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International Initiatives on Drug Safety. Linda R. Horton Partner Hogan & Hartson LLP Brussels & Washington, DC August 23, 2007. 3 rd Annual FDA Regulatory and Compliance Symposium Harvard University Campus, Cambridge, MA. What we will discuss today. EU Update

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International Initiatives on Drug Safety

Linda R. Horton


Hogan & Hartson LLP

Brussels & Washington, DC

August 23, 2007

3rd Annual FDA Regulatory and Compliance Symposium

Harvard University Campus, Cambridge, MA

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What we will discuss today

  • EU Update

    • Tightening Up: “First Time in Humans” Clinical Trials

    • Lightening Up: Biosimilars

    • Meds Made of Us: Advanced Therapies/Tissue-Engineering

    • Meds for Kids: EU Pediatrics Regulation

    • Truth or Consequences: EU Penalties Regulation

  • Clinical Trials in Developing Countries

  • Counterfeits and Sub-Standard Drugs

    • The Problem

    • IMPACT: WHO Initiative

    • EU and Council of Europe Initiatives

    • APEC Initiatives

    • China Initiatives

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EU Update

Tightening Up: “First Time in Humans” Clinical Trials

Lightening Up: Biosimilars

Meds Made of Us: Advanced Therapies/Tissue-Engineering

Meds for Kids: EU Pediatrics Regulation

Truth or Consequences: EU Penalties Regulation

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To recap from 2005 and 2006:

  • Looking over the Atlantic ≠ looking in a mirror.

  • There is no United States of Europe.

  • There is no EU FDA although, since 1995, there has been a European Medicines Agency (EMEA).

  • Each of the 27 Member States has or more agencies.

  • Although today 70% of new products enter via EMEA route, most products on the EU market were approved by Member State agencies.

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Isn’t the EMEA like the FDA? Not quite.

The EMEA is a secretariat for a network of experts.

  • There are (largely) uniform rules on testing, clinical trials, applications, pharmacovigilance, and GMPs.

  • But clinical trial regulation is entirely by Member States.

  • Enforcement is by Member States.

  • Review of EMEA/centrally authorized product occurs chiefly in the national regulatory agency where rapporteur works.

  • European Commission is the one who grants authorization.

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Tightening Up: “First Time in Humans” Clinical Trials - Issues

  • How should the transition from preclinical to first-in-man testing be regulated for novel therapeutic modalities?

  • How to make the transition from preclinical to human studies without creating unnecessary obstacles?

  • How to deal with the question of liability and insurance?

  • Do the national regulatory authorities and the ethics committees carry any responsibility in case of a problem?

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The TeGenero phase 1 trial Issues

  • A sponsor, Tegenero AG, wanted to conduct a human study of a novel superagonist anti-CD28 monoclonal antibody that directly stimulates T cells

  • The conventional battery of preclinical toxicity tests completed by TeGenero appeared to the UK and German regulators to justify approval of clinical trial

  • Eight healthy male volunteers were recruited and dosed by Parexel Clinical pharmacology research Unit (CPRU) on March 13, 2006. Two subjects received a placebo. Serious Adverse Events (SAEs) were reported in 6 of the 8 subjects:

    • Within 90 minutes: systemic inflammatory response characterized by a rapid induction of proinflammatory cytokines and accompanied by headache, myalgias, nausea, diarrhea, erythema, vasodilatation, and hypotension

    • Within 12 to 16 hours: they became critically ill, with pulmonary infiltrates and lung injury, renal failure, and disseminated intravascular coagulation

    • Within 24 hours: severe and unexpected depletion of lymphocytes and monocytes occurred

    • At 8 and 16 days: intensive organ support was required due to prolonged cardiovascular shock and acute respiratory distress syndrome developed in two patients

  • Despite evidence of the multiple cytokine-release syndrome, all six patients survived

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Investigations and Issuesfindings

  • Aim:

    • was the reaction seen due to contamination of the dose, an incorrect dose being administered, or an inherent flaw in the drug?

    • was the short timeframe within which the doses were administered a problem?

  • UK MHRA initial investigation:

    • no errors in the manufacture, formulation, dilution or administration of TGN1412. An unpredicted biological action of the drug in humans was the most likely cause of the adverse reactions in the trial participants

  • UK MHRA then commissioned an investigation by an expert scientific group committee:

    • the preclinical development studies that were performed did not predict a safe dose in humans, even though current formal regulatory requirements were met

  • German regulatory authorities:

    • no deficiencies in the manufacture, testing, storage and distribution of the TGN 1412 could have contributed to the serious adverse effects

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Initiatives - EU Issues

  • Committee for Medicinal Products for Human use (CHMP): Draft Guidelines on requirements for first-in-man clinical trials for potential high-risk medicinal products dated March 6, 2007

    • Criteria to classify new investigational medicinal products as potential high-risk medicinal products

      • Medicinal products are defined as potential high-risk medicinal products when there are concerns that serious adverse reactions in first-in-man clinical trials may occur. These concerns may be derived from particular knowledge or uncertainties on:

        • the mode of action; and/or

        • the nature of the target; and/or

        • the relevance of animal models

    • Guidance on quality aspects

      • Characterization, determination of strength and potency, comparability with the material used in non-clinical studies, reliability of very small doses

    • Guidance on non-clinical testing strategies and design for first-in-man clinical trials for high-risk medicinal products, including the calculation of the initial dose to be used in humans, the subsequent dose escalation and the management of risk

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Initiatives - UK Issues

  • UK expert scientific group committee on phase one clinical trial recommendations:

    • Pre-clinical Development:

      • The strategy should be to have science-based decisions made and justified on a case-by-case basis by investigators with appropriate training

      • Sharing and strengthening the collection of information

    • Transition From Preclinical to Clinical development

      • Broader approach to dose calculation

      • Maximum reduction of risk

      • Starting dose and dose escalation should be made on a case-by-case basis and should be scientifically justifiable

    • Clinical Development

      • Decision on whether to conduct a first-in-man trial should be carefully considered and fully justified

      • Principal Investigators and staff should have appropriate levels of training, expertise, and qualification

      • Where there is a predictable risk of certain types of severe adverse reaction, a treatment strategy should be considered beforehand

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Initiatives - UK Issues

  • UK expert scientific group committee on phase one clinical trial recommendations:

    • New agents should be administered sequentially to subjects with an appropriate period of observation between dosing

    • A similar period of monitoring between sequential dosing of subjects during dose escalation

  • Regulatory

    • More communication should be encouraged between developers and the regulator at an earlier stage before an application is filed

    • The regulator should have access to additional opinion from independent, specialist experts with research knowledge in their fields. An Expert Advisory Group (EAG) of the Commission on Human Medicines, or a similar body, might undertake this role

  • Future

    • Availability of ‘hands-on’ experience in the planning and conduct of clinical trials should be widened

    • Feasibility of developing specialist centers for phase one clinical trials of higher risk and for advanced medicinal products should be explored

    • Regulatory process for first-in-man trials of higher risk agents and advanced medicinal products should be subject to frequent review

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Lightening Up: Biosimilars – EU Regulatory Pathway Issues

  • Article 10(4) of the Community Code on Medicinal Products (Directive 2001/83/EC):

    • “Where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided. The type and quantity of supplementary data to be provided must comply with the relevant criteria stated in the Annex and the related detailed guidelines. The results of other tests and trials from the reference medicinal product's dossier shall not be provided.”

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General Guidelines Issues

  • Overarching Guideline on Similar Biological Medicinal Product

  • Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues

  • Similar Biological Medicinal Products containing Biotechnology-Derived Proteins as Active Substance: Non-Clinical and Clinical Issues

  • Other guidance documents such as the recently adopted EMEA document: “Questions and Answers on biosimilar medicines”

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Specific Product Guidelines Issues

  • Recombinant Human Erythropoietin

  • Recombinant Human Growth Hormone

  • Recombinant Human Insulin

  • Recombinant Human Granulocyte-Colony-Stimulating-Factor

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Status of biosimilars Issues

Authorized biosimilars:

  • Omnitrope® (somatropin): Recombinant human growth hormone - Reference product Genotropin®.

  • Valtropin® (somatropin): Recombinant human growth hormone - Reference product Humatrope

    Positive opinions from Committee on Medicinal Products for Human Use (CHMP); all with reference product Eprex/Erypo

  • Binocrit® (epoetin alfa): Erythropoietin

  • Hexal® (epoetin alfa): Erythropoietin

  • Abseamed (epoetin alfa): Erythropoietin

    Rejected as biosimilar (received a negative opinion from CHMP):

  • Alpheon: Recombinant interferon alpha – Reference product Roferon-A

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Naming and interchangeability Issues

  • INN International Nonproprietary Name (for marketing in EU and Japan)

  • USAN United States Adopted Name (for marketing in the U.S.)

  • Role: Identifies the compound within a family of compounds based on chemistry

  • Impact on:

    • prescription,

    • substitution of drugs, and

    • adverse event reporting process

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Naming and interchangeability Issues

  • Similar and not identical g entails problems that are not prevalent as to small-molecule generic medicines

  • For pharmacovigilance, it is important for records to be kept to distinguish between events associated with innovator products and biosimilars

  • Should there be special restricted substitution rules for biosimilars?

  • Does the EMEA possess the authority to recommend such rules? Can the Commission impose such rules?

  • New system of nomenclature?

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Naming and interchangeability: use of INN Issues

  • The EMEA guideline on Similar Biological Medicinal Productsrecommends that the specific medicinal product which is prescribed to the patient needs to be “clearly identified”

  • The EMEA guideline does not specifically address the suitability of using the same INN for both a biological product and any related biosimilar. It does, however, acknowledge that concerns exist as regards the differences that may materialise between biological products and related biosimilars

  • The 44th Consultation on International Nonproprietary Names (INNs) for Pharmaceutical Substances was held at WHO Headquarters in Geneva on 22-24 May 2007. The INN Expert Group noted the nomenclature systems in this field are generally working well. There appears to be no consensus for change

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Meds Made of Us: Advanced Therapies/Tissue-Engineering: Issues

  • Lack of an EU-wide regulatory framework for tissue engineered products led to divergent national approaches, creating obstacles to the internal market

  • The EU Regulation on Advanced Therapy Medicinal Products aims to address this regulatory gap

  • Introduces specific rules for the authorization and supervision of advanced therapy products for human use in the EU

  • Governs three types of advanced therapies: gene therapy, somatic cell therapy and tissue engineering

    • Gene and somatic cell therapy products had previously been defined and classified as medicinal products in the EU

    • Tissue engineered products had not

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What are advanced therapies? Issues

  • Defines advanced therapy products for human use including tissue engineered products as medicinal products

    • This means that their authorisation for marketing in the EU will be governed by the Community Code on Medicinal Products

  • Determines that cells or tissues are "engineered" if they have been subject to substantial manipulation, so that biological characteristics, physiological functions or structural properties relevant for the intended regeneration, repair or replacement are achieved, or if they are not intended to be used for the same essential function or functions in the recipient as in the donor

  • Where a medical device contains a tissue engineered product, irrespective of the role of the medical device, the pharmacological, immunological or metabolic action of these cells or tissues should be considered to be the principal mode of action of a combination product

    • Such combination products should always be regulated under the Regulation

    • Nevertheless, the medical device element should also meet the essential requirements of the Medical Devices Directives

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Advanced Therapies: Ethics, procedure and requirements Issues

  • A controversial subject of debate during the adoption procedure for the draft Regulation was the potential application of the Regulation to advanced therapy medicinal products that contain or are derived from human embryonic or foetal cells, primordial germ cells or cells derived from those cells

    • The final text does not address this issue

  • Establishes a compulsory centralized procedure for marketing authorizations for advanced therapy products

    • This includes the establishment of a new European Medicines Agency (EMEA) Committee for Advanced Therapies (CAT)

  • Introduces stringent requirements on risk management and post-authorisation traceability requirements

  • Clarifies the requirement that clinical trials on advanced therapy medicinal products including tissue engineered products must be conducted in accordance with the Clinical Trials Directive

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Advanced Therapies: Status Issues

  • Regulation approved by Council of Ministers on May 31, 2007

  • Regulation now needs to be translated in all EU official languages and formally adopted, signed and published

  • It will apply from 1 year after entry into force

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Meds for Kids: EU Pediatrics Regulation: Issues Issues

  • More than 50% of medicines used to treat children in Europe have not been tested for use in children and have not been authorized for use in the care of children

  • The EU Paediatrics Regulation (Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use) aims to balance:

    • the ethical issues raised by conducting trials on children; with

    • concerns arising in treating children with products which have not been tested on them

  • It imposes extensive system of requirements on companies and offers rewards and other incentives

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Meds for Kids: Requirements Issues

  • Requires applications for marketing authorizations for new medicines and line extensions to:

    • include results of studies in the paediatric population carried out in accordance with an agreed Paediatric Investigation Plan (PIP); or

    • proof of having obtained a waiver (e.g. because likely to be ineffective or unsafe in part or all of the paediatric population) or deferral from this obligation

  • Requirement applies irrespective of whether or not the medicine for which authorization is sought is intended to be administered in children

  • Requirement does not apply to generic products, biosimilars, hybrids, products containing substances acknowledged to have well-established medicinal use, herbal medicines and homeopathic medicines

  • The PIP must be agreed with a new expert Paediatric Committee (PDCO) within the European Medicines Agency (EMEA)

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Meds for Kids: Benefits Issues

  • For newer medicines benefits include:

    • six months extension of the SPC to which the product is entitled

    • two years extension of market exclusivity for orphan medicines

    • optional access to the centralized EU level procedure for marketing authorization applications that include one or more paediatric indications on the basis of studies conducted in accordance with the agreed PIP

  • For older medicines, a new type of marketing authorization, a Paediatric Use Marketing Authorisation (PUMA) will be available

    • This type of authorization, for which eight years’ data protection and ten years’ market protection are provided, will apply solely to products for which the patent has expired and which are not protected by an SPC

    • It covers therapeutic indications developed exclusively for use in the paediatric population in accordance with an agreed PIP

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Meds for Kids: Status Issues

  • Entered into force on 26 January 2007

  • Some provisions enter into force later on:

    • Obligation to agree a PIP

      • For medicines not authorised by 26 January 2007, enters into force on 26 July 2008

      • For line extensions enters into force on 26 January 2009

    • In the meantime, companies may approach the Paediatric Committee, which will be established by 26 July 2007, to agree a PIP

  • The PUMA will be available from 26 July 2007

  • Should lead to increased assurance concerning the quality, safety and efficacy of medicinal products prescribed for paediatric use

  • However, obligations are strict and it remains to be seen whether industry will consider that the benefits provide adequate compensation for the additional studies undertaken and costs involved

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Truth or Consequences: EU Penalties Regulation Issues

  • Commission Regulation (EC) No 658/2007 was finally adopted on 14 June 2007, and will enter into force on 5 July 2007

  • Commission can now impose fines, for breaches of certain regulatory obligations, on companies whose medicinal products have been authorized in accordance with the central authorization procedure laid down in Regulation 726/2004

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Penalties for breach of certain obligations Issues

  • Penalties can be imposed for breaches of certain obligations, such as:

    • the obligation to provide accurate and complete information in the marketing authorization application;

    • failure to comply with the conditions or restrictions included in the marketing authorization;

    • failure to notify the EMEA about the date of placing the product on the market; or about any prohibition or restriction imposed by the competent authorities of any country in which the medicinal product is marketed;

    • failure to supply the EMEA with any information that may influence the evaluation of the risks and benefits of the product;

    • breach of labelling and packaging obligations;

    • breach of pharmacovigilance obligations, etc.

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Types of penalties Issues

  • The Regulation provides for two types of financial penalties: fines and periodic penalty payments

  • Where the marketing authorisation holder has committed, intentionally or negligently, an infringement, the European Commission may impose a fine of up to 5% of the authorisation holder’s Community turnover in the preceding year. The Regulation provides that in determining whether to impose fines and in determining the appropriate fines the European Commission shall be guided by the principles of effectiveness, proportionality and dissuasiveness

  • Where the marketing authorisation holder does not terminate the infringement, the European Commission may impose periodic penalty payments per day not exceeding 2.5 % of the holder’s average daily Community turnover in the preceding business year

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Non-cooperation penalties Issues

  • The Penalties Regulation also permits the European Commission to impose fines on marketing authorization holders not exceeding 0.5 % of their Community turnover in the preceding business year where, intentionally or negligently they do not comply with requests by the EMEA or the European Commission during the investigation or they supply incorrect or misleading information in response such a request

  • Moreover, where non-cooperation of the marketing authorization holder continues, the European Commission may also impose periodic penalty payments per day not exceeding 0.5 % of the holder’s average daily Community turnover in the preceding business year

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Clinical Trials in Developing Countries Issues

The continued supply issue

Liability issues for sponsors

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The continued supply issue – World Medical Association Issues

  • Paragraph 30 of the WMA Declaration of Helsinki :

    • "At the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study.“

      *Paragraph 30 was added at the 52nd WMA General Assembly, Edinburgh 2000

  • Note of clarification on paragraph 30):

    • “The WMA hereby reaffirms its position that it is necessary during the study planning process to identify post-trial access by study participants to prophylactic, diagnostic and therapeutic procedures identified as beneficial in the study or access to other appropriate care. Post-trial access arrangements or other care must be described in the study protocol so the ethical review committee may consider such arrangements during its review.“

    • The note of clarification was added at the 55th WMA General Assembly, Tokyo 2004

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U.S. approach Issues

  • Foreign studies performed under an investigational new drug application (IND) or investigational device exemption (IDE) must meet the same requirements of 21 CFR Part 312 or 21 CFR Part 812, respectively, that apply to U.S. studies conducted under an IND or IDE

  • Under 21 CFR 312.120(c)(1), FDA will accept a foreign clinical study not conducted under an IND only if the study conforms to the ethical principles contained in the Declaration of Helsinki (Declaration), as set out in 21 CFR 312.120(c)(4), incorporating the 1989 version of the Declaration, or with the laws and regulations of the country in which the research was conducted, whichever provides greater protection of the human subjects

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U.S. approach Issues

  • The U.S. has not incorporated in its clinical trial regulations the amendments to the Helsinki declaration added at the 52ndWMA General Assembly in Edinburgh in 2000

  • The U.S. regulations follow the 1989 version of the WMA declaration, which does not incorporate paragraph 30

  • The EU Clinical Trials Directive 2001/20/EC refers to the 1996 version of the WMA declaration, which does not incorporate paragraph 30. However, the EU Community Code as amended by Directive 2003/63/EC refers more generally to the Declaration of Helsinki without specifying which version.

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Latin American countries’ approaches vary Issues

  • Brazil has enacted legislation (ANVISA Resolution 251-1997) which provides that the sponsor must guarantee the subjects of the trial access to the medicines under study if these prove to be superior to conventional treatments. More recently ANVISA has published a recommendation on how the sponsor should proceed, under certain circumstances, with the donation of the product to the subjects of the study once the clinical trial is over

  • Argentina follows the current version of the Helsinki declaration, but in practice the ANMAT and the Ethics Committee decide, on a case by case basis, whether the sponsor is required to continue the supply of the tested drug once the trials is over. In taking this decision the ANMAT and the Ethics Committee will take into account factors such as the availability of the drug in the market or the chronic character of the disease

  • Chile follows an approach similar to that of Argentina

  • Other countries like Mexico have no continued supply obligations

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Liability for International Activities: Abdullahi v. Pfizer Issues

  • Abdullahi v. Pfizer is an ongoing case about whether U.S.-based researchers and clinical trial sponsors can be held accountable in the United States for torts arising out of international clinical trials. This case arises out of a 1996 trial conducted in Nigeria to test Trovan on children with brain infections

  • Background

    • Plaintiffs, who are Nigerian residents, sued Pfizer under the Alien Tort Claims Act (ATCA), 28 U.S.C.A. 1350, which allows U.S. courts jurisdiction over a tort action committed in violation of the “law of nations or a treaty of the U.S.”

    • Plaintiff argue Pfizer violated international laws and ethical standards – including the Nuremberg Code, the Declaration of Helsinki, and other guidelines – when it, among other things, failed to secure informed consent when conducting a clinical study involving Trovan in Nigeria

    • Plaintiff’s are seeking almost $2 billion in compensatory and punitive damages for allegedly causing injuries or death to 64 children and an injunction that would prevent Pfizer from conducting any testing without proper informed consent

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Abdullahi v. Pfizer: Current status Issues

  • Current Status

    • In August 2005, the Southern District Court of New York granted Pfizer’s motion to dismiss the case for the second time after it was remanded by the U.S. Court of Appeals for the Second Circuit

    • After a closer consideration of the facts surrounding the decline of jurisdiction by Nigerian courts in the similar case, the District Court held that Nigeria was an available adequate forum for the litigation

    • In light of recent Supreme Court and Second Circuit precedent concerning the ATCA, the District Court held that there was no right of action under ATCA because the Nuremberg Code, the Declaration of Helsinki, and the other guidelines do not impose obligations sufficient to give rise to a private right of action under the ATCA

    • On September 6, 2005, the Plaintiff’s filed a notice of appeal, but there has been no decision from the Court of Appeals and oral argument was scheduled for July 12, 2007

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Abdullahi v. Pfizer: Current status Issues

  • In May 2006, the Washington Post obtained a copy of a previously unreleased report completed by a panel of Nigerian Medical Experts who investigated Pfizer’s Trovan trial in Nigeria

  • The panel allegedly corroborated the Plaintiff’s allegations as disclosed in their Court of Appeals brief

  • It is alleged that::

    • Pfizer Inc., developed the protocol in the U.S. and did so in 6 weeks (ordinarily, this takes over a year)

    • Pfizer did not receive government authorization to conduct the clinical trials

    • The protocol was not reviewed or approved by an Ethics Committee prior to conducting the trial

    • The “approval” letter that Pfizer submitted was backdated and possibly forged

    • The protocol “allowed the doctors the discretion of their clinical judgment,” but the panel who investigated judged some deviations to be serious deviations that compromised patient care

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Abdullahi v. Pfizer: Nigerian cases Issues

  • Pfizer is facing four separate lawsuits in Nigeria, two launched by State of Kano, where the trials took place, and two by the Federal Government of Nigeria

  • These cases have faced a number of delays due to procedural issues

    • In early July, 2007 the civil case filed by the State of Kano seeking 2.7 billion has been adjourned until July 30 to allow both parties to study their positions. Pfizer asked for it to be dismissed because of lack of jurisdiction

    • On July 20, 2007, at the request of the Federal Government, the Federal High Court struck the Federal Government’s 7 billion federal suit instituted. This was apparently a strategic move to allow the government to fix defects in the complaint as the government expressed its intention to re-file another suit

    • On July 25, 2007, the criminal case was delayed to allow prosecutor more time to prepare

    • On July 26, 2007, the Federal Government filed a criminal case against Pfizer International and Pfizer Nigeria and several individuals accusing them of bribing officials, forging documents, and illegal importation of the drug

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Counterfeits and Sub-Standard Drugs Issues

The Problem

IMPACT: WHO Initiative

EU and Council of Europe Initiatives

APEC Initiatives

China Initiatives

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The Problem Issues

  • According to WHO:

    • Fake packaging, correct quantity of correct ingredient (clone)

    • Fake packaging, wrong ingredient

    • Fake packaging, no active ingredient

    • Fake packaging, incorrect quantity of correct ingredient

    • Genuine packaging, wrong ingredient

    • Genuine packaging, no ingredient

    • Genuine packaging, incorrect quantity of correct ingredient

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Scope of the Problem Issues

  • WHO Survey

    • 60% of counterfeit medicine cases occurred in poor countries and 40% in industrialized countries from January 1999 to October 2000

  • Counterfeits make up more than 10% of the global medicines market and are present in both industrialized and developing countries.

  • Up to 25% of the medicines consumed in poor countries are counterfeit or substandard

  • Annual earnings from the sales of counterfeit and substandard medicines estimated at over US$ 32 billion globally

  • Up to 25% of medicines consumed in developing nations are estimated to be fake or substandard

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The Counterfeit Drug Market Issues


Photos courtesy of Lewis Kontnik

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What can be done in the United States? Issues

  • Trafficking in counterfeit, unapproved, adulterated, or misbranded products is a felony violation of the U.S. Federal Food, Drug, and Cosmetic Act (FDCA)

  • FDA’s “Long Arms”

    • Cease & Desist Orders

    • Import Alerts

    • Warning Letters

    • Civil Monetary Penalties

    • “Cybersmuggling”

  • Patent Infringement

  • Business & Professional Code Violations

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Jurisdiction Under FDA and Other U.S. Laws Issues

  • FDA Jurisdiction over Foreign Entities (including “Internet Pharmacies”)

    • If impact in U.S. (example: shipping products to U.S.)

    • Injunctions against or criminal prosecutions of foreign nationals

    • Seizures of product, injunctions, criminal prosecutions, and civil penalties

    • Conspiracy Laws

    • 18 USC 1001 (False Reports to the Government Act)

    • 18 USC 542 (relating to entry of goods by means of false statements)

    • 18 USC 545 (relating to importation contrary to law and smuggling)

    • Money laundering charges

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FDA’s February 2004 Report Issues



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FDA Recommendations – Summary Issues

  • Multilayered approach; no “magic bullet”

  • New Technologies

  • Stricter Licensing Requirements

  • Tougher Penalties

  • More Secure Business Practices

  • Reporting and Response

  • Increase Education

  • International Collaboration

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Securing the U.S. Drug Supply Issues

  • Technology:

    • Unit-of-Use Packaging

    • Tamper Evident Packaging

    • Authentication Technology

    • Identification of Products likely to be counterfeited

    • Radio-frequency Identification (RFID Technology)

  • FDA Conclusion:

    • Mass serialization and RFID would provide better protection if adopted as the standard track-and-trace technology

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Much teamwork is needed to stop counterfeiting Issues

  • FDA will collaborate with foreign stakeholders to develop strategies to deter and detect counterfeit drugs globally

  • FDA will work with WHO, Interpol, and other international organizations on worldwide strategies

  • FDA suggests that drug producers, distributors, and dispensers ensure legitimacy of business partners and refuse to do business with unknown or suspicious persons.

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What is being done?: WHO Issues

  • WHO: international framework convention

    • Concept paper

    • Goal:

      • To establish norms that countries should adopt and incorporate into drug laws and the manner in which to implement them

    • To include:

      • Development of national measures to strengthen drug regulatory authorities

      • Measures to ensure quality of drug supply

      • Penalties and sanctions

    • Participants agreed that further development needed

    • Recommendations:

      • Make counterfeiting specific crime

      • Raise public awareness

      • Increase cooperation

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IMPACT: WHO Initiative Issues

  • In February 2006, the WHO launched the International Medical Products Anti-Counterfeiting Taskforce (IMPACT) in response to the growing public health crisis of counterfeit drugs

  • Aims to build coordinated networks across and between countries in order to halt the production, trading and selling of fake medicines around the globe

  • A partnership comprised of the major anti-counterfeiting players, including: international organizations, non-governmental organizations, enforcement agencies, pharmaceutical manufacturers associations and drug and regulatory authorities

  • Comprised of working groups to address the areas where action is needed: legislative and regulatory infrastructure, regulatory implementation, enforcement, technology and communication

  • Expert group of lawyers, of which I am member, met in Brussels in July 2007 to work on draft legislative concept paper.

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EU Initiatives Issues

  • Council Regulation (EC) No 1383/2003 of July 22 2003 concerning customs action against goods suspected of infringing certain intellectual property rights and the measures to be taken against goods found to have infringed such rights

    • Identifies two categories of goods that infringe property rights: counterfeit goods and pirated goods

    • Enables customs authorities, in cooperation with right-holders, to improve controls at external border

    • Sets up a more efficient system by laying down:

      • the conditions for customs action where goods are suspected of infringing intellectual property rights; and

      • the measures to be taken against goods that have been found to infringe intellectual property rights

    • Simplifies the procedure for the lodging of applications for action with the customs authorities, in particular for small and medium-sized enterprises (SMEs), and for the destruction of fraudulent goods

    • Extends the scope of application of Community action to cover new types of intellectual property rights: new plant varieties, geographical indications and designations of origin

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EU Initiatives Issues

  • Directive 2004/48/EC of the European Parliament and the Council of April 29 2004 on the enforcement of intellectual property rights

    • Harmonizes national legislation on enforcement of intellectual property rights to ensure equality of rights for all rights holders in the EU

    • Establishes an effective information exchange system between the competent national authorities

    • Thereby aims to:

      • promote innovation and business competitiveness

      • safeguard employment in Europe

      • prevent tax losses and destabilization of the markets

      • ensure consumer protection

      • ensure the maintenance of public order

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Other EU Initiatives Issues

  • Draft Directive amending Directive 2004/48/ECon the enforcement of intellectual property rights

    • Adopted by the European Parliament on April 27, 2007

    • If agreed by the European Council, Member States would be obliged toadjust their penal codesand to establish harmonized criminal sanctions against IPR-infringers

  • Launch of coordinated customs actions at major EU ports and airports

  • Establishment of an Anti-Counterfeit Task Force of Customs experts to improve targeted customs controls

  • Introduction of an Integrated European Risk Management framework to target and prevent the entrance of high-risk goods at EU borders

  • Efforts to share intelligence with third countries, such as the US and China, on trafficking developments and the detection of high-risk consignments

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Council of Europe Initiatives Issues

  • Council of Europe Draft Convention on Counterfeit medicine/pharmaceutical crimes March 30, 2007

  • Classifies pharmaceutical offenses as serious crimes

  • Provides that Member States must penalize the manufacture and distribution of counterfeit medicines

  • Establishes a network of a Single Point of Contact in all sectors concerned

  • Requires the adoption at national level of provisions to control the quality of components for pharmaceutical use, packaging material and manufacturing processes in accordance with the standards laid down by the Pharmacopoeia

  • Intensifies co-operation between law enforcement agencies at the national and European level

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Asia-Pacific Economic Cooperation (APEC) Initiatives Issues

  • On 3 June 2005 APEC Trade Ministers endorsed a series of Anti-Counterfeiting and Piracy measures including guidelines for authorities to seize and destroy pirated goods and support to increase the capacity of economies to deal with counterfeiting

  • The APEC Anti-Counterfeiting and Piracy Initiative is part of efforts intended to strengthen intellectual property protection and overcome damage caused to regional innovation and commercial competitiveness, especially for small businesses

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APEC Initiatives Issues

  • It includes a range of measures to:

    • Reduce Trade in Counterfeit and Pirated Goods - Economies aim to reduce counterfeit and pirated goods trade and combat transnational networks that produce and distribute these items. Actions include establishing guidelines for authorities to inspect, suspend, seize and destroy goods and equipment used in counterfeit and pirated goods trade

    • Reduce Online Piracy - Appropriate legal regimes and enforcement systems will be enacted to curtail online piracy and to undermine the online trade in counterfeit goods. This includes the development of guidelines to prevent Internet sales of counterfeit goods

    • Increase Cooperation to Stop Piracy and Counterfeiting - Operational contact and the sharing of information between customs and law enforcement agencies will be increased to combat counterfeiting and piracy networks

    • Increase Capacity Building to Strengthen Anti-Counterfeit and Piracy Enforcement - Member Economies' ability to develop and manage effective anti-counterfeiting and piracy enforcement systems will be increased through education and training throughout the region

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China Initiatives Issues

  • In 2006, China reportedly investigated over 300,000 reports of counterfeit drugs worth about $6.3 million and closed 530 factories

  • China is reportedly currently investigating the issue of fake drugs in a number of Chinese hospitals:

    • Suspicion was raised in Jilin, where nearly 60 hospitals and many pharmacies were found selling a fake version of albumin

    • Over 2000 bottles of albumin, all packaged in legitimate boxes, have been seized

    • There are suggestions that large Chinese counterfeit gangs, who also manufacture fake credit cards, weapons and narcotics, are involved

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Technology Issues

  • FDA’s Recommendation

    • A multilayered approach that includes radio frequency track-and-trace and authentication features

  • Chipless ID

  • Issues

    • Cost

    • Availability

    • Reliability

  • Other Security Mechanisms

  • Pedigree???

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THE END Issues

Linda R. Horton


Hogan & Hartson L.L.P.

Brussels & Washington, D.C.