eu regulatory policy at pfizer placement report web viewpfizer was founded by charles pfizer and...

Worldwide Regulatory Strategy

Placement in EU Regulatory Policy

Pfizer

Edward CooperUniversity of BathSeptember 2011-August 2012

Course: BSc Biochemistry with Professional PlacementCompany: PfizerDepartment: WRS EU Regulatory PolicySupervisor: Nick Sykes

EU Regulatory Policy at Pfizer Placement Report

Table of Contents

1. Executive Summary2. Introduction

a. History of Pfizerb. Corporate Initiatives and the Future of Pfizerc. Pfizer in Numbersd. Pfizer at Discovery Park, Sandwich

3. Product Lifecycle and Regulatory Affairsa. Product Development and Lifecycleb. Regulatory Authorities

i. European Medicines Agencyii. National Competent Authorities

iii. Non-EU Regulatory Authoritiesc. Regulatory Procedures in the EU

4. Worldwide Safety and Regulatory at Pfizera. Organisation Structureb. Department Roles and Responsibilities

5. Regulatory Policya. Regulatory and Policy Environment 2011-2012b. Legislation and Guidances in the EUc. Trade associations and Policy Interactionsd. Regulatory Policy at Pfizer

6. Personal Activities and Responsibilities a. Key Topic Areas

i. Article 57(2) of Pharmacovigilance Directiveii. Paediatrics

iii. Biosimilarsiv. Others

b. Other Activities and Responsibilities 7. Placement Evaluation8. Appendices

a. Acronymsb. Annex I – Key Documents and Terminologiesc. Annex II – Annexed Resources

Edward Cooper Page | 2


Executive Summary

Introduction

2a. History of Pfizer

Pfizer was founded by Charles Pfizer and Charles Ehart in 1849 in Brooklyn, New York as a fine-chemicals business. The first product was a palatable form of santonin, an antiparasitic used to treat intestinal worms which were endemic in at the time in America. In the 1860s Pfizers growth is carried by providing supplies of drugs for the Union Army as demand soars. Other early products included tartaric acid and cream of tartar, both of which were vital to the food and chemical industries.

In 1880 Pfizer began manufacturing citric acid and soon became America’s leading producer. This coincided with a growth in popularity for new carbonated drinks increasing demand for citric acid. It became Pfizer’s most profitable product, spurring developments such as mould and later deep tank fermentation, and formed the economic basis for the growth to follow.

In the 1930s and 40s the development focus was on the production of vitamins. That was until in 1941 Pfizer responded to an appeal from the United States Government to expedite the manufacture of penicillin to treat allied soldiers fighting in World War 2. Pfizer was the only company to use deep tank fermentation for its production, a huge capital risk for the company which came good providing a means to produce much greater quantities of penicillin.

Terramycin® (oxytetracycline), a broad-spectrum antibiotic is Pfizer’s first innovative pharmaceutical and the product of the company’s first discovery program. It is first sold under the Pfizer label in the US in 1950. It is also at this time that Pfizer began expansion into overseas markets with operations starting in Belgium, Brazil, Canada, Cuba, England, Mexico, Panama and Peurto Rico.

Pfizer’s Research and Development (R&D) facility at Sandwich, Kent was first opened in 1954. It was partly driven by a requirement to circumvent the bulk importation restrictions placed on medical materials not fully manufactured in the UK imposed by the government at that time. The site grew throughout the 1950s as Pfizer’s portfolio continued to expand. By 1960 Pfzier Ltd employed over 2,000 staff at the Sandwich site.

In 1972 Pfizer crosses the billion-dollar sales threshold. Recognizing that the key to Pfizer's future growth lies in its ability to discover and develop innovative pharmaceuticals, Chairman Ed Pratt increases the company's Research and Development budget from about 5 percent to 15 to 20 percent of sales. He also leads the ongoing battle for intellectual property protection worldwide to encourage and safeguard innovation.

By early 1992 Pfizer had brought more new products to the market in a three year period than any other pharmaceutical company in Britain. Pfizer’s success in discovering new drugs continued throughout the 1990s with several of its best selling and most well known products such as Diflucan and Viagra (which was discovered in the Sandwich laboratories) coming to the market in this period. In 2000 Pfizer acquired Warner-Lambert to make it the world’s fastest growing pharmaceutical



company. In 2009 Pfizer announced its plans to acquire Wyeth in a bid to strengthen its biologics and vaccines sectors.

In February 2011 Pfizer announced its planned closure of its European R&D headquarters at Sandwich, UK. The aim was to address the profit shortfall resulting from heavy research expenditure failing to stimulate sufficient new products. In the time since Pfizer has continued to streamline its R&D enterprise worldwide in a bid to increase productivity based on more focused areas of research. (1) (2)



2b. Corporate Initiatives and the Future of Pfizer

At present the pharmaceutical Industry is operating in the hardest climate it has known. With the famed “Patent Cliff” approaching and an estimated x% of blockbuster drugs loosing exclusivity in the major markets by 2015(?14) and evidence showing lower numbers of new drug approvals in recent years than ever before Pharma is feeling the pinch.

Figure 1: Number of US FDA New Molecular Entity Approvals against R&D Spend over time.

The funding demographic is changing too with new pressures from cost containment schemes as well as shareholders. Whilst the ageing baby boom generation is providing plentiful demand for products, crippling economies are straining to pay for it. There is therefore a realisation that the Industry needs to adapt and reinvent itself.

The Mission and Vision of Pfizer

Mission Statement

“To ensure we can continue to deliver on our commitments to the patients, customers and shareholders who rely on us, we are focused on improving the way we do business; on operating with transparency in everything we do; and on listening to the views of all of the people involved in health care decisions. Through working in partnership with everyone from patients to health care providers and managed care organizations to world governments and non-governmental organizations, our goal is to ensure that people everywhere have access to innovative treatments and quality health care.”



Pfizer.com/About/

Pfizer is committed to the innovative pharmaceutical model, providing prescription medicines to patients. The overarching strategies outlined below are designed to promote the business’ continued success.

The 4 ImperativesDesigned to reflect Pfizer’s core values the key imperatives are CEO Ian Read’s communicated drivers for ongoing success as an innovative healthcare company.

1. Fix our innovative core – Generate medicines that profoundly impact health.Expresses the need to create a sustainable platform for growth through innovation focusing on disease areas in which Pfizer can ‘win’. Also provides an emphasis upon the importance of generating a greater return on investment.

2. Make the right capital allocation decisions that will maximize value for Pfizer and that create enhanced shareholder return.

3. Be respected by societyThe imperative focuses on closing the perception gap between how the company acts and how the public believes the company acts.

4. Creating an Ownership Culture – OWN ITThe aim is to create an environment where colleagues are encouraged to take the initiative and be accountable for the consequences, driving entrepreneurial behaviour.

Figure 2: OWN IT visual sourced from: http://world.pfizer.com/OwnIt/Pages/OWNIT.aspx



The Three HorizonsThe Worldwide Research and Development (WRD), one division within the current Pfizer organisation, Journey to the Three Horizons strategy underpins the First Imperative; Fixing the Innovative Core.

Horizon 1: Deliver the PortfolioHorizon 2: Innovate new capabilitiesHorizon 3: R&D Ecosystem of the Future

In a landscape where payors1 are increasingly becoming less willing to reward incremental improvements in therapy Pfizer’s WRD organisation is focusing its efforts on projects that will provide clear improvement in treatment options for patients. This not only means investing in assets for areas of unmet clinical need; for Pfizer it means shifting the development paradigm towards areas such as Precision Medicine, advanced therapeutics and biosimilars.

Pfizer is pioneering the Precision Medicine approach which targets small subsets of patients with certain characteristics aiming to achieve enhanced results. Pfizer has already gained approval for Crizotinib, trade named Xalkori, in the US where it is now available to patients. Crizotinib is a very effective treatment of non-small cell lung cancer (NSCLC) for Alk+ patients; that is only patients with a certain genotype (~5% of NSCLC patients diagnosed) which is determined through an accompanying diagnostic test. Under the Three Horizons Strategy, Mikael Dolsten, President WRD, has set ambitious targets for precision medicine development and expects that by 2020 4 out of every 5 products launched will be a precision medicine drug.

1 Payors are the organisations which fund the reimbursement to companies for the medicines they provide. In Europe this is generally state funded, for example in the UK NICE (National Institute for health and Clinical Excellence) pays for medicines used by the NHS excluding cost covered by prescription fee.



2c. Pfizer in Numbers

Pfizer is the world’s largest pharmaceutical by sales volume and employs in excess of 110,000 people worldwide.

Pfizer is performing well on the stock market despite loss of exclusivity in most major markets for Lipitor, the best selling branded medicine in history. This has however taken a clear effect upon net sales which have been down approximately 9% in the year to date compared to 2011.

Figure 3: Pfizer Stock Price Performance Jan-Jul 31st 2012 in comparison to DRG (Pharmaceutical Index) and S&P index (500 top publically traded American Companies)

Source: One Pfizer Quarterly Update Broadcast

Figure 3 shows the Pfizer stock price at 24.04, a 4 year high on July 31st when Pfizer reported its Q2 2012 earnings.



Figure 4: Q2 Income Statement Highlights and Demonstration of Growth in Emerging Markets

Source: One Pfizer Quarterly Update Broadcast

The negative effect of decreasing sales and foreign exchange rates2 has been to some extent offset by aggressive share-repurchasing3. Pfizer also experienced growth in the ‘emerging markets’ which helped to balance figures. This growth is lead by established products, branded or non-branded generic off patent medicines which Pfizer operates based on an opportunistic basis. The reduction of outgoings across the business through operational excellence initiatives has also been important in turning over positive figures. Pfizer was able to reaffirm projected earnings at the end of Q2 which is considered a strong result in this economic climate. Such reliable estimations improve investor confidence and as a result drive the share price.

2d. Pfizer at Discovery Park, Sandwich

In February 2011 Pfizer announced a full exit from its European R&D headquarters at the Sandwich Site. The closure and implicated job losses are of significant impact to the surrounding communities and economic climate of East Kent.

The original decision has been reverted to some degree with Pfizer maintaining a go-forward presence at the Sandwich site centred on the Pharmaceutical Sciences facilities. Currently there are approximately 700 employees on the site and the expectation is that these positions will be maintained. Pfizer is looking to sell the site and rent buildings 530, 510 and the Pilot Plant where operations are continuing. The site has been designated as an enterprise zone, providing preferential rates to business moving to the site.

Building 530 is now a facility shared with other companies; Mylan and Peakdale have some of the larger footprints of the other occupants. Several spin-off companies have been incorporated into the building.

2 Exchange rate of strong dollar working against Pfizer as a US reporting company due to revenues achieved outside the USA, particularly in Europe, being cut when converted to US $.

3 As Pfizer buys back shares in the company it decreases the proportion of revenue that must be provided to shareholders resulting in Pfizer earning more for each $ of revenue.



Product Lifecycle and Regulatory Affairs

3a. Product Development and Lifecycle

Medicines are the end product of a development program which can typically take as long as 15 years. Before a medicine can be marketed for use in humans it must be shown to safe and efficacious4 and that it can be manufactured to a high quality. There is therefore a journey from the discovery of the active product5 through pre-clinical, non-clinical and clinical6 development to regulatory evaluation and ongoing pharmacovigilance assessment.

The Research PhaseThe productivity gap where increased R&D spend has not produced more blockbuster medicines (2b) has lead to companies reassessing their research models. The trend has been cost cutting and outsourcing of early stage research combined with the in-licensing of promising candidate molecules. In effect big pharma is opting to buy in the research conducted in smaller biotech enterprises or conducted in partnership with the academic community. The later stage development of medicines is also being undertaken through partnerships more frequently, with the marketing rights for the product split post approval.

Regulatory AssessmentThe data generated from the 3 major data packages (quality, non-clinical and clinical) is critically assessed by regulatory authorities to establish whether the products quality, efficacy and safety profiles are acceptable and that any packaging and product claims are accurate relevant to available data (3). This review is fairly complex and centres on a determination of whether the product shows a positive benefit: risk balance. If a product is deemed to have a positive benefit : risk balance it is usually provided with a marketing authorisation, allowing it to be used to treat patients outside of the clinical trial setting.

Pharmacovigilance and Post Marketing CommitmentsAll medicinal products are subject to pharmacovigilance7 monitoring to extend knowledge beyond clinical trial data which is limited by population size and a controlled treatment environment. Through extensive reporting systems unwanted side effects of medicines are recorded and analysed. This takes advantage of the huge wealth of information available in the form of real world data to update the safety profile of medicines. This provides the data required to support the introduction and publication of new special warnings, precautions for use and in extreme cases product suspension or withdrawal.

4 Efficacious is defined as capable of having the desired effect, therefore in medicines efficacy is an ability to treat or prevent a disease (or halt disease progression).

5 Active product or active product ingredient (API) is the chemical entity within the pharmaceutical product which interacts with biological systems to stimulate the desired effect.

6 Pre-clinical is in-vitro research, Non-clinical is in-vivo (most commonly rodents) and clinical is in human.

7 Pharmacovigilance (PhV) is the practice of interpreting, understanding and preventing the occurrence of adverse events (typically side effects of medicines).



Post marketing commitments (PMCs) are agreed in the medicines marketing authorisation (MA) and represent studies and evaluations the sponsor is obliged to complete following authorisation. These typically include long term safety studies and deferred8 or longer term paediatric studies.

Post Approval Product DevelopmentPharmaceutical products are often further developed once authorised. This may include research into the products use to treat different conditions or provide a different means of administering the product. In these instances additional relevant data must be generated in a similar fashion to the original application for MA to prove safety and efficacy. Such applications are able to draw upon the conclusions of data previously generated where consistent.

Once available on the market more information will be learnt about the product. This may require a change to the information available to patients and prescribers or kept in competent authority9 records. Such information is updated in real time as change signals are recognised. Medicinal products licenses are also subject to renewal, encompassing a scientific review, on a cycle (typically annually) which may trigger the implementation of such changes. Loss of Exclusivity (LOE)The loss of exclusivity represents the last major milestone in an innovative pharmaceutical lifecycle. This is the point when other manufacturers can market copycat drugs, known as generics. Generics are licensed on a greatly reduced data package with a requirement to show that they are “essentially similar” to the reference product. Generics can therefore be sold at significantly cut prices requiring the innovator company to produce strategies to maintain the greatest possible market share.

8 Studies in children can in some cases be deferred until after adult development to prevent a lack of paediatric data delaying availability of treatment for the adult population, further information can be found in section 5a.ii.

9 The authority of scientific expertise responsible for evaluating the safety and efficacy of medicinal products.



3b. Regulatory Authorities

Regulatory Authorities, sometimes referred to as agencies or competent authorities, are the bodies of scientific expertise responsible for the evaluation of medicinal products. They typically hold the legal mandate to protect public health and are required to ensure that medicines are safe and effective but also to promote effective innovation and development of new medicinal products. Within the EU and around the world working practices and in some cases terminologies differ but the principle behind their activities is consistent.

3b.i. The European Medicines Agency (EMA)

Creation of the EMA and Legal BasisThe European Agency for the Evaluation of Medicinal Products was set up in 1995 with funding from the European Union and the Pharmaceutical Industry. It was later renamed as the European Medicines Agency in 2004. The intent was to harmonize, but not replace the work of the National Competent Agencies (NCAs) (3b.ii). Industry stood to gain on the basis that it would help reduce the cost of applying for licence in each individual member state and remove the potential for protectionist refusal of new medicines which may compete with those already produced by domestic drug companies.

The legal basis for the EMA is laid out in Regulation (EC) 726/2004 (4). The EMA is responsible for the protection and promotion of human and animal health, through the evaluation and supervision of medicines for human and veterinary use. The EMA achieves this by coordinating the existing scientific resources placed at its disposal by Member States. The EMA does not hold the legal authority for the authorisation, suspension or revocation of medicinal products and can only provide a recommendation based on its expert opinion. The European Commission is responsible for the adoption of the necessary provisional measures following consideration of the opinion.

Operation of the EMAThe European Medicines Agency is the decentralised regulatory agency of the EU and coordinator of most collaborative regulatory activities across Europe. The most obvious activity of the EMA is its role in the centralised procedure10 (CP) where it coordinates the competent review of a product to grant and maintain a “community licence” valid throughout the European Union (EU) and EEA-EFTA states11 (2c). The EMA can be considered the ‘hub’ of the European regulatory network and is therefore a key player in driving the development of regulatory science in the EU.

The EMA works with a network of over 4,500 ‘European experts’ who serve as members of the committees, working parties and assessment teams which form the basis of available scientific expertise. The scientific expertise available to the EMA is organised into committees in which scientific expertise of all member states, EU and EEA-EFTA, are represented. Some of the committees also include representatives of patient and health care professional (HCP) organisations.

10 The centralised procedure provides the facility for an applicant to apply for a single MA valid in all Member States of the EU.

11 Iceland, Liechtenstein and Norway.



Committee for Medicinal Products for Human Use (CHMP)The CHMP is the committee responsible for the competent evaluation and supervision of medicinal products authorised through the centralised procedure. In the Decentralised and Mutual Recognition procedure (2c) the CHMP arbitrates in cases of disagreement between member states. The CHMP plays an important role in EU-wide PhV activity, closely monitoring potential safety concerns and where necessary making recommendations to the European Commission regarding changes to a medicines MA, or its suspension/withdrawal from the market. The CHMP is also responsible for the provision of scientific advice and preparation scientific and regulatory guidelines for the pharmaceutical industry. The EMA has published on its website the rules governing the operation of CHMP as well as the CHMP work plan which sets out the priority objectives linked to the EMAs development (5a). (5) (6)

Other CommitteesCVMP – Committee for Medicinal Products for Veterinary Use: equivalent of CHMP relevant to veterinary products

COMP – Committee for Orphan Medicinal Products: responsible for reviewing applications for ‘orphan medicinal product designation’12.

HMPC – Committee on Herbal Medicinal Products

PDCO – Paediatric Committee: Responsible for agreeing the Paediatric Investigation Plan (PIP)13

CAT – Committee for Advanced Therapy Medicinal Products: Prepares a draft opinion on Advanced Therapy Medicinal Product applications prior to CHMP opinion.

PRAC – Pharmacovigilance Risk Assessment Committee: responsible for monitoring and assessing safety issues for human medicines. Its opinions are considered by the CHMP in adopting opinions.

Other Activities of the EMAThe EMA is responsible for the implementation of a set of pan-European systems and databases such as EudraVigilance (5a.i), EudraCT14 and EudraPharm15. (7)

3b.ii National Competent Agencies (NCAs)12 Orphan Designation is an incentive provided to products which are developed to treat rare diseases and would therefore be likely non-profitable. It provides for additional 10 years market exclusivity, preventing the authorisation of competing products using a similar substance unless it can prove exemption criteria described in the Orphan Drugs legislation; Reg (EC) 141/2000, for example Clinical Superiority.

13 Paediatric Investigation Plans are a requirement for all innovative medicinal products in the EU. They set out how a sponsor will research the use of the product in children, providing data to support prescribing guidance. See 5a.ii for further information.

14 Database of Clinical Trials conducted within the EU

15 Database of Medicinal Products authorised through the centralised procedure. Provides public access to SmPC and PiL.



Typically each country has its own regulatory agency responsible for the review and surveillance of medicinal products. In each country the remit of the NCA is individual and working practices can vary significantly. The decision on pricing and reimbursement16 remains a purely national issue and is increasingly undertaken with the aid of assessments from Health Technology Assessment (HTA) agencies which are sometimes incorporated into the NCA. HTA assessments typically involve a comparative assessment of therapeutic benefit against current standard of care.

Heads of Medicines Agencies (HMA)Established in 1995, the HMA is a network of the Heads of NCAs whose organisations are responsible for the regulation of medicinal products for human and veterinary use in the European Economic Area. It focuses on collaboration and harmonisation of national agencies and the smooth functioning of decentralised and mutual recognition procedures (3c). The HMA works in close collaboration with EMA and this framework is integral to the smooth functioning of the European Regulatory Network. (8)

3b.iii Non-EU Regulatory AuthoritiesOutside the EU medicines are typically regulated on a purely national basis although increasingly work sharing networks are being developed in Asia and Latin America. Each country has its own requirements and regulations providing a highly dynamic environment. Policies in the Emerging Markets17 are often influenced by political and economic drivers as well as healthcare provision. An example of this would be the requirement of China to conduct clinical trials in Chinese patients and therefore force an investment in the country. This is justified on ethical factors. Regulatory agencies in the emerging markets are developing quickly to meet the increasing demands being placed upon them. In many instances these countries will reference the decisions of the US FDA or EMA for the review of medicines, or adopt practices and legal frameworks already seen in these more developed environments.

16 Typically a medicine has a negotiated price for which the company sells the product and a negotiated reimbursement value, the amount which the payor (typically the state in Europe) will cover these costs.

17 Emerging Markets in the field of medicine regulation typically refers to all countries other than the USA, EU, Japan, Australia-New Zealand and Canada.



US Food and Drug Administration (FDA)The FDA is an agency within the department of Health and Human Services and has the responsibility for protecting public health. In addition to regulating the use of medicinal products for people and animals the FDA is responsible for regulating food and tobacco products. Unlike the EMA the FDA is a centralised agency which reports directly to the national government. (9) On the global stage the FDA is a key player in the International Conference on Harmonisation (ICH) along with EMA and the Japanese Health Authority. ICH provides a platform for the global harmonisation of regulatory requirements and to date more than 40 harmonised guidelines have been developed on technical matters in the areas of quality, efficacy and safety. (10)

World Health Organisation (WHO)The WHO plays a significant role in the global regulation of medicines producing many guidelines that are widely adopted. Perhaps the foremost of these are the guidelines on Good Manufacturing Practice (GMP) and Good Clinical Practice (GCP) which set out formalised standards that all medicinal products must adhere too. These are very similar to the guidelines present in the EU and USA which have been tempered slightly to fit with regional legislation.

3c Regulatory Procedures in the EU

The Centralised Procedure (CP)The CP, introduced in 1995, is governed by Regulation (EU) 2001/83 and provides a MA valid throughout the EU. The CP is mandatory for new products derived from biotechnology processes18 and Orphan drugs. It is also mandatory for products containing an active substance (not authorised in the EU before May 2004) which are intended for the treatment of AIDs, cancer, neurodegenerative disorders, auto-immune diseases, viral diseases and diabetes. For other products the procedure is optional provided it represents an innovation or its authorisation would be in the interest of public or animal health. In practice the majority of new chemical entities (NCEs) are authorised via the CP.

Products authorised through the centralised procedure are evaluated by a rapporteur and co-rapporteur, members of the CHMP representing Member States (MS), who hold specific expertise in the relevant therapeutic area. Their analysis and decisions are peer-reviewed through the CHMP which provide an eventual opinion on authorisation by majority vote.

18 This includes genetically engineered products (often referred to as biologicals) where the active ingredient is grown in a cell culture, and advanced therapy products including gene therapy, somatic cell therapy or tissue engineered medicines.



Outline of the CHMP (CP) Approval Process

Figure 5: Timeline for Centralised Procedure submission

Built into the procedure are several points of interaction between the sponsor company and the CHMP. Most significant of these are at Day 120 and 180. The clock stop following the Day 120 List of Questions typically lasts 3 months. It is for this reason that Pfizer anticipate a total length of a 15 month procedure. At the end of the procedure the CHMP will adopt a positive or negative opinion as to whether the product should receive a MA.

The CHMP opinion is provided to the European Commission who must take the decision on whether or not to licence the product. The Commission usually follows the opinion of the CHMP however there are exceptions. One such example is included; Annex II. Once a community MA has been granted it is valid for 5 years, once this has elapsed it is reviewed indefinitely.

The benefits of using the CP are that a single EU license is gained which covers all MS. This not only simplifies the procedure of applying for a licence but reduces the burden of maintaining the product as the MAH only has to interact with one regulatory agency and only provide updates to a single Summary of Product Characteristics (SmPC)19 and Patient Information Leaflet (PIL)20. One disadvantage to the procedure is that the sponsor cannot choose the CHMP members assigned as rapporteurs (which is possible in MRP/DCP). This procedure may not be appropriate for products which are only going to be marketed in a single or low number of MS.

19 A document designed to provide information to Health Care Professionals (HCPs). It is also the foundation for a products marketing programme.

20 The package insert provided to patients giving details of the medicine and instructions for use.



Mutual Recognition Procedure (MRP)The MRP procedure provides a framework to allow MS to reference the Marketing Authorisation decision of another MS. In this pathway the sponsor company chooses the MS in which to file for a national MA, known as the Reference Member State or RMA. The other countries in which the sponsor would like to licence the drug are requested to recognise this approval if successful and are termed the Concerned Member States (CMS). The RMS performs the initial product review and if successful grants the first regulatory approval. This will be the first country in which the product can be marketed. The CMS are then asked to mutually recognise the assessment report and SmPC provided by the RMS within 90 days.

The benefits of the MRP procedure are that the applicant has control over choosing the RMS and CMS. This can allow a sponsor to focus its resources on a few key markets. Also potentially beneficial where a product will be co-marketed with another company the MRP facilitates multiple trade names. The biggest downside to the procedure is that CMS often disagree with the assessment report produced by the RMS and this can hold up the procedure and cause delays. This is exasperated by countries with more developed regulatory agencies tending to conduct their own detailed reviews; and has the effect of duplicating work. The MRP provides a separate MA in each country, each with its own SmPC. This can represent a resource burden for the Marketing Authorisation Holder (MAH) to manage the additional interactions and requirements this creates.

Decentralised Procedure (DP/DCP)Introduced in 2005 the DP is an evolution of the MRP. The intention was to reduce the occurrence and impact of disputes between MS which cause delays to authorisation. The DP is similar to the MRP however timelines are shorter (maximum of 210 days, split into two assessment phases, with opportunities to close out procedure ahead of time if consensus is reached between RMS, CMS and applicant) and the MAA is submitted simultaneously to the RMS and CMS. The RMS prepares a draft assessment report which is shared with all the CMS for reflection and judgement. The rationale being that by providing CMS early input into the evaluation any potential concerns can be addressed in a timely manner. If approved the applicant receives the same MA in all chosen MS at the same time.



Figure 6: Diagram of DP review pathway

CMD = Coordination Group for Mutual Recognition and Decentralised Procedures. If after CMD opinion there is no agreement it goes to arbitration.

The procedure can be used for any products which are not authorised within the community and are not mandatory for the CP pathway. It is often favoured by less complex applications such as generics21.

National ProceduresNational procedures are rarely used for the filing of prescription medicines which are generally developed by large multinational corporations. Pfizer however still maintains a significant number of nationally approved licenses for older products which were authorised before the implementation of the procedures described above. National licences are now used more frequently by small and medium-sized enterprises producing generic or consumer health products. In these procedures the applicant applies directly to the NCA and follows national review procedures which vary significantly from country to country.

21 Copy Drugs which have to show they are “essentially similar” a product currently on the market. They therefore only have to provide comparative quality data. There is no requirement for full non-clinical and clinical data for generic drugs. Bioequivalence studies are usually sufficient.



Clinical Trial Applications (CTAs)To conduct a clinical study in any state it must first be approved by national procedures in accordance with the clinical trial directive (2001/20 EC). The approval of CTAs is within member state competence. The decision is split into a scientific approval by the competent authority and an ethical approval for which the assessment is typically made by ethics committees.



Worldwide Safety and Regulatory at Pfizer

Worldwide Safety and Regulatory (WSR) is the business line responsible for interactions between Pfizer and Regulatory Authorities.

4a. Organisational Structure

WSR is a functional line of Worldwide Research and Development (WRD).

Figure 7: Functional lines within WRD.

WSR has within it Worldwide Regulatory Strategy (WRS), Worldwide Safety Strategy (WSS) and Worldwide Safety and Regulatory Operations (WSRO).



4b. Department Roles and Responsibilities (Worldwide Regulatory Strategy (WRS))

Mission StatementWRS delivers excellence through trusted compliant and innovative strategies so patients, consumers and Pfizer will benefit from our valued products.

Figure 8: Poster documenting WRS roles and Activities, produced for Internal Sandwich Site Event

The primary function of WRS is developing strategies to bring products to market and maintain their authorisation through the quickest, most feasible route. In the discovery and pre-clinical and clinical phase WRS helps identify potential regulatory risks, create mitigation plans and manage relationships with regulatory authorities. Additionally in the clinical development phase (I – III) WRS colleagues open and maintain Clinical trial applications (CTAs) and Investigational new drug applications (INDs)22. In the registration phase WRS are the focal point for external contact and co-ordinate response actions to regulatory agency requests and questions. WRS also drives the label (SmPC) development, both internally and through negotiations with regulators, which is fundamental to the successful marketing of the product. Post authorisation WRS is responsible for coordinating the maintenance of authorisation; renewing products, providing updates to information and responding to safety signals etc.

Worldwide Regulatory Strategy (WRS) is responsible for managing the company’s relationship with regulatory agencies. All communications and submissions made to regulators are checked and signed by WRS. It is important to realise that this activity applies to all Pfizer products, in all

22 US equivalent of a Clinical Trial Application



countries at every stage in the product lifecycle. This role is also adopted at the above product level where WRS represents Pfizer in Policy level discussions, providing input and influence to future practices and requirements applicable to the regulation of medicinal products. Effectively managing these relationships to ensure that all information provided is accurate and advocacy positions adopted are reasoned is critical to Pfizers reputation.

Role of a Global Regulatory Lead (GRL)The majority of the WRS EU group is made up of product strategists and Regulatory Leads. A Global Regulatory Lead (GRL)23 is accountable for regulatory strategy. The RL is the “go to” person on the project team. The regulatory lead is responsible for communication and alignment within the regulatory sub-team. The RL is responsible for internal communication and reporting. By strategy it means plans and timelines including balancing risk vs time and working out the most appropriate (incorporates speed and cost) way of overcoming regulatory hurdles to getting and maintaining a product on the market.

Figure 9: Interactions of the GRL with Regulatory colleagues and the product’s core team.

What does a GRL Do? Provides advice on regulations and the implications to the core team. Defines and documents the regulatory strategy. Helps to develop the product label. Manages the regulatory risk log. Manage regulatory agency meetings and interactions. IND/CTA preparation. Optimize a marketable label (SmPC in Europe)

Regulatory do not prepare applications to regulatory authorities, this is done by the submissions group. However, WRS plays a leading role in defining the content of the applications.

23 GRLs are sometimes termed GRPLs - Global regulatory product leads however this acronym is also used for Global regulatory portfolio lead within Pfizer. Portfolio leads operate at an above product level on a group of products within the same therapeutic area.


RL

Jpn

EU

US

CMC

EMCoreTeam

Regulatorysub-team

GRPL


Regulatory Policy

The Regulatory Policy function monitors changes in the external environment, assesses the business implications and develops advocacy plans to influence the environment in a way favourable to Pfizer.

5a. Regulatory and Policy Environment 2011-2012

Regulator – Industry InteractionPresently regulator interaction, particularly with EMA, is more restricted to formal format than previously seen. Political pressure, fallout from the mediator scandal24 and the embarrassment caused by the consultancy role adopted by EMA’s previous executive director immediately after breaking affiliation with the agency are the principal reasons. Therefore most policy-related interactions with EMA have to occur through trade associations. On a product specific level, it is in some cases still possible for the sponsor to contact the rapporteur directly (3c) however any documentation must be shared through the formal process via the Project Team Leader (PTL)25. On the global scale ICH is another example where Industry involvement has been reduced as a result of political pressure from the EU which threatened to withdraw from the agreement if Industry continued to have any influence in the later decision stages.

TransparencyThere is a drive within the EMA for increased transparency throughout the regulatory process. In recent years the European Public Assessment Report (EPAR)26 has been revised to more clearly present the reasons for CHMP opinion in the Benefit/Risk Decision. This has been highlighted as an area of ongoing work in the EMA roadmap to 2015 (11). Sponsors can no longer expect to benefit from sweeping confidentiality of product information as facilities such as freedom of information requests and the EMAs policy of providing as much information as possible in accordance with EU law mean a MAH will have to justify the omission of information piece by piece from any given document. Furthermore the EMA plans to begin publishing much more information on medicinal products upon its website as soon as it has the IT infrastructure required.

The EMA has also responded to calls to tighten up its conflict of interest requirements however in the view of the European Parliament these efforts are not sufficient and the EMA needs to take further action. This was the reason cited for postponing signing off the EMA budget for 2011 in May which remains uncertain (12). Further information can be found in the EMA’s transparency Policy (13).

24 Mediator, a product of Servier (French company) has been identified as the cause of a significant number of fatalities. It was kept on the market in France for several years after withdrawal from most European markets following safety concerns.

25 Project team leader is the primary contact at the EMA who coordinates the exchange of information between applicant and scientific experts.

26 A publically available document which summarises the scientific assessment of medicinal products.



Stimulating Innovation and Innovative Medicines Initiative (IMI)It is within the remit of the EC and EMA to stimulate innovation for the benefit of public health. There are many initiatives which look to facilitate the development of medicines which would otherwise be non-economically attractive, for example orphan designation (3b.i). Through the EC DG Innovation and research the Framework Programme for Research provides funding for under-researched areas such as antimicrobial resistance and supports SMEs. Pharmaceuticals sector will receive the 3rd greatest sum under FP7 (2013) (14).

The Innovative Medicines Initiative (IMI) is a public-private partnership between the European Commission and EFPIA (representing the pharmaceutical Industry). Its aim is to address some of the blockages in the development of new medicines. IMI has many projects which are currently mostly focused upon research issues. The projects are long term however the impacts are expected to be significant. It is important that the scientific decisions resulting from IMI are accepted as valid for use in regulatory decisions. The focus of IMI is gradually shifting towards more regulatory focused projects, shown for example by the inclusion of “incorporating real life clinical data in drug development” in the 7th call for proposals (15). This trend will likely continue in IMI 2 due to Industry interest if it becomes a reality.

Non-Regulatory Specific Items

Patient Access to MedicinesThe greatest challenge facing European health care systems is sustainability. With tension applied on state purse strings healthcare, and medicine, budgets are being cut. With an ageing population which is better cared for the prevalence of chronic disease is increasing and the current model struggling to fund it. An ever increasing proportion of medicines being authorised are failing to achieve reimbursement and as a result access is denied to the majority of patients. At present the signs suggest that this phenomenon will be exaggerated in the future.

Falsified MedicinesThere has been an increasing movement seeking to protect the community from the detrimental health effects associated with fake medicine. In June 2011 the EU amending directive 2001/83 on falsified medicines entering the legal supply chain was released (14). The directive made certain provisions designed to protect the public from exposure to falsified medicines. Member states have until January 2013 to begin applying the measures in national law. The topic has also been a controversial area on the policy front with EFPIA and partnering associations proposing the European Stakeholder Model (ESM) (15) which has been criticised in some quarters for having implications serving to protect market exclusivity for innovative products.

Drug ShortagesThe drug shortages crisis seen in 2011 and 2012 has been largely confined to the USA however the ripple effect has been felt in Europe. Policy makers and regulators are now starting to look at the reliability of licensed manufacturing facilities as documented. To date the issue has focused on generic manufacturers listing several manufacturing sites for a product but in reality only manufacturing out of one, whilst the others are in a manufacture-ready state for the specific



product. The spotlight has not yet focused on the innovative industry where similar issues may exist in some capacity.

Further information is available in the EUCANZ Regulatory Policy Environment Scan in Annex . A summary of key policy topics can be found in 5d.

5b. Legislation and Guidances in the EUThe documents which detail requirements to be met by stakeholders in the provision of medicinal products to patients can be broadly split into legislation and guidance, sometimes termed soft law.

LegislationOn a pan-EU scale legislation is born from the European Commission (EC) and split into Directives and Regulations. Directives are binding in requiring MS to achieve a certain result without dictating the means of achieving that result. This affords MS some leeway as to the exact rules to be adopted. Regulations are self-executing and do not require any implementing measures. The legal basis for Directives and Regulations is set out in Article 288 of the Treaty on the Functioning of the European Union:

Article 288 To exercise the Union's competences, the institutions shall adopt regulations, directives, decisions, recommendations and opinions.

A regulation shall have general application. It shall be binding in its entirety and directly applicable in all Member States.

A directive shall be binding, as to the result to be achieved, upon each Member State to which it is addressed, but shall leave to the national authorities the choice of form and methods.

A decision shall be binding in its entirety upon those to whom it is addressed.

Recommendations and opinions shall have no binding force.

The implications to the Pharmaceutical Industry of implementing requirements as directives are that national authorities can introduce non-harmonious requirements which can be an additional burden to Industry. Regulations enforce more harmonious implementation of the text; however issues can arise if the legislation proves to be unwieldy and non efficient as there is less room to deviate from the exact text.

The legislative procedure in the EU is typically a slow process taking several years for new legislation or amendments to be adopted. The co-decision procedure used requires that the Council and the European Parliament (EP) both agree and approve the text, first drafted by the EC. The procedure is designed to ensure a balance of the 3 powers, the commission, council and EP. These represent the interests of the union, member states and democratic interests respectively.



Figure 10: The Co-Decision procedure for the enforcement of legislation in the EU.

Pharmaceuticals comes within the remit of Commissioner Dalli, DG SANCO27 at the commission. DG SANCO is therefore responsible for the first draft of any legislation referring directly to the Pharma Industry. This will be reviewed by other interested DGs at the commission, for example Enterprise and Industry. Any texts must be agreed by all Commissioners prior to release into the co-decision procedure.

27 Directorate General for Health and Consumers



GuidancesUnderpinning the legislation there are many guidelines pertaining to medicinal products for pharmaceutical manufacturers to follow. These guidelines hold no legal force and are usually produced with the intent of assisting Industry in meeting the obligations set out by legislation. Guidance can be broadly split into two categories, regulatory and scientific. Regulatory guidelines typically come from the EC and/or EMA and set out procedures. These provide industry with instruction on how to submit certain applications (e.g. renewals) and what can be expected from involved parties through the procedure. Scientific Guidelines are intended to provide a basis for practical harmonisation of the manner in which the EU Member States and the EMA interpret and apply the detailed requirements for the demonstration of quality, safety and efficacy contained in the Community Directives. They also help to ensure that applications for marketing authorisation are prepared in a manner that will be recognized as valid by the EMA.

5c. Trade Associations and Policy Interactions

Trade AssociationsFunded by their member companies trade associations provide a means for collaboration between members and a basis for lobbying as a unified voice for the Industry they represent. The two most significant trade associations serving large scale innovative pharmaceutical companies28 are PhRMA in the USA and EFPIA in Europe.

EFPIA The European Federation of Pharmaceutical Industries and Associations, EFPIA, is the principal trade association acting on behalf of pharmaceuticals Industry in the EU. Within EFPIA there are two member associations, EVM and EBE. These are the European Vaccine Manufacturers and European Biological Enterprises respectively and represent the interests of manufacturers of these subgroups of medicinal products. EFPIA has been a key driver in many initiatives in the EU. Perhaps the best known of these is the Innovative Medicines Initiative (IMI), a public-private partnership and joint undertaking of the EC and EFPIA. IMI aims to speed the development of better and safer medicines for patients (5a). Another area of great activity recently has been the controversial European Stakeholder Model proposal from EFPIA, in collaboration with wholesaler and pharmacy associations, to combat falsified and counterfeit medicines. (11)

The segment of EFPIA devoted to regulatory affairs is split into several committees: Scientific, Regulatory & Manufacturing Policy Committee (SRMPC) – this is the main policy

governance committee that determines overarching policy objectives at a high level. European Regulatory Liaison Committee (ERLC) – responsible for the production of more

detailed policy positions in the regulatory field

28 Innovative pharmaceutical companies are those which research and develop their own medicines as opposed to generic manufacturers which reproduce previously authorised medicines once they lose patent protection.



Clinical Development Committee (CDC) – oversees policy activities pertaining to clinical development.

Temporary Working Groups (TWG) – these are established on a temporary basis to focus on specific issues where a high level of policy activity is required in the short term. They report directly into SRMPC.

Other Trade AssociationsAt an EU level there are some other trade associations which have an advocacy role. Some of the more notable are:

Europabio – represents the biotechnology Industry, Pfizer is a member EGA – European Generics Association represents the non-innovative pharmaceutical

Industry EUCOPE – represents mid-sized innovative pharmaceutical companies

There are also many trade associations at a national level which may influence policy, predominantly focusing on the MS however scope of activity can have an influence on Pan-EU policy. In the UK the Association of British Pharmaceuticals Industries (ABPI) is an example of a national trade association active on European level, largely due to policy activity of MHRA (UK NCA).

Policy InteractionsA significant amount of interaction with regulators and legislators is achieved through the trade associations. Typically it is trade association representatives that are invited to stakeholder meetings and through trade associations that Industry is invited to comment on closed consultations29. Trade associations also provide the principle fora for interactions within Industry. These most commonly involve the drafting and agreement of positions and provision of data to support them.

There are also other platforms for policy discussions which provide the opportunity to influence regulators and Industry peers. Examples of these are DIA30 and TOPRA31 meetings. It is also in some cases possible to establish meetings directly with commission staff and Members of European Parliament as relevant on specific topics. It is very challenging for a company to engage directly with regulators on policy issues due to concerns of conflicts of interests (5a).

5d. Regulatory Policy at Pfizer

29 Many draft legal and guideline texts are put out for consultation prior to finalisation. These consultations are often public (particularly legal texts) however in some cases, for example where technical expertise is required, the consultation is closed. This is in effect an invitational consultation.

30 Drug Information Association – A non-profit organisation funded by its members supporting knowledge exchange an collaboration in Pharmaceuticals sector.

31 The Organisation for Professionals in Regulatory Affairs – member organisation focusing on sharing knowledge, ideas and education in Regulatory Affairs. Membership includes regulators, Industry professionals and freelancers.



The Regulatory Policy function within Pfizer has a regionally focused structure, with EU Regulatory Policy reporting through the WRS-International organisation. EU Regulatory Policy has a small core team which coordinates policy activity, some of the workload is shared with other WRS colleagues.

Figure 11: Activity of EU Regulatory Policy

The Regulatory Policy function monitors changes in the external environment, assesses the business implications and develops advocacy plans to influence the environment in a way favourable to Pfizer.

Changes in the environment can be very varied in nature. Some examples include new legislation or guidelines, the result of political pressure and reactions to crisis examples. The causation for environmental changes can be complex and the underlying reasons must be carefully considered in the development of policy positions.



Organisational Structure and Internal Interactions

Figure 12: EU Regulatory Policy Team and Reporting Structure

EU Regulatory Policy Reports through the WRS International line.

There is a strong collaboration between Regulatory Policy and Government Affairs/worldwide policy. This is crucial as many of the topics overlap these fields and it is important that activities are coordinated to prevent duplication of effort and ensure Pfizer is acting with “one voice”.

Regulatory Policy partners very closely with the regulatory function of the Business Units. This interaction helps bring the commercial relevance to the proposed changes and Pfizer positions by analysing the effect it will have on the portfolio. Regulatory Policy also maintains a close relationship with Regulatory CMC (Chemistry, Manufacturing and Controls) for counsel on issues pertaining to manufacturing.

Mechanisms of Internal Stakeholder Consultation and Policy GovernanceIn the development of Policy Positions there are 3 typical stages of consultation.

Policy Forum: Uses expertise from WRS to contribute to the policy agenda and hold in depth discussions on the formation of policy positions.

Standing Committee: A cross-functional team which helps develop policy positions, provides a first level of endorsement and supports Pfizers relationship with Regulators.

CMEI – Clinical Medical Excellence and Innovation board, provides a higher level of endorsement for positions where required.



Figure 13: EU Regulatory Policy Governance

Priority Policy TopicsTo focus advocacy activities on key areas of high importance Priority Policy Topics are identified and reviewed on a regular basis. These are selected based upon their impact to the Pfizer business and potential to have a positive impact. The current priority topics (July 2012) are summarised below, for more details see EUCANZ Regulatory Environment Scan in Annex II.

Market Access / HTA: The benefit/risk regulatory assessment and the health technology comparative effectiveness assessments overlap. This area of policy focuses on how the sector needs to develop to allow pharmaceutical companies to most efficiently meet the needs of both these assessments.

EU Clinical Trials Environment: The last ten to fifteen years has seen a marked decline in the number of clinical trials undertaken in the EU. There are several factors making the EU a less attractive region in which to conduct clinical trials including legislative bureaucracy. The aim is to increase the feasibility of conducting more clinical trials in the EU and ensuring that it provides for innovative trial paradigms that may be used in the future.

EMA Evolution: The EMA is continuously looking to develop and improve the way it operates. The focus here is to ensure it does so in collaboration with Industry to enhance the provision of safe and effective medicines and not create unnecessary hurdles.

Pharmacovigilance Legislation: The new PhV legislation provides regulators with the tools to more effectively reassess products post authorisation. This places new obligations on companies and regulators to monitor safety signals. There is also an opportunity to utilise these tools to speed patient access to medicines by collecting a greater proportion of data post authorisation. One initiative to utilise this is adaptive licensing. Insert Reference Here



o E-submission of medicinal product information (A57(2) database): A new requirement for Industry to submit and maintain the details of every license held within the EU to the EVMPD32. The focus of advocacy work is to ensure that EMA works with Industry to achieve this goal in a pragmatic way and uses the new facilties provided efficiently to reduce duplication of effort.

Biosimilars: Biosimilars are biological products which are developed as a copy of an already licensed reference product. In this comparatively juvenile area of regulatory science which is fast evolving advocacy work focuses on correctly presenting the science and encouraging biosimilar use whilst ensuring patient safety is maintained.

Paediatrics: Historically medicines have been poorly studied for use in children due to the poor economic return. Legislation in the EU has forced companies to study paediatric use where appropriate. The legislation and its implementation has however caused many bottlenecks of bureaucracy and been very difficult to manage. Work here focuses on effecting the necessary changes to reduce unnecessary burden upon industry.

Personalised Medicine: With Pfizer’s approach to medicine development shifting towards precision medicine for specific patients it is important that the environment is prepared to accept the new paradigm of drug discovery and provision. Advocacy efforts are focused on increasing the understanding that legislation adopted today must provide for the medicines of tomorrow.

Labelling in 21st century: The EC, regulators and Industry agree that the information provided to patients needs to be improved. Combined with this is a review of the SmPC provided to HCPs and pharmacists. Electronic provision of information is being considered. The aim is to provide up-to date information quickly and to allow more flexibility in presentation to improve patient understanding.

Transparency: A topic of high focus with considerable political pressure. Regulatory documents provided by MAHs are more frequently becoming publically accessible and public assessment reports are much more detailed. It is important here to protect confidential information and encourage regulatory agencies to adopt the same transparency principles as forced upon companies.

Benefit / Risk Decision-Making and Communication: The methodology of the Benefit Risk decision is currently receiving extensive consideration. There are initiatives looking at adding a quantitative element to the decision (ProACT-URL)33 and at allowing earlier access to medicines through continuous assessment (Adaptive Licensing)34. EMA are also interested in the possibilities of involving physicians and patients in the process. The EMA has already

32 Eudravigilance Medicinal Product Dictionary – A database of all medicinal products and a PhV tool which is under development by EMA and Industry.

33 A quantitative B/R Decision process developed by CHMP. ProACT-URL stands for Problems, Objectives, Alternatives, Consequences, Trade-offs – Uncertainty, Risk-tolerance, Linked Decisions.



made changes to the European public Assessment Report (EPAR) and is looking at further improving the communication of decisions. This is an area of significant interest to Pfizer who are involved in Adaptive licensing and supportive of programmes aiming to enhance the benefit / risk decision.

34 Adaptive Licensing is a project being run by NEWDIGS (a group at MIT) which has received some support from CHMP, most notably Hans Georg Eichler. It looks to initially authorise a product based on a small population most likely to benefit from the product. This can then be expanded as more data is generated.



Personal Activities and Responsibilities

6a. Key Topic Areas

Within the EU regulatory policy team activities were coordinated by splitting priority policy topics up and assigning them each a lead who was the main point of contact on the issue. Due to the maternity leave of a colleague my assigned responsibilities were juggled in the course of the year.

6a.i Article 57 (2) of Pharmacovigilance Regulation 726/2004 (EC)

IntroductionArticle 57 of Regulation (EC) No 726/200435 as amended by Regulation (EU) 1235/2010 and Directive 2010/84/EU (pharmacovigilance legislation) requires that a publically available database of all medicinal products authorised within the community is available by July 2nd 2012. Therefore MAHs are required to submit the relevant information on all medicinal products authorised or registered within the EU using the format outlined by the EMA. The Eudravigilance Medicinal Product Dictionary (EVMPD) is the database that will be used for this purpose. This presented Industry with a huge challenge in locating, preparing and submitting the information for all products. In the instance of Pfizer this represented thousands of licences.

BackgroundThe creation of this requirement in legislation stems from an appreciation that it is unacceptable for European Authorities not to have a complete list of products available upon the market within the EU. It was realised that in the event that a safety signal was realised with an active ingredient or other chemical within a product appropriate actions could be taken for that product but not for other products including the same ingredient. As a result the EU would need a complete database of all available products, their active product and excipients to protect the public in the instance of a pharmacovigilance signal. The database would be further used to asses adverse event reports known as Individual Case Study Reports (ICSRs).

Initial RequirementsIn the initial legal notice and ‘detailed guidance on submission of information on medicinal products for human use by marketing authorisation holders’ of July 1st 2011, the EMA required a huge amount of data, some of which went beyond the details included in a MAA. The short timeframe and huge scale of the work required to complete this task made it quite untenable and resulting in extensive lobbying from the Pharmaceutical Industry. As a result the scope of the requirements were reduced to only those essential to meet the obligation set out in the legal text and of direct benefit to public health, however the date of implementation could not be altered.

Reduced Scope RequirementsFor every individual medicinal product licence held in the EU the following had to be submitted to the EMA by July 2nd 2012.

Name of Product

35 Regulation of the European Parliament and of the Council; laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency.



Name, address and contact details for the qualified person responsible for pharmacovigilance (non-mandatory)

Location of the pharmacovigilance master file Therapeutic indication Description of the active substances, excipients and adjuvants Description of a medical device as part of the authorised product Description of the package (pack size) Submission of approved SmPC in the local language for each authorised product Designation of additional monitoring for products.

An updated legal notice detailing the reduced scope was published in March 2012.

In reality Industry was unable to comply completely with the deadline however huge efforts and resources were placed in aid of this project.

Maintenance of EVMPDOnce uploaded the product information in the dictionary will have to be kept up to date and reflect changes that occur to the licence of the product. This will be achieved through Industry submitting update messages making the relevant changes. At present the detailed requirements for Industry are not known with only a few concepts so far agreed with EMA. There will be a full day stakeholder meeting on September 12th where EMA and Industry will present proposals. Following this detailed guidance for Industry will be released by the EMA.

The details of maintenance requirements are of significant importance to Pfizer as the required timelines and the inclusion or otherwise of information fields and documents as mandatory for updates may force internal process modification. In the long term Pfizer will look to automate the process to the greatest degree possible.

Roadmap of EVMPDThe legislation requires that the migration of EVMPD to ISO IDMP36 standards is implemented by July 2nd 2016. These standards, once finalised, will determine the product information to be held in the EVMPD by legal requirement. The IDMP standards are being worked through the ICH process and could be finalised by the end of 2012. The EMA envisages the EVMPD becoming the ‘backbone of the European Regulatory Network’ (Noel Wathion, EMA) and whilst the regulatory agency’s full ambitions are unknown it is clear that they see it as an opportunity for development. The expansion of the database to additional data fields and submission requirements for newly mandatory information is yet to be detailed and agreed with Industry.

Policy ArgumentsAll policy positions advocated by Pfizer were worked up through EFPIA, due to the closed nature of the consultations Pfizer has not produced any individual policy positions.

Prior to the reduction in scope EFPIA’s lobbying focused on the unachievable nature of the requirement. The removal of several data fields and selection as some additional as not mandatory in February 2012 was a great success which brought the task into a reasonable proportion. Since the agreement at the stakeholder meeting in February the focus has been on maintenance activities and data clean up. Industry’s positions are seeking for efficient and pragmatic implementation of processes that provide accurate information to patients in a timely manner proportionate to the potential safety implications of the change. There has been some significant ground made in consultation with the EMA on these points however the details are yet to be agreed and much

36 International Standards Organisations International Dictionary of Medicinal Products. An ICH workstream that will set the harmonised international standards for medicinal product dictionaries.



remains agreeable to both parties only in concept. With respect to the Roadmap for EVMPD EMA has been enthusiastic to expand the database to included detailed substance information in the near term. Industry are arguing again for a pragmatic approach, waiting for the IDMP implementation guide (expected within about a year of IDMP standard finalisation) and allowing for an assurance of quality data in what is currently available before further expansion.

Tasks and ResponsibilitiesAs the policy lead for Article 57 I represented Pfizer on the EFPIA Temporary Working Group, contributing to presentations, positions and communications. I also attended stakeholder meetings with the EMA as an EFPIA representative and reported outcomes back into the Pfizer organisation. Further to this I worked in close collaboration with Europabio to achieve harmonised positions and gain additional allocation for Pfizer at the stakeholder meetings if required.

In collaboration with the operational team within WSRO responsible for managing the submission of the information I built policy positions for Pfizer which were escalated to EFPIA. Through regular interaction with WSRO and EU Qualified Person for Pharmacovigilance (QPPV) office developments were monitored internally and required external communications agreed. At an above country level I was the primary EU regulatory contact for the project and delivered several presentations and communications to colleagues explaining the requirements placed upon Pfizer and the implications to their working practice.

6a.ii Paediatrics

IntroductionThe Paediatric Regulation (1901/2006 EC) was introduced in January 2007. It required that all new medicinal products (Article 7) or existing products still benefiting from patent protection for which a new line extension, indication or dosage form was being applied for (Article 8) must, where appropriate, investigate its use in children (18). The requirement means it is compulsory to include the paediatric data resulting from an agreed Paediatric Investigation Plan (PIP) before submission of a MAA. A PIP is a research and development program agreed by the PDCO to ensure availability of data in a paediatric population. Exceptions apply in the case of a deferral (typically, in appropriate cases, until after studies are conducted in adults) or a waiver which is granted in circumstance where product is non-applicable to the paediatric population. Following completion of all the measures in the PIP and the registration of the resulting data by the EMA/EC or other competent authority rewards (SPC37 extension) may be available.

BackgroundThe regulation was introduced due to awareness that medicinal products were infrequently sufficiently labelled for children. A lack of commercial incentive to specifically develop medicines for children provided a population for which there was little knowledge in treatment effect. This resulted in physicians prescribing medicines without a basis of data to support their safety and efficacy in this population.

Children inherently metabolise medicinal products differently to adults and there are significant variants depending on age and other developmental factors such as renal function. It is therefore often inappropriate to prescribe a juvenile the same dose medication as an adult. HCPs were unguided on the dose to be administered and so took varied approaches to treating paediatrics. The dangers of overdose or under-dosing and so diminishing the required therapeutic effect are therefore increased.

37 Supplementary Protection Certificate – has an equivalent effect to extending the patent of a product.



The IssuesThe problems experienced by Pfizer and the wider industry are in part due to the rigid nature of the regulation which prevents the PIP procedure from being adapted on a case by case basis. There have also been issues with the implementation of the legislation and the feasibility of some of the requests made by regulators.

Highly detailed PIP submission early in Product Development: The regulation requires that a PIP is submitted to the PDCO upon completion of pharmacokinetic studies in adults. With some variability allowed in timing depending on the development process for the medicine this is at an early stage of clinical studies when relatively little is known about the product. The submission of detailed PIP therefore requires a level of assumption which frequently has to be revised through a bureaucratic and resource intensive modification procedure.

The Rushed Nature of the Procedure: Due to a poor format for interaction between applicant and regulators there have been multiple case examples where outstanding issues remain at the latter stages of the procedure. This leads to a period of frantic activity in which alterations have to be agreed in the lead up to the final decision. As the timelines for decision are set in legislation this has caused products to be withdrawn and resubmitted due to insufficient time to make the required alterations.

Divergent Global Requirements: The requirements for PIPs in the EU are poorly aligned with the US, where for a start they submit much later. This prevents efficient paediatric development on a global basis.

Scope of Studies Requested by the PDCO: There have been occasions where the PDCO has requested that sponsors undertake studies in therapeutic indications not intended for the development of the medicine in adults. There have also been examples where the PDCO have requested study designs which have been infeasible due to inability to recruit or rejection of CTA at member state level.

Applicability of the legislation to medicines developed for children: The regulation is poorly designed to accommodate products which are intended primarily for paediatric use. This is most common with vaccines and lead to a significant amount of activity at EVM (19).

Further detail can be found in the advocacy plan in annex II.

Pfizer has also experienced issues with the paediatric legislation Article 45 and 46, the requirement to submit details of previously conducted studies in paediatrics (including those not conducted by sponsor and literature review) and the obligation to submit study reports for paediatric studies completed within six months of study completion respectively (18).

Advocacy EnvironmentThe widely accepted view is that the Paediatric Regulation will not be revised in the 2014 review and so advocacy activity has been fairly low in the last 12 months. In 2011 EFPIA published the results of their paediatric survey aimed at highlighting some of the issues Industry experienced with the implementation of the legislation (20). The themes have remained of concern with EMA providing some proposed resolutions on certain points but these have not be satisfactorily implicated to date.



The European Court of Justice ruling on the waiver application pertaining to Nycomed’s diagnostic product Imagify backed the EMA in their refusal to grant a class waiver (21). This has been considered by the EMA as support for them to request investigations into any indication which could be of therapeutic benefit to children. The decision hinged on whether the EMA had the right to determine how a sponsor developed a product. The implications of the judgement are to some extent limited to diagnostics however the ripple effect spreads to therapeutics. The European Ombudsman’s (EO) draft recommendation found the EMA guilty of maladministration in a separate complaint procedure and has recommended measures been put in place focusing on increased transparency of the PIP decision (22). The EO considered the PDCO opinion to be valid and procedures followed correctly however they had failed to communicate the reasons for the decision to the complainant. The EMA must respond in September 2012. The minutes of PDCO meeting in June suggest that much more applicant data will be made publically available as a result of this ruling. Further information on both of these topics can be found in the advocacy plan in annex II.

Tasks and ResponsibilitiesWhen I took on the topic the policy positions were not finalised. The first task was therefore to determine the policy positions based upon Pfizer experience and get them endorsed through the Paediatric forum. I gathered all possible product examples supporting our policy positions and continuously updated these through the year. I monitored all available documentations on developments on the topic and assessed the merit of Pfizer actions in these areas. For internal communication I authored the paediatric Issue brief and Advocacy plan and gained endorsement for the planned activities. I was heavily involved in the interpretation of the ECJ Nycomed judgement and EO recommendation and provided internal briefs accordingly. I also lead the internal movement on drafting a ‘template PIP’ for proposal to the regulators (see annexed advocacy plan and Regulatory Rapporteur article), a work which is still in progress.

In response to an article in Regulatory Rapporteur, A TOPRA magazine, I authored and coordinated the review process for an open letter response. The article featured was an interview of Dr Daniel Brasseur, chair of the PDCO which addressed his views on some of the issues. The response was designed to highlight the ideas which we appreciated and suggest ways of progressing for the benefit of all stakeholders. The article can be found in annex II.

6a.iii Biosimilars

IntroductionBiologically similar medicinal products, biosimilars, are developed and authorised based upon a comparison with the reference product. The concept behind their production is similar to that of a generic product in as much as they copy the reference medicine and cannot enter the market until the reference product has lost patent protection. However because of the sensitive nature of the genetically engineered manufacturing process biosimilars will never be identical to the reference medicine and therefore require more extensive development and proof of similarity than generics. The assessment of biosimilars is a comparative exercise where quality, efficacy and safety are



analysed. A biosimilar cannot be better or worse than the reference product to gain authorisation based on an abridged dossier38.

Europe was the first region to establish a legal pathway for the authorisation of biosimilars and has remained the leading region in the field. As a result many other markets reference EU policies, legislation and guidelines. So far biosimilar medicines for filgrastim, somatropin and epoetin have been authorised. Relative to other biological medicinal products they are relatively simple medicines. The focus is now however moving to the more complex monoclonal antibodies (mAbs) with one MAA submitted so far for a biosimilar herceptin.

Biosimilars currently have relatively low market penetration in many EU member states however their uptake is increasing. This is driven by the cost containment policies adopted in response to pressure from reduced national healthcare budgets. Biosimilars are marketed at a price reduction relative to the reference product and the introduction of competition tends to reduce the pricing of the originator. It should be noted however that, due to the complex nature of the products and the high prices associated with biological medicines biosimilars remain considerably more expensive than generics. The bigger pharmaceutical companies are investing heavily in biosimilars which is seen as a significant market opportunity. This is partly based on a belief that the complex molecules will be difficult for traditional generics producers to manufacture to consistent GMP standards, making the peri-LOE space less congested. There are however many companies interested in the field, the traditionally innovative like Pfizer, generics manufacturers such as Teva or Mylan, and some unexpected players including Samsung.

The regulatory science of biosimilars is comparatively juvenile and highly dynamic. Several scientific guidelines have been released or revised in the past year, the most prominent of which being the mAb guidance released in June 2012. With a view to the future biosimilar developers and regulators are considering the required methodologies to expand the potential of biosimilars. The two areas of greatest focus are:

Extrapolation of Indications – Many of the biological products for which biosimilars are being developed are authorised for multiple indications. There is an ongoing discussion between stakeholders to decide what additional evidence is required to show that a product which is biosimilar in one indication is also sufficiently similar in another indication for which the reference product is authorised.

Proof of Interchangeability39 – At present it is not fully understood what level of evidence would be required to show that the reference product could be interchanged with a biosimilar (and in reverse) without influencing therapeutic effect. There are several schools of thought on this matter, notably the FDA have suggested that switching studies would likely be required. The EMA and within that the Biological Medicines Working Party (BMWP)40 have been hesitant to engage with this topic as interchange-ability is not incorporated in the marketing authorisation and the prescribing and switching of biosimilars

38 The biosimilar medicine relies upon the safety and efficacy data established in development of the reference product. Therefore it has to show that it is “similar to” the reference product.

39 Interchangeability: where two products can be exchanged one with another without a significant risk of an adverse health outcome. This term may be defined differently under different national laws.



is an issue dealt with at national level in the EU. Industry is placing increasing pressure upon the EMA to approach this from a scientific standpoint.

The IssuesThe biosimilar environment is influenced by the range of industry players lobbying for the benefit of their business plans. The policies of innovator only companies have a tendency to directly contradict those of generics manufacturers as one group seeks to protect their products from competition and the other to market such competing medicines. A sample of the issues are summarised here, further details are available in the advocacy plan in annex II.

Terminology: With the rapidly developing science new terms are being coined on a regular basis. Some of the terms which are used by various stakeholders are also used for generic medicines with a slightly divergent meaning. This has the effect of heightening confusion for patients, prescribers and payors.

Importation of Reference Product to EU: There is a legal obstacle which prevents the importation of medicinal products for use in clinical trials from outside the EU without providing a data package. The data required would not be available to the sponsor of the comparative biosimilar/reference product trial and this prevents EU patients being included when the reference product for the trial is sourced outside the EU. Industry has been very strong in advocating for a work-around solution using bridging data which has been acknowledged by regulators and the EC. The EC is said to be looking at the legal feasibility of this approach.

The Tajani Initiative: The Tajani Initiative comes from DG Enterprise and Industry at the European Commission. The majority of its workstreams have a low level of activity however the biosimilars workstream is an exception. The most important output from this initiative will be a brochure designed to increase consumer confidence in biosimilars and drive uptake. The Pfizer perception is that the EGA have been very successful in lobbying this initiative however the innovative industry has started to provide a greater influence. The result of this being that many of the details have to be omitted due to non-agreement.

Tasks and ResponsibilitiesI worked on this topic in collaboration with a colleague from the WRS Research Unit group who specialised in biosimilars in the EU. The most frequent task was commenting upon various documents produced by different stakeholders to ensure the Pfizer views were recognised. Policy activity in this area has been very high during the past twelve months with many documents being drafted by trade associations (both innovative and generic), the EMA and its scientific working parties and the Tajani initiative. There was also a significant amount of activity outside Europe for which I was involved in the compilation of comments. Other tasks included replacing the advocacy plan which was out of date and no longer fit for purpose and producing a slide deck providing training on the regulatory aspects of the topic for internal use. Providing competitive intelligence in the field was a further function of my role, supporting both the policy arguments and Pfizer biosimilar portfolio.

6a.iv Others

40 BMWP is a sub-committee of the CHMP responsible for authoring biological medicinal product guidance.



MediatorMediator was a Servier product labelled as an add-on treatment for patients with diabetes who were overweight. It was withdrawn from most major markets in the EU and US following safety signals of heart valve damage and disease. The product remained available in France for nearly ten more years before being withdrawn in 2009. One study estimated that the product was linked to at least 500 deaths in France. The inquest that followed in France lead to a reorganisation of the French national competent authority and it’s renaming as well as several changes to the legislation governing pharmaceuticals in the country. In the wake of the affair the French agency has began to re-evaluate medicines which have been on the market for at least 7 years or may have little therapeutic effect. The estimated list of products is greater than 4,000 in total including many Pfizer medicines. At a pan-European level the findings triggered a heightening of pharmacovigilance measures in legislation which were rushed through with great urgency. It also lead to the removal of the CHMP chair, Eric Abadie, after he was removed from the French NCA following an inquiry.

I maintained a watching brief on this topic, focusing on the pan-EU fallout. My main responsibilities were monitoring developments in France, assessing the implications and communicating this within the company. My main streams of communication were through articles in the Regulatory Policy Newsletter and an Issue Brief which I updated in real time.

Information to Patients (ITP)This was a proposal first brought forward by the EC in 2008 to allow Industry to provide more information on their medicines to patients. The first proposal, drafted by DG Enterprise and Industry41 was slammed for being too pro-Industry and blocked by the European Parliament. The 2011 proposal was more focused on patients needs however failed to navigate the political minefield associated with the topic. This area requires a difficult balance as direct to consumer advertising of prescription medicine is illegal in the EU. The amount of information available to patients differs considerably between MS and the EC sought to improve the situation so that all EU consumers could benefit from accurate, reliable information. The controversial proposal received little support from stakeholders as Industry bemoaned the bureaucracy and member states were concerned about the additional access pharmaceutical companies would have to patients. The proposal stalled amidst opposition from Member states in Council who failed to reach a qualified majority and was subsequently withdrawn. A further review of this legislation is unlikely to be conducted for several years.

The majority of the advocacy work on this topic was conducted by the Government Affairs and Public Affairs departments as the regulatory piece was small. There were, however some pharmacovigilance measures attached to the proposal briefly following the Mediator fallout in an attempt to rush them through the legislative procedure. When it became evident that the ITP proposal would be dropped they were split out from the legislation. I analysed the proposal for its implications and provided internal communications for colleagues. These were in the form of an Issue brief and newsletter articles.

Commercially Confidential Information

41 The Pharmaceutical sector was moved from DG enterprise and Industry to DG SANCO (Health and Consumers) around the turn of year 2009-2010.



The EMA are taking steps to release a greater amount of previously confidential company information and this trend is set to continue. The political pressure is in part derived from the lobbying of academics who wanted the clinical data supporting the authorisation of medicines to be publically available. In March 2012 the HMA/EMA released guidance on the classification of information within the MAA42 as releasable, confidential (personal data or commercially sensitive) and to be determined on a case by case basis. Simultaneously they opened a consultation on the principles to be applied in the following of these guidelines. The consultation has been closed but the final principles document is not yet available. It is the intention of the EMA to place the releasable information upon their website for public viewing as soon as their IT infrastructure can support it. More recently there are concerns that the European Ombudsman’s draft recommendation to the EMA may mean a similar disclosure for paediatric investigation plans. Such a move would require careful consideration as these are agreed prior to medicine authorisation and so release of data may have much more significant implications for the company’s competitive position depending on future circumstances.

Pfizer is supportive of increasing the level of transparency within the regulatory network as long as the commercial interests of sponsors are protected. Much of the advocacy in this field is focused on trying to improve transparency of the regulators procedures and some progress has been made here with the EMA now publishing minutes for all the meetings of its scientific committees. Work is this area involved commenting on the principles of releasing MAA information consultation, preparing an issue brief on the guidance and communicating its implications to colleagues.

Medicines for Older PeopleIn recent years the provision of medicines for the elderly has come under the political spotlight. There has been mounting pressure from European parliament for legislators and regulators to enforce that medicines are researched specifically with older patients in mind. This could provide for more information on treating the elderly and potentially specific dosages for elderly people. It is accepted that elderly patients are often excluded from clinical trials because of the complications they bring to assessing the benefits of the investigational product, for example when they are taking multiple concomitant medications. There is also the complication that chronological age is a poor determinant of an individual’s response to medication. Typically renal or hepatic function is more directly correlated to an individual’s metabolism of and tolerance to an active ingredient. There is some movement from within the pharmaceutical Industry to introduce frailty as a determinant and establish recognised endpoints associated with this. This is a direction being heavily advocated for by Sanofi and GSK whom are both known to be developing medicines for Sarcopenia43 and are seeking to ease the regulatory process and or benefit from any additional rewards which may be available should a regulation akin to the paediatric regulation be brought into force. The EMA have taken, in Pfizer’s view, a very pragmatic approach to the political storm to date.

42 The guidance applies only to medicines which have been approved. Data for withdrawn and refused medicines will not be published to the same extent as it may be commercially damaging if resubmitted at a later date.

43 The degenerative loss of skeletal mass and strength associated with ageing.



The advocacy work has focused on ensuring the voice of trade associations is balanced and not dominated by those companies seeking to develop medicines specifically for sarcopenia. From a political standpoint it is important that the EMA, in collaboration with Industry, is seen to be working on the issue to prevent escalation of pressure coming from quarters lacking the relevant expertise. Pfizer is represented on the EFPIA TWG by a colleague from pharmaceutical sciences, who is an expert on formulations. The hope is by advancing the development of age appropriate labelling and formulations the situation can be improved without the enforcement of bureaucratic legislation. My responsibilities in this area have been to provide this colleague with support on the more political and regulatory matters. I have also contributed to Pfizer policies and comments provided on external documents.

6b. Other Activities and Responsibilities

Pfizer Representative at Centre for Innovation in Regulatory Science (CIRS)I attended a 2-day workshop of CIRS held in the UK focusing on their Quality Scorecard programme. The aim of the programme is to create a scorecard to facilitate a numerical figure provided as feedback of performance. It was designed as bi-directional process with regulators scoring applicant submission and applicants scoring regulator performance. The discussions focused on balancing the elements of the scorecard so that individual fields were weighed in correlation with their perceived importance in provision of the overall results. To be successful in this role I had to familiarise myself with the work done by the programme to date and query colleagues regarding their perceived importance of the different factors prior to attendance. I provided a meeting report to feed back into Pfizer and maintained contact with CIRS to follow up on their post workshop commitments.

EU Regulatory Policy BriefingThis was a new communication piloted early in my placement. I was tasked with designing our newsletter and assumed the role of editor and coordinator throughout the year. The communication aimed to share with regulatory colleagues the current policy topics, external triggers and implications. It also provided a platform for EU regulatory policy to highlight some of its achievements to the surrounding organisation. The newsletter was distributed to regulatory colleagues in the country offices as well as above country regulatory strategists. An example issue can be found in annex II.

EU Regulatory Policy ForumI was tasked with coordinating the policy forum. This is a regular meeting including experienced regulatory strategists and the EU country regulatory leadership team allowing in depth discussion of specific topics used to help shape policy positions and gain new insights and ideas. Additional members are invited on an ad-hoc basis dependent upon the topic. The presentation and chairing of this meeting was shared within the EARP team on a topic dependent basis.

Regulatory Policy Global AlignmentI inherited the role of coordinator for these meetings from a retiree within the policy group in October 2011. There were bi-monthly telecoms in which the activity in the different regions was informally discussed. A key objective of these meetings was to ensure that Pfizer’s external advocacy worked as one voice and policies in the different regions were aligned. There are also insights to be



gained from the other regions as different sectors of regulatory science may develop at different paces, or with different drivers. I also coordinated the face to face meeting held in Brussels which I attended during which the aligned policy goals were determined and some key policy topics were discussed in detail. A representative from EFPIA, new into a global policy coordination role was invited to meet with us to explain her perspectives and objectives in the position. As is traditional for this meeting I also organised a field trip to the European Parliament ‘Parliamentarium’, which turned out educational for those of us living in the EU as well as US, resulting in a success.

Regulatory Policy Environmental Scan 2012The environmental scan provides an overview of the external stimuli exerting an influence on the regulatory environment. Updated on an annual basis the document provides internal stakeholders with a summary of the issues and their implications. I was responsible for coordinating the drafting of the document, authoring topics for which I was the lead, and providing a first review. The document was distributed internally to WRS leadership, WRS-EU and country managers.

Sharepoint site ManagementI was responsible for the maintenance and development of the EARP sharepoint site. This platform allows important information to be shared with colleagues and archived in a secure manner. Improvements included upgrading the navigation, adding additional information/webpages and the addition of new features, for example the external event calendar which was designed to drive collaboration between relevant colleagues.

Regulatory Strategy Support for CVMED portfolioI provided strategic support for the filing of Eliquis in the EU, and preparation for a potential Advisory Committee44 in the US. Eliquis is an anticoagulant for the treatment of venous thromboembolic events. It is a direct factor Xa inhibitor. The major market opportunity is in the prevention and treatment of atrial fibrillation. The accepted standard of care for these patients is Warfarin which has a very well documented efficacy but is notoriously difficult to manage. Errors in the management of Warfarin can be fatal and this deters many physicians. The alternative is Non-steroidal anti-inflammatory drugs, most commonly Aspirin. These have a much reduced efficacy and notable side-effects when maintained at moderate dose in the mid-term.

Eliquis, INN Apixiban, will be third to market in its class with Janssen Pharmaceutical’s Xarelto (rivaroxaban) and Boehringer Ingelheim’s Pradaxa (dabigatran) already available. Despite this competitive disadvantage clinical data supporting Eliquis is very strong and therefore it expected to be successful. The support I provided focused on comparability exercises between the proposed Eliquis labeling and the agreed labeling for the competitor molecules. I also analyzed the scripts of the Advisory Committees conducted during the approval of the competitor molecules to highlight potential issues.

Regulatory and Competitive Intelligence

44 An advisory committee is a panel of external experts who provide their opinions upon the authorisation of new medicines to the FDA. It is a public meeting used by the FDA to support their determination of the Benefit/Risk balance of a product, and ultimately whether or not it should be authorised and with what labelling to support its use.


http://en.wikipedia.org/wiki/Boehringer_Ingelheim

http://en.wikipedia.org/wiki/Direct_factor_Xa_inhibitor

http://en.wikipedia.org/wiki/Venous_thromboembolism

http://en.wikipedia.org/wiki/Venous_thromboembolism

http://en.wikipedia.org/wiki/Anticoagulant


In appropriate instances I provided intelligence support to regulatory strategists in certain fields. This included for products related to policy priorities such as the Biosimilar portfolio. I also conducted some market research associated with due diligence activities related to the in-licensing of products in the gender health field where a significant co-pay product45 market opportunity was identified.

Clinical Trial and Regulatory Success Metric AnalysisIn collaboration with the Regulatory Strategy Industrial trainee reporting into Speciality Care I led a project analysing the regulatory output following the successful completion of a subset of clinical trials. The trials used had been designed under a pilot project aiming to improve success rates. The metric analysis we were provided with at outset showed that these trials had an increased success rate by primary endpoint relative to baseline, and furthermore that the longer the project ran the greater the percentage of success. The project was to analyse whether this apparent improvement translated into regulatory success46. To determine this some key questions were identified, they were;

Was the clinical study report submitted in support of a regulatory claim47

Did the submission gain approval How long did the process take48?

Because of the subjective nature of interpretation associated with many individual cases the investigation had to be kept as binary as possible, allowing the identification of trends. The more detailed reasoning for each case was collected where possible and archived as a resource for future use in appropriate circumstances. Due to the size, and resource heavy nature, of the project we prioritised the trials deemed most likely to have significant economic implications, specifically Phase III trials. The project was designed to be passed on to the next years Industrial trainees for continuation.

The initial results identified that the trends were less clear in terms of regulatory output than against clinical trial endpoint. Some factors were identified as an influence in multiple cases. Overall the data set was not large enough to drawn reliable conclusions at present however it did provide some interesting insights.

People, Culture and Engagement The working environment of the Sandwich site, which was in the midst of widespread redundancies when I joined Pfizer, was an area I considered I could positively contribute towards. I volunteered my discretionary effort to workstreams focusing on fostering a productive, engaging and rewarding workplace ethos. Key deliverables associated with this included the ‘Launch Event’ which coincided with the consolidation of staff into three operating buildings and the ‘Sandwich Summer Fete’. I sat on the planning team for these events and was heavily involved in this process. Both events were

45 A product which is paid for, at least in part, by the patient as it will not be fully reimbursed. This is typical of products associated with well being or appearance of well being.

46 Regulatory success was defined as gaining approval for the inclusion of wording in the label, upon which the company could promote.

47 If approved, information upon which the company could promote the product

48 From top line report date (shortly after study completion) to submission, and to approval.



widely recognised as resounding successes, contributing the reconstruction of a positive atmosphere on the site.



7. Placement Evaluation

Key learnings and experiencesThis year spent on placement with Pfizer has contributed significantly to my professional development and provided insights into the reality of employment within the pharmaceutical industry. I have been able to garnish a top-line appreciation of the roles and functions of many colleagues across the business and had the opportunity to become involved in a wide range of projects. I was also provided with opportunities to represent the company externally and experience interactions with regulators and trade associations which were a fantastic learning experience.

The focus of my work has been within the regulatory arena and it is here that I will take away the most in-depth understanding.

I have worked with a wide variety of colleagues on a global basis in both small and large teams. I have had to deliver to deadlines, to a high standard on a regular basis. My colleagues would also expect me to provide a subject matter expert review on documents related to topics I worked on, typically prior to external release. This was at first daunting however I became much more confident in my own knowledge, and the value of my opinion where relevant, through the year.

Impression of the IndustryThe simplest and possibly single most important question in this evaluation is would I now go on to work in the Pharmaceutical Industry/for Pfizer? In short, I would very strongly consider it should the opportunity arise.

It is very difficult to assess such a question without a suitable comparison however this placement has not deterred me from following such a path. It is clear to me that there is a heavy pressure on the sector to adapt and this will have significant impact upon employees.

Regulatory is a dynamic environment that requires constant learning. In conversations with many colleagues one word that has never been used to describe the job is boring and this aligns with my own experience. If I were to return to the field I would probably look for a role in policy (or other above product function) or where the probability of working on products/indications pre-approval was reasonably high.

Personal DevelopmentThere are many things I will take away from this placement that have a scope wider than the workplace. My communication skills, particularly in terms of concise writing, have certainly improved, as has my organisation, adaptability and confidence to implement my initiative. The level of responsibility provided to me at times during my placement brought a degree of pressure but also my best work, reinforcing my belief that I respond well to such situations.

I have been exposed to a wide variety of people, with different perspectives and from different cultures; in circumstances I would not otherwise have seen. I was able to learn a lot from these interactions about the working world, society outside it and myself.

It is my belief that few things are harder to grasp entirely than a perspective of one’s self in the present and therefore I am certain the full benefit of the experience is yet to be realised.



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Annex 1: Relevant Terms and Documents

(e)CTD – electronic Common Technical Document: An internationally agreed format for applications to be submitted to the three ICH regions; USA, EU and Japan.

o In the EU the CTD is applicable to all procedures

Figure 14: Structure of the Common Technical Document (CTD)

Variations : Variation submissions are means of implementing changes to a products regulatory profile. In the EU there are 3 major classifications of variations (all examples given reflect Centrally Approved Products (CAPs):

o Type IA: Minor changes with minimal impact on quality, efficacy or safety. These are reviewed by the EMA without the involvement of the rapporteur. The MAH does not have to wait for approval to implement the change, “Do and Tell”.

o Type IB: Minor change which is neither Type IA or Type II nor an extension variation. These are reviewed by the EMA (within 30 days) without the involvement of the rapporteur. The MAH must wait for approval before implementation.

o Type II: A major variation which may have an impact on the quality, efficacy or safety of the product. A formal review is required, normally involving the rapporteur.

SmPC (Summary of Product Characteristics): Often referred to as the “label” this document is agreed with the regulatory agencies. It is publically available and the principal material referred to by doctors. The SmPC also provides the basis for promotional material delivered to prescribers. Pharmaceutical companies are only allowed to promote their medicines based on the wording agreed in the SmPC.

International Conference on Harmonisation (ICH): “ A joint initiative involving both regulators and research-based industry representatives of the EU, Japan and the USA in



scientific and technical discussions of the testing procedures required to assess and ensure the safety, quality and efficacy of medicines”. Key Achievements:

o Common Technical Documento Guidelineso MedDRA: a global dictionary for medicinal substances. Codes defined by rules with

terms at different levels. This provides a tool for tracking adverse events.

Annex 2

A. European Parliament, Annex I and II, Reasons to Refuse the Marketing Authorisation (Orphacol) European Commission and CHMP Opinion. Available from http://www.google.com/url?sa=t&rct=j&q=&esrc=s&frm=1&source=web&cd=4&ved=0CFMQFjAD&url=http%3A%2F%2Fwww.europarl.europa.eu%2FRegData%2Fdocs_autres_institutions%2Fcommission_europeenne%2Fcomitologie%2Fros%2F2011%2FD015522-03%2FCOM-AC_DR(2011)D015522-03(ANN1)_EN.doc&ei=wlP9T_wGxpmFB4OV8JQD&usg=AFQjCNGLabNvD8ZyeRF9ED0DAuNUCpKnqw

B. EUCanANZ Regulatory Policy Environmental Scan 2012C. Paediatrics Advocacy PlanD. Regulatory Rapporteur Article (Published July/August 2012, pg 25) Ghost Authored: The

European Paediatric Procedure: An Industry Perspective – written in response to article: The children’s advocate, May Issue of Regulatory Rapporteur.

E. Biosimilars Advocacy PlanF. Example edition of EU Regulatory Policy Briefing (May 2012)


http://www.google.com/url?sa=t&rct=j&q=&esrc=s&frm=1&source=web&cd=4&ved=0CFMQFjAD&url=http%3A%2F%2Fwww.europarl.europa.eu%2FRegData%2Fdocs_autres_institutions%2Fcommission_europeenne%2Fcomitologie%2Fros%2F2011%2FD015522-03%2FCOM-AC_DR(2011)D015522-03(ANN1)_EN.doc&ei=wlP9T_wGxpmFB4OV8JQD&usg=AFQjCNGLabNvD8ZyeRF9ED0DAuNUCpKnqw

