Clinical Trials: The Role of Regulatory Agencies, Pharmacovigilance Laws, Guidelines, Risk Management, Patenting, and Publicizing Results

The importance of the need for clinical research, clinical research types, groups, and phases of clinical research has assumed increased significance. Clinical research studies are undertaken to assess the safety and efficacy of a drug, vaccine, device, or medical diagnostic test assay in treating, preventing, diagnosing, and controlling diseases1,2. In most instances, clinical research is carried out to satisfy unmet medical needs that include discovering a treatment for a newly emerged microbial species, like the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)3-5. They can also be conducted to find treatment for an existing illness with no/limited therapeutic options, like various types of cancers (breast cancer, arthritis, Clinical Trials: The Role of Regulatory Agencies, Pharmacovigilance Laws, Guidelines, Risk Management, Patenting, and Publicizing Results


INTRODUCTION
The importance of the need for clinical research, clinical research types, groups, and phases of clinical research has assumed increased significance. Clinical research studies are undertaken to assess the safety and efficacy of a drug, vaccine, device, or medical diagnostic test assay in treating, preventing, diagnosing, and controlling diseases 1,2 . In most instances, clinical research is carried out to satisfy unmet medical needs that include discovering a treatment for a newly emerged microbial species, like the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) 3-5 . They can also be conducted to find treatment for an existing illness with no/limited therapeutic options, like various types of cancers (breast cancer, arthritis, The research carried out to find a better treatment, improve healthcare, and benefit the current medical practice is termed clinical research. Clinical trial includes the pharmacodynamics (mechanisms of action of a new drug), pharmacokinetics (drug metabolism inside the body), therapeutics (efficacy of the drug), and adverse effects (safety of the drug) of the novel medical products. Clinical research is a process that involves human subjects and their biological specimens. The clinical trial is a meticulously planned protocol-based study of a drug/device to discover a new/better way to prevent, diagnose, and treat a disease/illness. Considering the involvement of both healthy and diseased people in clinical trials, the regulatory authorities have a significant role in the processes involving the conduction of clinical research and carefully evaluate their potential implications on humans. Because clinical trials are usually aimed at assessing the safety and efficacy of novel pharmaceutical compounds and medical devices, pharmacovigilance laws and risk management assume increased significance while conducting clinical research/trials. In this review, we attempt to discuss the regulatory authorities' roles in different geographical regions, including the United States of America, The European Union, and India. We also focus on the importance of pharmacovigilance laws and risk management during clinical trials.  Clinical trials and research are undertaken to satisfy unmet medical needs, and this assumes increased significance in the era of antibiotic resistance and the emergence and re-emergence of both contagious and non-contagious diseases 21 . Clinical research demands the practice of ethical principles while conducting a clinical trial. It becomes a real challenge to conduct a clinical trial during an epidemic/pandemic situation 22 . An emergency-like situation arises due to the lack of an approved drug against a novel microbial infection, as noticed in the recent pandemic of SARS-CoV-2/Coronavirus disease-19 (COVID-19) 23 . It is interesting to note that the first description of clinical trials dates to 550 BC, and several ancient instances discuss and describe the process of a clinical trial. It was noted that the clinical trials started with dietary interventions (legumes and lemons), and after hundreds and thousands of years, we reached the status where we discovered and manufactured drugs 24 .

REGULATORY REQUIREMENTS IN CLINICAL RESEARCH
Clinical research and drug trials involve human participants and pose significant ethical concerns. History has witnessed many such instances where human participants were recruited in a drug trial, resulting in significant morbidity and mortality. Given such experiences, there needed to be regulatory bodies overseeing the clinical trials involving human participants 25 . The regulatory bodies and the episodes of unethical practices that occurred worldwide are depicted in chronological order in Figure 1.  96 before human trials and that the trial will not lead to death or permanent injury to study participants 26 . Given several reports of unethical practices related to clinical trials and research in the past, it was imminent that a regulatory body is present which takes responsibility for all the ethical concerns related to clinical research with special reference to patient safety and well-being. The first regulatory recommendation was the Nuremberg Code (August 9 th , 1947), followed later by the WMA's Declaration of Helsinki (June 1964). In 1974, the National Research Act was passed by the US Congress, which aims to protect human subjects for biomedical and behavioral research. The regulations under this act included an institutional review board (IRB) and 45 CFR46 (Title 45 Code of Federal Regulations Chapter 46) 27 . The objectives of regulatory bodies in satisfying ethics concerns include safeguarding the participant's dignity, justice, equality, protection against exploitation and injury/harm, truth, and trust. They also promote the importance of acting appropriately in each situation and provide necessary and strong reasons to support the act. The first ethical concept in medical practice dates to 400 BC, when Hippocrates proposed an oath that is deemed to be followed by all medical practitioners. Although the Belmont Report was introduced on April 18 th , 1979, its proposed principles include respect for the persons (informed consent), beneficence (causing no harm), and justice, which remains the mainstay even today for conducting clinical trials. While conducting a clinical trial, the first and foremost concern which needs to be addressed by the stakeholders is the assurance of the safety and well-being of the study participants 28 . A previous study 29 highlighted the significance of federal rules that govern participants' rights and safety. In a recent development, the ICMR prescribed guidelines for clinical research during the SARS-CoV-2 pandemic. Along with the basic principles, twelve more general principles were added. These include principles of essentiality, voluntariness, non-exploitation, social responsibility, ensuring privacy and confidentiality, risk minimization, professional competence, maximization of benefit, institutional arrangements, transparency and accountability, the totality of responsibility, and protection of the environment 30 .

GOOD CLINICAL PRACTICE GUIDELINES IN CLINICAL RESEARCH
Good clinical practice (GCP), as the name suggests, are specific guidelines prescribed for the physicians involved in patient treatment, management, and research involving humans. GCP statute dates to the Hippocratic oath, where the physicians take an oath that they do not harm the patients. Due to increasing complexities concerning patient management and scientific research involving human subjects, GCP guidelines have been formulated more elaborately. The GCP guidelines cover almost all aspects of clinical research, including design, conduct, termination, audit, analysis, reporting, and documentation of clinical trials among human subjects. The GCP guidelines ensure that clinical trials on humans are conducted after considering the rights and safety of the study subjects and that the data generated through the trial is reliable and authentic 31 . The systematic and regulated process of conducting clinical research that results in reliable data, which helps make public health-related decisions and improves health care, is called the GCP. The GCP guidelines were framed after considering the recommendations of the WHO, ICH, USFDA, European GCP guidelines, and the ethical guidelines for biomedical research involving human subjects of the Indian Council for Medical Research (ICMR). The terminologies included in the GCP guidelines 32-34 , which form the clinical research process, are shown in Tables IV to VII. The AE or an ADR that results in death, permanent disability, and hospitalization, including birth defects Escape treatment A therapeutic intervention in the control subjects (placebo) for symptomatic relief An individual or an institution which takes the responsibility of initiation, conduction, management, and financing the clinical trial/research Principal investigator An individual, qualified adequately, who oversees the clinical research at the trial site and co-ordinates with the investigators at other trial sites in case of multi-centric trials Investigator A qualified person who is responsible for trial at the site Co-investigator A qualified person who is designated to share the responsibilities of an investigator, they are usually a part of multi-centric studies Study subject A person who volunteers to participate in a clinical trial Monitor A person designated by the sponsor to ensure the trial is conducted in accordance with the protocol, and the standard operating procedures (SOP's)/Contract/clinical research organization (CRO) CRO The organization chosen (contract) by the Sponsor to make sure that the research trial at the site is conduct scientifically. Ethics committee A committee which works independently, and which approves the clinical research after a thorough evaluation Audit The independent body which verifies/inspects trail procedures are done according to protocol, and data validity A document stating modification in the protocol, which must be signed by the investigator and relevant parties, and approved by the ethics committee Quality Assurance (QA) The system/process developed to make sure that the clinical research is conducted in accordance with GCP guidelines Quality Control (QC) A fool proof check system that ensures that all the elements (planning, conduction, data collection, evaluating, and reporting) of a clinical trial are conducted under controlled environment Regulatory authority The central drugs standards control organization of India, the food and drugs administration of the USA are a few examples of regulatory authorities which approves clinical research and the pharmaceutical product Validation The process undertaken to confirm the authenticity of a clinical trial, and all the elements in it to establish the reliability of the results Binding/masking Type of intervention, double blind, single blinded, remove bias Randomization Assigning the patients into the study and control groups to minimize bias Multi-centric studies A clinical trial which is conducted at multiple sites but is done in accordance with the same protocol Non-clinical trial study A study that does not include human subjects Non-therapeutic study A study that does not result in any clinical benefit to the subjects Clinical research results are meant to be used for providing better health care. Statistics and their application assume increased significance in assessing and analyzing the data generated from clinical research. Clinicians need to understand the statistics to evaluate the current study results generated from evidence-based medicine and apply them in regular clinical practice 35 . A previous research study attempted to evaluate the clinician's abilities to understand the statistical concepts, knowledge of biostatistics, and familiarity with the statistical methods. It was observed that 75% of the physicians had better knowledge of statistical methods, which helped them to correctly interpret and understand the evidence-based research results and apply them while treating the patients 36 .

REGULATORY AUTHORITIES FOR PHARMACEUTICAL IN THE UNITED STATES
Clinical research or a trial must be done after adhering to the regulatory requirements, which are majorly done to ensure the reliability of the clinical trial results/data. The regulatory agency which is responsible for protecting human health by regulating/supervising the production and marketing of several products in the united states of America is the Food and Drugs Administration (FDA). It is the oldest consumer protection regulatory agency. The FDA regulates food (human and animal), tobacco, pharmaceutical drugs (prescription and on-the-counter drugs), medical devices, and cosmetics. The president of the USA appoints the commissioner of the FDA and reports directly to the secretary of health and human services 37 . The FDA has its headquarters in Maryland and has foreign offices in India, Belgium, Costa Rica, Chile, China, and the United Kingdom. First, federal laws were enforced against the use of harmful food colors, misbranding foods, and food adulteration. In 1820, the first publication on the regulations concerning pharmaceutical drugs was published as US Pharmacopeia 38 . Although the US had a regulatory agency that looked after food and pharmaceutical products from the early 1800s, the original FDA was passed on June 30 th , 1906, during President Theodore Roosevelt's leadership. From the year 1935, the USA started publishing the federal register. In 1999, the US FDA introduced the online portal called https://clinicaltrials.gov/, a registering agency for nationally funded and privately financed clinical research. The Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA) was passed in 2013. It regulates the programs under the Public Health Service Act and the Food, Drug, and Cosmetic (FDC) Act concerning public health security and all-hazards preparedness and response. The Drug Quality and Security Act (DQSA) was enacted in 2013, which regulates the electronic and interoperable system for prescription drugs. The federal register, which delineates the permanent rules and regulations, is published as the Code of Federal Regulations (CFR), which consists of 50 titles, each divided into chapters, parts, subparts, and sections, and is updated yearly. The regulatory requirements constitute laws and rules for research approval, registration, licensure, manufacture, handling, storing, import, export, and distribution or sale 39 . Although regulatory authorities are functioning worldwide, a recent research study has highlighted the need for increased assistance regarding the quality of the probiotics available in the market 40 . It is the responsibility of regulatory agencies like the US FDA to protect people's safety and welfare. It was suggested that a comprehensive information base is to be established which may provide reliable information and facilitate the decision-making process of regulatory agencies 41 .

REGULATORY AUTHORITIES FOR PHARMACEUTICAL IN EUROPEAN NATIONS
The European Union (EU) is not single but a consortium of many countries (27 member states). The EU constituted the European Medicines Agency (EMA), which evaluates medicinal products. It was established in 1995 with the aid of the EU, pharma industries, and member states' contributions. The EU contributes one third of the new pharmaceutical products introduced worldwide. The EU protects and promotes public and animal health by evaluating and supervising medicinal products. It provides technical guidance and scientific advice to the sponsors concerning medicinal products, including biologics, advanced therapeutics, and herbal medicinal products 42 . The EU medicines agency work process is shown in Figure 2.
The EU manufacturers follow a centralized approach to obtain permission from marketing authorization ( Table VIII.

THE PHARMACOVIGILANCE LAWS AND GUIDELINES
Pharmacovigilance is a process of assessing a drug's safety, and such a process will ensure that the drugs do not harm but benefit. The process of Pharmacovigilance is a lengthy one that involves four crucial phases that includes the collection of data, collation of data, analysis of data, and communication 49  Pharmacovigilance deals with the assessment of risks associated with pharmaceutical products. It deals with the activities that find, evaluate, understand, and prevent adverse drug reactions (ADR) and other unwarranted drug-related consequences. In India, pharmacovigilance activities date back to 1986, when for the first time, an adverse drug reaction monitoring system was proposed in India. India started participating in the WHO-ADR in 1998, and in 2004, it started a national pharmacovigilance program (PvPI). The ADR reporting system in India follows reports of ADR by healthcare workers, consumer reporting, and public health programs (PHP). It is regulated by the CDSCO, the ministry, and the India pharmacopeia commission headquartered in Ghaziabad, the national coordinating center (NCC) 53 . India, the third-highest active pharmaceutical ingredient (API) producing/testing country in the world, requires a robust system of ADR reporting, as noted by recent research 54 .

RISK MANAGEMENT AND SPONTANEOUS REPORTING IN CLINICAL RESEARCH
The most significant aspect of a clinical trial/research is data collection. Because there is a tremendous amount of patient/participant data that needs to be collected and because there are many medical terminologies, we need a harmonized approach 55 . We have what is called MedDRA or Medical Dictionary to solve this issue. MedDRA includes a clinically validated international medical terminology dictionary, which can be used by the regulatory authorities and the pharmaceutical industry during various clinical trial processes that include pre-and post-marketing activities, data entry, retrieval, evaluation, and presentation. MedDRA is now available in English, Japanese, Chinese, Czech, Dutch, French, German, Hungarian, Italian, Portuguese, and Spanish 56 . ICH also recommends an adverse event classification dictionary which can be used for reposting the adverse events through human phases of the clinical trial. The MedDRA (Version 19.0, March 2016, latest version) consists of internationally accepted medical terminology derived from various sources like the WHO-ART, COSTART, HARTS, ICD-9, and ICD 9-CM, which saves time, resources, and money. It is managed by the Maintenance and Support Services Organization (MSSO). The International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) is the trustee, and the ICH steering committee holds the intellectual property rights of MedDRA. MedDRA aims to provide a standard and uniform platform for communication between regulatory agencies and the pharmaceutical industry. MedDRA encourages online/electronic submissions for applications related to various phases of clinical research. MedDRA database includes disease, diagnosis, signs and symptoms, therapeutic interventions, diagnostic tests and their qualitative results, medical and surgical procedures, and medical and social history. The terms related to the patient demographic characteristics, drug product device failure, and clinical trial/study design are not included in MedDRA 57 . The MedDRA is organized into five levels; the System Organ Class (SOC) forms the first level, which has 26 terms that include Card-Cardiac disorder, Cong-Congenital, familial, and genetic disorders, Endo-Endocrine disorders, Gastr-Gastrointestinal Disorders, Genrl-General disorders, and administration site conditions, Inj & P-Injury, poisoning, and procedural complications, Preg-Pregnancy, puerperium, and perinatal conditions. Levels 2-4, respectively, are High-Level Group Terms (HLGT), High-Level Terms (HLT), Preferred Terms (PT), and finally into, Lowest Level Terms (LLT) forming. MedDRA also includes Standardized MedDRA Queries (SMQs), which define a medical condition within an area of interest 58 . Spontaneous reporting is an observation by the clinician/physician during their patient management procedure related to the activity of a drug. Because of their nature of spontaneity, such reports face criticism and demand confirmation before being accepted by healthcare practitioners 59 . Medical practitioners contribute to spontaneous reporting because they are motivated to advance clinical knowledge/understanding, a previously unknown reaction, the reaction in response to a novel drug, drug, and reaction associations, and the severity of ADR 60

PATENTING, PUBLICATION, ASSESSMENT, AND EVALUATION OF RESEARCH
Among the various essential aspects of clinical research/trials, the publication of the research results assumes increased significance. Also, the sponsor may proceed with the patent application with the help of the data generated from a clinical trial. Other significant issues include ethical concerns, conflict of interest (COI), and copyright-related aspects. The sponsors may influence the research publications drawn from a clinical trial, and only favorable results may be published by not revealing the study's negative results. Also, authorship problems could arise when a ghostwriter is chosen to write the manuscript and the authorship criteria do not follow the ICMJE recommendations 1 . Research publications also involve copyright issues, where the authors of previous research must be given due credit. All material should be cited only after acquiring the permission of the concerned parties. Journal publications can also be plagued by the issue of plagiarism and duplicate/redundant publications. The copy of an idea, words, and any other material from previously published content without citation and not giving due credit to the copyright holder is termed plagiarism. Protection of patient privacy is another critical aspect of journal publication, where the study's participants and their identities should not be revealed 70 . Scientific fraud may also arise because of improper study design, bias, inappropriate statistical methods to draw conclusions, fabrication, cooking up the data, and undue data trimming. The Committee on Publication Ethics (COPE) was constituted in the year 1997 in the United Kingdom to control unethical practices in the research and publication processes. The COPE vests the responsibility of the published content on the editors, and it was recommended that the journals retract the fraudulent papers after a thorough inquiry 71 . Assessment and evaluation of research is the most crucial step in a journal publication process. Mostly it is done through the peer-reviewing process. For the research to be useful/fruitful, the research results must be applied by patenting and manufacturing. Patents are legal documents that entitle the inventor with the rights to novel technical innovations/ideas 72 . Published research requires evaluation by peers in the respective field. More so, the parameter that is taken as the criteria for assessing the published article is its citations 73 . The number of times the published content has been cited by another researcher in their research publication reveals the citation's impact on the article/publication. Patents are also an indicator that determines the potential of the research in the industry 74 . In recent research from Germany, the main motive was to produce a publication, and in most instances, a patent has a commercial motive 75 .

THE CURRENT PERSPECTIVES
The clinical research process requires certain concepts that include the identification of a research problem. A thorough literature review is performed, and a conceptual framework is developed. Later experts in the related field are approached for collaboration and conduction of clinical trials. Another significant aspect of clinical research is identifying the population's opinion. Constructing a theoretical design is essential while conducting clinical research, achieved only through an extensive literature survey and expert collaboration. The pictorial representation of the clinical research type is shown in Figure 4 76 . Recent research has stressed the importance of establishing state-of-the-art research and development facilities in India. It also signifies the necessity for Indian pharmaceutical manufacturing companies to adhere to international (US and EU) regulatory requirements. Such practices by the Indian pharmaceutics firm may encourage the production of generic drugs and enhance drug exports to foreign countries. This study also observed that the expenditure on pharmaceutical R&D by Indian manufacturers had significantly increased in the last decade-and-a-half, and India contributed to 40% of the world's Abbreviated New Drug Applications (ANDA) 77 . Recently, the Association of Southeast Nations (ASEAN) was formed as a regional organization that could become a platform for Southeast Asian countries to harmonize drug regulatory requirements. There are currently ten countries, including the major country Singapore, Malaysia, Thailand, Indonesia, Philippines, Brunei Darussalam, Laos, Myanmar, Vietnam, and Cambodia, unfortunately without India 78 . Approval of novel drugs is essential to functioning regulatory authorities like the US FDA. Novel and repurposed drugs are significantly essential concerning improved patient care. A recent study assessed the trends in approving new drugs by the US FDA in the last decade (2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015)(2016)(2017). It was observed that the FDA's Centre for Drug Evaluation and Research (CDER), which summarizes novel drugs, is instrumental in advancing clinical research and improving clinical care. It was noted that there was an increased approval rate for new drugs against cancer and related biologics and relatively slow progress for the approval of neurological drugs (antipsychotic, anti-depression) and lifestyle diseases (obesity, diabetes, and others) 79 . There is no doubt about the contribution of clinical research to the advancement of healthcare, as evidenced by the reduction in the morbidity and mortality associated with several illnesses that include both contagious and non-contagious diseases. Vaccines against polio and many treatments for cardiovascular diseases are a couple of examples that signify the importance of clinical research 80 . The regulatory requirements for manufacturing pharmaceutical products vary between different countries. But the prominent function/role played by the regulatory bodies is to supervise the manufacture, distribution, and promotion and ensure that the medicinal products are safe and have quality and efficacy 81 . The efficiency of the regulatory bodies is instrumental in developing quality generic medicines. Generic drugs are remarkably like the innovator product (patented) and show an equal bioequivalence value as an innovator drug in terms of quality, safety, and efficiency 82 . The prevalent inconsistencies among various regulatory authorities worldwide have been highlighted by the perception/categorization of herbal medicine (HM) compared to five countries. This study noted that HM had a different definition and was under a different law, requirement, restriction, and preparation type. Except for the US, which considered HM a food supplement/herb that does not require prior permission before marketing, other countries, including the UK, Germany, United Arab Emirates (UAE), and Bahrain, offered simple regulatory requirements 83 . Good knowledge of the standards and procedures followed by national and international regulatory agencies could improve the standards of pharmaceutical manufacturing companies. It must be noted that the US FDA approves generic drugs following the same stringent regulatory approval procedures, and therefore the quality of the generic drugs will be very similar to that of an innovative/patented drug 84 . It has recently been emphasized that pharmacovigilance assumes increased significance in the era of 'Big data' where a large amount of clinical research data is generated. The post-marketing stage has been noted to have a significant role in pharmacovigilance, and it is instrumental in identifying additional safety issues with the drugs 85 .

CONCLUSION
Clinical trials and research related to developing, manufacturing, and marketing novel pharmaceutical drugs and devices have been instrumental in resolving many public health-related problems. However, this process is highly critical due to the national and international regulatory requirements. Also, because clinical research involves human participants, the role played by the regulatory authorities, pharmacovigilance laws, and risk assessment assumes increased significance. The patents obtained and the research publications consequent to the clinical research/trials are equally crucial for the pharmaceutical drug and devices to enter the markets and be available in the public domain for use among humans.