In case of PMS studies (observational study for a marketed drug), is it mandatory to conduct a Site Selection, Site Initiation visit and an Investigator's meeting as in phase 3 trials?

Please see an excerpt from EMA guidance. There is no regulatory requirement for these activities as GCP does not apply to such non-intervention studies.  Volume 9A of The Rules Governing Medicinal Products in the European Union - Guidelines on Pharmacovigilance for Medicinal Products for Human Use - A post-authorisation safety study is defined in Article 1(15) of Directive 2001/83/EC as “pharmacoepidemiological study or a clinical trial carried out in accordance with the terms of marketing authorisation, conducted with the aim of identifying or quantifying a safety hazard relating to an authorised medicinal product”. The definition of non-interventional trial is provided in Article 21 of Directive 2001/20/EC: “A study where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within the current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of the collected data”.

In this context it is considered important to clarify that interviews, questionnaires and blood samples may be considered as normal clinical practice. Based on these definitions a fundamental distinction can be made between non-interventional (observational) and interventional post-authorisation safety studies. The latter are considered clinical trials falling under the scope of the Directive 2001/20/EC. If the definition of non-interventional is not met, the study should be considered as interventional. For instance, studies exploring new indications, new routes of administration or new combinations, after a product has been authorised, should be considered as interventional. In such cases, Directive 2001/20/EC and the related guidance should be followed (see Volume 10 of The Rules Governing The guidance on Good Clinical Practice does not apply to non-interventional post-authorisation studies.

What is the current Indian scenario of govt doctors contracted by sponsors to conduct clinical trials using the patients visited in these hospitals? If that happening where do they get the EC approval? What are the regulations for conducting trials?

J. Vijayakumar

If a doctor is working in a public hospital, he should take approval from his hospital's ethics committee. If the hospital does not have any ethics committee, he can take approval from EC of another hospital or a private/independent EC. Regulations for clinical trials are described in Schedule Y.
See Schedule Y excerpt below:
Clinical trial on a new drug shall be initiated only after the permission has been granted by the Licensing Authority (LA) under rule 21 (b), and the approval obtained from the respective ethics committee(s). The Licensing Authority as defined shall be informed of the approval of the respective institutional ethics committee(s) as prescribed in Appendix VIII, and the trial initiated at each respective site only after obtaining such an approval for that site. The trial site(s) may accept the approval granted to the protocol by the ethics committee of another trial site or the approval granted by an independent ethics committees (constituted as per Appendix VIII), provided that the approving ethics committee(s) is/are willing to accept their responsibilities for the study at such trial site(s) and the trial site(s) is/are willing to accept such an arrangement and that the protocol version is same at all trial sites.

I have a basic query regarding the hepatic adverse events. Is it that if ALT value >=3 x ULN with clinical symptoms or TBL >=2 ULN should only be captured as AE and not if only ALT value >=3 x ULN? If according to investigator grade 1 laboratory abnormality is clinically non significant, is it still an AE?

Riddhi

CTC considers ALT >ULN - 2.5 x ULN as abnormal grade 1. Bilirubin >ULN - 1.5 x ULN as abnormal grade 1. Both will be AEs. There is no link to symptoms.  The GCP definition of AE does not depend on grade or clinical significance  An adverse event (AE) can therefore be any unfavorable 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.

Can you suggest the guidelines and approval process for the noncritical diagnostics like CD4 count (monitoring kit) in India?

Divya Ganapathy

Diagnostic comes under category of devices as per Indian GCP/ICMR guidance. CDSCO is currently revising guidance for devices. It would be better to check with CDSCO re: process to be followed.

We have applied for DCGI permission; however in the protocol submitted to the DCGI we have mentioned the test drug formulation of the FDC as tablet. But the final formulation of the FDC dosage form is capsule instead of tablet. Should we amend the protocol now or wait for DCGI approval? After DCGI approval can we just notify the DCGI about the protocol amendment?

Prasad

A change of formulation will be considered a major technical amendment. It is likely that DCGI office will not consider this minor especially as it is for an FDC. One option is to wait for approval of current protocol and then notify DCGI re: change of formulation. However, they may not accept the notification and would insist on an approval. It is likely that DCGI office may ask for data on the FDC capsule - stability. There is no certainty in this situation. One has to be ready for delay in the approval process of the amendment.