Administrative Structure and Functions of Drug Regulatory Authorities in India

Administrative Structure and Functions of Drug Regulatory Authorities in India

Frequently Asked Questions --- NEW DRUG REGULATIONS

The Drug Approval Process in India
The Indian Pharmaceutical Industry


Regulatory Issues in the Indian Pharmaceutical Industry

D rug Regulatory Aspects

generic drugs


Documentation Requirements for Generic Drug Application to be Marketed inIndia- A Review


CDER Center for Drug Evaluation and Research

CDER HOME PAGE

Investigational New Drug (IND) Application

Investigational New Drug WIKIPEDIA

New Drug Application (NDA) Homepage
NDA wikipedia

FDA Medicare Modernization Act

http://edition.cnn.com/2003/ALLPOLITICS/12/08/elec04.medicare/ 

Bush signs landmark Medicare bill into law

WASHINGTON (CNN) -- President Bush on Monday signed into law landmark Medicare reform legislation that includes prescription drug benefits and has sparked a bitter fight between opponents and supporters.

Speaking at DAR Constitution Hall in Washington, Bush characterized the measure as "the greatest advance in health care coverage for America's seniors since the founding of Medicare."

Backers say the $400 billion Medicare Prescription Drug Modernization Act will provide much-needed help for the nation's 40 million senior citizens to buy medications; critics say it is a giveaway to drug makers and insurance companies and a prelude to the dismantling of the program. (Interactive: Prescription coverage)

"Our government," Bush said, "is finally bringing prescription drug coverage to the seniors of America."

"With this law, we're giving older Americans better choices and more control over their health care, so they can receive the modern medical care they deserve," he said.

In addition to the prescription drug benefits, the measure provides billions of dollars in subsidies to insurance companies and health maintenance organizations, and takes the first step toward allowing private plans to compete with Medicare. (Interactive: Prescription for change)

It is the largest expansion of Medicare since the program was created in 1965, though most of its provisions won't take effect for several years. The drug benefit, for example, does not take effect until 2006. Before that, seniors will be able to purchase a discount card that could provide a 10 to 25 percent off prescription drugs.

"Our nation has made a promise, a solemn promise, to America's seniors," Bush said. "We have pledged to help our citizens find affordable medical care in the later years of life."

"These reforms are the act of a vibrant and compassionate government," Bush said.

How the bill is to work

In 2006, Medicare recipients will pay $35 per month with a $250 deductible for prescriptions. The plan will pay 75 percent of costs up to $2,250. The prescription drug provision left out a proposed guideline the president had originally sought -- requiring seniors to join an HMO to be eligible for the benefit.

The law also allows the importation of drugs from Canada -- where many are cheaper -- but only if the Food and Drug Administration has approved the drugs.

It also provides subsidies to private insurers to compete with traditional Medicare, giving seniors the opportunity to join managed-care plans, which typically cut costs by restricting patient access to specialists. That provision does not take effect until 2010.

Last month, the House passed the measure after Bush made late-night, last-minute phone calls asking members to support it. An unusually long three-hour vote was ended by GOP leaders at 6 a.m., after a 218 to 216 deficit flipped to a 220 to 215 victory.

The Senate's 54-to-44 vote was not entirely along party lines -- 10 Democrats voted in favor and nine Republicans voted no. (Senate passes Medicare bill)

On the day it passed the Senate, Majority Leader Bill Frist of Tennessee called the overhaul "epochal in the sense it modernizes Medicare to provide 21st century care for our seniors."

Opponents of the legislation warned that seniors would demand that Congress revisit the issue once they realized what the bill does and does not do. High on the list of things not covered in the bill is a mechanism to stem rising prescription drug costs. Sen. Dianne Feinstein, D-California, who supported the bill, said the lapse was a "major weakness in this bill."

"The theory is that private sector competition will drive down the cost of drugs," Feinstein said last month upon the bill's passage. "That may happen, or it may not happen. We need to watch that, and we will. I feel confident that the leadership will make changes if the cost containment is not kept.

Introduction to Regulatory Affairs

Introduction to Regulatory Affairs

http://www.regulatoryone.com/2011/09/introduction-to-regulatory-affairs.html

What is Regulatory Affairs?

Regulatory Affairs is a profession within regulated industries namely-pharmaceuticals, medical devices, energy and banking. It has specific meaning within healthcare industries namely- pharmaceuticals, medical devices, biologics and functional foods.(In this blog I am going to deal about Regulatory Affairs related to pharmaceuticals meant for human use).

Regulatory Affairs in the pharma industry may be defined as "The interface between the pharmaceutical company and the regulatory agencies across the world."

In the above presentation, I am conveying the fact that -among all the departments of a pharma company Regulatory Affairs Department acts as the interface between  the pharmaceutical company and the regulatory agencies across the world.

Regulatory agency in the present context may be defined as "The competent government agency which is responsible for ensuring that medicines work and are acceptably safe."

Origin of Regulatory Affairs-

• Elixir Sufanilamide, prepared using DEG (a poison) as solvent resulted in the death of more than 100   people  in the USA in 1937. This incident led to the passing of the 1938 Federal Food, Drug and Cosmetic act in USA.

• Thalidomide use by pregnant women for treating morning sickness was linked to the cause of birth deformities in more than 10,000 children in late 1950s and early 1960s. This incident led to the Kefauver-Harris Amendment in USA-it is a 1962 amendment to the Federal Food, Drug and cosmetic act.

Similarly, other tragic incidents led to various acts/amendments.

Goals of Regulatory Affairs as profession-

• Protection of human health
• Ensuring safety,efficacy and quality of drugs
• Ensuring appropriateness and accuracy of product information

Roles of Regulatory Affairs professionals-

• Act as a liaison with regulatory agencies
• Preparation of organized and scientifically valid NDA, ANDA,INDA ,MAA,DMF submissions
• Ensure adherence and compliance with all the applicable cGMP, ICH, GCP, GLP guidelines, regulations and laws
• Providing expertise and regulatory intelligence in translating regulatory requirements into practical workable plans
• Advising the companies on regulatory aspects and climate that would affect their proposed activities

Apart from the above main roles, there are various other roles which Regulatory Affairs professionals play.

Now,coming to the most important part of this post-

What work is done in Regulatory Affairs Department?

• A new drug/generic drug manufactured by a pharmaceutical company just cannot be released into the market for human use.

• Here the Regulatory Affairs Department comes into play. 

• Regulatory Affairs Department of a pharmaceutical company files all the information related to the development, manufacture, control, stability studies, packing, labeling , safety and efficacy studies of drugs with the Regulatory agencies in a prescribed format as ANDA/NDA/MAA/DMF etc.

•  The Regulatory agency reviews the information provided in accordance with regulations, guidelines and if they are satisfied with information provided, approval will be  granted for marketing of the drug by pharmaceutical companies for human use.

General work profile of a Regulatory Affairs professional in an API (Active Pharmaceutical Ingredient) manufacturing company-

•   Filing a DMF/ASMF with regulatory agencies in support of the NDA/ANDA/INDA/MAA filed by a Formulator (Drug Product manufacturer who uses API of that particular API manufacturing company).

•  Filing dossier of API with EDQM for obtaining CEP.

• Assessing and filing amendments/variations to the information (which may be related to manufacture, control, stability studies etc ) in DMF/ASMF/Dossier of particular API with the Regulatory agencies. Major amendments are to be reported prior to their implementation while minor amendments may be reported annually. The classification of amendments will be dealt in the later posts.

• Taking approval of customers of API before implementing any major changes regarding the information mentioned in DMF/ASMF/Dossier. The updated DMF/ASMF may be submitted to the customer simultaneously along with amendments/variations filed with the agency.

• Preparing and submitting Open part/Applicant’s part of DMF to the customers of API (Drug products manufacturer) which may be filed by customer with the Regulatory agency.

• Preparing and submitting the LoA (Letter of Access/Letter of Authorisation) to the API customers and Regulatory Agencies. LoA is the letter which authorizes the regulatory agency to review the DMF /ASMF of the API manufacturer against the NDA/ANDA/MAA of the API customers (Formulators).

• ·Preparing Technical Packages for existing/prospective customer for initial assessment of the API.   

• Filing Annual/Biannual/Quinquennial reports (Which contain list of changes to the   DMF/ASMF/Dossier) with the regulatory agencies.

• Maintenance of the complete history of each API (Filing history with agencies/customers, amendments, annual reports).

• Taking part in the drug development process by advising the R & D scientists regarding various guidelines,laws and regulations. 

Note: Apart from the above work profile there may be other responsibilities for Regulatory Affairs professionals too.

                    

 General work profile of a Regulatory Affairs professional in a Drug Product /Finished  

 product/Formulation manufacturing company -

•  Filing a NDA/ANDA/MAA of drug products with regulatory agencies for getting marketing approval.

• Assessing and filing supplements/amendments/variations to the information (which may be related to manufacture, control, stability studies etc ) in NDA/ANDA/MAA with the Regulatory agencies for prior approval or after their implementation. Major supplements/amendments are to be reported prior to their implementation while minor supplements/amendments may be reported annually. The classification of amendments will be dealt in the later posts.

• Filing Annual/Biannual reports (Which contain list of changes to the NDA/ANDA/MAA) with the regulatory agencies.

• Reporting any adverse effects which have occurred/may occur due to the use drug products.

• Maintenance of the complete history of each Drug products (Filing history with agencies/customers, amendments, annual reports)

• Taking part in design and revision of drug product labels, packing leaflets.

• Taking part in the Formulation development process by advising the R & D scientists regarding various guidelines,laws and regulations. 

Note: Apart from the above work profile there may be other responsibilities for Regulatory Affairs professionals too.

PS 

You may be wondering what the abbreviations NDA,ANDA, CEP etc are all about..????


I am presenting the full forms of all the abbreviations below and will explain them in my next post.

NDA-    New Drug Application
ANDA- Abbreviated New Drug application
INDA  - Investigational New Drug Application
MAA  -  Marketing Authorisation Application
DMF   - Drug Master file
ASMF -Active Substance Master File
CEP-     Certificate of suitability to the monograph of European Pharmacopoeia
cGMP- Current good Manufacturing Practice
ICH,-    The International Conference on Harmonisation of technical requirements for registration of
              Pharmaceuticals for human use.
GCP-    Good clinical Practice
GLP-    Good Laboratory Practice

What is IIG limit, how it is useful in formulation?

IIG is abbreviation of  Inactive Ingredient Guide. Now it is used as IID( Inactive Ingredient database or also called as Inactive ingredient guide)but now FDA changed from the old guide to a database many years ago. The limits represent the maximum level of use of an excipient in a dosage form that has been approved by the U.S. FDA in a certain route of administration. It does NOT represent the maximum daily intake, just the amount in one dosage form. If the drug may have only had one dosage form approved per day, then, and only then, would it represent a maximum daily intake. There is no database which currently contains the real maximum daily intake at the FDA. However, they expect that the ANDA sponsor will provide some type of assurance that the maximum daily intake they will be using in their drug is below the highest maximum daily intake that has a prior precedence of use in that route of administration. Obviously, if your daily level of use is below what is listed in the IID for one dosage form, then you should have no problem with your ANDA. However, if your daily level of use would be higher than the max. potency level listed in the IID (or Inactive ingredient guide) then you should see if you may have other drugs that you have already gotten approved with a higher level. If so, you can use that as a reference. If not, then you should send FDA a controlled correspondence and ask them if your daily level of use is below what has previously been approved in the route of administration used for your drug. You can than include this controlled correspondence in your ANDA filing.

The IID limits (Inactive ingredient guide limits)   are simply the level of an excipient that has a precedence of use in a previously approved dosage form for a particular route of administration. Again remember the IID limit is not the daily limit. You can only investigate the daily limit through controlled correspondence and the daily limit is what FDA will need to know is below what has been previously used. If FDA gets back to you and says that your level exceeds the daily precedent level, then you would have to submit detailed safety/toxicology data on the excipient itself along with an argument about why this safety data supports your proposed level of use. It would have to be an argument based on the detailed toxicology data and the ADIs that the data supports for your specific route of administration. This will typically take quite a number of months for them to review.

Remember, the key thing to remember is that the IID or Inactive ingredient guide level is only the amount per dosage form that has been approved. It is NOT the maximum daily intake (MDI)! What FDA really needs you to verify is that your MDI is below what has been used in a previously approved drug for the same route of administration. If your MDI exceeds the IID maximum potency for one dosage form, then you typically would need to submit a Controlled Correspondence to FDA which lists your specific MDI for the specific excipient you are using in your formulation and ask them if this MDI is lower than what has been previously approved. There is no current database that contains this information. FDA will then manually research this and provide an answer to that question that can be used in your filing. It may take a number of months to get an answer so these questions need to be asked early in development not when the dossier is being developed for filing. If the FDA says that your MDI exceeds a prior precedence of use for that excipient, then you would need to submit specific safety information to support the safety of your level of use. Typically, FDA will want more than just summary information on the toxicology. They will ask for a reference to detailed toxicological studies in a DMF or from another source for the particular grade you are using. However, this is not usually realistic since rarely are toxicology studies run on all the different grades within a family of excipients. Therefore, realize that suppliers of excipients will not normally have specific tox studies for the grade you are using but should typically have access to data on the family based on bracket studies. Ultimately, FDA expects the drug sponsor to build a good bridging argument to support the grade you are using in your specific application that is then submitted in your filing that includes a reference to where the existing studies are located (DMFs, literature, etc.). The suppliers can sometimes help but ultimately the drug product sponsor must put this argument together. IPEC-Americas is working with the FDA to try to improve the IID and the processes used related to the MDI precedence issue.

Source: Dave Schoneker (Director  Global regulatory affairs at colorcon

reference

http://www.pharmashastra.com/regulatory/inactive-ingredient-guide/

difference between indian and US patent System

patent.htmlhttps://justlegalip.blogspot.in/2011/11/difference-between-indian-us-patent.html

IPR and INdustry

The Role of Intellectual Property Rights in Technology Transfer and Economic Growth: Theory and Evidence imp

http://www.unido.org/fileadmin/user_media/Publications/Pub_free/Role_of_intellectual_property_rights_in_technology_transfer_and_economic_growth






























http://unctad.org/en/PublicationsLibrary/osgdp20155_en.pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3217699/?report=printable


http://www.theglobalipcenter.com/why-are-intellectual-property-rights-important/

haldi,neem.basmati case

http://www.countercurrents.org/bhargava140709.htm

http://www1.american.edu/TED/basmati.htmhttp://www1.american.edu/TED/basmati.htm

http://www.tribuneindia.com/2007/20070617/spectrum/main1.htm
http://www.tribuneindia.com/2007/20070617/spectrum/main1.htm

http://birac.nic.in/webcontent/dib.pdf

The Novartis Case

Novartise File product  patent applcation in 1998.
India was in transion phase beteen 1995 to 2005 under TRIPS agreement and some act mad before 2005 also played very crucial role.
The patent application claimed the final form of Gleevec (the beta crystalline form of imatinib mesylate)
2003 they got EMR.

When examination of Novartis' patent application began in 2005, it came under immediate attack from oppositions initiated by generic companies that were already selling Gleevec in India and by advocacy groups. The application was rejected by the patent office and by an appeal board. The key basis for the rejection was the part of Indian patent law that was created by amendment in 2005, describing the patentability of new uses for known drugs and modifications of known drugs. That section, Paragraph 3d, specified that such inventions are patentable only if "they differ significantly in properties with regard to efficacy." At one point, Novartis went to court to try to invalidate Paragraph 3d; it argued that the provision was unconstitutionally vague and that it violated TRIPS. Novartis lost that case and did not appeal. Novartis did appeal the rejection by the patent office to India's Supreme Court, which took the case.

The Supreme Court case hinged on the interpretation of Paragraph 3d. The Supreme Court decided that the substance that Novartis sought to patent was indeed a modification of a known drug (the raw form of imatinib, which was publicly disclosed in the 1993 patent application and in scientific articles), that Novartis did not present evidence of a difference in therapeutic efficacy between the final form of Gleevec and the raw form of imatinib, and that therefore the patent application was properly rejected by the patent office and lower courts.


Novartise argued even though polymorphs  discussed in Zimmerman patents no directly mentioned and no person  having knowledge of it was ableo sepwerate it with current knoledge.Furtermore it argued it physical efficacy.
The arguments were countered by the fact that  it was prior art as the research was published in science and Zimmerman patents and it doesnt shown therapeutic efficacy.

Supreme Court decided the matter de novo looking into matters of both fact and law.

The court first analysed the question of prior art by looking into Zimmerman patent and the related academic publications. It was clear from the Zimmerman patent that imatinib mesylate itself was not new and did not qualify the test of invention as laid down in section 2(1)(j) and section 2(1)(ja) of the Patents Act, 1970.^[37] The court then examined the beta crystalline form of imatinib mesylate and wrote that it, "for the sake of argument, may be accepted to be new, in the sense that it is not known from the Zimmermann patent. (Whether or not it involves an “inventive step” is another matter, and there is no need to go into that aspect of the matter now). Now, the beta crystalline form of Imatinib Mesylate being a pharmaceutical substance and moreover a polymorph of Imatinib Mesylate, it directly runs into section 3(d) of the Act with the explanation appended to the provision".^[38]

In applying 3(d) of the Act, the Court decided to interpret "efficacy" as "therapeutic efficacy" because the subject matter of the patent is a compound of medicinal value. Court acknowledged that physical efficacy of imatinib mesylate in beta crystalline form is enhanced in comparison to other forms and that the beta crystalline form of imatinib mesylate has 30 per cent increased bioavailability as compared to imatinib in free base form.^[39] However, as no material had been offered to indicate that the beta crystalline form of imatinib mesylate will produce an enhanced or superior efficacy (therapeutic) on molecular basis than what could be achieved with imatinib free base in vivo animal model, the court opined that the beta crystalline form of imatinib mesylate, does not qualify the test of Section 3(d).

Thus in effect, Indian Supreme Court upheld the view that under Indian Patent Act for grant of pharmaceutical patents apart from proving the traditional tests of novelty, inventive step and application, there is a new test of enhanced therapeutic efficacy for claims that cover incremental changes to existing drugs.^[42]

The Court took pains to point out that the subject patent application was filed during a time of transition in Indian patent law, especially with regard to striking Section 5, which had barred product patents and adding section 3(d), for which there was no case law yet.^[43] The Court also took care to state the decision was intended to be narrow: "We have held that the subject product, the beta crystalline form of Imatinib Mesylate, does not qualify the test of Section 3(d) of the Act but that is not to say that Section 3(d) bars patent protection for all incremental inventions of chemical and pharmaceutical substances. It will be a grave mistake to read this judgment to mean that section 3(d) was amended with the intent to undo the fundamental change brought in the patent regime by deletion of section 5 from the Parent Act. That is not said in this judgment."