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Documents to be submitted to DCGI for grant of BA / BE NOC – Updated FEB 2014



DCGI has revised the list of documents that needs to be submitted for grant of DCGI BA / BE NOC. This will be effective from 01st February 2014. This article provides the micro details of the updated list of documents required by DCGI for grant of BA / BE NOC
Intuitive Pharma - CDSCO

In an effort to streamline the review and approval process for providing permission to conduct BA / BE studies [BA / BE NOC]in India for export purposes, with healthy human subjects or patients, the DCGI has issued a revised checklist for documents. The revised list of documents to be submitted to DCGI for grant of BA / BE NOC will become effective from 01st February 2014. If you want to have a look at the salient features of the new revised list required for DCGI BA / BE NOC application check our post on "Revised list of documents to be submitted to DCGI for grant of BA / BE NOC - Updated JAN-2014". As promised we are posting this detailed article to provide the micro details on the updated list of documents required by DCGI for grant of BA / BE NOC.

The documents required for grant of DCGI BA / BE NOC to conduct a clinical BA / BE study with a drug, varies based on the approval status of the study drug under consideration in India. To find in detail how drugs are classified in India based on their approval status check this post on "Classification of drugs in India based on their approval status."

A: Approved in India for more than 4 years except for modified release dosage form [old drugs]

The below specified documents should be provided for DCGI BA / BE NOC application for drugs approved in India for more than 4 years. However this does not applies to modified release dosage form (i.e) all modified release formulations will be considered as new drugs inspite of thier approval status. It should be noted as per previous gulation you need not get DCGI BA / BE noc for a drug available in India for more than four years.

  1. Form-12 application along with treasury challan for Rs. 15000/.
  2. Application for BA / BE NOC in Form-44 duly signed, by the authorized signatory of the company applying for BENOC with details of name and designation.
  3. Duly executed Sponsor’s authorization letter in company letterhead signed by the authorized signatory of the company whose investigational medicinal products are being tested.
  4. Undertaking letter from the sponsor that the sponsor will provide complete medical care as well as compensation for the injury or death and the detail of compensation provided in such cases would be intimated to The Office of Drugs Controller General (India) as per Rule 122 DAB of D&C Act 1940 & Rules there under
  5. Duly signed undertaking by the Principal Investigator (PI) on a company letterhead as per appendix VII of Schedule "Y" of Drugs and Cosmetic Rules. The undertaking should be signed by the principal investigator in original. No one including the co-investigator should sign on the principal investigator's behalf with a "For" tag.
  6. The approval copy issued by DCGI for the BA / BE Centre along with details of number of beds for which approval was provided. Details of the number of beds at the intensive care unit [ICU] of the BA / BE Centre for effective handling of SAEs in emergency situations should also be provided. This can be provided in the form of a declaration in the BA / BE Centres letter head
  7. The Office of Drugs Controller General (India) issued registration certificate [under Rule-122DD] for the Independent/Institutional Ethics Committee (IEC), which approved the protocol, should be included in the submission
  8. Address details of the sponsor, IEC location and study site location. This will be provided in the protocol. However it should be noted that DCGI is in particular stern about the location of the IEC and study centre. The IEC and study site location should be in close vicinity so as to enable the IEC to monitor the study.
  9. The study protocols, protocol IEC approval letter [if available], Informed Consent Form [ICF] or Patient Information Sheet [PIS] along with SOP or system for audio-visual recording to be implemented in the study under consideration as per Schedule Y guidelines should be submitted
  10. A statement to that the sponsor will provide complete medical care as well as compensation for the injury or death should be incorporated in the Informed Consent Form.
  11. A short brief summary of the study briefing the process and procedures to be followed in the study should be part of the submission. The synopsis section of the protocol will serve the purpose in most cases.
  12. Details of dosage form & strength of the investigational medicinal products to be tested [study drug] in the proposed study and their current regulatory status in India should be provided
  13. Report of any study related deaths that occurred in the study site during last 3 years while using the drug for which DCGI BA / BE NOC is being applied should be reported
  14. The pharmaceutical data of the Test formulation including stability data for three months should be shared. If data for three months is not available, current available data [at least one month] can be shared at the time of application. However an update should be filed when the three months data is available.
  15. Certificate of Analysis (COA) of representative batches of Test & Reference formulations to be used in the BE study should be submitted. If BA / BE NOC is applied for Oral solid dosage forms, dissolution profile of Test & Reference formulations intended to be used in the study should also be submitted.
  16. For Multiple dose BE study adequate supporting safety data & PK/PD data should be submitted covering the duration of period for which the study has to be conducted. If Regulatory Guidance is available and recommends the need for multiple dosing provide a copy of the guidance.
  17. If BA / BE NOC involves injectable formulations, the sub-acute toxicity of the test formulation studied in at least two species of animals for a minimum of 14 days should be submitted
  18. For BE studies involving patients, treated with cytotoxic, hormonal, narcotic or psychotropic drugs/preparations/substances a scientific justification and proper risk mitigation strategy with special emphasis on safety should be submitted
  19. Depending on the nature of the drug, disease and studies further specific information may also have to be furnished by the sponsor to secure BA / BE NOC
  20. All BA / BE NOC applications should be accompanied with the above mentioned documents consisting of proper index with page numbers in legible form.

B: New Drugs approved in India for a period of more than 1 year but less than 4 years

For New Drugs approved in India for a period of more than 1 year but less than 4 years, the below specified documents in addition to that specified in Section A, should be provided for DCGI BA / BE NOC application

  1. Chemical data of the study drug

C: Drug products in modified release form irrespective of their approval status

For Drug products in modified release form irrespective of their approval status , the below specified documents in addition to that specified in Section B, should be provided for DCGI BA / BE NOC application

  1. Form-12 application along with treasury challan for
    1. Rs. 15000/- In case if the study drugs approved in India
    2. Rs. 25000/- In case if the study drugs is not approved in India

D: New drugs approved in India within a period of one year

For New New drugs approved in India within a period of one year , the below specified documents in addition to that specified in Section C, should be provided for DCGI BA / BE NOC application

  1. Form-12 application along with treasury challan for Rs. 25000/.
  2. Published articles, reports or regulatory dossiers with Pharmacokinetic and Pharmacodynamics data of the study drug from studies carried out in healthy subjects/ patients demonstrating safety and tolerability of the study drug
  3. The patient package insert and or the prescribing information leaflet of the study drug

E: New molecule not approved in India but approved in other countries

For New New drugs approved in India within a period of one year , the below specified documents in addition to that specified in Section D, should be provided for DCGI BA / BE NOC application

  1. Names of the countries where the study drug is currently being marketed to be mentioned in the covering letter of the application
  2. The regulatory approval status of the study drug in other countries should be presented along with details of approved strength and dosage form
  3. The Non-clinical data and clinical data of the study drug should be provided as per Appendix I of Schedule Y

It should be noted that one cannot perform bio studies in India on Indian population for a drug not marketed/approved anywhere in the world. If you have any doubts or require clarification regarding the content please feel free to post in the comment section, we will try to answer your queries at the earliest to the best of our knowledge





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Classification of drugs in India based on their approval status



Drugs are classified under five categories in India based on their approval status. These classification forms the basis on which document requirement for DCGI BENOC application are being determined
Intuitive Pharma - CDSCO

Drugs are classified under five categories in India based on their approval status. These classification forms the basis on which document requirement for DCGI BENOC application are being determined.

Classification of drugs in India based on their approval status:

  • Drugs approved in India for more than 4 years except for modified release dosage form [old drugs*]
  • New Drugs approved in India for a period of more than 1 year but less than 4 years
  • Drug products in modified release form irrespective of their approval status
  • New drugs approved in India within a period of one year
  • New molecule not approved in India but approved in other countries

*Drugs that are official in the Indian pharmacopeia are also considered as old drugs with the exception for modified release formulations.
It should be noted that one cannot perform bio study in India on Indian population for a drug not marketed/approved anywhere in the world.

Extensive documentation is required for DCGI BA / BE NOC application for new molecule not approved in India but approved in other countries. On the other hand comparatively less documentation is required for issuance of DCGI BA / BE NOC for drugs approved in India for more than 4 years. The degree of scrutiny of the BA / BE NOC application also follows the same scale i.e. ascending from A to E.

Sources to find approval status of a drug in India:

The latest updated list of drugs approved in India with month of approval, dosage form including strength can be found at http://cdsco.nic.in/listofdrugapprovedmain.html. Be informed that older approvals [prior to 1999] are without information on dosage form and strength. The respective dosage form and strength details for the approvals can be found in the respective years Indian Pharmacopeia.

Alternative sources to find if a drug was approved for over four years is to refer to MIMS or CIMS published four years prior to the current year. As such booklets portray drugs approved for marketing in Indian by DCGI, a drug published in such publications should have been approved by DCGI in that month/year.





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Revised list of documents to be submitted to DCGI for grant of BA / BE NOC - Updated JAN-2014



DCGI has revised the list of documents that need to be submitted for grant of BA / BE NOC. The new revised requirement if approved will be effective from 01st February 2014
Intuitive Pharma - DCGI BA / BE NOC
To ensure uniformity in documents submitted to the Directorate (Drug Control General of India, DCGI) for review and approval of permission to conduct BA / BE studies in human subjects or patients for export purpose, the DCGI has issued a revised draft checklist. The revised draft checklist for DCGI BA / BE NOC will become effective from 01st February 2014.

The salient features of the revised draft checklist of documents required for issue of BA / BE NOC that will be effective from 01st February 2014 are,

  1. *BA / BE NOC need to be applied to conduct clinical trials with drugs approved and available in India for more than 4 years
  2. Undertaking letter from the sponsor stating that the sponsor will provide complete medical care as well as compensation in instances of study related injury or death. This is in addition to the statement to this effect incorporated in the Informed Consent Form
  3. The study protocols, Informed Consent Form (ICF) or Patient Information Sheet (PIS) along with audio-visual recording system as per Schedule Y guidelines
  4. Report of any study related deaths during last 3 years if any that has occurred in the study centre
  5. For all new molecule not approved in India, new drugs approved in India within a period of one year, modified release formulations for which the DCGI has issued BA / BE NOC, all BA / BE centres should furnish an annual status report of the project details, the start and end date of the project, study location, Serious Adverse Events if any encountered, study results and outcome etc to DCGI for its review and record purpose. This exercise should be carried out on or before 15th January of every year to ensure the safety and wellbeing of the participating healthy human subjects and or patients
*Till now DCGI BA / BE NOC is not required, to conduct clinical trials with drugs approved and available in India for more than 4 years. These drugs are deemed as old drugs.

A detailed post on the DCGI BA / BE NOC document requirement will be posted over here once the draft list is finalised. Watch this space or sign up for our newsletter to get updates automatically in your inbox.





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The format and elements of an Informed Consent Form



An ideal format of Informed Consent Form should have following three sections - Introduction, Information Sheet & Certificate of Consent
The format and elements of an Informed Consent Form - Intuitive Pharma

The investigator must provide information about the study to the prospective subjects who are willing to participate in the study. This information should be provided to the subject through verbal and audio visual aids. The details of the trial should also be provided in a written document, patient information sheet. The patient information sheet is called ICF or Informed Consent Form.

The Informed Consent Form contains details of processes and procedures involved in the trial, the potential risk and benefit that the subject may obtain by participating in the study in a language that is non-technical and easily understandable by the study subject. The Subject's consent to participate in the study must be obtained in writing using the Informed Consent Form. The informed consent form should be written to a format to comply with international ethical and regulatory requirements.

An ideal format of Informed Consent Form should have following three sections namely,
  1. Introduction - To provide information on the investigator, organisation & sponsor involved in the study
  2. Information Sheet - To share information about the research with the subject
  3. Certificate of Consent - For declaration and signatures, if the subject agree to take part in the study

I. The "Introduction" section of an Informed Consent Form

The following information should be provided in the introduction section of the Informed Consent Form.
  • Name of Principal Investigator
  • Name of Organization
  • Name of Sponsor
  • Proposal and its version

II. The "Information" section of an Informed Consent Form

The section on information of an Informed Consent Form provided to prospective subjects participating in a study contains two types of elements
  • Essential elements
  • Additional elements
The write-up content for the essential element of an Informed Consent Form provided to the prospective subjects participating in a study contains details that are imperative for comprehension of the proposed study procedure and processes that the subject will have to undergo while participating in the study
  1. Statement that the study involves research
  2. Explanation of the purpose of the research
  3. Expected duration of the subject's participation
  4. Description of the procedures to be followed, including all invasive procedures and identification of any procedures which are experimental
  5. Description of any reasonably foreseeable risks or discomforts to the subject participating in the study
  6. Description of criteria for participant selection in the study, Inclusion and exclusion criteria
  7. Statement that participation of the subject in the study is voluntary
  8. Statement that the subject can withdraw from the study at any time and that refusal to participate will not involve any penalty or loss of benefits to which the subject is otherwise entitled to
  9. Information on the study drug [Name of Drug] to be used in the study
  10. Expected side effects with the study drug(s) to be used in the study
  11. Studies of investigational articles (drugs, biologics or devices) should include a statement that a purpose of the study includes an evaluation of the safety of the test article. Studies that involve efficacy should also include the effectiveness of the test article, as a study purpose, but should not make claims of effectiveness.
  12. Study treatment schedule(s) and the probability for random assignment to each treatment (for randomization and placebo control studies)
  13. A description of any reasonably foreseeable risks or discomforts to the subject
  14. Processes and procedures involved in the study as described in the protocol
  15. Description of any benefits to the subject or others reasonably expected from research. If no benefit is expected subject should be made aware of this.
  16. Disclosure of specific appropriate alternative procedures or therapies available to the Subject if any, that might be advantageous to the subject.
  17. Statement describing the extent to which confidentiality of records identifying the subject will be maintained and who will have access to subject’s medical records
  18. An explanation about whom to contact for answers to pertinent questions about the research and research subjects rights, and whom to contact in the event of a research-related injury to the subject
  19. The anticipated prorated payment, if any, to the subject for participating in the study
  20. Rights of subjects and in the event of any injury
  21. Statement describing the financial compensation and medical management as under:
    • In the event of an injury occurring to the clinical study subject, such subject shall be provided free medical management as long as required
    • In the event of a study related injury or death, the sponsor or his representative, whosoever has obtained permission from the licensing Authority for conduct of the clinical study, shall provide financial compensation for the injury or death
  22. Subject's responsibilities while participation in the study
  23. Any other pertinent information
The write-up content for the additional element of an Informed Consent Form provided to the prospective subjects participating in a study details elements of information that are currently unforeseeable, but may have to be provided to subject.
  1. Statement of anticipated circumstances under which the subject's participation may be terminated by the Investigator without the subject's consent.
  2. Additional costs to the subject that may result from participation in the study.
  3. The consequences of a subject’s decision to withdraw from the research and procedures for orderly termination of participation by subject.
  4. Statement that the subject or subject's representative will be notified in a timely manner if significant new findings develop during the course of the research which may affect the subject's willingness to continue participation will be provided.
  5. A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or foetus, if the subject is or may become pregnant), which are currently unforeseeable.
  6. Approximate number of subjects enrolled in the study

III. The "Certificate of Consent section" of an Informed Consent Form

The section on Certificate of Consent of an Informed Consent Form provided to prospective subjects participating in a study should contain
  1. Questions to test if the subject understood the verbal, audio visual presentation and the information consent form in its entirety
  2. Confirmation by the subject that he had opportunity to ask questions (and if asked, were answered) about study to the Principal Investigator or appropriate individual
  3. Statement of acknowledge that the subject has read and understood the information consent form
  4. Declaration of consent by the subject to participate in the study
  5. Provision for signature of the subject in section on Certificate of Consent of the information consent form

An audio-visual recording of the informed consent process should also be performed. Both the written and audio visual documentation of subject consent to participate in the study should be preserved adhering to the principles of confidentiality.





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How to get DCGI NOC without query



Though no official guidelines have been published CROs and Sponsors have been receiving deficiency letters from DCGI. We depict some important points to be kept in mind while drafting protocols, ICF for clinical trials and the supportive documents that should be provided along with DCGI NOC application so as to obtain DCGI NOC without queries.
Intuitive Pharma - CDSCO
Due to recent uproar in Indian parliament over the credibility/safety of clinical trials conducted in India and concern over the people exposed to drugs, DCGI of late has been cautious over providing NOC for clinical trials in India. For the records, 250 clinical trials were approved by DCGI during 2010, but the same over a period of six months during this year (2011) stands at 25. There have been reports of non intimated deaths and declined compensation to subjects for various trials held in India.
Though no official guidelines have been published CROs and Sponsors have been receiving deficiency letters from DCGI. we depict some important points to be kept in mind while drafting protocols, ICF for clinical trials and the supportive documents that should be provided along with DCGI NOC application so as to obtain DCGI NOC without queries.

  1. Study Related Injury and Compensation:
  2. As the concern is more on study related injury and compensation, please ensure that these areas are addressed as per ethical guidelines and Indian regulatory requirements in appropriate sections of your protocols and ICF's.

    1. Study Related Injury:
    2. The onus on study related injury will be with the organisation that's applying for NOC. If the application is delegated through a CRO by the sponsor then statements should be mentioned in appropriate sections of the protocol and ICF that In case of study related injury {CRO Name} will provide complete medical care along with compensation for injury. If NOC is applied through sponsor, then the sponsor should take the responsibility of study related injury and compensation.

    3. Compensation:
    4. As feedbacks reveal that the subjects/patients are not compensated proportionately for their participation in the trial you are requested to add the following statement in protocol and ICF, Compensation for participation in the study will be paid proportionately at the end of each period of the study.

  3. Age limit:
  4. As the probability of getting an insurance reimburisement in the event of death/disease decreases with ages beyond 45 yrs, (you are required to undergo a medical test with the insurance agency designated doctor, if you are above 45 years of age) the agency now wants studies to be performed with subject within an age limit of 18 - 45 yrs both inclusive. Note: A thorough literature research should be done before deciding on the same. If a different range is desirable (e.g. safety issues) the same should be communicated to the regulatory authorities with supportive data.

  5. No of Subjects:
  6. Sponsors/CROs should provide proper justification for the number of subjects to be recruited for the trial. Though this should be justifiable for a clinical trial its not the same with bioequivalence study. If you are proposing a subject size of more than 50 for a bioequivalence study, you are sure to get a query to justify the same. This is fair, as a subject size of 40 should be more than sufficient to prove bioequivalence with sufficient power for a non highly variable drug. A higher number of subject number for a bioequivalence study, may raise doubts of forced bioequivalence at the cost of drug exposure to subject. If you are to include subjects more than 50 for any study it's advisable to provide proper justification for the same with ISCV from pilot data or with reference to published literature. If you are skeptic about your pivotal fortunes you may propose an arbitrary sample size in pivotal protocol and mention that the sample size will be finalized based on pilot study results.

  7. IEC Approval:
  8. The DCGI now wants the active participation of IEC/IRB in the NOC process of the trial. As per new requirement only IEC approved protocols should be included in application of DCGI NOC. All ethical committees (if formed as per regulatory requirements) will have a doctor/lawyer/Layperson/Scientist in place as its members. DCGI feels that the IEC would have thoroughly reviewed the protocol and if any issues relating to safety of subjects were present, objection would have been raised and deficiencies resolved before IEC approval of the protocol.

  9. IEC Approval Process:
  10. All the documents with respect to IEC application, composition and approval should be enclosed. The minutes of the IEC meeting should be documented along with the DCGI NOC application. This will give a brief idea to DCGI about objections raised with regards to protocol and ICF if any, and the resolution of the same before approval.

  11. Methods used to recruit volunteers for the study:
  12. During IEC approval CROs are to provide the details of methods used for volunteer recruitment for that study, which includes but are not limited to advertisements, hand outs etc. DCGI has now made it mandatory to provide the same during NOC application so as to scrutinize for any fiddling claims to woo the subjects into the trial.

  13. Informed consent process followed for the study:
  14. Sponsors/CROs are to provide the informed consent process that will be followed during the study. They will have to submit the ICF forms to be used in the trial along with NOC application. Presentations and questionnaires that will be provided to the subjects during the Informed consent process are also to be provided during the NOC application. Note: Many CROs are providing their SOPs on volunteer recruitment, Informed consent process and IEC approval process for the requirements Nos. 5, 6 & 7 discussed above. But it's not as
    • The same SOPs would have been audited by the DCGI during CRO facility approval.
    • The same documents would be recycled for all NOCs applied through that CRO, which is quiet ridiculous.
    We strongly recommend providing the documents as discussed above to avoid any queries from DCGI.
Note: This is first in series of articles on instructions to get DCGI NOC without query. The Other basic requirements for DCGI NOC application has been provided in this article titled Documents to be submitted to DCGI for grant of BE NOC





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Notification to DCGI regarding amendment to approved protocol



DCGI feels due to lack of clarity applications received for amendment to approved protocol of clinical trials are incomplete and lot of avoidable correspondence is being carried out. DCGI has come up with guidelines on notification to the agency regarding amendment of approved protocol.
Intuitive Pharma - CDSCO

DCGI has come up with guidelines on notification to the agency regarding amendment of approved protocol. Changes made to the Protocol and resultant amendments effected needs to be informed to the DCGI.

Amendments are categorised into three categories,
  1. Those amendments which do not require any infomation or permission.
  2. Those amendements which require to be infomed but need not wait for permission.
  3. Those amendments which require prior permission before implementation of the amendments.

A. Amendments that does not require notification to or permission of the Licensing Authority

  1. Administrative and Logistic changes.
  2. Minor protocol amendments and additional safety assessments in case the institutional ethics committee has already approved these changes.

B. Amendments that require notification to the Licensing Authority but need not wait for permission

  1. Additional Investigator sites.
  2. Change in investigator with the consent to withdraw from the earlier investigator.
  3. Amended Investigators Brochure, amended informed consent.

C. Amendments that require prior permission of the Licensing Authority

  1. Additional Patients to be recruited.
  2. Major changes in protocol with respect to study design, dose and treatment options.
  3. Any change in inclusion or exclusion criteria.
According to DCGI, due to lack of clarity applications received are incomplete and lot of avoidable correspondence is being carried out.





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