Annexure-4

 Drug Regulatory Framework - need for stengthening of Central Drug Regulatory Agency

 It is the basic responsibility of the Government to ensure that drugs to be used by the public meet the established standards of quality, safety, bioavailability and efficacy. 

 In India the import, manufacture, sale and distribution of drugs and cosmetics in India is regulated under the Drugs and Cosmetics Act 1940, and Rules 1945 made thereunder, (hereinafter referred to as the Act and the Rules) respectively.  Standards of identity, purity, freedom from toxicity and strength in respect of every medicine and related products used for diagnosis, prophylaxis and treatment of diseases in human beings or animals have to be specified. Under the Act, distinct statutory functions and responsibilities have been assigned to Central and State Govts. The Central Drug Standards Control Organisation (CDSCO) Dte. General of Health Services, Ministry of Health & FW is entrusted with the enforcement of regulatory responsibility at the Govt. of India level. Some of the important activities of the CDSCO includes direct interface with R&D activities in pharmasector at National and International level and are discussed below from the point of view of providing an efficient regulatory framework. The fast-changing scenario in drug-related fields requires the CDSCO to become a vibrant and dynamic organisation.

 Quality control and Good Manufacture Practices (GMPs)

 The pharmaceutical industry in India has made remarkable progress over the years.  India is manufacturing most of its requirements of drugs and is also in a position to export a significant quantity of medicines of internationally acceptable quality to many countries including those of the developed world. The quality of drugs has to be closely monitored so that drugs of doubtful quality are not manufactured.

 The Rules provide in Schedule ‘M’ the Good Manufacturing Practices (GMPs) which a manufacturer is obliged to follow.  A drug is of acceptable quality under the Act not only if it meets the finished product specifications but also more importantly if it is manufactured in a plant complying with GMPs. The responsibility for enforcement of GMPs in respect of most drugs rests with the state drug control authorities but the level of enforcement and competence of auditing personnel does not appear to be uniform among states. In view of the serious problems encountered with certain categories of drugs like blood and blood products, large volume parenterals (LVPs), vaccines, etc, joint inspections are required to be carried out under Rule 68A of the Rules  by inspectors of the CDSCO and the concerned State Government before a licence for the manufacture of the notified drugs can be granted or renewed by the Central Licence Approving Authority (CLAA) appointed by the Central Government under the Act.  This list is expected to be enlarged as other specialised items like medical devices including transfusion sets, sterile syringes, etc. are notified in this category. Even for this remedy the infrastructural support has to keep pace with the work demand.

 Though the Drugs Controllers of the states are empowered to licence the manufacture and sale of drugs in their respective states under the Act, the DCG(I) in order to ensure uniform implementation of Rules, is enjoined with the responsibility of coordinating their activities and decisions under the Drugs and Cosmetics Act through the Drugs Consultative Committee (DCC).  In addition, the Drugs Technical Advisory Board (DTAB), a statutory body under the Act, is required to advise the Central Govt. and State Govt. on technical matter arising out of the administration of the Act.

 For a manufacturer intending to export drugs, a GMP certificate under the WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce is the generaly accepted. The WHO Certification Scheme is a mechanism by which the importing country is in a position to ascertain whether it has been manufactured in accordance with internationally accepted GMPs. These certificates are issued after joint inspections by teams from the Central and State Governments. Many importing countries, however, lay down their own stringent procedures of inspection and approval of the plant, facilities, manpower, procedures, etc. before a drug manufactured by the applicant is allowed to be imported.  We may consider to introduce similar procedures in respect of import of drugs into India to safeguard the health of the citizens and to have level playing.

 With the growth of the pharmaceutical industry, there has been considerable impetus to research and development activity on drugs.  A number of medicines are now exported.  This requires proper regulation so that safety, efficacy and quality issues are attended to in a globally accepted manner.  This has become all the more important with the coming into existence of the International Conference on Harmonization of Technical Requirements of Pharmaceuticals for Health Use, commonly known as the International Conference on Harmonization (ICH), which promotes scientific and technical aspects of registration of pharmaceutical products.

 Registration of drugs

 Most countries of the world, including developing ones, have a well-organised system of registration of  drugs permitted to be imported or manufactured.  Thus, master files of products are submitted for evaluation by the regulatory agencies.  It is only after the furnished data has been found adequate that the product is registered in the country.  No such centralised system exists in India. There is need for checking this deficiency by introduction of the registration procedures which will also help in elimination of irrational/sub therapeutic products. Adequate  machinery has to be created in the CDSCO for the purpose.

 Quality control and registration of herbal drugs:

 A number of countries including Germany, France, Canada, USA, China, etc. are registering standardised plant extracts of proven clinical efficacy and safety obtained from natural sources as herbal drugs or dietary supplements.  Inspite of the fact that India has a vast resource of drugs of natural origin, we are unable to exploit the vast world market because we have an unsatisfactory system of their quality control and registration.  On account of the importance of herbal drugs and TSMs in India, it may be necessary to create a separate division in CDSCO to regulate the quality of such drugs, and to provide proper focus on all related aspects. A system of registration of TSMs with acceptable standards of quality control and GMP’s need to be put in position.

 Approval for new drugs

 A new drug is defined in Rule 122 of the Rules as :
 (a)   a new substance of chemical, biological or biotechnological origin in bulk or as a prepared dosage form,
(b)   a drug already approved by the licensing authority which is now proposed to be marketed with modified or new claims,
(c)   a fixed-dose combination (FDC) of two or more drugs, individually approved earlier for certain claims, which are proposed to be combined in a fixed ratio,
(d)   all vaccines.
 As the range of products which are classified as new drugs is wide and practically all pervading, we need expertise in specific areas of specialisation to evaluate the proposals is necessary.

 Schedule ‘Y’ to the Rules specifies the requirements and guidelines on clinical trials for import and manufacture of new drugs.  It is a set of comprehensive procedures the primary objective of which is to safeguard the well-being of patients. Thus there is need for a proper regulatory and marketing environment which encourages investment on research and development towards discovery of innovative medicines and promotes their expeditious introduction. The present set-up of CDSCO has not kept pace with the increasing demands of multi disciplinary drug evaluation needs. Applications submitted to the DCG(I) for permission for clinical trials in respect of new drug applications (NDA) and abbreviated new drug applications (ANDA) are often referred to outside agencies like the Indian Council of Medical Research (ICMR) and the Department of Biotechnology, Government of India (DBT) for review.  This arrangement often leaves very little control with regard to the time runs.  In order that the applicant is enabled to complete the investigations in the shortest possible time, it is imperative that adequate infrastructure for fast track clearances is created in the CDSCO.  The DCG(I) should have under his direct supervision a number of divisions/departments with officers and support staff adequate and competent for the job.  Each division/department may avail of the expertise drawn from various organisations but the responsibility and accountability for the decisions and their timeliness must rest on the shoulders of the DCG(I) and/or the divisional or departmental heads. It has to be clearly understood that authority and responsibility must go hand in hand.  This will be possible only if the right systems, expertise and infrastructure are created.

 The process of evaluation and review of applications of new drugs needs close collaboration with many organisations which may include the following:

 ¨      Universities, hospitals and health care experts:  For evaluating clinical trial data and other relevant information.

¨    Industry and industrial associations:  For assistance in evaluation of data of new drugs.

¨    Professional bodies:  For clarifications on relevant professional issues affecting the quality of drugs.

¨    Central and state government agencies:  For obtaining views of these agencies on matters relating to introduction of a new drug.

¨    Consumers and consumer organisations:  For inputs from the consumer angle.

¨   Foreign governments and international organisations:  This may include the US FDA, WHO, etc. with a view to harmonising the requirements with the international standards of quality of drugs.

 Thus there should be chemists/pharmaceutical technologists/chemical engineers to review areas connected with manufacture, in-process control, packaging, stability, purity, and similar parameters of the product.  Biotechnology-based and genetically-engineered drugs are getting introduced with greater frequency.  Many of these are proteinous molecules and need to be delivered by invasive/non-invasive routes requiring non-conventional delivery systems.  We, therefore, need to associate experts in these areas in the evaluation process.  Pharmacologists/toxicologists should be there to evaluate the short term and long terms effects, including teratogenic and carcinogenic effects, in laboratory animals.  To evaluate the therapeutic effects and adverse drug reactions of a new drug, physicians must be associated in the review process.  There should also be adequate number of competent regulatory experts to ensure that not only the requirements of the Act are taken care of effectively but also to guard against the possibility of an over-zealous approach and overshooting the mark.  Many drugs have serious bioavailability problems.  Thus there should be bio-pharmaceutical scientists available to evaluate data on the rate and extent to which the active medicament in the preparation is actually available to the body as well as on the distribution, metabolism and excretion of the drug molecule.  As the applications submitted are expected to contain considerable data statistically analysed by the applicants, statisticians capable of evaluating the design of statistical tests performed and the validity of statistical analyses would also be necessary.  Association of microbiologists will also be necessary for evaluation of information in case of applications for anti-microbial drugs.  Similarly, persons with specialised knowledge in specific areas may have to be brought in for evaluation of the data presented by the applicant.  For instance, veterinary vaccines and other veterinary products may have to be evaluated by veterinarians; blood and blood products would need help from blood transfusion experts and haematologists; radiopharmaceuticals will need expert evaluation by nuclear scientists. In this age of specialisations and super-specialisations, there will always be need for taking help from experts in a particular field if we wish to achieve excellence.

 The clinical trial centre and Bioequivalence laboratories also need to be audited from time to time.

 India has accepted the responsibilities under the WTO regime.  With the Government of India approving the EMR route for implementing provisions of the new patent regime, applications for marketing approval will start being received.  CDSCO must get ready to meet the situation well in time by creating adequate infrastructure for the critical role it will have to play as a regulatory authority for development of the pharmaceutical sector.

 Pharmacovigilence activities which includes. Post marketing suveillence, Adverse Drug Reaction Monitoring etc. is also a critical function of Drug Regulatory Agency. For this, a participative system involving Medical Community, Pharmacists and the Industry needs to be developed. This area appear to have remain neglected.

 

Provision of charging fees from applicants for drug evaluation activities also needs to be introduced. This ammount can be utilised to meet the expenses incurred in utilising the services of external experts.

 Continuing education and training

 We need to review the continuing education programmes so that all categories of staff from the Grade A officers down to the technical assistants get opportunities to upgrade their knowledge by suitable in-service training courses.  This is particularly important because pharmaceutical sciences and technology are amongst the areas of fastest growth and development. Benefits from investment  in this activity will  be intangible in  the initial stages but  the improvement in the quality of work will ultimately give a sense of satisfaction.  It is common practice in regulatory agencies abroad and by pharmaceutical manufacturers of good standing to organise regular training and continuing education programmes for their staff.

 Infrastructure creation

 It would thus be seen that CDSCO, needs to be given an independent it status as available to National Drug Regulatory agencies  in most countries. This agencies is required to carry out multifarious functions but expertise in technical, administrative and vigilance functions is not sufficient. Full-time experts must be there with CDSCO for timely evaluation of the papers submitted by the parties.

 The committee therefore recommends:-

 (I)         To create adequate infrastructure for efficient management of various activities listed above

(II)        To reorganise the CDSCO in such a manner that it is in a position to provide effective regulatory safeguards to ensure that the patient is protected from the hazards to health by poor quality and counterfeit medicines by comprehensive regulatory procedures and effective inspection and enforcement arrangements.

(III)               To ensure uniform standards of drug productions as well as the regulatory systems throughout the country.

(IV)            To provide adequate autonomy to manage the various activities in accordance with the requirements of the Act and the mandates of the Ministry.