Vaccine Clinical Trials Regulations in India

       A vaccine trial is a clinical trial that aims at establishing the safety and efficacy of a vaccine prior to it being licensed. It is always better to prevent a disease than to treat it. Vaccines prevent diseases in people who receive them and protect those who come into contact with unvaccinated individuals. It is only due to vaccination against infectious diseases, millions of people do not succumb to morbidity and mortality from viral and bacterial infections in the modern world.

      Vaccination is generally considered to be the most effective and cost-effective method of preventing infectious diseases. The material administered can either be live but weakened forms of pathogens (bacteria or viruses), killed or inactivated forms of these pathogens, or purified material such as proteins. Live vaccine has the characteristics to replicate in the host and attenuated in pathogenicity. Killed vaccines are unable to replicate in the host and gets inactivated by either radiation, heating & formalin. Vaccine-preventable diseases have a costly impact, resulting in doctor's visits, hospitalizations, and premature deaths. Sick children can also cause parents to lose time from work.

      The advantages of live vaccines include relative ease of production, very small amount of immunogens required; only single inoculation is needed in most cases, and induction of appropriate immune response. However, the drawbacks are potential for reversion to virulence, limited shelf life, and potential interference by co-infection with a naturally occurring wild type virus.

      On the contrary, the killed vaccine has an advantage of non-infectivity of the immunogen & relative product stability. The drawbacks are that it requires large quantities of immunogen, need for complete inactivation, needs high purity of final product, needs multiple vaccinations and potentially limited immune response. The characteristics of vaccine (live or killed) have high impact on the process of Regulatory approval in India.

      Vaccines are responsible for the control of many infectious diseases that were once common in India, including polio, measles, diphtheria, pertussis (whooping cough), rubella (German measles), mumps, tetanus, hepatitis, chickenpox and Haemophilus influenza type b (Hib).

      Early forms of vaccination were developed in ancient China as early as 200 B.C. Scholar Ole Lund comments: "The earliest documented examples of vaccination are from India and China in the 17th century, where vaccination with powdered scabs from people infected with smallpox was used to protect against the disease. Smallpox used to be a common disease throughout the world and 20% to 30% of infected persons died from the disease. Smallpox was responsible for 8% to 20% of all deaths in several European countries in the 18th century.

      Current guidelines concerning the development of new medicines and the conduct of clinical trials are based on more conventional, small molecule compounds. The results of the vaccine trials therefore raise the following question: are the current guidelines for pre-clinical testing appropriate and sufficiently rigorous for the new wave of biological medicines. The appropriateness of conventional clinical trials in the assessment of biological medicines should also be considered and, in particular, whether the present clinical trial guidelines are suitable for monoclonal antibodies and other biological medicines.

      Under the Drug and Cosmetics Act 1940, the regulation of manufacture, sale and distribution of drugs is primarily the concern of the state authorities while the central authorities are responsible for approval of new drugs, clinical trials in the country, laying down the standards for drugs, control over the quality of imported drugs, coordination of the activities of state drug control organizations and providing expert advice with a view of bring about the uniformity in the enforcement of the drugs and cosmetics act. Drugs Controller General of India is responsible for approval of licenses of specified categories of Drugs such as blood and blood products, I. V. Fluids, Vaccines and Sera.

      The manufacture and distribution of biological products for human use are regulated under the following two statutory authorities:
          ● Drugs Controller General of India (DCGI)
          ● Genetic Engineering Approval Committee (GEAC)

      Depending on the type of vaccine (live or killed) the approval or waiver from GEAC is sorted for all vaccine trials conducted in India. The ownership of a vaccine developed in India will be a crucial factor in having an affordable vaccine for public health use. The Department of Biotechnology (DBT) has been given the process for the development of a vaccine. PharmaLeaf has experience in garnering DCGI approval first, followed by GEAC waiver based on robust data and opinions from several participating countries.

      The guidelines for the vaccine clinical trial are as follows:
          ● Schedule – Y, Amendment version 2005, Drugs and Cosmetics Rules, 1945
          ● Biological guidelines
          ● GCP guidelines published by CDSCO, DGHS, Govt. of India.

      Ethical Guidelines for Biomedical Research on Human Subjects published by Indian Council of Medical Research, 2008 in New Delhi.

      The regulatory agency also takes the assistance of central institutions like Central Drug Laboratory, Kasauli, National Institute of Biologicals, Noida and Indian Veterinary Research Institute. Central Drug Laboratory at CRI Kasauli is a Central laboratory engaged in the testing of vaccines. It is a notified laboratory under the Drugs and Cosmetics Act, 1940 to function as Central drugs laboratory for testing of the following drugs or classes of drugs; Sera, Solution of serum proteins intended for injection, Vaccines, Toxins, Antigens, Anti-toxins, Sterilized surgical ligature and sterilized surgical suture, and Bacteriophages, including Oral Polio vaccine.

      The logistics for vaccine are vital since most of the biological product requires cold chain management in Immunization. However, potent a vaccine may be, if the cold chain is not maintained from the source of vaccine manufacture to the site of vaccine administration - the vaccine efficacy will grossly suffer. To maintain the potency of the vaccine a safe zone of temperature is mandatory.

      The logistics for vaccine are vital since most of the biological product requires cold chain management in Immunization. However, potent a vaccine may be, if the cold chain is not maintained from the source of vaccine manufacture to the site of vaccine administration -- the vaccine efficacy will grossly suffer. To maintain the potency of the vaccine a safe zone of temperature is mandatory.

      The cold chain system is a means for storing and transporting vaccines in a potent state from the manufacturer to the person being immunized. This is a very important component of an immunization programme, since all vaccines lose potency over time, especially if exposed to heat, and in addition, some also lose their potency when frozen. It is obviously pointless to immunize with an impotent vaccine, and efforts to reach extremely high levels of immunization coverage will be useless if the vaccine being administered has insufficient potency to give the necessary protection.

      Attention to maintaining correct temperatures during storage and transport of vaccine is thus a major task for health workers.

      The cold chain system comprises three major elements:
          ● Personnel, who use and maintain the equipment and provide the health service;
          ● Equipment for safe storage and transportation of vaccines; and
          ● Procedures to manage the programme and control distribution and use of the vaccines.

      Competent personnel and efficient procedures are a vitally important part of the cold chain system. Not all countries have an identical system, but the vaccine must always be maintained at a safe temperature throughout its entire journey.

      The safe zone for vaccine storage for short term i.e. 1 to 2 months is +2°C to +8°C. For long-term storage, -20°C as preferred only for BCG, OPV and Measles / MMR. This vaccine should not be freezed. Domestic refrigerators / Ice lined refrigerators (ILR) are used for short-term storage and deep freezer for long-term storage. Vaccine carriers are used for carrying the vaccine to an outreach centre which maintains the ideal temperature of 2°C to 8°C with the help of 4 fully frozen ice packs contained in them. Cold boxes are used in fixed centers as alternative vaccine storage equipment in the event of short duration of electricity failure.

      The storing of vaccines in a domestic refrigerator should be used only for vaccine storage. OPV in the freezer compartment and the rest of the vaccines in the non-freezing lower compartments. No vaccine should be stored in the tray or the door shelves. Repeated thawing of OPV should be avoided for all practical purposes. Never carry vaccines in a flask for an outreach place.

      In summary, multiple regulatory agencies are involved in India for managing, manufacture and conduct of clinical trials of biological samples in the well controlled environment. Pharmaceutical companies are seeking single window clearance system which will facilitate the approvals to conduct the vaccine clinical trials successfully in India. Pharma industry is working closely with both regulatory and central lab which is supportive in issuance of relevant licenses. These clinical trials with vaccines are useful to patients with poor immune responses for which the benefit far outweighs the risk. If vaccination is not done at the young age then chances of getting the disease per se is high in old age with high risk involvement. Hence vaccination plays a crucial role in children for preventing infectious diseases.