Regulatory requirements for drug approval - Industrial pharmacy II

 

Regulatory requirements for drug approval 

INDUSTRIAL PHARMACY ll

B.PHARMA SEMESTER 7

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Drug Development Teams, Non-Clinical Drug Development, Pharmacology, Drug Metabolism and Toxicology, General considerations of Investigational New Drug (IND) Application, Investigator’s Brochure (IB) and New Drug Application (NDA), Clinical research / BE studies, Clinical Research Protocols, Biostatistics in Pharmaceutical Product Development, Data Presentation for FDA Submissions, Management of Clinical Studies  INTRODUCTION  Currently different nations have to follow different requirements for the regulatory approval of novice drug. It is almost difficult for every country to have the same regulatory approach for the Marketing Authorization Application (MAA), Therefore it is necessary to have knowledge about regulatory requirements for MAA of each country.

 New Drug Application (NDA) is an application submitted submits and  preclinical and clinical test data for analyzing the drug information and description of manufacturing procedures.

After agency received the NDA possibilities :

•        Approval
•        Approvable
•        Not Approvable

Drug Development Teams

Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery.

The process of drug discovery and development is very long and needs 10-12 years which includes the close interaction of large number of scientific disciplines.

The Responsibilities of these Project Teams

NON-CLINICAL DRUG DEVELOPMENT

Pre-clinical trial: A laboratory test for a novel drug or a new medical device is usually done on animal subjects, to see if the hoped-for treatment really works and if it is safe to test on humans.

includes various studies

• in silico : via computer simulation
• in vivo : within the living
• in vitro within the glass (outside the living organism)

The primary aims of the non-clinical (or pre-clinical) development phase is to analyze and determine which candidate has the greatest probability of success, assess its safety, and raise firm scientific foundations before transition to the clinical development phase.

This process of non-clinical development of medicine is very complex, time consuming and regulatory driven.

The selected candidate compound should also meet non-medical objectives, which also include defining the IPR and making enough medicinal products available for clinical trials.

Pharmacology As an academic principle Pharmacology can be loosely defined as the study of effects of chemical substances on living systems.

This definition is so broad that it holds all the aspects of drug discovery, ranging from details of interaction between drug molecule and its target to consequences of placing the drug in the market

Selectivity Testing: It consists of two main stages i.e. screening for selectivity and Binding assay. To determine the potency of drug, the selectivity of a compound for a chosen molecular target needs to be assessed.

Pharmacological Profiling: This includes the determination of pharmacodynamics effect of new compound, either on in-vitro models  or in-vivo models.

SAFETY PHARMACOLOGY

• This includes the scientific evaluation and study of potentially life threatening pharmacological effects of a potential drug which is unrelated to the desired therapeutic effect and therefore may present a hazard.
•  These tests are conducted at doses not too much in excess of the intended clinical dose.
• Safety pharmacology seeks to identify unanticipated effects of new drugs on major organ function 
• It is aimed at detecting possible undesirable or dangerous effects of exposure of the drug in therapeutic doses.

TOXICOLOGICAL APPROACHES TO DRUG DISCOVERY

Acute Toxicity:

• Acute toxicity studies should be carried out in at least two species, usually mice and rats using the same route as intended for humans.
•  In addition, at least two more routes should be used to ensure systemic absorption of the drug; this route may depend on the nature of the drug. Mortality should be looked for up to 72 hours after parenteral administration and up to 7 days after oral administration.
• The symptoms, signs and mode of death should be reported, with appropriate macroscopic and microscopic findings where necessary

 Long-Term Toxicity:

•  These studies should be carried out in at least two mammalian species and out of these two mammalian species one should be a non-rodent.
• The duration of study will depend on the factor that whether the application is for marketing permission or for clinical trial, and in the later case, on the phases of trials.
• If a species is known to metabolize the drug in the same way as humans, it should be preferred in long-term toxicity studies. The drug should be administered 7 days a week by the route intended for clinical use in humans.

INVESTIGATIONAL NEW DRUG (IND) APPLICATION

 is a program by which any company can approach to obtain permission for initiation of human clinical trials and to ship an experimental drug across state lines before a marketing application for the drug has been approved.

IND application is to provide the data showing that it is reasonable to begin tests of a new drug on humans.

The IND application is also the vehicle through which a sponsor advances to the next stage of drug development known as clinical trials.

During a new drug's early preclinical development, the sponsor's primary goal is to determine if the product is reasonably safe for initial use in humans and if the compound exhibits pharmacological activity that justifies commercial development.

When a product is identified viable candidate for further development, the sponsor

then focuses on collecting the data and information necessary to establish that the product

will not expose humans to unreasonable risks when used in limited, early-stage clinical

studies.

FDA's role in the development of a new drug begins when the drug's sponsorhaving screened the new molecule for pharmacological activity and acute toxicity potential in animals, wants to test its diagnostic 

At that point, the molecule changes in legal status under the Federal Food, Drug, and

Cosmetic Act and becomes a new drug subject to specific requirements of the drug

regulatory system.

TYPES OF IND APPLICATIONS

• Investigator IND application
• Emergency Use IND application
• Treatment IND application
• Screening IND application

Layout chart for IND Application

INVESTIGATOR’S BROCHURE (IB)

 is a compilation of the clinical and non-clinical data on the investigational product that are relevant to the study of the product in human subject.

 Purpose 

•  provide information to the investigators and others involved in the trial such as the dose, dose frequency/interval, methods of administration and safety monitoring procedures.
• also provides insight to support the clinical management of the study subjects during the course of the clinical trial. The information should be presented in a concise and simple manner.

Contents of Investigator’s Brochure

1. Table of contents.

2. Summary not exceeding 2 pages, highlighting 

3. Introduction: Chemical name, API, pharmacological class, anticipated therapeutic/diagnostic indication(s). General approach to be followed in evaluating the IP.

4. Description of I.P.: Physical, chemical and pharmaceutical properties of I.P. Storage

and handling of I.P.

5. Non-clinical studies: The results of all relevant non-clinical pharmacology, toxicology, pharmacokinetic, and investigational product metabolism studies should be provided in summary form. The information provided may include: Species tested, Number of sex in each group, Unit dose , Doseinterval, Route of administration and Duration of dosing.

6. Effects in Humans: A thorough discussion of the known effects of the investigational

product(s) in humans should be provided, including information on pharmacokinetics, metabolism, Pharmacodynamics, dose response, safety, efficacy, and other pharmacological activities. (a) Pharmacokinetics and Product Metabolism in Humans.

7. Summary of Data and Guidance for the Investigator: This section should contain

non-clinical and clinical data of IP.

 NEW DRUG APPLICATION (NDA)

The vehicle through which drug sponsors formally propose that the regulatory body approves a new pharmaceutical for sale and marketing, and the data gathered during the animal studies and human clinical trials of an investigational new product becomes a part of the NDA.

 Aim of NDA

• Safety and effectiveness of drug,

• Benefits overweigh risks,

• Is the drug’s proposed labeling appropriate, and what should it

contain?

• Are the methods used in manufacturing (GMP) the drug and the controls used to maintain the drug’s quality adequate to preserve the drug’s identity, strength, quality, and purity? Risk Benefit.

 NDA Review Process

Once the application is submitted, the FDA has 60 days to conduct a preliminary review which will assess whether the NDA is "sufficiently complete to permit a substantive review“. If everything is found to be acceptable, the FDA will decide if the NDA will get a standard or accelerated review and communicate the acceptance of the application and their review choice in another communication known as the 74-day letter.

 BIO EQUIVALENCE STUDIES

essential to ensure uniformity in standards of quality, efficacy and safety of pharmaceutical products so that reasonable assurance can be provide for the various products containing same active ingredient, marketed by different licensees are clinically equivalent and interchangeable.

Both Bioavailability and Bioequivalence focus on

release of drug substance from its dosage form and subsequent absorption in circulation. Similar approaches to measure bioavailability should be followed in demonstrating bioequivalence.

Bioavailability:means the rate and extent to which the active ingredient

or active moiety is absorbed from a drug product and becomes available at the site of action.

Equivalence: It is a relative term that compares drug products with respect to a specific

characteristic or function or to a defined set of standards.

CLINICAL RESEARCH PROTOCOLS

• It is a complete written description of and scientific rationale for a research activity involving human subjects.

• Sufficient information is to be gathered on the quality of the non-clinical safety to conduct the protocol and health authority/ethics committee approval is granted in the country where approval of the drug or device is sought.

• The clinical trial design and objectives are written into a document called a clinical trial protocol. It is a document that states the background, objectives, rationale, design, methodology and statistical considerations of the study. It also states the conditions under which the study shall be performed and managed.

• Look for better ways to prevent disease in people who never had the disease or to

prevent a disease from returning.

• The protocols means:

- To clarify the research question.

- To compile existing knowledge.

- To formulate a hypothesis and objectives.

- To decide about a study design.

- To clarify ethical considerations.

- To apply for funding.

- To have a guideline and tool for the research team.

Parts of the Protocol:

1. Title Page.

2. Signature Page.

3. Content Page.

4. List of Abbreviations.

5. Introduction/Abstract.

6. Objectives.

7. Background/Rationale.

8. Eligibility Criteria.

9. Study Design/Methods

10. Safety/Adverse Events.

11. Regulatory Guidance.

12. Statistical Section 

13. Human Subjects Protection/Informed Consent.

 DATA PRESENTATION FOR FDA SUBMISSIONS

Study data standards describe a standard way to exchange clinical and non-clinical study

data. These standards provide a consistent general framework for organizing study data,

including templates for datasets, standard names for variables; identify appropriate

controlled terminology and standard ways of doing calculations with common variables. Data

standards also help FDA receive, process, review, and archive submissions more efficiently

and effectively.

• FDA has been working towards a standardized approach to capture, receive and analyze study data.
•  Standardization of study data is vital to integrate pre-marketing study data and post-marketing safety data to improve public health and patient safety.
• Central to this vision is the creation of an enterprise data infrastructure (Janus) within FDA to improve the management of all structured scientific data.

MANAGEMENT OF CLINICAL STUDIES

Clinical trial management is most simply defined as the process that an organization follows to ensure that quality (defined as minimized risks and clean data) is delivered efficiently and punctually. It refers to a standards-driven process that a project manager initiates and follows in order to successfully manage clinical trial sites, clinical research associates, and workflow by using clinical trial management tools or software prolonged timelines and heavy costs related to large trials have been prompted a new focus on more efficient clinical trial management. It is possible to dramatically reduce the total cost of a

clinical trial by 60% - 90% without compromising the scientific validity of the results.

Life Cycle of Clinical Trial Project: A more accurate control, regardless of the therapeutic area or trial stages is ensured by typically breaking down the life cycle of each clinical trial project into 4 phases: Conceptual, Planning, Implementation and Analysis. Clinical Trial Protocol: A protocol is a document that describes the purpose, design, methodology, statistical considerations and organization of a study, and provides basic information and rationale for the clinical study. The contents that should be present in the protocol are described by the GCP. The protocol writing is a task for one person, usually the

principal investigator, not a committee.

There are various challenges of Project management in clinical trials. Clinical trials all need the same coordinated processes and systems, irrespective of the size, scope, costs, or period. The key challenge is then to implement and maintain effective management systems and techniques in response to the needs of the trial project.

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