Q. Is it ethically right to administer the highest/ maximum dose of drugs to normal volunteers which are usually administered in escalating dose in clinical practice (particularly when the drug is known for its ADR)? What is the role of IEC?
● Dr Mira Patel

This does cause a problem especially with neuropsychiatry drugs. IEC can ask for supporting evidence from literature for safety in volunteers before approving such a study. Alternatively, IEC can permit a pilot study with strict medical supervision prior to a full study.

Q. What is the differences in a protocol & CRF of the BA/BE study & regular clinical study for a new molecule?
● Abhishek Gune
The principles of protocol are same for Clinical Trial and BA/BE. The CDSCO's (www.cdsco.nic.in) Guidelines for Bioavailability and Bioequivalence Studies for the BA/BE guidelines discuss the following specific issues:
- Criteria of selection of healthy subjects
- Sampling time points
- Study design
- Bioanalytical Method
- Study conditions - Fasting / Fed
- Pharmacokinetic endpoints
- Statistical criteria for bioequivalence

Q. Can a firm manufacture and market fixed dose combination of vitamins, minerals and tea leave extract without prior permission of DCGI?
● Dinakaran Mahesh

In recent years, DCGI office has been monitoring irrational combinations. New Schedule Y describes different FDCs as follows. Please see in which category proposed combination falls.

FDCs can be divided into the following groups and data required for approval for marketing is described below:
(a) The first group of FDCs includes those in which one or more of the active ingredients are a new drug. For such FDCs to be approved for marketing data to be submitted will be similar to data required for any new drug (including clinical trials) [see rule 122E, item (a)].

(b) (i) The second group FDCs includes those in which active ingredients already approved/marketed individually are combined for the first time, for a particular claim and where the ingredients are likely to have significant interaction of a pharmacodynamic or pharmacokinetic nature [see rule 122E, item (c)]. If clinical trials have been carried out with the FDC in other countries, reports of such trials should be submitted. If the FDC is marketed abroad, the regulatory status in other countries should be stated. (see Appendix I, item 9).

(ii) For marketing permission, appropriate chemical and pharmaceutical data will be submitted. In case such a combination is not marketed anywhere in the world but these drugs are already in use concomitantly (not as an FDC but individually) for the said claim, marketing permission may be granted based on chemical and pharmaceutical data. Data showing the stability of the proposed dosage form will also have to be submitted.

(iii) For any other such FDCs, clinical trials may be required. For obtaining permission to carry out clinical trials with such FDCs a summary of available pharmacological, toxicological and clinical data on the individual ingredients should be submitted, along with the rationale for combining them in the proposed ratio. In addition, acute toxicity data (LD 50) and pharmacological data should be submitted on the individual ingredients as well as their combination in the proposed ratio.

(c) The third group of FDCs includes those which are already marketed, but in which it is proposed either to change the ratio of active ingredients or to make a new therapeutic claim. For such FDCs, the appropriate rationale including published reports (if any) should be submitted to obtain marketing permission. Permission will be granted depending upon the nature of the claim and data submitted.

(d) The fourth group of FDC includes those whose individual active ingredients (or drugs from the same class) have been widely used in a particular indication(s) for years, their concomitant use is often necessary and no claim is proposed to be made other than convenience. It will have to be demonstrated that the proposed dosage form is stable and the ingredients are unlikely to have significant interaction of a pharmacodynamic or pharmacokinetic nature. No additional animal or human data are generally required for these FDCs, and marketing permission may be granted if the FDC has an acceptable rationale.

Q. If the clinical trial is completed but drug is not approved yet for marketing, can the investigator continue that treatment of investigational product to the patients?
● Mukesh Patel

WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI

Ethical Principles for Medical Research Involving Human Subjects 2004 paragraph 30

At the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study.

It is necessary during the study planning process to identify post-trial access by study participants to prophylactic, diagnostic and therapeutic procedures identified as beneficial in the study or access to other appropriate care. Post-trial access arrangements or other care must be described in the study protocol so the ethical review committee may consider such arrangements during its review.