Pharmacovigilance and the Process of ADR reporting and Monitoring in India

Pharmacovigilance is defined as the science of detection, assessment, and prevention of adverse drug reactions in humans. Under-reporting of drug reactions is the major problem and has various reasons. The WHO has initiated the program of reporting all adverse drug reactions now coordinated by the Uppsala Monitoring Centre in Uppsala, Sweden, with oversight by an international board. This review presents in brief the relevance, functioning, importance, and the procedure of reporting adverse drug reactions and how pharmacovigilance plays major role in it. Pharmacovigilance has been confined, mainly to detect adverse drug events that were previously either unknown or poorly understood. Pharmacovigilance is an important and integral part of clinical research and these days it is growing in many countries. Today many pharmacovigilance centers are working for drug safety monitoring in this global pitch, however, pharmacovigilance faces major challenges in aspect of better safety and monitoring of drugs.^[1]

History of pharmacovigilance:

Earlier, very few novel drugs were discovered in India and hence the need for pharmacovigilance system was less. However, India is now rapidly progressing in the field of drug discovery. There is also rapid increase in the marketing of foreign branded drugs. Such developments have led to the emergence of a strong pharmacovigilance system in our country. Pharmacovigilance system in India is regulated by Schedule Y of the Drugs and Cosmetics Act 1940, and Rules, 1945. This Schedule contains all specifications for conducting clinical trials on animals and humans for the development of a new drug and requirements of clinical trial for the import, manufacture and approval of marketing of a new drug in India. The Schedule contains a section on post-marketing surveillance which outlines the details about the format to be followed for Drafting periodic Safety Update Reports (PSURs), their submission and PSUR cycle. It also contains time frames in which these reports should be submitted to the concerned authorities. Unexpected and serious adverse effects in clinical

Concept of pharmacovigilance:

WHO defines the Pharmacovigilance (PV) as the pharmacological science relating to the detection, evaluation, understanding and prevention of adverse effects, particularly long term and short-term side effects of medicine. Pharmacovigilance refers to the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects and other drug- related safety problems. Related to this general definition, the underlying objectives of pharmacovigilance are to prevent harm from adverse reactions in humans that arise from the use of health products within or outside the terms of marketing authorization and in relation to the life cycle of these health products.^[4][5] The main goal of pharmacovigilance is thus to promote the safe and effective use of health products, in particular by providing timely information about the safety of health products to patients, health-care professionals, and the public. Pharmacovigilance is therefore an activity contributing to the protection of patients and maintaining public health.^[4][5]

5. The main objectives of pharmacovigilance

1.It involves exhibiting the efficacy of drugs by monitoring their adverse effect profile for many years from the lab to the pharmacy.

2.tracking any drastic effects of drugs improving public health and safety in relation to the use of medicines.

3.encouraging the safe rational and cost-effective use of drugs.

4.promoting understanding, education and clinical training in pharmacovigilance.

5.effective communication to the generic public. In addition, providing information to consumers, practitioners and regulators on the effective use of drugs along with designing programs and procedures for collecting and analysing reports from patients.[4][5]

Components of pharmacovigilance system

Based upon the aim and scope of pharmacovigilance, certain elements and capabilities are very essential to a fully functioning pharmacovigilance system as shown in Figure 1.  These include as follow [6]:

• A qualified person for pharmacovigilance –Officer In-charge (PvOI) (India)

• Safety system (database) support

• Safety case processing and review

• Medical writing and aggregate reporting

• A sound quality management system including standard operating procedures (SOPs)

• Quality standards, metrics, and training

• Signal detection and risk analysis

• Global safety reporting

Pharmacovigilance program of India  

Pharmacovigilance Programme of India (PvPI) is a highly specialized organization of medical science dealing with activities related to detection, assessment, understanding, prevention and control of adverse effects or any other possible drug related problems. An Indian government agency called the Pharmacovigilance Programme of India (PvPI) detects and addresses issues related to medication safety. Receiving reports of adverse medication occurrences and taking appropriate steps to address issues are among its activities. The initiative was started in July 2010 by the Central Drugs Standard Control Organization, with the All India Institute of Medical Sciences in New Delhi serving as the National Coordination Centre. On April 15, 2011, it moved to the Indian Pharmacopoeia Commission in Ghaziabad. After the Thalidomide scandal in the 1960s, pharmacovigilance programs were established in several developed nations. In the 1980s, India established its program. The Central Drugs Standard Control Organization created the current Pharmacovigilance Program of India in 2010 after this broad idea of drug safety monitoring underwent several iterations. The initiative is currently well-integrated with government laws, a research facility run by the Indian Pharmacopoeia Commission, and a regulator acting as a leader. There were 250 centers in India as of 2018 that could handle reports of severe adverse reactions. Training physicians and hospitals to report adverse medication reactions when patients experience them is one of the organization's challenges. Although the Pharmacovigilance Program generates these reports, any clinic should ideally be the source. The goal of the Pharmacovigilance Program is to promote a social norm and culture that encourages reporting drug issues. As a collaborating center, the Pharmacovigilance Programme assists the WHO in developing international policy for other countries to manage their own drug safety programs. Whi le the United States and Europe have pharmacovigilance systems which are developed well in some ways, the Indian programme has more and specialized expertise to apply for the unique circumstances of India. The program's ability to identify side effects in Indian patients using carbamazepine was one of its achievements. People from South Asia are more prone to have issues when using this medicine because of their different genetic makeup, even if it is safer for native Europeans. The Pharmacovigilance Programme was successful in identifying this issue, which other nations would not have been able to do. The Pharmacovigilance Program's creation increased India's appeal as a global location for clinical trial research for multinational businesses.  International researchers conducting trials in India must have a thorough understanding of the Caliber of India's pharmacovigilance program. The program works with the World Health Organization on safe pharmaceutical projects both domestically in India and abroad.^[7][8] The aims of this program were multiplier to produce knowledge on ADR in the community of Indians; to increase understanding between medical services practitioners of the importance for PV; to actively track the profit risks of medicinal products; to establish unbiased, impartial, evidence-based guidelines on the protection of medicinal products; to urge regulators to pursue safety-related judgments; Convey results to all relevant investor and set up a National Centre of Excellence under national wide guidelines for drug safety.^[2][8]

The structure of PvPI consists of the following two committees.^[9]

1. Steering Committee

The Steering Committee consists of 10 members with Drug Controller General of India (DCGI), CDSCO, as ex-officio chairman and officer in charge along with other additional members. This committee is responsible for supervising and giving directions to PvPI.

2. Working Group

The Working Group consists of 11 members with secretary-cum-scientific director and Indian Pharmacopoeia Commission as the chairperson. This committee provides technical support to the programme and serves as a,

(a) Signal review panel

(b) Core training panel

(c) Quality review panel.

The objectives of PvPI are given below ^[10]:

1. To create an international system for patient safety reporting

2. To identify and analyse new signals (ADR) from reported cases

3. To monitor the benefit-risk ratio from marketed medications list

4. To generate evidence-based information on safety of medicines

5. To support agencies like CDSCO in formulating safety related regulatory decisions for medicines

6. To communicate safety information on use of medicines to various stakeholders to minimize risk

7. To create a National Centre of Excellence at par with global drug safety monitoring

8. To collaborate with National Centres for exchange of information and management of data

9. To provide training and support to other National Pharmacovigilance Centres.

Introduction To Clinical Research

The importance of drug trials in promoting health services cannot be over emphasized. New drugs and therapies can improve the quality and lifespan of patients. While it is imperative that the number of clinical trials increase, the Government is also trying to ensure that the rights and safety of the subjects are protected and the quality of the trials performed in India improve to international standards. The regulatory guidelines in terms of serious adverse events (SAEs) reporting, informed consent, compensation in case of injury or death in clinical trials have been recently modified. It is essential that now all clinical trials conducted in India should as per the international conference of Harmonization-Good Clinical Practices Guidelines (ICH- GCP) for clinical trials and follow the recently amended Schedule Y of the Drugs and Cosmetics Act.^[11][12]

Clinical Trials

A clinical trial is a research study that tests a new medical treatment or a new way of using an existing treatment to see if it will be a better way to prevent and screen for diagnose or treat a disease. For any new drug to enter in clinical trial, it must pass preclinical studies. Preclinical studies involve in vitro (i.e. test-tube or Laboratory) studies and trials on animal populations. Wide range of dosages of the study drug is given to animal subjects or to an in-vitro substrate in order to obtain preliminary efficacy, toxicity and pharmacokinetic information. It is important for anyone preparing a trial of a new therapy in humans that the specific aims, problems and risks or benefits of a particular therapy be thoroughly considered and that the chosen options be scientifically sound and ethically justified.^[11][12]

Phases of trials

1.Phase I or clinical pharmacology study: Initial safety trials on a new medicine. An attempt is made to establish the dose range tolerated by volunteers for single and for multiple doses, pharmacodynamic effects, pharmacokinetics and nature and intensity of adverse reactions (s).

Normally, a small group of 20-100 healthy volunteers will be recruited.  These trials are often conducted in a clinical trial clinic, where the subject can be observed by full-time staff. Investigators involved in Phase I trials should be trained in clinical pharmacology and should also be provided with necessary facilities which would help them in closely observing and monitoring the subjects.^[12]

2.Phase II or exploratory trials

Phase IIa: Pilot clinical trials to evaluate efficacy and safety in selected populations of patients with the disease or condition to be treated, diagnosed, or prevented. Objectives may focus on dose-response, type of patient, frequency of dosing, or numerous other characteristics of safety and efficacy.

Phase IIb: This trial is to evaluate efficacy (and safety) in patients with the disease or condition to be treated, diagnosed, or prevented. These clinical trials usually represent the most rigorous demonstration of a medicine’s efficacy. Sometimes referred to as pivotal trials. Phase II trials are performed on larger groups (100-300 individuals) and are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. ^[12]

3.Phase III or confirmatory trials

Purpose is to obtain sufficient evidence about the efficacy and safety of the drug in a larger number of patients, generally in comparison with a standard drug and/or a placebo as appropriate. This also helps in determining the dose-response relationship and its use in wider population in different stages of disease. In this phase, the group is between 1000-3000 subjects.^[12]

4.Phase IV trials or post-marketing phase

Studies or trials conducted after a medicine is marketed to provide additional details about the medicine’s efficacy or safety profile. Different formulations, dosages, durations of treatment, medicine interactions, and other medicine comparisons may be evaluated. New age groups, races, and other types of patients can be studied. Detection and definition of previously unknown or inadequately quantified adverse reactions and related risk factors are an important aspect of many Phase IV studies. If a marketed medicine is to be evaluated for another (i.e., new) indication, then those clinical trials are considered Phase II clinical trials. The term post-marketing surveillance is frequently used to describe those clinical studies in Phase IV that are primarily observational or non- experimental in nature, to distinguish them from well controlled Phase IV clinical trials or marketing studies.^[12]

Drug Controller General of India (DCGI)

Drug Controller General of India (DCGI) is the full name of the organization. DGCI is in charge of the department known as the Central Drugs Standard Control Organization (CDSCO). The Indian Government is in charge of the department. Licenses for particular drug classes in India must be approved by the DCGI. Drug quality requirements and standards are also outlined in the DCGI. In India, it has to do with producing, distributing, importing, and selling medications. With the Drugs and Cosmetics Act, the DCGI seeks to standardize enforcement.^[13]

1. The DCGI develops and maintains the necessary drug reference standards.
2. The DCGI guarantees consistency in the implementation of the D&C Act of 1940.
3. The DCGI is in charge of training Analysts from State Drug Control Laboratories.
4. The DCGI is in charge of issuing licenses for medical devices covered by Act Medical Device Rules 2017.
5. The DCGI also approves medications under the medications and Cosmetics Act.
6. The DCGI is in charge of conducting clinical trials.

Central Drugs Standard Control Organization (CDSCO)

The Central Drugs Standard Control Organization (CDSCO) is the Central Drug Authority for discharging functions assigned to the Central Government under the Drugs and Cosmetics Act. CDSCO has six zonal offices, four sub-zonal offices, 13 port offices and seven laboratories under its control. ^[14] The following are the major functions of CDSCO ^[14]:  Regulatory control over the import of drugs, approval of new drugs and clinical trials, meetings of Drugs Consultative Committee (DCC) and Drugs Technical Advisory Board (DTAB), approval of certain licenses as Central License Approving Authority is exercised by the CDSCO headquarters.

Types of regulatory applications:

1. Investigational new drug: An Investigational New Drug (IND) application is a request for authorization from the Food and Drug Administration (FDA) to administer an investigational drug to humans. This is the first step in the drug approval process and is required before clinical trials can begin. The IND application contains comprehensive information about the drug's composition, manufacturing, and preclinical testing to demonstrate that it is reasonably safe for use in humans. ^[15]

There are three IND types:

• An Investigator IND is submitted by a physician who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed.  A physician might submit a research IND to propose studying an unapproved drug, or an approved product for a new indication or in a new patient population.^[15]
• Emergency Use IND allows the FDA to authorize use of an experimental drug in an emergency situation that does not allow time for submission of an IND in accordance with 21CFR, Sec. 312.23 or Sec. 312.20.  It is also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist.^[15]
• Treatment IND is submitted for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.^[15]

2. New Drug application: A New Drug Application (NDA) is a comprehensive document submitted to the Food and Drug Administration (FDA) to seek approval for the marketing and sale of a new pharmaceutical drug in the United States. The NDA is a critical step in the drug development process, as it provides the FDA with the necessary information to evaluate the drug’s safety, efficacy, and quality. The data gathered during the animal studies and human clinical trials of an Investigational New Drug (IND) become part of the NDA. ^[16]

The goals of the NDA are to provide enough information to permit FDA reviewer to reach the following key decisions:

• Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks.
• Whether the drug’s proposed labelling (package insert) is appropriate, and what it should contain.
• Whether the methods used in manufacturing the drug and the controls used to maintain the drug’s quality are adequate to preserve the drug’s identity, strength, quality, and purity.

The documentation required in an NDA is supposed to tell the drug’s whole story, including what happened during the clinical tests, what the ingredients of the drug are, the results of the animal studies, how the drug behaves in the body, and how it is manufactured, processed and packaged.^[16]

3. Abbreviated New Drug Applications: An Abbreviated New Drug Application (ANDA) is a request to the Food and Drug Administration (FDA) for the approval to market a generic version of a previously approved brand-name drug. The ANDA process is streamlined compared to the New Drug Application (NDA) because it relies on the safety and efficacy data already established by the original, or “reference,” drug. Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, lower cost alternative to the brand-name drug it references.^[17]

Generic drug applications are termed “abbreviated” because they are generally not required to include preclinical (animal) and clinical (human) data. Instead, generic applicants must scientifically demonstrate that their product performs in the same manner as the innovator drug.

The ANDA must demonstrate that:

• The generic drug is bioequivalent to the brand-name drug.
• The generic drug has the same active ingredients, dosage form, strength, route of administration, and intended use as the brand-name drug.
• The generic drug meets the same high standards for quality and manufacturing as the brand-name drug.^[17]

Ich good clinical practice

Good Clinical Practice (GCP) training is a basic need for anyone conducting clinical research. GCP is standard and set of rules that apply to all research. GCP is a set of globally accepted standards for scientific and ethical quality that need to be followed at every turn during clinical research. The most promising therapies are advanced into clinical trials after laboratory testing and animal research. GCP or Good Clinical Practice refers to an international quality Standard provided by the ICH for the purpose of regulating clinical Trials that involve human subjects. ^[18]

The objective of Good Clinical Practice (GCP) is to ensure the safety, rights, and well-being of scientific patients while maintaining the credibility and integrity of data collected in clinical studies

5. Key objectives include ^[18][19]:

1. Participant Protection: Ensuring that the rights, safety, and well-being of participants are prioritized.
2. Ethical Conduct: Conducting clinical trials in accordance with ethical principles, including obtaining informed consent.
3. Data Integrity: Ensuring that clinical trial data is credible, accurate, and reliable.
4. Regulatory Compliance: Ensuring that trials are conducted in compliance with applicable regulatory requirements and guidelines.
5. Quality Assurance: Promoting high-quality practices in clinical research to support sound scientific decision-making.

5. Its scope covers several key aspects ^[18][19]:

1. Ethical Conduct: Ensures the safety, rights, and well-being of trial participants are protected, consistent with the principles of the Declaration of Helsinki.
2. Regulatory Compliance: Provides a framework for ensuring that clinical trials comply with regulatory requirements across different countries.
3. Quality Assurance: Ensures the credibility and accuracy of the data collected and reported, which is critical for the reliability of the trial results.
4. Informed Consent: Requires that participants are fully informed about the trial, its risks, and benefits, and voluntarily agree to participate.
5. Responsibilities of Investigators and Sponsors: Outlines the roles and responsibilities of clinical investigators, sponsors, and other key parties in ensuring trial integrity and participant safety.
6. Monitoring and Reporting: Establishes guidelines for monitoring clinical trials, managing and reporting adverse events, and ensuring that the trials are conducted as per the approved protocol.
7. Documentation: Specifies the need for proper documentation of the trial process, including protocols, case report forms, and other essential documents.

New drug clinical trial rule 2019

New Drugs and Clinical trial rule 2019 are regulated on 19 March 2019. Their objective is to implement a dependable, comprehensible, and uniform methodology for clinical trials. With these rules, Indians will perhaps have faster access to novel medications and clinical trials. The new drug and clinical trial rules 2019, rule 97 includes 122DAA in the drugs and cosmetic rules 1945. It includes the disregard for specific regulations for novel medications and novel drugs under study for use in humans. For new and experimental medications intended for human use, Part XA and Schedule Y will not apply.^[20]

Objective NDCT ^[20][21]:

The new rules include a time-bound evaluation of applications and give additional flexibility to researchers. They are intended to promote clinical research and ensure predictability and accountability in the regulatory process.

1. Primary objective are promotion of research and development in India.
2. Faster accessibility of new drug.
3. Predictability and transparency in approval process.
4. To reduce costs and lower healthcare expenses.
5. To maintain the integrity of data, the safety and well-being of trial participants, and the quality assurance of clinical research done in India.

Scope of NDCT ^[20][21]:

1. New Drug Approval Process: The rules simplify the process for approval of new drugs, making it faster, especially for drugs already approved in other regulated markets. If a new drug is approved in countries like the USA, EU, Japan, etc., and there's no significant difference in Indian demographics, the requirement for local clinical trials may be waived under certain conditions.
2. Clinical Trials: The rules lay down detailed guidelines for the conduct of clinical trials in India, focusing on the protection of participants and the quality of data. Ethical aspects of clinical trials have been emphasized, including mandatory registration of Ethics Committees and Institutional Review Boards (IRBs).
3. Post-Trial Access: The rules include provisions for post-trial access to investigational drugs for participants, if found beneficial during the trial and if no alternative treatment is available.
4. Orphan Drugs: Special provisions for the approval of orphan drugs (drugs for rare diseases) are outlined, including incentives such as reduced fees and fast-track approval.
5. Biomedical and Health Research: The rules establish a framework for conducting biomedical and health research in India, ensuring that such research is conducted ethically and with the protection of participants' rights and safety.
6. Regulatory Reforms: The Central Drugs Standard Control Organization (CDSCO) is empowered to oversee and regulate the approval process and conduct of clinical trials.
7. Penalties: The rules also provide clear penalties for non-compliance, ensuring that both sponsors and investigators adhere to the prescribed guidelines.

Process of clinical trial application

A Clinical Trial Application provides comprehensive information about the investigational medicinal product(s) and planned trial, enabling regulatory authorities to assess the acceptability of conducting the study. Health authorities’ assessment covers the investigational medicinal product properties, the benefit/risk ratio of the study, the quality of the information provided to the trial subjects, and the suitability of the clinical sites and investigators.^[22]

Adverse drug reaction monitoring

The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, of which the World Health Organization (WHO) and the United States Food and Drug Administration (FDA) are members, defines an ADR as "A response to a drug which is noxious and unintended, and which occurs at doses normally used for prophylaxis, diagnosis, or therapy of disease or the modification of physiologic function." An adverse drug event, on the other hand, is defined as: "Any untoward medical occurrence that may present during treatment with a pharmaceutical product, but which does not

Table 1: List of ADR Monitoring centre ^[25]

Function of AMCs ^[26]:

1. It caters information about quality and safety of pharmaceutical products.
2. It initiates risk-management plans.
3. It prevents the predictable adverse effects and helps in measuring ADR incidence.
4. It instructs health care team, patients, pharmacists and nurses about adverse drug effects and creates Awareness regarding ADRs.
5. The main objective of ADR monitoring is to disclose the quality and frequency of ADRs and to identify the risk Factors that can cause the adverse reaction.
6. Proper information about safety of drugs and medicine.

Design and conduct of observational studies

Carefully designed and conducted pharmaco-epidemiological studies, specifically observational (non-interventional, non-experimental) studies, are important tools in pharmacovigilance. In observational studies, the investigator "observes and evaluates results of ongoing medical care without 'controlling the therapy beyond normal medical practice.^[27] Observational studies, crucial in pharmacovigilance, involve monitoring medical care without altering standard practices. Before starting such studies, a finalized protocol should be prepared, consulting experts like pharmacovigilance professionals and biostatisticians. Regulatory authorities should review the protocol and early termination conditions. Study protocols must outline objectives, methods, and analysis plans. Upon completion, a detailed report should be submitted. Adherence to good epidemiological practices, international guidelines, and local laws is essential. Professional conduct and confidentiality, along with data protection laws, must be upheld throughout the study.^[28]

Adverse Drug Reaction Monitoring Form

A "Drug Monitoring Form" is used to collect and document data regarding the safety, efficacy, and adverse effects of a drug. In the context of Indian Pharmacopoeia (IP) or the Indian regulatory system, drug monitoring is particularly associated with pharmacovigilance. Below is an outline of a typical drug monitoring form (IP). Information provided in this form is handled in strict confidence. The causality assessment is carried out at AMCs by using WHO-UMC scale. The analyzed forms are forwarded to the NCC-PvPI through ADR database. Finally the data is analyzed and forwarded to the Global Pharmacovigilance Database managed by WHO Uppsala Monitoring Centre in Sweden.The reports are periodically reviewed by the NCC-PvPI. The information generated on the basis of these reports helps in continuous assessment of the benefit-risk ratio of medicines.[29]

Assessment of ADR by naranjo scale

The Naranjo Adverse Drug Reaction (ADR) Probability Scale is a tool used to determine the likelihood that an adverse event is related to a drug rather than other factors. It provides a structured way to assess causality, commonly used in clinical settings and pharmacovigilance.

The scale consists of 10 questions, each with a possible score of -1, 0, +1, or +2 depending on the answer. The total score helps categorize the adverse event:

? 9: Definite ADR

5-8: Probable ADR

1-4: Possible ADR

? 0: Doubtful ADR

Table 2: Naranjo Algorithm - ADR Probability Scale ^[31]