I have questions about phase IV studies in India and wondering whether you can help. What are the regulatory or associate approval requirement in addition to IRB/EC approval? Is an approval from MCI needed for this?
Dr Grace Pei

For phase IV studies, the Indian regulatory scenario is bit complex. Schedule Y covers phase IV as follows:

Post marketing trials (phase IV): Post marketing trials are studies (other than routine surveillance) performed after drug approval and related to the approved indication(s). These trials go beyond the prior demonstration of the drug's safety, efficacy and dose definition. These trials may not be considered necessary at the time of new drug approval but may be required by the licensing authority for optimizing the drug's use. They may be of any type but should have valid scientific objectives. Phase IV trials include additional drug-drug interaction(s), dose-response or safety studies and trials designed to support use under the approved indication(s), e.g. mortality/morbidity studies, epidemiological studies etc.

In India, regulatory authorities ask the sponsor to conduct a PMS study when they approve a product for marketing. These studies require approval of protocol from regulatory authorities.

However, there are other phase IV studies, which require a different consideration. See the excerpt from Indian Council of Medical Research guidance.

Phase IV: The phase IV studies should have valid scientific objectives. After approval of the drug for marketing, phase IV studies or post marketing surveillance is undertaken to obtain additional information about the risks and benefits resulting from long term usage of drug. It is an important aspect of drug trial on the long-term effects of the drugs and the adverse reactions induced by drugs, if any, should be brought to the notice of the Ethics Committee. There is a need to correlate the adverse events reported during phase IV trials with the toxicity data generated in animals, to draw markers for future warnings of potential adverse events likely to occur with other drugs. These trials may not be necessary for approval of new drug for marketing but may be required by the licensing authority for optimizing its use. These studies also include those on specific pharmacologic effect, drug-drug interaction(s), dose-response studies, trials designed to support use under approved indication(s) e.g. mortality/morbidity studies, clinical trials in a patient population not adequately studied in the pre-marketing phase, e.g., children; and epidemiological studies etc. Bioequivalence and bioavailability study also falls under this category.

In addition there are phase IV studies that are designed to evaluate the marketed drug in specifically designed studies, which have inclusion/exclusion criteria, objectives and end points. The drug is used for the labelled indication in these studies.Therefore licensing authority permission is not needed. However, EC permission is needed.

A third type of post-marketing study involves evaluation of the drug for a new indication of a marketed drug, e.g. studies with letrozole. Here, DCGI permission and EC approval are needed which really makes the trial a phase III study.

At present there is no requirement of permission from Medical Council of India.

In case you are relabelling the investigational product do you need to inform DCGI and Ethics Committee both or only DCGI or only EC?
Priyanka Matekar
In clinical trial setting, relabelling is done usually to change the expiry date of the trial sample batch, when new stability data are available. You need to inform both DCGI and Ethics Committee of the relabelling.

Please see the relevant sections from Indian regulations Drugs & Cosmetics Act p 261 - Any change in the process of manufacture, method of testing, labelling, packaging, designing of the sale pack, medical literature and documentation is to be intimated to the licensing authority forthwith and permission to be obtained from him within 30 days time period.

Indian GCP 3.1.9. Supply, storage and handling of pharmaceutical products. The sponsor is responsible for supplying the investigational products, including comparator(s) and placebo if applicable. The products should be manufactured in accordance with the principles of GMPs and they should be suitably packaged in the manner that will protect the product from deterioration and safeguard blinding procedures (if applicable) and should be affixed with appropriate investigational labelling. The sponsor should determine the investigational product's acceptable storage conditions, reconstitution procedures and devices for product infusions if any, and communicate them in writing to all involved parties, besides stating them on the product labels wherever possible.
In case any significant formulation changes are made in the investigational product during the course of the study - the results of any additional studies of the new formulation (e.g. stability, bioavailability, dissolution rate) should be provided to the involved parties to enable them to determine their effects on the pharmacokinetic profile of the product prior to the use in the study. The sponsor should not supply an investigator / institution with the product until the sponsor obtains all required documentation (e.g. approval / favourable opinion from Ethics Committee and Regulatory Authorities).

Can clinical trial be done by individual government approved ayurvedic, unani and herbal physician in their own clinic? If yes, where can they get the EC approval?
Dr J. Vijayakumar

Yes. The physicians can conduct trials of herbal preparations in their own clinic. However, they need to follow specific Indian GCP guidelines for herbal preparation. You can approach an independent ethics committee or an institutional ethics committee for approval.

Dr Arun Bhatt is currently, president, ClinInvent,
Research Pvt Ltd, Mumbai.
Readers can send their queries at: arunbhatt@clininvent.com