Pharmaceutical Regulation and Quality Assurance: The FDA and Other Regulators around the World

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Pharmaceutical Regulation and Quality Assurance
The FDA and Other Regulators around the World

• Brenda Waning
• Warren Kaplan

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Outline

• I. Why regulate at all? General principles of
  drug regulation
• II. Comparison of Drug Regulatory Authorities
  (DRAs) in developed and developing countries
• III. Quality Control
• IV. Regulation of Promotion/Marketing/Pharmacies
• V. Generic Drug Policy
• Gaming the system? Patents/regulatory
  interaction

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Subjects to be Covered

• I. Why regulate at all? General principles of
  drug regulation

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Regulation in medicine is 4000 years old
Hammurabis Code 2000 BCE Needs-based fees
215 a physician shall receive ten shekels
in money 217 if the patient be a slave two
shekels
Sanctions for malpractice 218 If a physician
make a large incision with his knife and kill the
patient or .. cut out the eye, his hands shall be
cut off.
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Purposes of drug regulation

• Distinguish permissible or lawful from
  impermissible or unlawful
• Specify rights, duties, powers
• Provide a legal basis for regulation
• Specify sanctions and penalties to be imposed
  upon those who violate legislation or regulations.

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Scope of drug regulation

• What products should be regulated
• What companies/institutions should be regulated
• What activities should be regulated
• To what extent should the above be regulated
• Who should be responsible for regulation
• What sanctions should apply in case of violations

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WHOs concept DRAs to ensure that

• all premises, persons practices engaged in the
  development, manufacture, importation,
  exportation, wholesale, supply, dispensing
  promotion of drugs comply with approved
  standards, norms, procedures and requirements
• drug products are safe, effective and of
  acceptable quality
• product information is unbiased, accurate and
  appropriate
• drugs are available ()
• drugs are used rationally ()

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Basic functions in drug regulation

• Licensing of manufacturers, importers,
  distributors, wholesale and retail outlets
  (premises, persons and practices)
• Marketing authorization for drug products
• Quality control laboratory testing
• Provision of drug information and monitoring of
  drug promotion and advertising

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Basic functions in drug regulation

• Inspection of manufacturing and distribution
  channel premises
• Adverse drug reaction monitoring ()
• Authorization of clinical trials
• Monitoring of drug dispensing and prescribing
  practices ()
• Monitoring of drug utilization and promotion of
  rational drug use ()
• Application of sanctions

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In a perfect world, DRAs should operate as
follows

• Consideration given to the public health value of
  the regulated pharmaceutical
• DRA accountable to both the government and the
  public- not to the pharm. industry
• Sanctions are regularly applied
• Evaluators should have appropriate skills and
  training
• Transparent procedures and policies

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The approach to drug regulation must be attuned
to the available resources problems in
establishing drug control have too often resulted
from the adaptation of provisions successful
elsewhere but of a complexity that precludes
their effective implementation in the country of
adoption...
WHO Expert Committee on Specifications for
Pharmaceutical Preparations, TSR 790, 1990
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Should the DRA be Autonomous?

• Advantages
• Improved efficiency can contract out testing,
  inspections, experts.
• The DRA is less influenced by governmental
  policies
• DRA can keep all user and license fees- ability
  to use fees to cross-subsidize other operations
  of DRA
• Stable human resources-building up of expertise
• Isolated from political changes of bureaucracy

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Should the DRA be Autonomous?

• Disadvantages (I)
• High user/application fees may discourage
  generics
• May be influence by private interest groups
• May not have adequate funding
• Problems with enforcement of regulations

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Should the DRA be Autonomous?

• Disadvantages (II)
• Creation of personal fiefdoms
• Human resource fluctuations
• High capital cost to maintain equipment, supplies
• Lack of political power

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Regulating Traditional Medicines

• Keep the same regulatory requirements for all
  products, whether traditional or not (Korea,
  Brazil)
• Keep the same regulatory requirements for all
  products, with certain types of evidence not
  required for herbal/traditional medicines
  (Vietnam)
• Exempt herbal/ traditional medicines from all
  registration, manufacturing, dispensing,
  marketing, and distribution-related regulatory
  requirements (many LDCs)
• Exempt herbal/ traditional medicines from only
  those regulatory requirements concerning
  registration or marketing authorization

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• Huge differences in regulatory environment do
  exist. What can regulators do?
• Wait for political will, improved legislation,
  more resources to appear ?
• Or rather try to improve regulatory work
  within current environment and resources in order
  to maximise its potential for improving public
  health?

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II. Comparison of DRAs

• United States some history
• Europe
• Japan
• Less developed Countries
• Stages of drug regulation

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Public Health Events and FDA Evolution

• Reactive
• Public health tragedies
• Consumer activism
• Political pressures
• Business interests

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1906 The Pure Food and Drugs Act
Labeling accuracy to eliminate adulteration Inter
state transport Purity strength
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1937 Sulfanilamide DiEthyleneglycol Federal
Food, Drug, and Cosmetic Act (FDCA)
Truthful labeling and SAFETY New Drug Application
(NDA) required NO requirement for EFFICACY
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Thalidomide and phocomelia1962 Keafauver-Harris
Amendments to FDCA
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Harris-Kefauver Amendments

• Required animal testing prior to human
• Data submitted as an Investigational New Drug
  application (IND)
• Proof of EFFICACY
• Documentation of risk to benefit ratio
  relative safety
• Increased the cost and time to market of new drugs

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1982 Tylenol laced w/ CyanideTamper-Resistant
Packaging Regs
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The Federal Anti-Tampering Act (Reacting to the
Tylenol cyanide murders) Federal Ant-Tampering
Act established Federal criminal jurisdiction
over tampering with foods, drugs, cosmetics other
consumable products. The act specifically
targets 1) tampering with the product 2)
modifying the labeling of a product 3) falsely
reporting that a consumer product has been
tampered and 4) threatening to tamper with a
consumer product.
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1983 Orphan Drug Act
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Orphan Drug Act

• The Orphan Drug Act provides a 50 percent tax
  credit for expenses related to clinical tests on
  humans for drugs used to treat rare conditions
  or diseases.
• Obtaining an orphan designation is easy. The Act
  does not require any consideration of a drug's
  economics. The Act requires only that the drug be
  used to treat a disease with a client population
  less than 200,000.
• Biogens orphan is Avonex treats 400,000
  patients

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• Drug companies are also allowed to file for
  orphan drug status for very narrowly defined
  treatment groups and later add new orphan
  designations for different applications of the
  drug ("salami slicing) e.g., different forms of
  MS (relapsing/secondary progressive)

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• Orphan Status awards exclusivity to the first
  firm with NDA approval Congress provided for
  seven years of market exclusivity for approved
  orphan drugs.  21 U.S.C. 360cc(a)
• Leads to strange results
• One patented orphan can block entrance to other
  drugs which have their own patents and arguably
  different medical characteristics
  (Berlex/Biogen).
• If drug without patent gets Orphan designation,
  it is possible that firm holding FDA orphan drug
  exclusivity must license the patent from the firm
  barred from the market.

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1984 Waxman-Hatch Act

• Drug Price Competition and Patent Restoration Act
• Designed to lower drug prices by increasing
  competition
• Abbreviated NDAs (ANDA)
• Accelerated approval of generics in which patent
  on drug is about to expire

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Prescription Drug Marketing Act (1988)
Intended to safeguard prescription drug products
(http//www.usdoj.gov/usao/eousa/foia_reading_room
/usam/title4/civ00113.htm.) 1. Designed to
minimize the chance that counterfeit,
adulterated, misbranded, subpotent, or expired
drugs would enter the nations distribution
system. 2. Bans the re-importation of
American-made prescription human drugs from
foreign countries (BUT SEE X-border Canadian
visits) 3. Regulates the distribution of drug
samples 4. Prohibits the resale of
prescription drugs purchased by hospitals and
health care institutions 5. Regulates
prescription drug wholesale distributors .  
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• 1992 Response to AIDS Activists and AZT
• (lasts 5 years)

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Table 2.1 FDA Prescription Drug User Fees (US)
and Times to Approval  
 
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1997 Extends PDUFA for 5 more years
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FDA strong Phases I-III, WEAK phase IV voluntary
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Limitations of Preclinical Testing

• Time consuming and expensive
• Need lots of animals to collect data
• Extrapolation of toxicity data to humans
• Rare adverse events unlikely to be found

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Phase I Clinical Trials

• Safety only Small number (25-30) of healthy
  volunteers
• Dose response studies pharmacokinetics/
  half-life, metabolism
• Short term

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Phase II Clinical Trials

• Efficacy/Safety /Optimum Dose
• In sick patients Small number (25-300)

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Phase III Clinical Trials

• Large number (1000s) to further establish safety
  and efficacy
• Designed to minimize errors by placebo effects
  and variable course of the disease
• Done in different centers
• Difficult to design and execute
• Very expensive (millions)

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Main Questions

• Phase I Side effects? Is it safe enough to test
  in large numbers?
• Phase II Does it work at all as a treatment?
  What are the dosage ranges?
• Phase III Is it better than placebo? Is it
  better than other treatments? the next best
  alternate treatment? ()
• Side effects? ()

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Phase IV

• AFTER market approval
• Long term safety, efficacy under actual use in
  many thousands of patients ADR, pharmacoepi
• Used for special populations
• Used for new formulations
• Used by drug companies as marketing(!)
• FDA Phase IV requirement is the exception, not
  the rule

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Pharmacovigilance

• Recent examples of ADR and responses
• NSAIDS and GI Bleeding (cox2 inhibitors?)

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Pharmacovigilance

• Third Bragg soldier took malaria drug (Larium)By
  Mark Benjamin and Dan OlmstedFrom the Washington
  Politics Policy DeskPublished 8/17/2002 300
  PMFAYETTEVILLE, N.C., Aug. 17 (UPI) -- Friends
  of the three Fort Bragg soldiers suspected of
  killing their wives this summer say the men
  exhibited unusual anger and incoherence after
  returning from Afghanistan where they were given
  an anti-malaria drug associated with aggression
  and mental problems.

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Pharmacovigilance

• ADR often not seen until many 1000s of patients
  and many years after approval
• For many drugs in developing countries, virtually
  NO post-marketing surveillance
• Lack of knowledge about ADR
• Fear of legal action
• Under-reporting (no patient follow up)
• Lack of baseline data
• Central International database WHO Uppsala,
  Sweden (60 countries)

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Drug Regulation in the European Union

• National system- each separate country
• Each country has broadly similar registration
  requirements
• Decentralized mutual recognition
• Initial registration granted by one member and
  this is recognized by the DRAs of the other EU
  members- most used system
• EMEA single system-compulsory only for biotech
  products
• Approval given by a commission, NOT by a DRA
• EMEA funded by drug companies ()

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Drug Regulation in Japan

• Approval through a series of committees and
  consultants- overall similar to FDA
• Approval required BEFORE drugs can be imported
  into Japan
• Efficacy and safety can be re-examined by DRA 6
  years after approval
• Anyone can request documents and DRA must
  disclose the contents of all reviews (April 2000)

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Drug Regulation in Most Other Places

• Stages in DRA evolution
• Notification system
• Standardized information is obtained on all
  pharmaceutical products offered for sale and
  entered into a register. Provided the information
  is complete, if later problems arise with drug
  quality or evidence of contamination, the DRA
  will at least know whether the drug is on sale in
  the country.
• Product name, batch number
• Sri Lanka (pre 1987) Zambia (l999)

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Drug Regulation in Most Other Places(II)

• Authorization system
• Authorization schemes are the most basic form of
  proactive drug registration system
• DRA relies on policies established in other
  countries for drug registration information
• Drug exporter must provide documented answers to
  certain questions, or provide a WHO-type
  certificate WHO certification Scheme
• Sri Lankan DRA Canada, the USA, the UK,
  Scandinavia, Australia, and New Zealand are their
  reference DRAs and tends to approve only those
  chemical entities that are registered by these
  authorities

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Design your own DRA

• Here is another way
• What are the problems

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• Drug testing and review of the application for
  marketing approval performed by NGO,
  FDA-certified entities.
• The FDA thereby becomes primarily a certifier of
  certifiers, rather than a certifier of products
• Delegating oversight responsibility to NGO
  certifiers generates competition for drug
  companies business and create pressure for
  greater efficiency in the oversight process.

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• EXAMPLES
• Underwriters Laboratories Certify more than
  16,000 categories of consumer products
• Regulation of medical devices in the European
  Union (EU)relies on various sets of product
  standards and does not involve government
  regulators directly in product oversight.
• Approval of new medical devices in Europe takes
  only half as long as in the United States,
  shortening the development process by roughly two
  years.

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Harmonization of Regulatory Procedures

• International Conference on Harmonization of
  Technical Requirements for Registration of
  Pharmaceuticals for Human Use (ICH)
• Common set of technical requirements relating to
  quality control (validation of procedures), drug
  safety, and certain aspects of manufacturing
  practice for active ingredients- not safety,
  efficacy

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Harmonization of Regulatory Procedures (II)

• Members United States, Japan, European Union and
  trade associations
• 80 of pharmaceutical market
• Developing countries cant influence ICH
• WHO excluded from ICH membership
• Consumer, medical groups little influence
• Conflicts of interest?

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Harmonization of Regulatory Procedures (III)

• CADREAC DRAs of Central/Eastern Europe
• ASEAN Association of SEAsian Nationsno formal
  DRA harmonization
• Central/South America Few harmonization
  activities- MERCOSOUR
• ANDEAN Group, CARICOM

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III. Quality Control

• Requires vigilance throughout the manufacturing
  and distribution chain

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Systems need to have an assured quality
pharmaceutical

• Establishment of a drug regulation and
  registration system
• Establishment of a functioning drug quality
  control laboratory
• Establishment of a system for storing and
  transferring drugs
• Establishment of drug legislation that can be
  enforced

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What is the DRAs Role in Assuring Quality

• Problem Manufacturers may be operating in a
  country with a weak DRA
• DRA should inspect the manufacturing facilities
  and the process stream and provide sanctions for
  noncompliance
• Testing of the finished product isnt good enough
• Quality must be built in to the process

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IV. Regulation of Promotion Distribution/Pharmac
ies

• Before 1962, promotion under FTC.
• 1962 FDCA amended giving power to FDA
• hearing abuses of marketing to MDs
• FDA regulates advertising and promotion of Rx
  meds, FDA regulates switching from Rx to OTC,
  FTC regulates OTC meds

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Off label use/promotion

• Docs can prescribe meds for uses not on the label
• Drug companies can NOT promote their meds for off
  label uses
• If a drug company does a study on an off label
  use and publishes this info in a journal, is this
  unlawful promotion or basic research?
• Pharmacias Bextra (chronic pain) study showed
  it was good for toothache (acute)

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FDA Enforcement

• Issue letters to companies in violation
• Warning letters
• Dear health care professional letters
• Mandate employee training
• Mandate preclearance of any new promotional
  materials for a period of time
• Consent decrees used for more serious violations

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Regulating Pharmacies (U.S.)

• Federal regulations provide the framework
• i.e., licensed practioner dispenses Rx
• State regulations fill in the details
• State boards of pharmacy
• how and who to license
• who dispenses
• National professional associations/accreditation
  groups
• NABP (sets standards for licensing)
• ACPE (accredits pharmacy schools)

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Enforcement Capability

• Mandatory Counseling OBRA
• Federal law
• Inspection of dispensing facilities
• Board of Pharmacy

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Issues in Regulating Pharmacies

• Physician and pharmacist licensing is state-based
• Reprimands enforced at state level
• How and who should regulate pharmacies?
• Pharmacy licensed in MA filling Rx for pt in NH
  written by MD in CA..which state law applies?
• FDA has authority to take action against
• Import of adulterated or misbranded drugs,
  illegal promotion, sale w/o RX, counterfeit drugs
• FDA wants state agencies to monitor (no staff)

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Regulating Pharmacies (other places)

• Various accreditation organizations exist in
  other countries
• South Africa/Zambia hospital accreditation
  schemes ()
• In many LDCs, pharmacies are not well regulated
• Viet Nam unusually good regulation
• Much of SSA unusually poor regulation

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Regulating Pharmacies (Nigeria)

• NIGERIAs PHARMACY LAWS
• Drugs and Related Products (Registration, etc.)
  Decree 19 of 1993
• Consumer Protection Council Decree No. 66 of 1992
• Trade Malpractices (Miscellaneous Offenses Decree
  No. 67 of 1992)
• Counterfeit and Fake Drugs Miscellaneous
  Provisions Act (Cap 73, Law of the
• Federation, 1990)
• Counterfeit and Fake Drugs and Unwholesome
  Processed Foods (Miscellaneous Decree 25 of 1999)
• Patent and Proprietary Medicines Vendors License
  (PPMVL)
• National Drug Law Enforcement Agency (NDLEA) Act
  (Cap 253 LFN 1990, as amended)
• Food and Drugs Act (Cap 150 LFN 1990, as amended)
• Poisons and Pharmacy Act (Cap 535 LFN 1990)

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Regulating Pharmacies (Nigeria)

• NIGERIAs PHARMACY LAWS
• Few are enforced
• Drug registration cumbersome (2 yrs)
• Provisions of most laws lack true deterrent
  capabilities (weak fines, etc.)
• No human resources to meet scope of law
• Access to Drugs for HIV/AIDS And Related
  Opportunistic Infections in Nigeria
• By Kristin Peterson and Olatubosun Obileye
• September 2002 (POLICY Project Nigeria)

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What is the role of internet pharmacies?

• Virtually unregulated
• 1999 ltJanuary30 internet pharmacies
• By July gt400 internet pharmacies
• US has NO authority over internet pharmacies
  based outside US
• Technology expanding faster than regulation
  ability
• Prices 1/10 retail

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Next stop Canada.or Mexico
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Canada

• Price Controls
• Patented Medicines Price Review Board
• Govt agency negotiates final price with company
• Cannot charge more than highest price for similar
  drug
• Delays federal approval process
• 13 longer than US
• Viagra approved 1 year after US
• Federal and Provincial approval needed
• Mandatory generic substitution

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Purchasing medicine from countries with lower
prices

• Argument in Favor
• Increase access and affordability
• Arguments Against
• Savings is to middlemen, not consumer
• Sales are reinvested into research
• Counterfeit drugs, quality
• 2 infant deaths Orange County from counterfeit
  drugs from Mexico
• GlaxoSmithKlinethreaten legal action re Canada

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V. Regulation of Generics

• Definitions
• Federal/State Regulation
• Gaming the system

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Definition of a generic drug

• Usually follows an off-patent drug
• Drug that is therapeutically interchangeable with
  the once-patented original drug
• Made by generic manufacturer
• Made by manufacturer of the original drug
• Branded generics (Prilosec---Nexium)
• Non-branded generics

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Definition of interchangeable

• Generic manufacturer must prove that its drug is
  (compared to patented drug)
• Pharmaceutically equivalent same API, same
  dosage, route of administration, same strength
  AND
• Bioequivalent no significant difference in rate
  and extent of absorption/metabolism than the
  patented drug

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Generics Abbreviated New Drug Application (ANDA)

• Generally NOT required to show a new set of
  preclinical and human data
• Must prove its drug is interchangeable with
  patented drug
• BUT, pharma. have found legal loopholes to keep
  generics at bay
• Hatch-Waxmans unintended consequences

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Differential approval process and fee structure
for brand vs generic
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Why Generics?

• In U.S. generics 40-50 by volume
• Only about 10 of expenditure by VALUE
• Branded Rx 90 of market by value
• Branded Rx fastest growing healthcare expense
• Getting cheaper generics on market a good
  idea...yes?
• Big pharma in U.S. spent 15 Billion (!) in
  promoting brandname drugs (2000)

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Generic Substitution

• Mandatory in most states
• Does NOT require physician approval
• Evolution of state laws permit (customer
  asks), encourage (R.Ph. automatically
  substitute unless patient says no), require
  (always a generic)
• Enforcement not a problem

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1990s

• 1992 Generic Drug Enforcement Act
• In response to generic drug scandals (bribery,
  fraud, misconduct)
• FDA may deny generic approvals of a company for
  18 months if found guilty of bribery, fraud,
  misconduct
• FDA may suspend distribution of generic drugs
  made by companies suspected of misconduct
• Civil penalties of 1 million per company and
  250,000 per individual
• Require NDA and ANDA to have certification that
  no debarred individuals were used

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Hatch-Waxman Act 271(e) (1) use of a
patented invention solely for purposes
reasonably related to gathering data to support
an FDA application is NOT patent
infringement THIS IS THE BOLAR AMENDMENT
(FDA SAFE HARBOR) WHICH IS SUPPOSED TO PROTECT
GENERIC COMPANIES AS THEY GEAR UP TO PRODUCE A
PATENTED DRUG
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• Courts will interpret 271(e)1 broadly and
  literally (protects brandname mfgs. also)
• 35 U.S.C. 271(e)1 has provided a safe harbor
• displaying products at trade shows
• conducting studies of consumer response
• selling products to international distributors to
  sell to foreign clinical investigators
• making arrangements for overseas manufacture and
  import of the product

86

• Argentina Law No. 24.766, Article 8 Article 8
  substantially identical language to U.S.
• Canada same
• Japan (1999) Clinical testing performed by
  generic manufacturers is not infringement
  (Bolar covers testing for further development
  but also testing for obtaining marketing
  approval)
• Germany not yet U.S.-type Bolar language

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• Hatch-Waxman Act Patents and Drug Regulation
• Manufacturer seeking to market a generic version
  of a patented drug must certify in an ANDA
• ONE of four things
• (1) that the drug for which the ANDA is submitted
  has not been patented (a "paragraph I"
  certification)
• (2) that any patent on such drug has expired (a
  "paragraph II" certification)

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• 3) if not expired, the expiration date (a
  "paragraph III certification) or
• (4) that the patent on such drug "is invalid or
  that it will not be infringed by the manufacture,
  use, or sale of the new drug" for which the ANDA
  is submitted (a paragraph IV" certification). 
• Generic mfg. must give the owner of the relevant
  patent notice of the para IV certification.  

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• If the ANDA contains a paragraph IV
  certification
• Drug approval shall be made effective
  immediately" unless the patent owner brings an
  action for infringement under within forty-five
  days of receiving the notice.
• If patent owner brings infringement action FDA
  must suspend ANDA

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• The suspension continues -- and the FDA cannot
  approve the ANDA until the earliest of three
  dates
• (i) if the court decides that the patent is
  invalid or not infringed
• (ii) if the court decides that the patent has
  been infringed date that patent expires or
•  (iii)thirty months from the patent owner's
  receipt of notice of the filing of the paragraph
  IV certification.  Ben Venue Lab., Inc. v.
  Novartis Pharm. Corp., 146 F. Supp. 2d 572, 579
  (D.N.J. 2001) (purpose of 30-month stay not
  necessarily to prolong the monopoly held by the
  pioneer manufacturer, but to create a window of
  time to allow a court to resolve the issue of
  infringement)

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• Bottom Line
• As long as the patent infringement litigation
  between the pioneer manufacturer and the first
  generic challenger is ongoing, or  even if it has
  settled and the generic challenger has not yet
  launched its product, the generic market is
  essentially held closed

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• More Potential to abuse the system Collusive
  agreements between generic and brand name
  companies
• In re Abbott Laboratories and Geneva
  Pharmaceuticals (FTC) Geneva informed Abbott
  that it would launch its generic product unless
  Abbott paid it not to enter the market   

93
Conclusions

• Drug regulatory systems vary widely around the
  world
• Quality control is a major bottleneck lack of
  trained personnel, inspectors etc.
• Most LDC DRAs rely on the DRA certification of
  developing countries
• Increasing reliance on regional pooling of DRA
  and/or quality assurance systems
• DRA should be appropriate to the current
  circumstances (, legal, political)