The regulatory regimei Classification
India has a federal form of government and the regulatory framework is divided between national and state authorities. The Drugs and Cosmetics Act 1940 (DCA) and the Drugs and Cosmetic Rules 1945 (DCR) regulate the manufacture, sale, import, export and clinical research of drugs and cosmetics. The Central Drugs Standard Control Organization (CDSCO) under the Ministry of Health and Family Welfare regulates pharmaceutical products through the Drug Controller General of India (DCGI). The DCGI registers all imported drugs, new drugs and drugs in selected categories. It also has responsibility for clinical trials and quality standards. The state licensing authorities (SLAs), which are currently 35 in number, register all other products, accredit manufacturing plants and conduct the bulk of quality monitoring and inspections.
In addition to the DCA and the DCR, the other pieces of legislation that regulate the approval mechanism of drugs, cosmetics and food include the Pharmacy Act 1948, the Drugs and Magic Remedies (Objectionable Advertisement) Act 1954 (the DMR Act), the Narcotic Drugs and Psychotropic Substances Act 1985, and the Drugs (Prices Control) Order 1995 (under the Essential Commodities Act). Food-related substances other than those referred to above are covered by the Food Safety and Standards Act 2006.
With the increasing market for biologics expected to touch US$250 billion by 2020, the CDSCO issued in 2012 the Guidelines on Similar Biologics, which laid down the regulatory pathway for a biologic claiming to be similar to an already authorised reference biologic.
The DCA and DCR apply to the following categories: (1) 'cosmetics', which means any article intended to be rubbed, poured, sprinkled or sprayed on, or introduced into, or otherwise applied to, the human body or any part thereof for cleansing, beautifying, promoting attractiveness or altering the appearance, and includes any article intended for use as a component of a cosmetic; (2) 'drugs', which means all medicines for internal or external use of human beings or animals and all substances intended to be used for or in the diagnosis, treatment, mitigation or prevention of any disease or disorder in human beings or animals, including preparations applied on the human body for the purpose of repelling insects, such as mosquitoes; (3) such substances (other than food) intended to affect the structure or any function of the human body or intended to be used for the destruction of vermin or insects that cause disease in human beings or animals; and (4) 'devices' intended for internal or external use in the diagnosis, treatment, mitigation or prevention of disease or disorder in human beings or animals.ii Non-clinical studies
Pre-clinical trials on animal models are regulated by the protocols outlined in Schedule Y of the DCA. Prior to conducting animal studies, statutory approvals from an institutional biosafety committee and an institutional animal ethics committee must be submitted. The studies should ideally be conducted pursuant to good laboratory practices (GLPs). Standard operating procedures should be followed for all tasks related to these studies. Further, a Committee for the Purpose of Control and Supervision of Experiments on Animals has been constituted under the Prevention of Cruelty to Animals Act 1960 to ensure that animals are not subjected to pain or suffering before, during or after the performance of experiments. An amendment to the Breeding of and Experiments on Animals (Control and Supervision) Rule 1998 was made in 2001 and 2006 to regulate animal experimentation. The government prohibited animal testing for cosmetics and made further amendments to prohibit the import of cosmetics tested on animals.iii Clinical trials
In India, clinical trials are regulated through various mechanisms, including the Drugs and Cosmetics Act 1940 and Rules 1945, Schedule Y regulations for conducting clinical research issued by the CDSCO, and guidelines for interpreting the regulations, such as the Indian Council of Medical Research guidelines and the Indian Good Clinical Practice (GCP) Guidelines. While not legally binding, these guidelines for conducting clinical trials have been accepted by the industry in India.
The prerequisites for conducting clinical trials in India are permission from the DCGI, ethics committee approval and mandatory registration of the trials. The Clinical Trials Registry – India was set up by the National Institute of Medical Statistics to compulsorily register clinical trials. The ethics committee is required to review and accord its approval to the clinical trial (CT) protocol. The ethics committee will not approve any clinical trial protocol without it being registered with the licensing authority. In addition to having a clinical protocol registered with the licensing authority, the trial site will also have to be registered. It is mandatory for clinical trials to be conducted in compliance with the approved protocol requirements of Schedule Y of the GCP guidelines.
A three-tier process was put in place in 2014 for reviewing and evaluating CT applications: first by the Subject Expert Committees (SECs) (formerly New Drug Advisory Committees (NDACs)) or the Investigational New Drugs (IND) committee, next by the Technical Committee, and thereafter the Apex Committee will review the recommendations of the SEC or IND committee.
A Supreme Court order in 2013 stayed approximately 157 clinical trials in India and directed that no trials for new drugs should be permitted unless the consent of the subject is recorded through an audiovisual medium. The Supreme Court also emphasised the need for a balanced approach and laid down three principles for approving trials, namely assessment of risk versus benefit to patients, the need for innovation with regard to existing therapeutic options, and the unmet medical needs in the country.
Through a series of amendments to the DCR, the government introduced provisions relating to free medical management and financial compensation for clinical trial subjects, specifying the prerequisites for obtaining licensing authority permission to conduct clinical trials with human subjects, creating a system for the pre-screening of ethics committee registration applications, creating procedures for analysing the reports of serious adverse events occurring during clinical trials, and procedures for payment of compensation in cases of trial-related injury or death.
On 15 December 2014, the government inserted a new rule, Rule 122 DAB, providing a compensation formula to determine clinical compensation in cases concerning a serious adverse event of death during a clinical trial. Pursuant to the provisions of the amendment, an independent expert committee has to be constituted to examine the report of a serious adverse event of death and give its recommendation to the licensing authority within the prescribed period. The DCGI shall decide the quantum of compensation to be paid by the sponsor or representative, as the case may be.iv Named-patient and compassionate use procedures
There is no provision under the DCA and DCR that provides for compassionate use of medicines and medical devices. However, Rule 34(a) of the DCR permits the importation of small quantities of new drugs for the purpose of treatment of patients suffering from life-threatening diseases or diseases causing serious permanent disability, or such diseases requiring therapies of unmet medical needs. Rule 36 further provides for imports of small quantities of drugs for personal use. Further, Rule 122A of the DCR authorises the licensing authorities to waive local clinical trials in the public interest and grant permission for the importation of new drugs based on clinical trials done in other countries. There has also been an increase in the off-label use of drugs by medical practitioners. Currently, there is no guideline that regulates off-label use. However, if any company is advertising or selling a drug for an indication that has not been approved, they can be liable for an action under the DMR Act.v Pre-market clearance
For commercial distribution and sale of any medicine and drug, approval from the licensing authorities is necessary. Under Rule 122E of the DCR 1945, a new drug includes (1) a drug, be it chemical or biotechnological, that has not been used in the country to any significant extent and that – except during local clinical trials – has not been recognised in the country as effective and safe for the proposed claims; (2) a drug already approved by the licensing authority for certain claims but that is now proposed to be marketed with modified or new claims, namely indications, dosage, form (including sustained release dosage form) and route of administration; or (3) a fixed-dose combination (FDC) of two or more drugs, individually approved earlier for certain claims, which are now proposed to be combined for the first time in a fixed ratio, or if the ratio of ingredients in an already marketed combination is proposed to be changed, with certain claims, namely indications, dosage, form and route of administration.
The Central Licensing Authority (CLA) is responsible for approving new drugs. A new drug continues to be considered as a new drug for a period of four years from the date of its first approval or its inclusion in the Indian Pharmacopoeia, whichever is earlier. Once a drug ceases to be a new drug, manufacturing approvals can be obtained from the state regulatory authorities. The form prescribed for seeking approval of a new drug is Form 44. For the importation of a new drug, permissions have to be obtained from the licensing authority on Form 44 accompanied by a fee of 50,000 rupees. The rules further provide for a reduced official fee in the event that the same applicant applies for approval of the same drug in a modified dosage form or a new claim alone. Besides having to submit forms and paying the prescribed fee while seeking an import licence, the importer has to submit data, including those released from local clinical trials carried out in accordance with the guidelines prescribed by the Act. After the licensing authority is satisfied, permission is granted to import the raw material or finished formulation on Forms 45 and 45A.
In view of the definition of a 'drug' including certain medical devices and drugs, a similar approval procedure prescribed for chemical or biotechnological drugs will also apply to medical devices. In India, approval of medical devices has been quite unregulated. The CDSCO has introduced guidelines applicable to medical devices and has appointed the Central Licensing Approval Authority to oversee the approval of such medical devices. In practice, regulated medical devices that are imported can be legally sold in India after submission of the technical dossier to the Central Licensing Approval Authority. The bill of 2015 is an attempt by central government to regulate the medical device approval process. This follows the incorporation, in August 2014, of the amendment of the DCR provisions regarding the manner of labelling, and the qualification of competent persons to manufacture and test medical devices.
Schedule Y of the DCR prescribes the approval process of generic drugs and the biosimilar guidelines for the approval of similar biologics. Appendix 1A of Schedule Y provides an outline of the nature of data that has to be submitted to the licensing authority to import and manufacture a new drug already approved in the country and includes submission of bioavailability (BA) or bioequivalence (BE) and comparative studies in accordance with the BA and BE guidelines.vi Regulatory incentives
In India, there are no regulatory incentives and therefore patent term extensions, patent linkage, data protection or data exclusivity for the originator's products are not provided. By conducting BE studies, the second applicant can obtain regulatory approval of the innovators product. In the Bayer v. CIPLA case, the Supreme Court of India clearly held that India neither provides nor recognises patent linkage. However, the Delhi High Court in Bristol Myers Squibb v. Hetero Drugs made the following observation with regard to patent linkage: 'It is expected that the Drug Controller General of India while performing statutory functions will not allow any party to infringe any laws and if the drug for which approval has been sought by the defendants is in breach of the patent of the plaintiffs, the approval ought not to be granted to the defendant.'
There is no procedure in India for expedited approval. However, in the public interest, the DCGI can expedite the approval process for important products. Recently, in the public interest, the DCGI agreed to a fast-track approval for a licence for Sovaldi, a drug for the treatment of hepatitis. Further, India does not have any legislation akin to the US Orphan Drug Act.vii Post-approval controls
Schedule Y of the DCR 1945 prescribes post-approval controls (PSUR), which require marketing authorisation holders to submit a report every six months for the first two years after drug approval is granted. For the subsequent two years, the PSUR report must be submitted annually. Post-market surveillance includes procedures for the distribution of records, complaint handling, adverse incident reporting, product recall and taking of corrective measures. Schedule Y also requires the applicant to inform the licensing authority if the marketing of the new drug is delayed after having obtained marketing approval. In the event that the applicant and manufacturer fail to launch the product in the market within a period of six months from obtaining a licence from the CDSCO, the licence would be treated as cancelled. Also in 2010, the CDSCO launched the Pharmacovigilance Programme of India (PvPI) with a view to safeguarding the safety of the Indian population by monitoring drug safety and reducing the risks associated with the use of medicines. PvPI was initiated with the All India Institute of Medical Science as the National Coordinating Centre for monitoring adverse drug reactions (ADRs); 22 ADR monitoring centres were also set up – the number of these was increased to 90 in 2012–2013.viii Manufacturing controls
In the case of imported drugs, the licensing authority, the DCGI, approves the manufacturing site, following inspection, and grants a Registration Certificate. The SLA is authorised to grant manufacturing licences following inspection of the premises. The manufacturer is required to maintain the quality standard as specified in the ICH Q6A guidelines and follow the good manufacturing practice (GMP) prescribed by Schedule M to the DCR. The second schedule to the DCA also provides the standards that have to be complied with by drugs manufactured and marketed in India.ix Advertising and promotion
The DMR Act, inter alia, regulates the advertising of drugs for treatment of diseases specified in the Schedule. Section 2(a) of the DMR Act states that advertisements include any notice, circular, label, wrapper and other documents and any announcement made orally or by any means of producing a transmitting light, sound or smoke. However, the Act has certain provisions wherein the advertising of drugs can be carried out subject to certain conditions laid down by Section 14, which includes any signboard or notice displayed by a registered medical practitioner on his or her premises, indicating that treatment of any disease, disorder or condition specified in Section 3 of the Schedule and the rules are undertaken in those premises. Schedule J of the DCR also regulates the advertising and marketing of drugs to some extent.x Distributors and wholesalers
The state licensing authorities provide wholesale and retail licences for distribution and sale of products.xi Classification of products
The classification of drug products under DCR has been based on their intended use. Broadly, there are two categories of products: prescription-only drugs and non-prescription drugs. Schedules H, H1 and X deal with prescription drugs, whereas Schedule G drugs are considered non-prescription drugs. Additionally, Schedules C and C1 cover drugs derived from biological origin and other related special products, Schedule X covers some narcotic drugs and Schedule F is for vaccines, serums, and the like. New drugs can also be categorised on the basis of their approval status.xii Imports and exports
Obtaining approvals for the importation of drugs into India consists of three main phases: (1) new drug approval (not necessarily for new drugs only); (2) an import drug registration certificate; and (3) an import licence.
Insofar as the export of drugs are concerned, the Pharmaceuticals Export Promotion Council of India is an authorised agency set up under the provisions of the Foreign Trade Policy by the Ministry of Commerce and Industry in 2004. The Ministry of Foreign Trade has provided some guidelines for the export of special chemical organism materials and equipment and technology items. The CDSCO has published a guidance document on the government submission form for the issuance of no-objection certificates (NOCs) for the export of unapproved or approved new products or banned drugs. To obtain a NOC the applicant has to provide a valid export order and identify the premises where the drug is manufactured.xiii Controlled substances
The DCA includes several provisions for regulating the manufacture, sale and import of controlled substances listed in Schedule X. Essentially, Schedule X drugs cannot be sold without prescription. They have to be stored under lock and key in a cupboard or drawer reserved solely for the storage of these substances, and comply with special packaging and labelling requirements. Further, controlled substances have to be labelled with the symbol 'Rx' in red with a special warning. Besides the DCA and DCR, India also enacted the Narcotic Drugs and Psychotropic Substances Act (the NDPS Act) in 1985 to achieve a dual objective of limited use of narcotic drugs and psychotropic substances for medical and scientific purposes as well as preventing abuse of the same. The NDPS Act was framed to comply with three international conventions to which India is a signatory, namely the Single Convention on Narcotic Drugs 1961, the Convention on Psychotropic Substances 1971 and the UN Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances 1988, as well as Article 47 of the Constitution of India.xiv Enforcement
Section 27 of the DCA sets out the penalties for the manufacturer for the sale of drugs in contravention of the provisions of the Act. The DCA provides for punishment under the Indian Penal Code in the event that a drug is deemed to be adulterated or spurious and likely to cause death or such harm as amounts to grievous hurt; such offences are punishable with imprisonment and fine. In addition to imprisonment and a fine, the DCA under Section 31 provides for confiscation of goods. Prosecution under the DCA and DCR can be instituted only by an inspector or any gazette officer of the central government or a state government authorised in writing on behalf of the central government or the state government by general or special order, or by a person aggrieved or by a recognised consumer association. Special designated courts have been put in place for the trial of offences under the DCA.