Investigational New Drug

The laws prohibit administration of products in humans that have not been approved by the FDA. IND application is filled in USFDA after the necessary safety and toxicological preclinical study in animals. IND application is filed to conduct human clinical Trial in US.  

Under the Food, Drug, and Cosmetic Act of 1938, sponsor require to file IND application before any unapproved medicine is transported or distributed across state lines in US.

Sec. 312.23 IND content and format

• Cover sheet
• A table of contents
• Introductory statement and general investigational plan
• Investigator's brochure
• Protocols
• Chemistry, manufacturing, and control information
• Pharmacology and toxicology information
• Previous human experience with the investigational drug
• Additional information

The FDA has 30 days to review IND application to determine whether the proposed trial appears reasonably safe to proceed or to impose clinical hold if it does not. If FDA does not raise any issue with the applicant within 30 days from receipt of the application, sponsor may proceed for the clinical trials.

At any time a sponsor may withdraw an effective IND without prejudice. If an IND is withdrawn, FDA shall be so notified, all clinical investigations conducted under the IND shall be ended. There are various types of IND filled with USFDA.

Types of IND:

1. Investigator/Research IND: An Investigator IND is submitted by a physician who both initiates and conducts an investigation, and under whose supervision investigational drug is administered or dispensed. A physician might submit a research IND to study an unapproved drug, or an approved product for a new indication or in a new patient population.

2. Emergency IND: Need for an investigational drug may arise in an emergency situation that does not allow time for submission of an IND. In such a case, FDA may authorize shipment of the drug for a specified use in advance of submission of an IND. A request for such authorization may be transmitted to. 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. 

3. Treatment IND: A drug that is not approved for marketing and may be under clinical trials for a serious or immediately life-threatening disease condition in patients for whom no comparable or satisfactory alternative drug or other therapy is available. During the clinical investigation of the drug, it may be appropriate to use the drug in the treatment of patients, in accordance with a treatment protocol or treatment IND. In the case of an immediately life-threatening disease, a drug may be made available for treatment use earlier than Phase 3, but ordinarily not earlier than Phase 2.

Marketing Exclusivity in US

An innovator pharma company invests millions of dollars for the development and placing the new lifesaving medicine into the market. By provide the exclusivity to innovator for specified duration in the market governments encourage the research and development in pharmaceutical at the same time approving the lower cost generic for the same medicine after expiration of the exclusivity.

Under the article 39.3 of TRIPS Agreement, WTO Members States requires to protect pharmaceutical test data but only undisclosed test data originated from new chemical entities and that required considerable effort to generate.

Before 1984 in the United States pharmaceutical test data was protected as a trade Secret. The basis for protecting trade secrets is unfair competition. There was no legal prohibition against relying upon published data to establish safety and efficacy of drugs.

Under the current US exclusivity approach, generic drug manufacturers and national drug regulatory authorities cannot rely upon the originator’s test data to approve generic applications during a pre-determined period of time.

The current U.S. data exclusivity regulations are quite complex and co-exist with a number of other non-patent provisions that extend marketing exclusivities, including:

1. New Drug Product exclusivity

2. Supplementary product exclusivity

3. Orphan drug exclusivity

4. Paediatric drug exclusivity

5. Generic drug exclusivity

6. Rx to Over the counter switch

7. Patent term extension

All the above exclusivity is discussed in below:

1. A 5 year period of data exclusivity from the date of the FDA approval is granted to new drug products containing new chemical entities. The main condition is that the approved new drug application must contain a new active ingredient that is a New Chemical Entity or new active moiety, never approved previously by the FDA alone or in combination. The effect of this exclusivity is that no ANDA or 505(b)(2) applications are not be submitted during the 5 year exclusivity period.

There is an exception: the five-year period may be reduced to 4 years if the generic application contains a certification of patent invalidity or noninfringement (Paragraph IV Certification).

2. A 3 year period of marketing exclusivity from the date of the FDA approval is granted to new uses or indications of drug products containing an active moiety that has been previously approved, when the application contains new clinical investigations (other than bioavailability studies) which were essential for the approval of the new drug application or supplement. Contrary to the 5 year exclusivity, this three-year exclusivity allows the FDA to receive and review ANDA or 505(b)(2) applications before it has expired. The FDA can even grant tentative approval, but the approval becomes effective only after 3 year period has elapsed. The second applicant can thus market its product immediately following expiry of the three-year exclusivity.

3. A 7 years of exclusivity is granted to drugs or biologics intended to treat rare or orphan diseases or conditions which has the disease prevalence of <200,000 cases per year in US. This exclusivity prevents approval of another version of the same drug for the same indication for 7 years called as Orphan drug exclusivity.

4. Pediatric exclusivity or extended exclusivity of 6 months is granted in case where Sponsor conducts FDA requested pediatric studies. This exclusivity extends any applicable patent or regulatory exclusivity by an additional 6 months. Two separate 6 month extensions are possible. Pediatric studies can also support 3 year exclusivity.

5. Under the Drug price competition and patent term restoration act 1984 (Hatch Waxman Act) 180 days of marketing exclusivity is grated to the first application contains a certification of patent invalidity or noninfringement (Paragraph IV Certification).

6. The USPTO grants patent extensions to compensate for delays in USPTO examinations and prosecution that extend past three years. Thus the average 1.4 years past the three year mark during prosecution may be tacked onto the 20 year patent term. The Hatch Waxman act provides a maximum 5 year extension, and is limited to a 14 year term from the time of FDA approval. The calculation of extension is complex and depends on patent prosecution and approval factors.

REACH - Registration, Evaluation, Authorisation and Restriction of Chemical

EMEA, European Medicine Evaluation Agency, regulates the drugs, biologicals and medical device for human and veterinary products. REACH, Registration, Evaluation, Authorisation and Restriction of Chemical, is the European Community Regulation on chemicals and their safe use (EC 1907/2006). It deals with the chemical substances. The law entered into force on 1 June 2007.

The aim of REACH is to improve and protect human health as well as environment through the better and earlier identification of the harmful properties of chemical substances. REACH also works on encourage innovation and competitiveness of the EU chemicals industry. The benefits of the REACH system will come gradually, as more and more substances are entered into REACH.

The REACH Regulation places control on industry to manage the risks from chemicals and to provide safety information on the chemical substances. Manufacturers and importers are required to submit the information on the properties of their chemical substances, which include their handling and to register the information in a central database run by the European Chemicals Agency (ECHA) in Helsinki

The Regulation also demands for the advanced replacement of the most dangerous chemicals with the suitable alternatives. One of the main reasons for developing and adopting the REACH Regulation was that a large number of substances have been manufactured and placed on the market in Europe for many years, sometimes in very high amounts, and yet there is insufficient information on the hazards that they pose to human health and the environment. REACH regulations fulfil these information gaps to ensure that industry is able to assess hazards and risks of the substances, and to identify and implement the risk management measures to protect humans and the environment from the chemical exposures.

Friability Test

 

Tablets are prone to abrasion during transport and handling. Friability test is used to determine the physical strength or tablet breaking force for compressed, uncoated tablets. Friability test enabling us to check for the tablet strength under application of force in different manner.

The friability test is carried out in an instrument called a friabilator. A friability test apparatus should stimulate the conditions that the product will be exposed during the process of production. This test is a method to determine physical strength of uncoated tablets upon exposure to mechanical shock and attrition.

The commonly used friabilator in laboratories is the Roche friabilator.

Remove any loose dust from the tablets and accurately weigh 10 tablets. They are placed in the drum which rotates at 25±1 rpm. Rotate the drum 100 times, and remove the tablets.

The sample fails the test, if any of the 10 tablets cracked, cleaved, or broken is present. If the weight loss is more than 1.0%, the test is repeated for twice and the mean of three tests is calculated. The mean not more than 1.0% is considered acceptable.

Please note that for Effervescent tablets and chewable tablets the friability limits may differ.

If the tablet size or shape becomes irregular adjust the drum so that base forms an angle of about 10 degrees with bench top and the tablets fall freely when drum is rotated.

 

CFR - Code of Federal Regulation

Code of Federal Regulation (CFR) is the coding system of the general and permanent rules, laws and regulations in United States. They become official after the publication in Federal Register by the executive departments and agencies of the federal government of the United States.

The CFR is published by the Office of the Federal Register, an agency of the National Archive and Records Administration.

The CFR is divided into 50 titles that symbolize different functional areas subject to Federal Regulation.

CFR is identifies by the citation, such as 21 CFR 210.1 would be read as, “Title 21, Part 210, Section 1” represent Status of Current Good Manufacturing Practice Regulations.

While new regulations are becoming effective constantly the printed volumes of the CFR are issued once each calendar year, on the following schedule:

Title 1 – 16 are updated on 1 January

Title 17 – 27 are updated on 1 April

Title 28 – 41 are updated on 1 July

Title 42 – 50 are updated on 1 October

As a Pharmaceutical Professional Title 21 is import for Food and Drugs.

21 CFR is further divided into parts which denote the specific regulation for the following enlisted categories:

Parts	Topics covered
1 – 100	Administrative issue and protection of Human Subjects
100	Foods
200	Labelling, cGMP and Controlled substance
300	Drugs for Human Use
500	Drugs for Veterinary Use
600	Biologicals
700	Cosmetics
800	Medical Device
1000 - 1400	Miscellaneous