A trial patient visited the site complaining breathlessness and tachycardia. The investigator advised hospitalization but as subject could not afford the expenses, he refused for admission. Is this an SAE because investigator advised hospitalization?
G Praveen Kumar.
If the patient was not hospitalized, it does not fall into SAE criteria of hospitalization. However, it appears from your mail that the PI felt that the event was serious enough to admit the subject for treatment. This makes it an “important medical event." As per ICH E2A such event also are considered serious. See the ICH E2A excerpt below:
Medical and scientific judgement should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardise the patient or may require intervention to prevent one of the other outcomes listed in the definition above. These should also usually be considered serious.
There is also one more problem here. As per Indian GCP, and recent DCGI directive, the cost of medical treatment has to be covered by the sponsor. Hence, the PI should have treated the patient free of charge and recovered the cost from the sponsor.
How often should the ICF be updated considering there are CIOMS generated on an ongoing basis during the course of a trial?
As per ICH E6, section 4.8.2, the written ICF and any other written information provided to subjects should be revised whenever important new information becomes available that may be relevant to the subjects consent. It also states that the IRB/IEC, the subject or the LAR should be informed in a timely manner if new information becomes available that maybe relevant to the subjects willingness to continue participation in the trial.
If the CIOMS contains information that is relevant to the subject’s consent then the ICF needs to be updated. Also 21 CFR 50.25 (b) states that significant new findings developed during the course of research which may relate to the subjects willingness to continue participation will be provided to the subject.
IB needs to be updated annually, but what if there are no safety updates in a particular year?
As per ICH-GCP, the IB should be reviewed at least annually and revised as necessary in compliance with a sponsor's written procedures. More frequent revision may be appropriate depending on the stage of development and the generation of relevant new information. However, in accordance with GCP relevant new information may be so important that it should be communicated to the investigators, and possibly to the (IECs and/or regulatory authorities before it is included in a revised IB. Given this, the IB has to be revised annually even if there are no safety updates with a mention of the same.
What are the labelling requirements for clinical trials in India?
Dr Sunita Vashishtha
The labelling for clinical trials is as per relevant GMP requirements. However, we accept the labels as per International labels for clinical trials. Indian GCP has given a format
18.104.22.168. Handling of the Product(s)
- Measures to be implemented to ensure the safe handling and storage of the pharmaceutical products.
- System to be followed for labelling of the product(s) (code numbering etc.)
- The label should necessarily contain the following information: the words - “for clinical studies only”, the name or a code number of the study, name and contact numbers of the investigator, name of the institution, subject’s identification code.
Kindly advise us whether we require DCGI or Ayush approval for conducting a post-market clinical trial on an ayurvedic product. And please advise us whether it is mandatory to register such trials with CTRI.
Ayush GCP guideline defines Phase IV as follows:
Phase IV: Studies performed after marketing of the ASU medicine / other TM. Trials in phase IV are carried out on the basis of the product characteristics on which the marketing authorization was granted and are normally in the form of post-marketing surveillance, assessment of therapeutic value, treatment strategies used and safety profile. Phase IV studies should use the same scientific and ethical standards as applied in pre-marketing studies.
After a product has been placed on the market, clinical trials designed to explore new indications, new methods of administration or new combinations, etc. are normally considered as trials for new ASU medicines / TM.
ICMR 2006 recommends 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 letrazole. Here, DCGI permission and EC approval are needed which really makes the trial a Phase III study.
If the objective of post-marketing clinical trial is to assess safety of the formulation, no regulatory approval is needed. However, if the study is a clinical trial in a new indication, regulatory permission is needed. For herbal products, the regulatory issues are reviewed by Department of Ayush.