Approval Process of Investigational New Drugs Application for Chemotherapeutics Drugs in INDIA (CDSCO) Comparison with USA (USFDA) & EUROPE (EMA)

1.1 Anticancer Agents ¹

Anticancer medications, often referred to as antineoplastic operators, are used to treat cancer by either preventing the growth of cancer cells or directing their death. Malignancies are treated using anticancer medications. Medication can be used either on its own or in conjunction with other medications, such as radiation therapy or surgery. Anticancer medications kill cancer cells by first arranging energy, which implies lower concentration. Anti-cancer medications are used to kill all malignant cells because they are the only ones capable of causing cancer.

Bladder cancer, breast cancer, colorectal cancer, kidney cancer, non-small cell lung cancer, non-hodgkin lymphoma, melanoma, oral and oropharyngeal cancer, pancreatic cancer, prostate cancer, thyroid cancer, and uterine cancer are among the several forms of cancer.Treatment for cancer varies depending on the type and stage of the disease. Most patients receive a combination of treatments, some of which are "local" treatments like radiation therapy or surgery that are designed to treat a particular tumor. Because they impact the entire body, systemic treatments including chemotherapy, immunotherapy, targeted therapy, etc.

Surgery, radiation therapy, chemotherapy, immunotherapy, targeted therapy, hormone therapy, bone marrow or steam cell transplantation, photodynamic therapy, and hyperthermia are some of the cancer treatment options.Radiation therapy uses high energy particles or radiation such as x - ray gamma rays electron beams or protons todestroy or kill cancer cell it is one of the most widely used cancer treatment. Chemotherapy is a type of cancer treatment that uses drug to kill cancer cells or slow their growth, it is a systemictreatment, meaning it affects the entire body and is often used in combination with other treatment like surgery,
radiation therapy or immunotherapy and chemotherapy is also called as “chemo”.

2. Classification of Anticancer Drugs ²

2.1 Alkylating Agents

By forming an azindinium ion connection with the nitrogen atom at the seventh position in the guanine of DNA, these drugs directly damage or disrupt the DNA of cancer cells. These drugs are effective against multiple myeloma, breast cancer, Hodgkin's disease, and lymphomas. Mechlorethamine, cyclophosphamide, chlorambucil, thiotepa, and cisplatin are a few examples.

2.2 Antimetabolites

These are a class of anticancer medications that disrupt the synthesis of DNA and RNA. They are integrated into DNA or RNA and resemble the typical substrates of cellular metabolism, which disrupts cell development and division.

2.3 Natural Product

The discovery of anti-cancer medications has been greatly aided by natural products; many of the chemotherapeutic medicines in use today come from plants, microorganisms, and marine species.

2.4 Antitumor antibiotics

Antitumor antibiotics are a class of anticancer drugs that interfere with DNA function and structure. Unlike traditional antibiotics that fight bacterial infections, these drugs are used specifically to treat cancer. They are derived from natural products produced by soil microorganisms, primarily from the genus Streptomyces. Their main mechanism of action involves damaging DNA and inhibiting essential cellular processes like replication and transcription, leading to cell de. Examples are: Anthracyclines, Bleomycine, Doxorubicin, Daunorubicin.

2.5 Hormonal Agents

A family of anticancer medications known as hormonal agents targets hormone-sensitive tumors. These drugs are most frequently used to treat hormone-dependent malignancies, such as prostate and breast cancer. The basic idea underlying hormonal treatments is to either lower certain hormone levels or prevent them from having an impact on cancer cells.

2.6 Miscellaneous

Examples are Hydroxyurea, L-Asparginase, Arsenic trioxide. Mechanism of action: By inhibiting ribonucleoside diphosphate reducase, hydroxyurea prevents RBC from being converted to DNA, which stops DNA production. Asparaginase breaks down asparagine, an amino acid that some cancer cells are unable to produce on their own and must obtain from outside sources. It starves these cells by depleting asparagine, which causes them to die.

2.7 Signal transduction inhibitors

A class of anticancer medications known as signal transduction inhibitors disrupts the processes that regulate the development, survival, and spread of cancer cells. Dysregulated signaling pathways in cancer cells frequently result in unchecked cell proliferation. In order to interfere with the operation of cancer cells, signal transduction inhibitors target certain molecules within these pathways. Another name for these is Tyrosine Kinase Inhibitors (TKIs).

Figure 1. Classification Of Anticancer Drugs ²

3. Methodology

3.1 Cancer trials ecosystem in India ^3-12

One of the main causes of sickness and death worldwide is cancer. In 2022, there were about 1.46 million new cases of cancer in India, with the most common forms occurring in the stomach, breast, lung, and oral cavity. In 2016, cancer accounted for 5% of all disability-adjusted life years and 8.3% of all deaths in India. Five factors—increasing average life expectancy, sedentary lifestyle, food, tobacco use, obesity, metabolic illnesses, and pollution—are responsible for the rising absolute incidence of cancer in India. The 5- and 10-year survival rates for cancer patients are trending upward worldwide due to advancements in surgical methods, precision radiation, new targeted treatments, and immunotherapies.

Clinical trials must be well planned in order for new anticancer treatments to be developed and approved. Sponsors are increasingly searching for patients from other regions, particularly India, due to the sheer volume of candidate compounds and the competitive environment in the developed countries. Approximately one-fifth of all cancer sufferers reside in India, which is home to 17% of the world's population. However, the percentage of ongoing international clinical trials in India is less than 2%. When the pharmaceutical business thinks about using Indian sites for international clinical trials, they have encountered regulatory obstacles, particularly in the last ten years, such as less-than-ideal review and approval periods. It is gratifying to see that the Indian government significantly changed clinical research regulations under the New Drugs and Clinical Trials Rules, 2019, bringing them closer to international standards. The authors of this review first give a brief overview of how India's clinical trial landscape has changed over the past few decades before concentrating on the most recent modifications to the regulatory framework, with a particular focus on cancer trials.

Figure 2: Number of clinical trials registered on the Clinical Trial Registry of India (CTRI) website. ¹³

3.2 Estabilishing India as Research Hub for Oncology

Clinical research for cancer medications in India encounters a number of difficulties and obstacles in addition to regulatory requirements; some of the most significant ones are outlined here.

3.3 Barriers to Oncology Clinical Research

3.3.1 Lack of Awareness for Research in Cancer Care ^14-17

Providing patients with regular and timely therapy is the top goal for oncologists and cancer clinics. Clinical research is therefore frequently deprioritized due to India's enormous patient burden. Furthermore, the time-consuming and resource-intensive procedures needed to perform clinical trials impede the advancement of clinical research. Another challenge is the absence of well-established academic research networks around the nation.

Any nation's national cancer data registries provide a strong foundation for carrying out clinical research. Research capacity will be increased nationwide with the establishment of the National Cancer Grid (NCG) and the six new Tata Cancer Centers that are planned.

3.3.2 Poor Support for Clinical Trials As a Care Option

Only a small number of patients are referred inside the same or neighboring institutions; the majority of patients participating in cancer clinical trials come from the investigator's own database. In order to give patients the chance to access clinical trials as one of the possible treatment options, oncologists must be aware of the availability of clinical trials in a certain condition and be willing to send patients to the site.

3.3.3. Lack of Oncology Medical Professionals and Facilities ^15-19

The oncologist-to-patient ratio in India is rather low; in 2021, it was approximately 1:2000. Oncologists in India see about 475 new patients annually on average (median of 35 patients each outpatient clinic), which is significantly more than in high-income nations. In addition, there is a lack of paramedical personnel with expertise in the therapeutic field of oncology. While the majority of India's major cities have created medical facilities, semiurban and rural areas lack the necessary infrastructure for establishing hospital genetic testing labs and clinical research sections. Biosamples from patients must be sent to central laboratories in certain centers. Another obstacle to clinical research is the logistical challenge of transporting viable patient material.

3.3.4 Insufficient Resources for Clinical Research ^{11, 19-20}

India is a large market for the pharmaceutical industry, but because the majority of drug development in pharmaceutical companies is concentrated in the US and/or Europe, there is little money set aside for clinical research in India. However, the situation is shifting as a result of recent developments and reforms. Clinical research is funded by government or commercial organizations, as well as pharmaceutical and biotech sponsors. According to a recent study, government-funded interventional trials are only available in six states in India, where there is a significant gap in the number of trials and financing received for industry-sponsored trials versus academic studies. The Indian Department of Biotechnology is currently giving institutions and individual researchers more cash and resources to carry out basic, practical, and translational oncology research.

3.3.5 Economic Aspect ^{21, 22, 23}

The sponsor pays the majority of the medical and related expenses incurred during clinical studies. However, it is necessary to take into account a number of non-medical substantial out-of-pocket expenses—social determinants of health—such as travel and the loss of employment for oneself and caregiver (if necessary). Due to rising medicine and cancer care costs, one of the largest obstacles to post-trial drug access is still financial. Data gathered from the ongoing study on the cost-effectiveness and health-related quality of life of  anti-cancer medications will be used to assess the direct and indirect costs of cancer care in India. . Access to the post-trial market for the approved medication is a significant financial obstacle for sponsors. The majority of cancer patients in India are frequently unable to afford novel therapies due to the country's insufficient insurance coverage, which means that people bear the majority of health care costs.

3.3.6 Geographical, Cultural, and Social Factors ^{20, 24-29}

India is a multilingual and multicultural nation. Early cancer screening and detection may be hampered by cultural barriers. Female gynecologic cancer diagnostic delays are mostly caused by cultural and societal hurdles, such as humiliation and a lack of family support. As a result, many individuals are unable to receive cancer treatment at an early stage. Additionally, patients with cancer have a high chance of being lost to follow-up, which has a significant impact on the availability of survival statistics. There are difficulties in upholding uniformity of informed consent because different languages and dialects are prevalent throughout India. India is a multilingual and multicultural nation. Early cancer screening and detection may be hampered by cultural barriers. Female gynecologic cancer diagnostic delays are mostly caused by cultural and societal hurdles, such as humiliation and a lack of family support. As a result, many individuals are unable to receive cancer treatment at an early stage. Additionally, patients with cancer have a high chance of being lost to follow-up, which has a significant impact on the availability of survival statistics. There are difficulties in upholding uniformity of informed consent because different languages and dialects are prevalent throughout India. Less than 10% of patients with newly diagnosed cancer in India have access to a therapeutic cancer clinical trial, indicating significant geographic variation in cancer clinical trial availability.  Even for common cancer forms like breast cancer, a significant interstate discrepancy in access to interventional trials was noted in a study measuring geographic disparities in cancer clinical research in India. It was found that the median sample size per year per state (SSY) was 1.55 per 1,000 incident cancer cases. When cancer site-wise SSY was taken into account, disparities were even more pronounced. Only 29.7% of newly diagnosed cancer patients have a spot available in a therapeutic cancer clinical trial, even in the state with the greatest SSY.

3.4. Investigational New Drugs (IND) and Its Importance ^30-32

A novel chemical or biological substance that has not been authorized for widespread use and is being assessed for quality, safety, and efficacy in human subjects is known as an Investigational New Drug (IND). Between preclinical research and clinical trials, the IND procedure acts as a scientific and legal link. The sponsor must submit a thorough IND dossier to the CDSCO in order to receive clearance before beginning any human trials. Typically, an IND dossier includes:

1. Data from toxicology and animal pharmacology showing safety in preclinical studies .
2. Chemistry, Manufacturing, and Controls (CMC) data that guarantees the consistency and quality of the product .
3. Clinical trial protocols that specify the goals, design, dosage, and safeguards for patients.

The purpose of IND review is to guarantee that ethical and scientific standards are upheld and that prospective clinical studies do not subject human participants to unjustifiable risks. The IND permits the sponsor to lawfully start Phase I–III clinical trials in India after it has been approved.

Figure 3: Contents of an Investigational New Drug (IND) Application. ³³

Table 1: Regulatory Framework of Investigational New Drugs Application for Chemotherapeutic in India vs. USA vs. EMA ^34-55

Table 2: Investigational New Drugs Application Approval Pathway for Chemotherapeutic In India vs. USA vs. EMA ^56-62