Human Vaccines

Human Vaccines: The Developmental Paradigm in India


Vaccines are one of the most beneficial and valuable disease prevention measures contributing to long-term health gains. Advancements in research have led to the development of novel vaccines and delivery technologies and this is has caused a paradigm shift in the way diseases are prevented and treated. Even though the field of vaccines have evolved and the trends seem encouraging, there is a global need for new vaccines to address current health threats such as Dengue, Ebola, and Zika.

Clinical trials (CT) are the cornerstone for the introduction of new vaccines. CT provides the safety and efficacy data to support the approval of new vaccines; it helps evaluate risks versus benefits of a prospective vaccine and thus plays a major role in the evaluation of marketing authorization applications. Additionally, CT provides data to support recommendations for the inclusion of a specific vaccine into national immunization programs.



The Transition from the Laboratory to Clinical Trials

Not all discovered vaccines reach the clinical trial stage. The transition of a novel vaccine candidate from the laboratory to clinical trials depends on the fulfilment of certain important criteria. Animal immunogenicity data, toxicity data, possible impact on public health, cost-effectiveness and pre-existence of a vaccine with a satisfactory risk-benefit profile are usually considered to advance vaccine development.

Before clinical evaluation of a prospective vaccine, a developmental plan should be formulated to ensure successful development. An ideal development plan would include the following:

  • Identification of the target population and their sociocultural factors
  • isk assessment of the target disease and the vaccine itself
  • Understanding the incidence of the target disease and environmental factors
  • Identification of the dose and route of administration
  • Regulatory strategies

Vaccine candidate undergoes three phases of development in humans - Phase I, Phase II, and Phase III. Phase IV studies or post-marketing surveillance studies (PMS) are carried out following licensure of the product. Real-world data from PMS help to monitor the vaccine for safety and effectiveness in the population.

Conducting Clinical Trials in India

Clinical trials require regulatory and ethical oversight to ensure the protection of the trial participants as well as to ensure the scientific integrity of the resulting data.

The Central Drugs Standard Control Organization (CDSCO) is the national regulatory authority in India which ensures the safety, efficacy and quality of drugs, cosmetics and medical devices. The Drugs Controller General of India (DCGI) heads the CDSCO and is the final regulatory authority for the approval of CT in India.

Process of obtaining CT NOC in India

SUGAM is an e-Governance system to discharge various functions performed by CDSCO. The software system is an online web portal where applicants can apply for No objection certificates (NOCs) to conduct clinical trials. As per the CDSCO, for permission to conduct CTs/import/manufacture of vaccines in India, Form CT-06/CT-20/CT-23NOC should be used.

For any clinical trial, the study sponsor is the responsible person and has all the information. After receiving the CT-NOC from CDSCO and trial registration in the Clinical Trials Registry-India (CTRI), it is the responsibility of the sponsor to initiate and monitor the clinical trial in all the participating sites.

Sample size requirement and endpoints selection for vaccine studies

CDSCO requires the rationale and calculation for sample size requirement, anticipated drop- out rate etc. The sample determination may include H0 testing and desired power of the study.

Before initiating a vaccine study, the trial endpoints need to be defined; this aids in trial design and hypothesis formulation. It also guides the analysis of the data upon study completion and enhances the credibility of the study results. The following points should be considered while selecting endpoints for vaccine studies 7

  • The rate of occurrence of the endpoints in the population under consideration
  • The relevance of the vaccine effect on the endpoint
  • Reliability in measuring the endpoint

Some common endpoints used in vaccine studies include seroprotection rate, seroconversion rate, geometric mean antibody concentrations (GMCs) or titres (GMTs) and geometric mean titer pre-/post-vaccination ratio (GMRs).

The New Drugs & Clinical Trials Rules 2019

The Schedule 1st, 2nd, 3rd, & 5thand the Rules 21, 22, 23, 52, 59, 60, 67, 75 & 80 of theNew Drugs & Clinical Trials Rules 2019 governs clinical research in India. All clinical research that falls within the scope of said rulesmust comply with the necessary requirements. Rules, 2019has 13 chapters which comprises of 8 Schedules and formats for clinical trial protocols, informed consent forms, ethics committee (EC) approval templates and a format for serious adverse event (SAE)reportingand clinical trial reports.

Ethical Guidelines of the Indian Council of Medical Research (2017)

The Indian Council of Medical Research (ICMR) guideline covers the general principles that need to be followed while conducting biomedical and health research in India. It also provides guidance related to special areas such as research in children or herbal research.

ICH-Good Clinical Practice Guideline

The International Conference on Harmonisation (ICH)-Good Clinical Practice (GCP) is an international ethical and scientific standard for conducting trials involving human participants. The GCP ensures that the rights, safety, well-being, and confidentiality of trial participants are protected and the data collected in clinical trials, as well as the reported results of clinical trials, are credible and accurate.

The Indian guideline on Good Clinical Practice Guideline was released by CDSCO in 2001.

Important Considerations while Conducting Clinical Trials in India

For conducting clinical trials in India the investigator must ensure that clinical trials are conducted as per the rules outlined below10

  • In compliance with an Ethics Committee and a DCGI approved protocol
  • In the case of IISs (Investigator-initiated studies) with 'new drugs', DCGI approval is no longer needed; only an EC approval is required
  • In compliance with GCP guidelines
  • All applicable regulations

All clinical trials need to have approval from a registered Institutional Ethics Committees (IECs). IECs registration should be renewed at the end of 5 years. Before the first study participant is enrolled, it is recommended that all studies are registered in the Clinical Trials Registry of India (CTRI). CTRI is a free, online portal that allows both investigator-initiated and regulatory studies to be registered.10

Important Considerations during trial conduction

The study investigator is in-charge of conducting the study and is responsible for the conduct of the trial at a site by personally supervising the investigations.11 Informed consent from each study participant is a mandatory prerequisite; investigators must ensure that written, informed consent is obtained from all participants in a clinical trial. An audio-visual recording of the informed consent process should be ensured for trials that involve vulnerable participants and involve a new chemical entity or a new molecular entity. The study investigator should follow the protocol thoroughly and ensure that all personals assisting in the study are suitably trained.

All serious adverse events (SAEs) encountered during the trial should be reported by the investigator to the DCGI, the sponsor and the IEC, within 14 days of their occurrence.

Conducting Clinical Trials in India – The Hurdles

Robust economic growth, proven capabilities in medical skills, IT capacity, and a large pool of scientific manpower, have advantageously positioned India for the conduct of clinical trials. However, challenges are still encountered while conducting clinical trials in India.12

  • Limited exposure to research in medical education has led to limited experience with clinical trials conduction. Lack of qualified investigators; lack of government-accredited clinical-research training institutions, biostatisticians, and epidemiologists further adds to the problem.
  • Media disseminating, unfavourable and inaccurate depictions abound clinical research is another concern – this may undermine trust and participation in clinical research.
  • Future Implications - Goals of Modern Vaccination

    The ultimate goal of vaccination is to prevent or cure as many diseases as possible with the development of novel vaccines against emerging infections, cancers, and chronic diseases. Increasing the number of vaccine clinical trials and incorporating changes to foster medical expertise is the need of the hour. Another target is to improve the efficacy and safety of vaccines. Adjuvants are an essential component for increasing the efficacy of vaccines. Moreover, the advancements in genomic techniques and new vaccine-design methods have enabled the high-throughput screening of vaccine candidates with better safety profiles.

    Concluding Remarks

    With the increase in the quantity and quality of clinical vaccine development, the coverage of vaccines against diverse diseases will be broadened faster than ever. Developing efficient vaccine development strategies and streamlining the regulatory approval processes may help achieve these ambitious goals and save millions of lives.

    References

    1. Singh K, Mehta S. The clinical development process for a novel preventive vaccine: An overview. J Postgrad Med. 2016;62(1):4–11. doi:10.4103/0022-3859.173187
    2. Han S. Clinical vaccine development. Clin Exp Vaccine Res. 2015;4(1):46–53. doi:10.7774/cevr.2015.4.1.46
    3. Central Drug Standard Control Organization (CDSCO). Available at: https://cdsco.gov.in/opencms/opencms/en/Home/. Accessed on: 01 August 2019.
    4. Central Drug Standard Control Organization (CDSCO) User Manual For e-Governance Solution for CDSCO. Available at: https://cdsco.gov.in/opencms/export/sites/CDSCO_WEB/Pdf-documents/SUGAM_user_manual.pdf. Accessed on: 01 August 2019.
    5. GSR 227(E): New Drugs and Clinical Trials Rules-2019, Ministry of Health & Family Welfare, Department of Health and Family Welfare, Government of India, 19 March 2019
    6. Central Drug Standard Control Organization (CDSCO). Guidance for Industry on Submission of Clinical Trial Application for Evaluating Safety and Efficacy. Available at: https://www.kem.edu/wp-content/uploads/2019/06/CDSCO-Guidance-For-Industry.pdf. Accessed on: 01 August 2019.
    7. Hudgens MG, Gilbert PB, Self SG. Endpoints in vaccine trials. Stat Methods Med Res. 2004;13(2):89-114.
    8. ICH harmonised tripartite. Guideline for good clinical practice E6. 1996. Available at: https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf . Accessed on: 01 August 2019.
    9. Saxena P, Saxena R. Clinical trials: changing regulations in India. Indian J Community Med. 2014;39(4):197–202. doi:10.4103/0970-0218.143018
    10. Gogtay NJ, Ravi R, Thatte UM. Regulatory requirements for clinical trials in India: What academicians need to know. Indian J Anaesth. 2017;61(3):192–199. doi:10.4103/ija.IJA_143_17
    11. Burt T, Sharma P, Dhillon S, Manchanda M, Mittal S, Trehan N. Clinical Research Environment in India: Challenges and Proposed Solutions. J Clin Res Bioeth. 2014;5(6):1–8. doi:10.4172/2155-9627.1000201



    Frequently Asked Questions

    What is an “orphan drug” as per the New Drugs and Clinical Trial Rules, 2019?

    “Orphan drug” means a drug intended to treat a condition which affects not more than five lakh persons in India.

    The extrapolation of the safety and efficacy data of a particular clinical indication (for which clinical studies has been done) of a similar biologic to other clinical indications may be possible if following conditions are met: Similarity with respect to quality has been proven to reference biologic Similarity with respect to preclinical assessment has been proven to reference biologic Clinical safety and efficacy is proven in one indication Mechanism of action is same for other clinical indications Involved receptor(s) are same for other clinical indications New indication not mentioned by innovator will be covered by a separate application.

    The permission to initiate clinical trial granted in Form CT-06 or automatic approval in Form CT 4A shall remain valid for a period of 2 years from the date of its issue, unless extended by the CLA.

    Yes. Clinical trial at each site shall be initiated after the approval of the clinical trial protocol and other related documents by the Ethics Committee for that site, registered with the CLA.

    Yes. Before enrolment of first participant in any clinical trial, registration in CTRI is mandatory

    The three tier mechanism comprises the following authorities: 1. Institutional Biosafety Committee (IBSC) at the Institute/ company – To ensure biosafety on-site 2. Review Committee on Genetic Manipulation (RCGM) in the Department of Biotechnology - Managed genetically engineered cell banks 3. Genetic Engineering Appraisal Committee (GEAC) in the Ministry of Environment & Forests (MoE&F)- for genetically modified organisms/ living modified organisms

    Any person or institution or organisation having permanent establishment in India who intends to conduct clinical trial of a biological product can submit application for clinical trial.

    After obtaining permission in CT-11 or CT-14 or CT-15 as the case may be, the person, who intends to manufacture the biological product for CT, shall make an application for grant of license to manufacture the biological product by the respective State Licensing Authority (SLA) in accordance with the provisions of the Act and the Drugs and Cosmetics Rules, 1945.

    No. For biological product and substances discovered or developed in countries other than India, Phase I data should be submitted along with the application. After submission of Phase I data generated outside India to the Central Licensing Authority, permission may be granted to repeat Phase I trials or to conduct Phase II trials and subsequently Phase III trial concurrently with other global trials for that biological product.

    “New drug” means, (i) a drug, including active pharmaceutical ingredient or phytopharmaceutical drug, which has not been used in the country to any significant extent, except in accordance with the provisions of the Act and the rules made thereunder, as per conditions specified in the labelling thereof and has not been approved as safe and efficacious by the Central Licencing Authority with respect to its claims; or (ii) a drug approved by the Central Licencing Authority for certain claims and proposed to be marketed with modified or new claims including indication, route of administration, dosage and dosage form; or (iii) a fixed dose combination of two or more drugs, approved separately for certain claims and proposed to be combined for the first time in a fixed ratio, or where the ratio of ingredients in an approved combination is proposed to be changed with certain claims including indication, route of administration, dosage and dosage form; or (iv) a modified or sustained release form of a drug or novel drug delivery system of any drug approved by the Central Licencing Authority; or (v) a vaccine, recombinant Deoxyribonucleic Acid (r-DNA) derived product, living modified organism, monoclonal anti-body, stem cell derived product, gene therapeutic product or xenografts, intended to be used as drug; Explanation: The drugs, other than drugs referred to in sub-clauses (iv) and (v), shall continue to be new drugs for a period of four years from the date of their permission granted by the Central Licencing Authority and the drugs referred to in sub-clauses (iv) and (v) shall always be deemed to be new drugs;

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