Regulatory aspects of drug development

Dr Vipin Bihari Guptagives an overview of regulatory dossier preparation

New product development is an ever-increasing activity in Indian pharmaceutical industry. Rapid developments are not the only reason; India due to its technical-competence and cost-effectiveness is surging ahead to become global R&D hub. Improved patent protection has done what the country was lacking; and hence, now CRAM (Contract Research and Manufacturing) is the new mantra for Indian pharmaceutical companies.

Even the share market is responding to this mantra and the shares of companies intensifying on CRAM are moving northward. Globally, pharmaceuticals are considered to be highly controlled commodities and some sort of regulation applies on them at all stages. Such as, in India, as per the Drugs and Cosmetics Act a Test License is required for carrying out developmental work on the drugs, Clinical trial regulations applies for studying drug products on human subjects and manufacturing license is required for commercial production of drugs.

The regulations in most of the other countries are more or less same in the spirit; however, their intensity, severity and the extent to which they are exercised or administered vary. There also exists variation from state to state. Perhaps, United States and Europe are considered to be the most strictly regulated markets; hence, dossier preparation for these countries makes one prepared enough for submission to other countries. The detailed information could be obtained either form the respective offices or their websites. The website of US FDA is www.fda.gov.

Pertaining to the new drugs, mainly three kinds of documentations exists ie. Investigational New Drug Application (iNDA), New Drug Application (NDA) and Abbreviated New Drug Application (aNDA). NDA is the main marketing authorisation document while iNDA and aNDA are ancillary to this. iNDA is applicable for conducting Clinical Trials and aNDA to the drugs that are not completely new and are generic or identical to an already existing approved new drug. This license is issued as per Waxman-Hatch Amendment or Drug Price Competition and Patent Term Restoration Act of the United States.

What is a new drug?

Contrary to the common belief, the newness is not limited to a New Chemical Entity (NCE) or a new Active Pharmaceutical Ingredient (API). For the regulatory purpose, newness includes all those effects on which a previous approval is not available, it encompasses:

1. Use of any new substance (the one which is not listed in the Pharmacopoeia or otherwise officially recognised book) as a component of drug product either as an active ingredient or an excipient. (It is important to note here that this clause is not limited to API, it extends to excipients too)

2. A new combination of two or more substances, none of which is new drug.

3. A proportion of a substance in a combination, even though such combination containing such substances in other proportion is not a new drug.

4. The newness of use of the drug in diagnosing, curing, mitigating, treating, or preventing a disease, or to affect a structure or function of the body, even though such drug is not a new drug when used in another disease or to affect another structure or function of the body. (It is important to note that off-label uses of an NDA-approved drug are illegal. Drugs could be used for only as per approved label information).

5. The newness of a dosage, or method of duration of administration or application, or other condition of use prescribed, recommended, or suggested in the labelling of such a drug when used in other dosage, or other method or duration of administration or application, or different condition, is not a new drug.

Investigational New Drug Application

In the United States for conducting clinical trials the sponsor of the study is required to notify the FDA of its intention at least 30 days prior to the proposed date of the of the study. If during this period FDA does not impose any objection then the studies could be initiated. The components of a Notice of Claimed Investigation Exemption for a New Drug are as listed below:

• Best available descriptive name of the drug product and how it is to be administered.
• Complete list of components of the drug product.
• Quantitative composition of the drug product.
• Description of the sources and preparation of any new drug substance used as a component.
• Description of the methods, facilities, and controls used to prepare and distribute the new drug.
• Information available from the preclinical investigations and any clinical studies that may have been conducted.
• Copies of the labels or labelling to be used in the study.
• Scientific training and experience to qualify the investigators.
• Complete information of each investigator, including training and experience.
• Outline of any phase or phases of the planned clinical investigation.
• Assurance that the FDA will be notified if the studies are discontinued.
• Assurance that the investigators will be notified if a new drug application is approved or the studies discontinued.
• Explanation of why a drug product must be sold during the study.
• Agreement not to start a study for 30 days after notice of receipt of IND by FDA.

The drug product released for clinical trials must bear the statement “Caution: New Drug-Limited by Federal Laws to Investigational Use” and the sponsor must maintain record of drug distribution for two year from the date of approval or from the date of last shipment, if not approved.

New Drug Application

Once a new drug is through phase III of clinical trial, NDA could be submitted. Perhaps, because of today’s myriad regulations huge amount of data is required to be accompanied with NDA and it may consists of as many as 200 volumes, exceeding to any well-known encyclopedia in size. The application on submittal to FDA is granted a particular identification number and then put under scheduled review, which may take from days to months. After review the response is returned to the sponsor along with the questions.

The sponsor then attempts to satisfy the questions raised by the FDA, this process continues till the FDA is convinced of the Safety and Efficacy of the product, which may take months to years. Once FDA is satisfied, license is granted for the manufacture and distribution of the product to the public. Currently it takes about 10 years time after the first synthesis till the drug is reached to the market alongwith the total development cost approaching half a billion dollars.

NDA is required to contain the following:

• Table of contents
• Summary
• Evaluation of safety and effectiveness
• Copies of the label and all other labelling to be used for the drug
• A statement as to whether the drug is (or is not) limited in its labelling and by this application to use under the professional supervision of a practitioner licensed by law to administer it
• A full list of the articles used as components of the drug
• A full statement of the composition of the drug
• A full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of the drug
• Samples of the drug and articles used as components
• Full reports of preclinical investigations that have been made to show whether or not the drug is safe for use and effective in use
• List of investigators
• Full reports on clinical investigations that have been made to show whether or not the drug is safe for use and effective in use
• If this is a supplemental application, full information on each proposed change concerning any statement made in the approved application.

Abbreviated New Drug Application

This is applicable to those drugs for which FDA has already grated a license to somebody (usually the inventor or his licensee); and hence, it is already has previously acquired data. The intention of this is to avoid or minimise the duplication of the efforts. The information that is normally not required is data establishing safety and efficacy of the drug because drug is already in the market for several years.

What is required is the assurance that the manufacturing procedures, specifications and labelling are adequate. Perhaps not a rule, for most of the products it is necessary to demonstrate that the product is bioequivalent to currently available standard product or to the original NDA-approved product. The commonly required information in aNDA is:

• Description of the components and composition of the dosage form to be marketed
• Description of the manufacturing method
• Description of the packaging
• Labelling
• Stability data
• Data adequate to assure drug’s biological availability (when so specified)
• Brief statements that identify the place where drug is to be manufactured
• Name of the supplier of the active ingredients
• Assurance that the drug will comply with appropriate specifications
• Facilities used in manufacture and packaging
• Undertaking that the drug will be manufactured in compliance with current GMP j

The writer is Head, Department of Pharmaceutics, L M College of Science & Technology, Jodhpur