option, you will have 1) issues in monitoring and audit and 2) you will have issues in accounting for the patients enrolled with current protocol in your data management and final report. Hence, it would be prudent to wait for the approval of amendment and then begin the recruitment.

There is also a need to consider the ethical issue. An amendment, which based on removing certain exclusion criteria, may have impact on safety of patients. The decision whether the amendment is ethical or not depends on the judgement of EC and regulatory authorities.


Q. As per GCP - ICH section 8.3.12 signed informed consent form during the trial should be located at Investigator / Institution. In contrast Indian GCP Appendix V describes that signed informed consent form during the trial should be located at Investigator/Institution (Original) and copy should be in Sponsor's/CRO file. Which GCP should be followed?
● Raju Pandey

We have to follow ICH-GCP. The consent forms are a confidential transaction between the investigator and the subject. Hence, the signed consent forms cannot be taken out of the institution by the sponsor/CRO for their files. There seems to be an error in Indian GCP list of essential documents.


Q. Is there any guidance on retention of IP at study site or third party after completion of bioequivalence study?
● Surendra Vaze

As per Indian BE guidelines, the samples have to be retained for 3 years after the conduct of the study or 1 year after expiry of the drug, whichever is earlier.


Q. A What are the criteria at sponsor's end to select a 'reference product' for a bioequivalence study?
● Amol K

As per bioequivalence guidelines issued by CDSCO, the reference product is a pharmaceutical product identified by the licensing authority as designated reference product and contains the same ingredient as the new drug. This is usually a global innovator's product.


Q. We have one patient who was screened on 11-Apr-08. ICF was signed on the same day and blood sample was collected on the same day as per screening procedures. The laboratory reports suggest urinary tract infection. Should we consider this an adverse event?
● Jigar Mody

ICH-GCP definition suggests that there has to be a temporal relation between IP and the event. As the patient is still under screening and the IP is not administered, this is not an adverse event. See the definition below:

ICH GCP 1.2 Adverse Event (AE)

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.


Q. The protocol was rejected by the EC of one of the sites which has potential subjects for the study. The investigator of this site is planning to refer them to another investigator in whose site the EC has approved the study. An investigator is planning to include a co-investigator who is not a part of the hospital. His role would be to refer patients who satisfy the inclusion and exclusion criteria from his hospital. What are the different approvals and documentation to be obtained for these?
● Sravan

There are major issues with what the investigator plans to do. If the EC has rejected the protocol, the investigator's plan to refer the patients to another investigator is unethical. The investigator at second site where the study is approved has to inform the EC about decision of the first hospital and his plans to recruit patients from the first investigator whose site rejected the study. Although the investigators may find their solution practical, it will have major problems during audit and inspection. The person who is just referring patients cannot be considered a co-investigator. As per GCP guidelines, co-investigator/ sub-investigator is a tem member of the investigator site with specific trial elated responsibilities. See the definitions below:
Indian GCP Co-investigator/ Sub-investigator

A person legally qualified to be an investigator, to whom the Investigator delegates a part of his responsibilities.
ICH GCP 1.56 Sub-investigator

Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g., associates, residents, research fellows).