Nobuo UEMURA 08/30/2010
Foreword
In mid-February I moved to the United States Pharmacopeia (USP) secretariat office as a visiting scientist of USP General Chapter team from Japan and a liaison official of MHLW/PMDA ("Ministry of Health, Labour and Welfare" and "Pharmaceuticals and Medical Devices Agency").
This is the third report on the USP and FDA issues. However this report is my personal views and opinions, and it does not necessarily represent the formal position of MHLW, PMDA, FDA and USP.
1. USP 2010 - 2015 new cycle
On July 1, 2010, USP started the 2010-2015 cycle with new organization, following the USP Convention member meeting in April that had adopted resolutions and Bylaw, and had elected the member of Trustees and the Council of Experts.
The expert committees are reorganized into 20 committees, and have started their individual first meetings from July to October with new committee members, having introductions and orientations for work plan and new directions based on the legacy documents of previous committees.
The reorganized 20 Expert Committees are classified into committees for vertical or horizontal standards; the former mainly considers the monographs and reference materials, the latter considers the crossover issues of analytical methods in General Chapters, etc. In order to consider the issues over multiple committee categories, Expert Panel is established on this topic with the joint members of relating expert committees, and reports the discussion result to the Expert Committee.
Reorganized Expert Committees are;
<Monographs>
- Small Molecules 1,2,3,4 Expert Committees
- Biologics & biotechnology 1,2 Expert Committees
- Excipients Expert Committee
- Dietary Supplements Expert Committee
- Food Ingredients Expert Committee
<General Chapters>
- Chemical Analysis Expert Committee
- Physical Analysis Expert Committee
- Biological Analysis Expert Committee
- Dosage Forms Expert Committee
- Microbiology Expert Committee
- Packaging, Storage, and Distribution Expert Committee
<Others>
- Reference Standards Expert Committee
- Statistics Expert Committee
- Toxicology Expert Committee
- Nomenclature, Safety, and Labeling Expert Committee
- Compounding Expert Committee
2. USP's relationship with FDA
As I explained the history and role of USP in the first report, the USP is the official standards recognized by the Federal Food, Drug, and Cosmetic Act, and these standards are enforced by FDA.
This USP's role is described in Sec.201(Definitions), Sec.501(Adulterated Drugs) and Sec.502(Misbranded Drugs) of the FD&C ACT (21 U.S.C. 321).
For instance,
- the Sec.201(g)(1)(A) says that the term "Drug" means the articles recognized in the official United States Pharmacopoeia(USP), official National Formulary, or any supplement to any of them, etc.,
- the Sec.201(j) defines them as "official compendium",
- the Sec.501(b) says that a drug shall be deemed to be adulterated if it purports to be represented as a drug the name of which is recognized in an official compendium, and its strength differs from, or its quality or purity falls below, the standards set forth in such compendium,
- and the Sec.502(e) says that a drug shall be deemed to be misbranded if it is a drug, unless its label bears, to the exclusion of the established name that means official title in the official compendium when it is an article recognized in such compendium.
Then drugs with name recognized in USP must comply with compendial standards for strength, quality or purity, unless labeled to show all differences.
Current Good Manufacturing Practice (CFR 165 (a) and (f)) also requires that for each batch of drug product there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, and that drug products failing to meet established standards or specifications and any other relevant quality control criteria shall be rejected.
USP standards' compliance focused on the manufacturer-approved specifications and GMP are enforced by FDA. (FD&C Act defines the authority as "Secretary"; the Secretary of Health and Human Services.)
As mentioned above, compliance with USP standards is a criterion of decision whether the drug in market is legal or is to be withdrawn from market as adulterated one.
The Convention Resolution adopted at the meeting in April describes strengthening USP's relationship with FDA, and USP is establishing the legally enforceable and effective public standards, while discussing at the meeting with attendees from FDA staff members, and seriously considering the FDA's comment to the draft standards.
3. Drug Names/Nomenclature and USP
In general drug names are classified into 1) Drug Substance Name(non-proprietary name) and its Chemical Name, 2) Drug Product Name, and 3) Brand Name(Proprietary Name) of the Drug Product.
1) Drug Substance Names (non-proprietary names)
Non-proprietary names for drug substances (also known as generic name) are usually assigned by the United States Adopted Names Council (USANC).
The USAN Council activity started as the Nomenclature Committee jointly formed by the American Medical Association (AMA) and United States Pharmacopeia (USP) in 1961. The American Pharmacists Association (APhA) became the third sponsor in 1964. The FDA liaison representative joined the USAN Council in 1967.
The USAN Council members are appointed by their sponsors, and accepted by the other sponsors. In addition, the three organizations jointly select a member-at- large, so the USAN Council has five members including a FDA representative.
FDA announced in 1984 that the name assigned by the USAN Council is an "established name" for labeling of drug products marketed in the United States.
Drug manufacturers apply for the non-proprietary names of their lead compounds by submitting a form to the USAN Council. The name is reviewed by the Council, and after its approval the USAN name is usually used in the IND application by the sponsor during the drug development stages.
Also the name applied to USAN Council is filed in the application to and negotiated with the International Nonproprietary Names Council (INN Council) sponsored by the WHO.
2) Drug Product Names
The United States Pharmacopeia and National Formulary (USP-NF) titles for monograph articles are legally recognized under the Federal Food, Drug and Cosmetic Act (FD&C Act) as the designated names used in the labeling of such articles.
The "established name" under section 502(e) of the FD&C Act will ordinarily be either the compendia name of the drug or, if there is no compendia name, the common and usual name of the drug. Under the terms of the Amendments of 1962 to the FD&C Act, the FDA ("the Secretary of Health and Human Services" in the law text) is authorized to designate an established name.
Compendial names for the drug products are based on the principles described in the General Chapter ;<1121;> Nomenclature in the USP-NF. Generally the name for a drug product has the following format; ( [Drug] [Rout of administration] [Dosage form] ) .
Drug product name is directly relating with the monograph title in the official compendium, and it is important for recognition of generic drugs and for avoiding medication errors. Therefore, USP is working with FDA on establishing names for new drug products and naming new dosage forms.
3) Brand Name of the Drug Product
The individual drug product brand name (proprietary name) is created by the manufacturer and is used on the label of the product approved by the FDA. The brand name is considered by the USAN Council when there is a conflict with nonproprietary name.
4. USP's Operating Revenue and Expenses
USP is a non-profit organization, and is exempt from Federal income taxes under the provisions of Internal Revenue Code, because of no unrelated business to the Federal law based compendium activities; official standard setting and its dissemination.
But the USP India, USP Brazil and USP China are subject to local country taxes per the countries' regulations.
The main operating revenues in year ended June 30 are;
- Reference standards $89883,000 (51% of total operating revenue)
- Publications $14029,000 ( 8% of total operating revenue)
- Contributed Reference Standards $52825,000 (30% of total operating revenue)
- Contributed Services $11397,000 ( 6% of total operating revenue)
And the USAID Grant is $ 4034,000 for international cooperating activities.
The main expenses in year ended June 30 are;
- Compendial Activities $160861,000 (95% of total expenses)
The activities of Standard setting and Reference Standard dissemination are dominating, and until June 30, 2009, there was no provision for federal income taxes.
USP Convention recognized this financial report at the meeting in April.
5. USP Worldwide Activities
USP regularly meets EDQM(European Directorate for the Quality of Medicines & HealthCare/Council of Europe (EP) and MHLW/PMDA (JP) to promote harmonization of pharmacopeial standards through the Pharmacopoeial Discussion Group(PDG).
On the other hand USP have partnership with other countries' and regions' organizations around the globe to improve the public health of people around the world through public standards and related programs.
USP's worldwide activities can be classified by 8 regions; North America(US and Canada), Latin America and Caribbean, Western Europe, Eastern Europe, Middle East and North Africa(MENA), Sub-Saharan Africa, South Asia, and East Asia(including Japan, Australia, New Zeeland).
Besides the headquarter in Rockville, USP has International Locations in Basel(Switzerland), Hyderabad(India), Shanghai(China) and San Paulo(Brazil), and they are key institutes of USP's activities in their regions.
Also USP has and expands Pharmacopeial Education Programs and other Collaborations with various countries in the world.
For example, USP has international collaborations on first-line treatment for malaria, potential increased use of Monographs and Reference Standards, Scientific Meetings and Workshops(Brazil, Argentina, Turkey, Egypt, Jordan, China, India), Pharmacopeial Education Programs. And USP signs several memorandums of understanding with relating organizations(UK, Russian Federation, India, ASEAN and China).
With the funding of the U.S. Agency for International Development(USAID), USP managed the various drug quality assurance programs for establishment of the Network of African Medicine Quality Control Laboratories, Workshop on Anti-malarial Drug Quality in Tanzania, seizure of counterfeit anti-malarials in Ghana, technical assistance to local manufacturers to earn World Health Organization prequalification in Africa and South Asia, assessment of the quality of anti-malarials in Thailand and Cambodia.
In addition USP releases its official translated version of the USP-NF in Spanish and Russian, and is translating into simplified Chinese language.
The Convention Resolution adopted at the meeting in April says "the Support and Advance Global Public Health Initiatives", and the countries that are using USP as their official standards are increasing. USP is aiming and expanding the worldwide activities.
6. FDA FY 2011 budget request
The President of U.S. must submit budget proposal of federal administrations (The Budget Message of The President) to the Congress by 1st Monday in February every year. The President's request for fiscal year 2011 budget, which covers the period of October 1, 2010 through September 30, 2011, was submitted on February 1, 2010 to the Congress.
In United States, while referring to the President's request, the Congress makes, considers and approves appropriation bills of Federal administrations, after hearing the agency's opinion by both House and Senate Committees.
House and Senate respectively hold hearings on the budget, taking testimony from Administration officials, experts etc., at the Appropriations Committee, the Budget Committee, and other relating Committees.
Budget Committee draft and markup concurrent resolution on the budget, which establishes various budget totals, divides spending totals into functional categories.
Appropriation bill for administrative measures in each category is discussed by the Appropriations Committee. Each full Committee respectively has 12 subcommittees in divided categories. FDA appropriation bill is discussed by the Agriculture subcommittee along with USDA appropriation bill. On the other hand, the appropriation bill for HHS including NIH and CDC (Labor-HHS-Education Appropriations Bill) is discussed by the Labor, Health and Human Services, Education, and Related Agencies subcommittee.
The subcommittee holds testimony of administrative officers (ex. FDA commissioner) and draft and report the appropriations bill to the full Committee.
The Appropriations Committee Markup recommended by the subcommittee is approved by the voting of the full committee. Senate and House respectively vote their appropriations bills. The appropriations bills were decided unanimously or by majority. After the reconciliation process, the appropriation bill is enacted and enforced from October 1. When all action on the appropriation bills is not completed, the Continuing Resolution enables the administrative activities tentatively.
FY 2011 FDA Appropriation Bill was approved by the Senate Appropriations Committee of 17 to 12 on July 15, 2010.
7. Administration's FY2011 Budget Request for FDA
The FDA FY2011 budget request, which was submitted in the President's FY2011budget for the Federal Government on February 1, 2010, represents 23% increase over FY 2010, has four initiatives as the major highlights; 1) Transforming Food Safety Initiative with a new food safety system, 2) Protecting Patients Initiative for safe, quality health care, 3) Advancing Regulatory Science Initiative to harness the power of science, 4) Tobacco Initiative to implement the Family Smoking Prevention and Tobacco Control Act.
These are affiliating with the Department of Health, Human Services(HHS)' Strategic Goal; 1) Improvement of Health Care, 2) Public Health Promotion and Protection, Disease Prevention, and Emergency Preparedness, 3) Scientific Research and Development etc.
The components for Protecting Patients are as follows;
1) Import Safety : launching an electronic drug registration and listing system, and expanding foreign inspections, etc.
2) Safety of High-Risk Products : improving the safety of the blood supply, vaccines, human tissue and cord blood, and increasing inspections of high-risk medical products.
3) Expand Partnerships for Patient Safety : expanding post-marketing surveillance systems, reducing unnecessary adverse events focused on child and elderly etc., and improving pediatric drug safety.
4) Generic Drug Review : increasing FDA's capacity to review generic drugs applications.
5) Re-inspection User Fee.
Also the components relating with medical devices are;
1) Import Safety : leveraging device inspections with international collaboration.
2) Safety of High-Risk Products : building a National Medical Device Registry.
3) Expand Partnerships for Patient Safety : reducing medical radiation exposure, and improving pediatric device safety.
This request includes 215 FTE new staff members (FTE : full-time equivalents).
In addition, the components for Advancing Regulatory Science are as follows;
1) Leadership and Coordination : providing scientific support, leadership and coordination by establishing the Office of Science and Innovation.
2) Core Capacities : building core scientific capacity and expertise in nanotechnology, recruiting scientific staff for high-technology orthopedic prosthetic devices and innovative analytic methods, developing tools to modernize product development and evaluation.
3) Update medical product regulatory standards and provide regulatory pathways for new technologies : updating review standards and providing a scientifically sound and safe pathway to better characterize and develop biosimilars.
This request includes 50 new staff members (FTE : full-time equivalents).
In order to support these initiatives and components, FDA FY 2011 budget request ($4.03 billion) represents $747 million increases (23%) over FY 2010 budget ($3.28 billion), including increases of $146 million in budget authority and $601 million in user fees.
8. Bill for fiscal year 2011 FDA appropriations by the U.S. Senate Committee on Appropriations
The Committee recommendation for FDA appropriations bill, which was approved by the U.S. Senate full Committee on Appropriations after receiving the subcommittee report, represents increases of $5 million above the request to CDER programs, even though the total amount without new proposal of user fee categories is same level as FDA's request while reducing the other spending.
These increases are 1) $2 million for Generic Drugs, 2) $2 million for Orphan Product Development Grants, 3) $1 million for the office of the Associate Director for Rare Diseases.
However the committee recommendation does not include proposed language regarding generic drug review user fees, re-inspection user fees etc. because they have not been authorized by Congress yet.
The Senate Committee recommendation addresses that FDA is a scientific regulatory agency whose mission is to promote and protect the public health and safety of Americans, and that its work is a blend of science and law. And the Committee recommends the same level of salaries and expenses of FY 2011 appropriations as the FDA's request to implement the FDA Amendment Act of 2007.
The Committee expects FDA to continue all projects, activities, and programs as included in the fiscal year 2011 budget request, unless otherwise specified as follows;
1) Antibiotic Development : guidance on community-acquired bacterial pneumonia, guidance for multi-drug and pan-resistant organisms, development and/or appropriate use of priority anti-bacterial drugs for humans.
2) Antimicrobial resistance : overall review of the use of antibacterial drugs in food-producing animals and anti-microbial resistance, etc.
3) Critical Path and Modernizing Drug Safety
4) Prevention, diagnosis and treatment of tuberculosis(TB).
5) Demonstration Grants for Improving Pediatric Device Availability.
6) Orphan Product Development Grants.
7) Office of the Associate Director for Rare Diseases in the CDER.
8) Electric track and trace system for prescription drugs to improve the security of drug supply chain from counterfeit or other substandard products.
9) Generic Drugs.
10) H1N1 Emergency Use Authorizations : report to Congress.
11) Mammography : improving quality of mammography
12) Office of Women's Health : ensuring safe and effective products for women.
13) Nanotechnology Core Facility at the National Center for Toxicological Research(NCTR)
Among the food safety investments, the Committee specified Banned Antibiotics in Shrimp, Accurate Food Labeling, Seafood Economic Integrity and Seafood Safety, Standard of Identity for Honey, Traceability.
9. House Appropriations Committee
In ordinary case the House considers appropriations bills first by custom. But this year the House has not approved the budget resolution, and the House Appropriations Committee has not voted on the FY 2011 FDA Appropriations bill, though the chairwoman of the House Agriculture, Rural Development, Food and Drug Administration and Related Agencies Appropriations Subcommittee made a statement on June 30, 2010, when the Committee received the subcommittee report of its bill marked up.
This chairwoman's statement refers to her believe on strong leadership at the FDA under Commissioner, and includes increase of resources for the office of generic drugs, direct consumer advertisement, medical devices, imported food safety, etc., and pointed out the need to create an independent office on post-market drug evaluation and a report on the status of developing standards for a track and trace system for prescription drugs.
After the approval and report of the House Appropriations Committee and completion of authorized bills by both House and Senate, the new fiscal year 2011 will start from October 1, 2010.