INTRODUCTION:

New drug development can improve quality and lifespan of patient. As clinical trial plays important role in development of new drug, government is trying to safeguard that the safety as well as rights of the human subjects are secure and the quality of the trials completed in India expand to international standards. Indian regulation has set guidelines for informed consent, compensation in case of injury or death and serious adverse events (SAEs) reporting. The clinical trials which are performed in India should comply with schedule Y of Drugs and Cosmetics Act and International Committee of Harmonization-Good Clinical Practices (ICH-GCP) Guidelines for clinical trials.

Table 1: Phases of clinical trials

Phase	No. of subjects	Description
Phase 1	10-30	Detection of highest dose of treatment can be given safely without side effects.
Phase 2	200-300	Detection of safety, efficacy and unexpected side effects.
Phase 3	1000-3000	Safety and efficacy of drug for specified indication
Phase 4	-	Detection of unforeseen side effects.

Objective of this study is to provide regulations as well as approval process involved in clinical conducting clinical trials in India and to study challenges involved in it.

DISCUSSION:

1. Regulations in India:

Regulations has been set to ensure integrity of the data collected from clinical trials which assure the safety, right and welfare of the subject. ^[1][2]

Regulations involved:

· Law: Drugs and Cosmetics Act 1940 and Rules 1945.

· Regulation: Schedule Y for clinical research by CDSCO.

· Guidelines:

ICMR guidelines.

GCP guidelines.

1.1 The Drugs and Cosmetics Act 1940 and Rules 1945

Table 2: Drug and Cosmetic Act1940 and rules 1945

Rules	Description
Rule 122DA	Approval to perform clinical trial
Rule 122 DAA	Clinical trial definition
Rule 122 DAB	Compensation in case of trial-related injury or death
Rule 122 DAC	Conditions of Clinical Trial approval and audit
Rule 122 DD	Ethics Committee registration
Rule 122 E	Definitions of New Drugs

Table 3: Amendments to Drug and Cosmetic Rules (DCR), 2013^[3]

122DAB

First Amendment

-Providing free medical services to subject in case of injury.

-In case death or injuries provide compensation

- Report requirements for serious adverse events has been provided.

122-DAC

Second Amendment

- Approval for clinical trial

- Permission of ECs before trial initiation.

- Annual reports of clinical trial status.

- Audit at trial site and personnel by CDSCO to check GCP and schedule Y compliance.

122-DD

Third Amendment

- Ethics committee’s registration.

- Requirements and guidelines for Ethics committee registration with application, record maintenance.

1.2 Schedule Y:

Guidelines and requirements for approval to import or manufacture new drugs for sale or to start clinical trials. ^[4]

Table 4: Appendices of Schedule Y provide guideline to conduct clinical trials

Appendices	Description
Appendix V	Informed consent
Appendix VII	Undertaking by the Investigator
Appendix VIII	Ethics Committee
Appendix X	Protocol content
Appendix XI	Data elements for reporting serious adverse events.

1.3 Guidelines:

India follows ICH-GCP guidelines to conduct clinical trials which describes responsibilities of ethics committee, sponsor and investigator and the requirements of a protocol, the investigator's brochure (IB) and documents to pass audits and inspection. ^[5][6]

GCP Requirements:

· Safety assessment

· Finance and insurance

· Quality assurance

ICMR requirements

· Study timeline.

· Explanation for placebo, plan to withdraw from trial, risk-benefit assessment. Explanation for the standard therapies to be withheld.

· Policy to continue the secrecy and maintain confidentiality of the human subject.

· Adverse event reaction

· Plan for management of minimum risk

· Proposed reward, compensation of incidental expenses for injury or death

· Facility to take care for distinct illness during research

· Maintaining data obtained during clinical trial.

2. Fundamentals of conducting a clinical trial in India:

Step 1: Approval from the Drugs Controller General, India.

Step 2: Permission from particular Ethics Committee where the clinical study is designed.

Step 3: Compulsory registration on the ICMR website www.ctri.in.

2.1 Approval procedure for clinical trials in India:

To reduce the time lag for permitting clinical trials in India, a “three-tier” review process has been implemented on Feb 2013. Application is first reviewed by Technical committee and then Apex Committee after an initial approval from Subject Expert committee. After obtaining approval from all three stages DCGI will grant approval for conduct of clinical trials.^[7]

2.1.1 Timeline for approval of clinical trial:

Initially 6 months was the approval timeline for clinical trials from DCGI, but now Ministry of Health and Family Welfare notified New Drugs and Clinical Trial Rules, 2019 according to which clinical trial approval timeline reduced to 30 days for the clinical trials conducting inside the India. For the clinical trials to be conducted abroad, approval timeline for clinical trial is 90 days.^[7]

2.1.2 Documents required^[8]

· Clinical trial application form

· Treasury Challan

· Source of bulk drugs

· Information in chemicals and pharmaceutical drugs

· Pharmacology data of Animals

· Toxicology data of animals

· Clinical pharmacology information

· Regulatory conditions in other countries

· Information given/ prescribed

· Protocol for quality control

· Protocol for clinical study

· Investigator’s Brochure

· Case Report Form

· Patient data sheet and informed consent form

· Investigator list in India and site address

2.1.3 Clinical Trial agreements:

Before starting the clinical trials sponsor has to sign clinical trial agreement with Investigator. Agreement specifies the financial support, fees, payment and honorium.

It also includes duties of sponsor towards:

1. GCP compliance

2. Data reporting and recording

3. Retaining trial related essential documents.

2.2 Ethics committee approval for review and approval for clinical trials:

It is mandatory for sponsor to obtain confirmation of EC analysis and approval for clinical trial. Sponsor should obtain following before starting clinical trial:

· Profile of ethics committee members which includes name, address, qualification and experience of each member

· GCP compliance confirmation from ethics committee

· Documented approval from ethics committee

· Copy of Ethics Committee approvals in case its approval is based on changes if any.

· Copy of Ethics committee documents involving re-evaluations/re-approvals with favourable suggestions, and of any removals or suspensions of favourable opinion.

2.3 Registration for clinical trial:

It is compulsory for the sponsor to register for clinical trial before initiating clinical trial. Clinical trial has been registered with Indian Council of Medical Research’s Clinical Trials Registry, India. Once the sponsor registered at the CTRI, the designated REF number indicates successful registration of clinical trial.

3. Progress reporting of clinical trial:

Investigators, sponsors, or visiting ethics committees can submit study progress reports periodically to the Ethics committee. Periodic report of study can submitted by the investigator.

Types of report:

· Annual report: It is mandatory for sponsors to submit an annual status report of clinical trial to the Drugs Controller General of India. If trial have been stopped early for any cause, sponsor need to submit a summary report within three months. The summary report includes study details, total participants exposed to the drug, period and exposure dose, information of adverse drug reactions occurred in any situation and the purpose for discontinuation of study.

· Final report: It is submitted by investigator with his sign and date on the final report with declaration of terminating the study to the institution, and have verification of ethics committee and the sponsor for the data’s validity. All the data along with signature can be forwarded to the sponsor and the ethics committee. In case of multicentre study, sign of coordinating investigator is also taken into consideration for some case or if agreed in the protocol.

4. New drugs and clinical trials rule 2019:

Union Ministry for Health and Family Welfare notified New Drugs and Clinical Trials Rules on March 9, 2019for promoting clinical research in India. The aim is speedy approval process and transparency in clinical trials. The novel rule is related to new drugs, ethics Committee and investigational new drugs proposed for clinical trial, bioequivalence study and for human use against disease condition.

By considering suggestions and objections from stakeholders, Central Government notified final rules in Gazette of India vide G.S.R.227(E). Schedule Y and Part XA are no longer applicable for new drugs and investigational new drugs except for the drugs approved prior to initiation to the new rules. G.S.R.227(E) contains 13 chapters, 107 rules and 8 schedules. According to new rules, The Drug Controller, India is referred as Central Licensing Authority (CLA).^[9]

Table 5: Revised application fees for clinical trials and BA-BE studies (covered under 6^th schedule)^[9]

Application

Fees(Rs)

Approval to initiate Phase I Clinical Trial

· For reconsideration of application

3,00,000

50,000

Approval to initiate Phase II / III Clinical Trial

· For reconsideration of application

2,00,000

50,000

Approval to initiate Phase IV Clinical Trial

· For reconsideration of application

2,00,000

50,000

Approval to initiate BA/BE study with new drug

· For reconsideration of application

2,00,000

50,000

*No fee is required to pay for manufacturing permission of new drugs depend on fruitful completion of Phase I to Phase III of clinical trials.

Table 6: Forms for application and issuance of permission:^[9]

Application towards	Apply in	Permission in	Valid for
Ethics Committee registration for performing CT or BA/ BE study.	CT-01	CT-02	5 Years
For conducting Phase I / II / III / IV clinical trials with new drug or investigational new drug.	CT-04	CT-06	2 Years
To perform BA/BE study with new drug/ investigational new drug.	CT-05	CT-07	1 Year

4.1 Biomedical and health Research:

GSR 227(E) has included “Biomedical and health research” (under chapter IV) and laid out the requirements for carrying out such studies. Rules applicable to biomedical and health research have been given an extension, in the sense that they shall come into force after six months of publication of GSR 227(E).

Table 7: Timeline for review of application:^[9]

Application	Timeline for review	If, no communication within timeline:
CT application for new drug/ investigational new drug	Within 30 working days	· Approval to conduct clinical trial have been granted. · Prior to initiate of clinical trial applicant has to submit Form CT-04
New drugs already available in market in countries given by central licencing authority.	Within 90 working days	-
BA-BE studies of new drug/ investigational new drug	Within 90 working days	-

4.2 Academic Clinical Trials:

· Academic clinical trials required to follow ICMR guidelines.

· Observations obtained from academic clinical trials are not used for any promotional purpose.

· There is no need to submit CLA for review and approval of academic clinical trials.

4.3 Clinical Trial Registry:

Before enrolling patients for clinical trials, it must be registered under CTRI portal. According to GSR 227(E), it is mandatory to register BA/BE studies of investigational new drugs under CTRI before enrolling patients for clinical trials.

4.4 Archival of records and retention samples: According to GSR 227(E), it is mandatory to maintain the data and records for 5 years once trial completes or BA/BE study or at least two years after the expiration date of the batch of the new drug product, whichever is later. Schedule Y did not mention retention of sample but according to GSR 227(E) rules, it is mandatory to retain all the test samples and reference drug products used in BA/BE studies for 5 years after conducting the study or 1 year after expiry of drug, whichever is later.

4.5 Post marketing studies:

The requirements for phase IV clinical trials/ post marketing trials and post marketing surveillance has differentiated by G.S.R.227(E):

· Post marketing trials: These trials need to be conducted according to approved protocols with defined objective of trial, inclusion criteria, exclusion criteria, safety and efficacy criteria.

· Post marketing surveillance studies: In these studies, the study drugs are fragment of the treatment of the patient in the perception of the prescriber involved in the protocol. The regulatory guidelines for the CT of a new drug are not valid in these cases, as the drugs are already in market.

4.6 Pharmacovigilance system:

It is mandatory for applicant to have Pharmacovigilance system and it is reported to licensing authority.

4.7 Clinical trial of indigenously developed drug: Any drug developed in India proposed to conduct clinical trial and its manufacturing in India will be granted approval for clinical trials within 30 working days by Central Licensing Authority. If no response has been received from the CLA to applicant, the approval to perform CT have been granted.^[10]

4.8 Clinical trial of Drug developed outside of India: For the clinical trial conducted outside India, which is previously permitted and marketed in a country, 90 working days is set for the CLA to respond. The validity of clinical trial approvals has determined as two years for pharmaceutical companies to begin a study, which is extendable by one year.^[10]

4.9 Post-trial availability of new drug:

If no substitute therapy is available for specific indication and the investigational new drug is found to be advantageous to subject by the investigator then new drug is available for that indication. The rules has laid conditions for providing post-trial access of drugs to patients who has need for the first time. Sponsor is supposed to provide the investigational drug to subject without cost according to the new rules.

4.10 Import of drug for sale or distribution:

For drug marketed in abroad, local clinical trials has been exempted according to the new rules for import of drugs for sale and distribution. Early availability of drug is possible because of this rule by DCGI provided that-

· If only no or less unanticipated serious adverse events stated for the drug

· If applicant is ready to conduct post marketing surveillance for safety and effectiveness of drug.

· If the drug is designated in fatal diseases or treatment for rare diseases in Indian population for which the drugs are unavailable in the market or offered in high cost.^[10]

4.11 Compensation and monitoring:

Patient safety is the main goal for this rule, for any observed adverse event, there must be compensation provided and strict monitoring against the same has to be done. Informed consent should contain the process of monitoring and compensation in case of adverse event.

It is mandatory that if any injury happens during clinical trial to the subject and if it is confirmed that injury is due to clinical trials, medical management is provided to the subject. For cases like permanent disability or death while performing clinical trial, compensation will be decided by the Drug Controller General of India.^[10]

4.12 Orphan drugs:

Orphan drugs are defined for the first time as a drug used to cure condition doesn’t extend more than 5 lakh population in India. According to the new rules, no fees will be charged for application of clinical trials which has been conducted for rare diseases in India. The rules exempt local clinical trials for already approved orphan drugs for import in India for the purpose of sale and distribution.^[10]

5. Challenges for performing clinical trials in India

1) Ethical concerns:

a. Although India has manpower and regulations set for the clinical trials because of history of clinical trials in India and due to unethical practices international companies are losing trust in Indian institutes.

b. Till now there was no need for ethical committee to register under DCGI which lead to independent working and manipulation in clinical trial result which might result in occurrence of adverse event in future which is challenging situation for India.

c. Protection of human subject and keeping confidential data is more challenging during clinical trial.

d. Unable to maintain transparent procedure in informed consent process.

e. Participation of major vulnerable people like villagers, pregnant women, illiterates in clinical trials resulting in mistreatment of the human subjects and manipulation in the results.

2) Quality considerations:

a. Data protection, improper documentation, data quality and GCP issues.

b. Diverse quality standards for local clinical trials and global clinical trials.

c. Casual attitude for some of the significant ethical steps in clinical trials which includes improper documentation.

3) Regulatory consideration:

a. Delays for approval of clinical trials: Due to shortage of technical staff or trained staff.

b. Lack of clinical trial approval transparency, standardisation and improper audit during clinical trial.

4) Cultural consideration:

In India, the physician strongly impacts patient decision which might develop ethical issues with patient enrolment unless the process is transparent. Informed consent should be in local language. The translation needs to be performed in all the regional local language.

5) Media and advertisement:

There has been lot of damaging advertising of clinical trials in India due to incorrect safety data provided by media related to clinical trial, which results in false assumptions in human subjects, industry and government resulting in restrictive development of laws than supportive development.

6) Training or Mentoring:

Deficiency of GCP and Clinical trial training of medical practitioner including consistent upgradation and maintenance of certification is a major consideration.

7. CONCLUSION:

New drug development rules, 2019 are comprehensive, well balanced and have increased ethical balance, which is beneficial for the patient. Approval for clinical trials in India within 30 days will speed up the trial process and encourages the drug development process in India. An opportunity for early access to innovative medicinal product is given by new rules ensuring compliance to ethical principles and protection of patients’ rights. These changes lead to increase in sponsor’s responsibilities and mandate higher level of management control to ensure compliance.

8. ACKNOWLEDGEMENT:

The authors thank JSS Academy of Higher Education and Research and JSS College of Pharmacy, Mysuru for providing the necessary facilities for carrying out this work.

9. CONFLICT OF INTEREST:

The authors have no conflicts of interest that are directly relevant to the content of this review and there has been no financial support for this work that could have influenced its outcome.

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Received on 23.07.2019 Modified on 02.01.2020

Research J. Pharm. and Tech 2020; 13(3):1517-1522.

DOI: 10.5958/0974-360X.2020.00276.0