Accelerating drug development and approvals in India

Feature ArticlesFeature Articles | 30 November 2022 | Citation  |  PDF Link PDF

India’s Central Drugs Standard Control Organization (CDSCO) implemented the New Drugs and Clinical Trials Rules in 2019 to expedite the drug development and approval processes. This article provides an overview of those processes; explains the rule-specific terminology, such as the definitions of “drug” and “new drug” under Indian law; and outlines strategies for speeding up the approval processes and optimizing registration of prescription medicines in India.
 
Keywords – accelerated approval, CDSCO, clinical trials rule, CMC, India, new drugs
 
Introduction
Since India’s CDSCO implemented the 2019 New Drugs and Clinical Trials Rules (2019 new rules),1 the drug approval process has been faster and a greater number of innovative medicines and orphan-designated medicines for rare diseases are now available. Under the new rules, clinical trials may be abbreviated for the approval of orphan-designated medicines. Sponsors of orphan drugs can apply to the CDSCO for an expedited review process, waiving the requirement for local clinical trials in recognition of significant unmet medical needs.1
 
There are several other measures aimed at reducing timelines for the approval of clinical trials and expediting the new drug approval process. As a result, a large number of vaccines and drugs were approved in India, backed by pandemic-related accelerated regulatory processes as well as plans outlined by the Indian government to increase biotech and pharmaceutical innovation in the country. This regulatory flexibility is needed to make India an attractive market to sponsors of new, innovative drugs and biologics and pharmaceutical companies eager to expedite the launch of their medicines and expand globally.2
 
Under the 2019 new rules, applicants may apply to the licensing authority for an expedited review process in which the evidence of clinical safety and efficacy has been established even if the drug has not completed all the normal clinical phases. This will accelerate the application review and the clearance process to initiate a clinical trial as well as facilitate earlier entry of effective new drugs to the market and reduce the costs associated with development. These new provisions aim to encourage more indigenous research and development for diseases affecting patients in India.1 In addition, the flexibility and expedited processes will help position India as one of the major markets in Asia for pharmaceutical companies to market their drugs.2 India is well suited as a venue for this plan. It is a developing country, with a population of approximately 1.4 billion, about 17.7% of the world’s population,3 and there is considerable untapped research and manufacturing potential. In addition, many medical needs for serious diseases such as diabetes, cancer, tuberculosis, and AIDS are unmet, creating a demand for therapies. For example, the government has implemented a national strategic plan for rapidly reducing tuberculosis-related morbidity and mortality in India by 2025. The plan is facilitated by supportive government policies integrated into the four strategic pillars of “detect, treat, prevent, and build.”4
 
In India, a sponsor may apply to the licensing authority for an expedited review of new drugs developed for use in a disaster or for defense in an extraordinary situation (e.g., war or radiation exposure) when specific, rapid preventive and treatment strategies are required in circumstances in which a real-world clinical trial may not be possible.1 Permission for the manufacture of a new drug may be granted if the following conditions are satisfied:
 
  • Preclinical data makes a case for claimed efficacy;
  • There is no possibility of obtaining informed consent from a patient or patient’s legally acceptable representative regarding inclusion and exclusion criteria and protocol adherence by each participant;
  • There is no established management or therapeutic strategy available, hence making a proposed intervention has clear possible advantage; and
  • Such approval can be used only once. Subsequent approval will be granted after a detailed efficacy report of such intervention has been generated.1
 
Sponsors of orphan drugs can also apply for an expedited review, waiving the requirement for local clinical trials in recognition of significant unmet medical needs. In India an “orphan drug” is one intended to treat a condition affecting fewer than 500,000 patients. A drug already approved by the central licensing agency (CLA) for certain claims and proposed to be marketed with modified or new claims, including indication, route of administration (e.g., a novel drug delivery system), dosage, and dosage form, is a subsequent “new drug.” A subsequent new drug also includes a new drug already approved in the country. In these instances, the pharmaceutical company must receive prior permission from the CLA before obtaining the manufacturing license from the state licensing authority for the new drugs. 5
 
Drugs versus new drugs
Under the 2019 New Drugs and Clinical Trials Rules, a “new drug” is:
 
  • A drug that either has not been approved or is already approved in India for certain claims and proposed to be marketed with modified or new claims;
  • A fixed-dose combination of two or more drugs;
  • A modified- or sustained-release form of a drug or novel drug delivery system of any drug approved; or
  • A vaccine, rDNA-derived product, living modified organism, monoclonal antibody, stem-cell‒derived product, gene therapeutic product or xenograft, intended to be used as a drug.1
 
Under Section 3(b) of the 1940 Drugs and Cosmetics Act, “drugs” are:
 
  • Medicines and devices intended for use in the diagnosis, treatment, mitigation, or prevention of any disease or disorder in humans or animals;
  • Substances intended to affect the structure or any function of the human body; and
  • Substances intended for use as components of a drug including empty gelatin capsules.
 
These categories of drugs shall continue to be new drugs for 4 years from the date of their permission granted by the CLA.6
 
CDSCO: Structure, strategy, and responsibilities
Structure
Drug regulation falls under the Constitution of India. The CDSCO is the national regulatory and licensing authority for approving drugs in India. The implementing authorities are the central government, through the CDSCO, and state governments, through the state drug licensing authorities.7
 
Regulatory strategy
The CDSCO oversees regulatory strategy. It issues guidelines for manufacturing regulatory pathways and quality aspects for drugs. These guidelines also address regulatory requirements for marketing authorization. The regulatory environment in India has expanded during the past 5 years, with numerous regulatory measures introduced to streamline processes and promote ethical, science-based new drug approvals and clinical trials.7
 
Responsibilities
The main responsibilities of the CDSCO include:
 
  • Approval of new drugs and clinical trials in India;
  • Establishing drug control standards for the quality of imported drugs;
  • Coordinating the activities of state drug control organizations;
  • Providing expert advice in the enforcement of the Drugs and Cosmetics Act; and
  • Issuing amendments to laws, rules, and pharmacovigilance.8
 
Regulatory framework
The new drug approval process in India falls under the 2019 new rules. New clinical trial regulations have also been implemented to expedite registration of orphan-designated and innovative medicines. The new rules and regulations apply to all types of new drugs, INDs for human use, clinical trials, bioavailability/bioequivalence (BA/BE) studies, and ethics committees, which has further streamlined the approval process.1
 
The drug approval process involves two steps – application to the regulatory authority to conduct a clinical trial and application for marketing authorization of drug.
 
Advantages and disadvantages of the 2019 new rules
Advantages
Under the 2019 new rules, the drug approval process accelerates market entry of advanced new treatments. There are also provisions for improving transparency and accountability and promoting ethical and scientific research. These allow for a waiver of local clinical trials, resulting in faster approval times and stronger intellectual property protection in India, an additional attraction for companies wanting to register new drugs.9
 
The qualifying products can now be launched in India without companies having to conduct phase 3 clinical trials to test for efficacy and safety in the Indian population, provided the associated global studies include Indian patients. In addition, there is now a new conditional approval pathway for innovative and orphan-designated medicines that have been approved in the Europe, the US, Australia, Canada, or Japan. This may result in a waiver of local clinical trials.
 
All the applications are submitted online in the electronic common technical document format. These reforms of the clinical trial approval process expedite the approval processes for these products.9
 
Disadvantages
The sponsors or biopharmaceutical companies must commit to conducting postmarket, phase 4 trials to evaluate the long-term effects of the approved product, which may present a challenge for companies.1 In addition, the authority’s review documents and summary of the approval process for new drugs are not available in the public domain. This makes it difficult to gather regulatory intelligence and understand the authority’s expectations for certain new dosage forms.
 
Regulatory pathways
All drug substances and drug products intended to be launched in India fall under the “new drug” category. A new drug must undergo extensive nonclinical and clinical trials to prove its safety and efficacy before being considered for marketing authorization.5 The choice of a regulatory pathway for new drug approval depends on numerous factors. These include:
 
  • The nature of a drug substance and/or drug product, for example, a vaccine, rDNA-derived product, living modified organism, monoclonal antibody, stem-cell‒derived product, gene therapeutic product, or xenograft intended to be used as a drug is considered a new drug. These types of drug substances or products must undergo extensive nonclinical and clinical trials to prove their safety and efficacy;
  • Type of formulation, for example, modified- or sustained-release forms of a drug or a novel drug delivery system of any drug approved by the CLA are considered a new drug and must undergo a clinical trial and/or BA/BE study before consideration for marketing authorization;
  • Whether the drug has already been approved in India;
  • Whether the IND requires extensive research and trials both clinical and nonclinical;
  • Whether the drug is designated as an orphan drug. Various requirements for orphan drugs may be waived on a case-by-case basis but will require approval from the CLA and a presubmission meeting with the CDSCO to discuss and agree upon the required pathway.
  • Drug products with new molecules, combinations, dosage forms, indications, dosages, or routes of administration must undergo clinical trials and/or BA/BE studies before consideration for marketing authorization.1
 
Regulatory strategy
Sponsors are required to obtain permission from Indian regulators to conduct BA/BE studies and clinical trials. Data must be submitted for an unapproved new drug and should include dosage form, composition, master manufacturing formula, and stability study data. Drugs already approved in India will require same information as for a phase 3 clinical trial. The clinical trial for a new drug may be conducted only after obtaining permission from the licensing authority. If the clinical study protocol or outcome is inadequate, then the licensing authority may consider granting permission, provided the applicant meets the conditions set by the licensing authority.5
 
The following are the phase-appropriate applications for permission to conduct clinical trials:
 
  • For phase 1 trials, applications should be submitted to the Licensing Authority in Form 44, accompanied by a fee and required data under Schedule Y;
  • For exploratory clinical trials (phase 2), applications should be made based on the data from the phase 1 trial, accompanied by a fee; and
  • For confirmatory clinical trials (phase 3), applications should be made based on the data from phase 1 and phase 2, accompanied by a fee.
 
No fees are required with the application for manufacture of a new drug after the phase 1-3 clinical trials have been completed successfully in India under the 2019 new rules.5
 
Submissions are eligible for accelerated registration if any of the following requirements have been met:5
 
  • There is no change to the manufacturing requirements;
  • The local clinical trial requirement has been waived for drugs marketed outside India (US, UK, Canada, Japan, and Australia) for at least 4 years;
  • The clinical trial has been deferred or abbreviated at the discretion of the CDSCO for life- threatening or serious diseases;
  • The products are indicated for diseases of relevance to Indian health;
  • Recommendations have been obtained from technical review and subject expert committees;
  • The clinical trial protocol has already been approved by certain foreign authorities (US, Australia, UK, Germany, Switzerland, Canada, South Africa, Japan, and Europe);
  • The CDSCO considers the submission as a national emergency, extreme urgency, or epidemic related, or as an orphan drug or drugs indicated for conditions or diseases without available therapy; and
  • A commitment by the sponsor to conduct strict postmarket surveillance or a phase 4 trial.
 
Stability study requirements
Phase-appropriate stability data must be submitted to satisfy the chemistry, manufacturing, and control (CMC) requirements in the applications (Figure 1).1
 

Figure 1. Regulatory strategy for submitting phase-appropriate stability data
 

 
DP, drug product; DS, drug substance.                                                                                                                                                                                Source: CDSCO1
 

The stability studies of the new drugs should include testing the attributes of the drug substances and products that are susceptible to change during storage and are likely to influence product quality, safety, or efficacy. For example, India falls under climate zone IVb because of its heat and humidity, so stability studies must be designed under appropriate stability conditions to generate stability data as required by the International Council for Harmonisation (ICH). The CMC requirements under the 2019 new rules call for validated, stability-indicating analytical procedures during stability studies. For long-term studies, frequency of testing should be sufficient to establish the stability profile of the drug substance and drug product.10
 
Sponsors should also provide evidence on how the quality of a drug substance or product varies with time under the influence of environmental factors (e.g., temperature and light) and establish the formulation’s shelf life and recommended storage conditions.1
 
Other requirements regarding stability include:
 
  • A drug substance stress test to identify degradation products and establish the degradation pathways to evaluate the molecule’s intrinsic stability;
  • Validated stability-indicating methods – for long-term studies, frequency of testing should be sufficient to establish a drug-substance stability profile. Storage conditions and duration of studies should be sufficient to establish conditions for storage, shipment, and subsequent use; and
  • Data on the:
  • Effect of temperature and humidity;
  • Effect of oxidation and photolysis of the drug substance;
  • Photostability on at least one primary batch of the drug substance and drug product; and
  • Susceptibility of the drug substance to hydrolysis across a range of pH values when in solution or suspension.1
 
CMC requirements for new drugs
CMC regulatory requirements for the IND application include information on active ingredients and drug product formulation (Figure 2).1,11
 

Figure 2. Chemistry, manufacturing, and control requirements for new drugs
 

 
INN, international nonproprietary names; CMC, chemistry, manufacturing, and control.
 aAligned with International Council for Harmonisation requirements.                                                                                                                                      Source: CDSCO1,11
 
Application review timelines
The review periods for new drug applications have become shorter since the implementation of the New Drugs and Clinical Trials Rules, 2019. Table 1 shows the longer product review periods, in years, before the implementation of the new rule.10 By comparison, Table 2 shows targeted internal timelines by the CDSCO for processing and disposal of applications from 7 to 180 working days.12 Table 3 shows list of some of the new drugs approved between January and May 2022 in India for serious and life-threatening diseases. About 30 new drugs have been approved in India this year due to the implementation of accelerated pathway.13
 

 
 

 
 

 
 
Since 2019, there have been more oncology drug approvals with phase 3 clinical trial waivers than those without (Figure 3).
 

Figure 3. Oncology drugs approved in India with and without clinical trial waiver
 
                                                                                                                                                  Source: Cortellis10
 
Conclusion
Asia-Pacific regulatory systems are diverse and can be challenging to access and navigate without an awareness of recent developments. The Indian Ministry of Health and Family Welfare Authority has streamlined the drug approval process so that patients with serious and/or unmet medical needs can access safe and efficacious drugs without unnecessary delay. The recent regulatory agency developments were implemented to enhance efficiencies and flexibility and include the regulatory pathway, CMC regulatory requirements, collaborative initiatives with international regulators, exemptions, and clinical trial reforms to expedite the drug approval processes for prescription and orphan-designated medicines.
 
Industry data and real-life case studies help to determine the optimal registration strategy with an understanding of the regulations in determining the most efficient strategy to obtain approval. Major biopharmaceutical companies are required to determine the regulatory strategy that can speed up the drug approval process.
 
Key takeaways
India has issued new clinical trials rules to expedite new drug approvals. The clinical trial approval process was reformed to speed up the drug approval processes for prescription and orphan drugs. India’s regulatory authority, the CDSCO, has taken steps to improve transparency and accountability and promote ethical and scientific clinical research and development of new drugs. This resulted in high number of waivers for local phase 3 clinical trials and new conditional approval pathway for new drugs already approved and licensed by health authorities in the EU, US, Australia, Canada, or Japan. In addition, intellectual property protection is stronger with the implementation of 2019 new rules, making India an attractive marketplace for proprietary biopharmaceutical companies to register their new products.
 
Abbreviations
BA/BE, bioavailability/bioequivalence; CDSCO, Central Drugs Standard Control Organization; CLA, central licensing authority; CMC, chemistry manufacturing control; ICH, International Council for Harmonisation; IND, investigational new drug.
 
About the author
Arundhati Sengupta, MS, MBA, RAC, is a senior manager in regulatory affairs-CMC at AbbVie Inc. She has almost 24 years of professional experience in the biotechnology and pharmaceutical industries, with more than 12 years of those in regulatory affairs. Before joining AbbVie, Sengupta worked in various capacities in the research and development area of drugs and biologics in multinational firms such as Novartis, Genentech, and AstraZeneca. She has experience in regulatory requirements for early and late stages of drug development for both small molecules (new chemical entity) and large biomolecules (new biologic entity), indicated for several therapeutic areas such as oncology, hematology, cardiovascular, neuroscience. Sengupta has regulatory filing and product approval experience in the US and global markets. She has experience in lifecycle management of drug products, assessing and evaluating changes, authoring, and reviewing regulatory submission documents for a range of applications. Sengupta has master of science degrees in microbiology (Nagpur University, India) and chemistry (University of Nebraska, Lincoln) and an MBA degree in healthcare management business administration from the Paul Merage School of Business at the University of California, Irvine. She has also earned a project management certificate from the University of California, Berkeley; a Regulatory Affairs Certificate from the University of California, Santa Cruz; and has held RAPS Regulatory Affairs Certification (US) since 2018. She is a volunteer leader and board member of the RAPS Bay Area San Francisco Chapter. Sengupta can be contacted at senguptaa4@gmail.com
 
Acknowledgment This article was adapted from a presentation at RAPS 2022 Convergence in Phoenix, Arizona, on 12 September 2022.
 
Disclaimer The opinions expressed in this presentation are those of the author. They do not purport to reflect the opinions or views of the author’s employer or any other organization.
 
Citation Sengupta A. Accelerating drug development and approvals in India. Regulatory Focus. Published online 30 November 2022. URL
 
References
All references accessed and/or verified on 28 November 2022.
 
  1. Government of India, Central Drugs Standard Control Organization. New Drugs and Clinical Trials Rules, 2019. Dated 19 March 2019. Amended 18 January 2022. https://cdsco.gov.in/opencms/opencms/system/modules/CDSCO.WEB/elements/download_file_division.jsp?num_id=OTIzMA==
  2. Ghangurde A. 2021 saw India enable accelerated regulatory pathways – Can it become the norm? Pink Sheet. Published online 13 January 2022. https://pink.pharmaintelligence.informa.com/PS145512/2021-Saw-India-Enable-Accelerated-Regulatory-Pathways--Can-It-Become-The-Norm.
  3. World Population Review. India population 2022 (Live). https://worldpopulationreview.com/countries/india-population
  4. Purty AJ. Detect – treat – prevent – build: Strategy for TB elimination in India by 2025. Indian J Community Med 2018;43:1-4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842465/   
  5. Government of India, Central Drugs Standard Control Organization. Frequently asked questions (FAQs) on new drugs and clinical trials. Not dated. https://cdsco.gov.in/opencms/resources/UploadCDSCOWeb/2018/UploadPublic_NoticesFiles/faqnd.pdf
  6. Government of India, Ministry of Health and Family Welfare. The Drugs and Cosmetics Act, 1940; The Drugs and Cosmetics Rules, 1945. Last updated 31 December 2016. https://cdsco.gov.in/opencms/export/sites/CDSCO_WEB/Pdf-documents/acts_rules/2016DrugsandCosmeticsAct1940Rules1945.pdf
  7. Government of India, Central Drugs Standard Control Organizations. Directorate General of Health Services. Ministry of Health and Family Welfare. Home. Last updated 27 November 2022. https://cdsco.gov.in/opencms/opencms/en/Home/
  8. National Institute of Allergy and Infectious Diseases, ClinRegs. Regulatory authority – Scope of assessment. Last updated 28 April 2022. https://clinregs.niaid.nih.gov/country/india#scope_of_assessment
  9. Baggili S. India issues new clinical trial rules to expedite new drug approvals. Pharm Technol.   Published 17 April 2019. https://www.pharmaceutical-technology.com/pricing-and-market-access/india-issues-new-clinical-trial-rules-expedite-new-drug-html/
  10. Cortellis website. https://www.cortellis.com/intelligence/home.do
  11. Government of India, Central Drugs Standard Control Organization. Subject: Requirement of CMC documents for approval of additional indication of an already approved drug product – reg. Dated 13 March 2020. https://cdsco.gov.in/opencms/resources/UploadCDSCOWeb/2018/UploadPublic_NoticesFiles/Requirement%20of%20CMC%20documents%20for%20approval%20of%20additional%20indication%20of%20an%20already%20drug%20product.pdf
  12. Government of India, Central Drugs Standard Control Organization. Targeted internal timeline for processing and disposal of application by CDSCO. Last updated 20 February 2020. https://cdsco.gov.in/opencms/resources/UploadCDSCOWeb/2018/UploadPublic_NoticesFiles/timeline.pdf
  13.  Government of India, Central Drugs Standard Control Organization. List of approved new drugs. Last updated 24 August 2022.  https://cdsco.gov.in/opencms/opencms/en/Approval_new/Approved-New-Drugs/
 

 

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