№ 7. Subject: Pharmaceutical Industry.Pharmaceuticals in Great Britain.

Medicines contribute enormously to the health of the nation. The discovery, development and effective use of drugs have improved many people’s quality of life, reduced the need for surgical intervention and the length of time spent in hospital and saved many lives. Our consumption of drugs is vast and is increasing. About 650 million prescriptions are written each year by GPs alone. Medicines cost the NHS in England over Ł7 billion every year, 80% of which is spent on branded (patented) products. The industry which has produced these drugs has understandably been described as “world class and a jewel in the crown of the UK economy”. It is the third most profitable economic activity after tourism and finance. While the United States is the industry’s largest market and is the site of most drug research and development, the UK industry, nevertheless, has a remarkably impressive record. It is a centre of world class science, accounting for 10% of global pharmaceutical R&D expenditure. It has been estimated to fund 65% of all health-related R & D in the UK. However, there are disadvantages in the increasing use of and reliance on medicines. The inappropriate or excessive use of medicines can cause distress, ill-health, hospitalisation and even death. Adverse drug reactions are responsible for about 5% of all admissions tohospitals in the UK.

The interests of pharmaceutical companies and those of the public, patients and the NHS often overlap but they are not identical. For the industry, medical need must be combined with the likelihood of a reasonable return on investment. An effective regulatory regime to ensure that the industry works in the public interest is essential. Unfortunately, the present regulatory system is failing to provide this. The system is at times frustrating, arguably with excessive attention to unimportant detail, but it is, as we describe below, insufficiently effective.

The Department of Health has for too long optimistically assumed that the interests of health and of the industry are as one. This may reflect the fact that the Department sponsors the industry as well as looking after health. The result is that the industry has been left to its own devices for too long. It may be relevant that this is the first major select committee inquiry into the pharmaceutical industry for almost one hundred years – the last was undertaken by the Select Committee on Patent Medicines which reported in August 1914.

The consequences of lax oversight is that the industry’s influence has expanded and a number of practices have developed which act against the public interest. The industry ffects every level of healthcare provision, from the drugs that are initially discovered and developed through clinical trials, to the promotion of drugs to the prescriber and the patient groups, to the prescription of medicines and the compilation of clinical guidelines.

We heard allegations that clinical trials were not adequately designed – that they could be designed to show the new drug in the best light – and sometimes fail to indicate the true effects of a medicine on health outcomes relevant to the patient. We were informed of several high-profile cases of suppression of trial results. We also heard of selective publication strategies and ghost-writing. The suppression of negative clinical trial findings leads to a body of evidence that does not reflect the true risk:benefit profile of the medicine in question. Guidance produced by NICE and others relies on the published evidence. If all the evidence is not published, or if negative findings are hidden, accurate guidance cannot be issued and prescribers cannot make truly evidence-based decisions.

Once licensed, medicines are intensely promoted to prescribers. The very high costs of developing a new drug make it vital that a company recoups its costs as quickly as possibly after licensing. Coupled with company-sponsored information from medical journals and supplements, ‘medical education’ materials, advertisements and sponsorship to attend conferences, workshops and other events, it is little wonder that prescribing practices are affected. GPs are particular targets; they have more prescribing freedom than hospital specialists and their prescribing practices are not limited to hospital formularies.

Promotion of medicines to patients and links between drug companies and patient

organisations may add to this problem, leading patients to demand new drugs from their doctors. The problem is far less to do with any particular activity; rather the volume may distort prescribing practice. At the heart of the problem may be the trend for the industry to become ever more driven by its marketing force.

The most immediately worrying consequence of the problems described above is the unsafe use of drugs. Over-prescription of the COX-2 inhibitors, Vioxx and Celebrex, has been linked to thousands of deaths and many more cases of heart failure. These case illustrate a series of failures. Manufacturers are known to have suppressed certain trials for these drugs in the US and may have done the same in the UK. In addition, there were inadequacies in the licensing and post-marketing surveillance procedures and excessive promotion of the drugs to doctors.

What has been described as the ‘medicalisation’ of society – the belief that every problem requires medical treatment – may also be attributed in part to the activities of the pharmaceutical industry. While the pharmaceutical industry cannot be blamed for creating unhealthy reliance on, and over-use of, medicines, it has certainly exacerbated it. There has been a trend towards categorising more and more individuals as ‘abnormal’ or in need of drug treatment.

The UK pharmaceutical industry

The pharmaceutical industry is a global enterprise. It is dominated by a few

multinationals. The US is the industry’s largest and most profitable market.

Nonetheless, Europe, and the UK in particular, provide a strong market for medicines and have traditionally been important sites for drug-related R&D. Two of the largest pharmaceutical companies, questioned as to the relevance of UK health policies to their global businesses, testified to the importance of the UK as a site for the marketing and development of medicines:

Both those involved in the UK pharmaceutical industry and its critics have given

evidence of its strength and success. It is fifth largest in the world by total sales,

representing 7% of world sales, after the US, Japan,  Germany and France.14 The UK is the third largest direct exporter of pharmaceuticals; has the third largest world trade surplus; and accounts for 10% of world pharmaceutical R&D expenditure. The pharmaceutical industry is an important employer and contributor to the economy of this country.15 The UK industry operates within a highly regulated environment. The way in which it undertakes research, produces, licenses and markets its products are all subject to a detailed regulatory system. In this chapter were discuss the industry. We later go on to look at systems for controlling it.

Research and development

R&D facilities in the UK are world-class and British-based companies have a long

history of success in drug development. The pharmaceutical industry invests some Ł3.3 billion a year into R&D in the UK. Drug companies based in the UK employ 29,000 individuals in R&D, making it one of the largest employers of science graduates. The industry funds more healthcare-related research in the UK than every other source combined – six times as much as the Department of Health; five times as much as medical charities; eight times as much as the Medical Research Council (MRC)  Funding of health-related R&D

The pharmaceuticals sector conducts 65% of health-rated R&D, and accounts for

around 40% of all industrial R&D expenditure in the UK, spending about Ł10 million each day. The leading UK companies in R&D are GSK, AstraZeneca, Pfizer, Eli Lilly, Wyeth,  Roche, Merck Sharpe & Dohme and Novartis.17

The combination of a strong history and favourable environment means that the UK pharmaceutical industry is able to “punch well above its market weight”: only 3% (by value) of the world’s prescription medicines are sold here, yet the UK attracts around 10% of global investment in pharmaceutical R&D.18 This is more than half of the total pharmaceutical R&D investment in Europe as a whole (see Figure 2, below). Twenty-five of the world’s leading medicines have their origins in this country, which is more than any country except the US.

. The development of effective medicines has contributed significantly to the welfare of patients, over the last 50 years in particular. Examples include the development of vaccines against infectious diseases, the use of H2-antagonists in the treatment of peptic ulcers and the discovery of AZT for the management of HIV/AIDS. The effective treatment of heart disease with clot-busting medicines and anti-hypertensive drugs has helped reduce related mortality rates by 40% in the last decade alone.21 According to the Association of the British Pharmaceutical Industry (ABPI), the UK pharmaceutical industry’s representative body, improved treatments in 12 areas of serious illness since the 1950s have reduced hospital bed days by a number equivalent to Ł11 billion NHS savings per year. This is 4 billion more than the total annual spend by the NHS on medicines in England.22 A successful pharmaceutical industry therefore has unquestionable healthcare as well as economic benefits. Advances in medicines and devices can mean greater convenience in use as well as sometimes significant improvements in treatment.

Generic medicines

All the major pharmaceutical companies produce branded products. Another section of the industry has traditionally produced generic medicines, which come to market once the branded drug’s patent expires. Generic drugs play a major part in containing NHS drugs expenditure. In 2002, unbranded medicines accounted for 53% of all prescriptions dispensed in England, but 20% of total drug costs. Four years after patent expiry of a branded product, generic drugs will account for about half of the drug’s market (UK average) and the average price differential between branded and generic versions of the same drug is approximately 80%.

In the UK, those prescribing in the community are encouraged to write the generic

drug name, whereas in many other countries (and in UK hospitals) there is an automatic generic substitution system in place. Nevertheless, the rate of generic prescribing is still very high compared with other major European pharmaceutical markets, and substantial costs savings are achieved. In 2003, 77.8% of prescriptions were written generically, a ecord of which the Department is proud.24 Since 1997, the proportion of prescriptions written and dispensed generically has significantly increased, though cost savings appear to have slowed.

Over the past decade, there have been significant changes in the pattern of UK generic manufacturing ownership, leading to increasing domination by large international generic manufacturers. In general, these manufacturers operate independently of, and in competition with, the major brand name companies. However, the Ł4.4 billion acquisition of two major generic producers by the Swiss firm, Novartis, in February 2005, may presage a major change. Novartis, the world’s sixth-largest producer of branded drugs, is now theworld’s largest manufacturer of generics.

The Pharmaceutical Industry Competitiveness Task Force

Despite its continuing success during the 1990s, there were increasing concerns about the competitiveness of the UK pharmaceutical industry that were voiced at a meeting in November 1999 between the Prime Minister and the Chief Executive Officers (CEOs) of AstraZeneca, Glaxo Wellcome and SmithKline Beecham. The CEOs argued that the traditional factors that underpinned the UK’s past success in pharmaceuticals were no longer sufficient to guarantee good performance, and that an initiative was required to ensure the UK retained its competitive edge. They expressed particular concern about difficulty in getting their products to the UK market, and intellectual property protection.  This led to the establishment of the Pharmaceutical Industry Competitiveness Task Force (PICTF).

The overall aim of PICTF was to look at ways of ensuring that the UK remained an

attractive location for the pharmaceutical industry, with specific reference to international competitiveness, the free movement of medicines within the EU and European licensing of medicines, the UK as a site for R&D (including partnerships with academia) and the NHS as a location for clinical studies. The group was co-chaired by Lord Hunt, then Parliamentary Under Secretary of State for Health, and Sir Tom McKillop, CEO of AstraZeneca, with equal representation from Government and the industry.

PICTF published a report in March 2001 that proposed specific measures and

commitments by Government to assist the UK pharmaceutical industry. It also defined‘Competitiveness and Performance Indicators’ for the industry, to be recorded and published each year to assess trends over time. These indicators provide the objective data to underpin assessments of how well the UK is performing in the key areas that are crucial.

The first set of indicators was published in March 2001 and the most recent set was

published in December 2004. They show that the UK currently has:

A pharmaceutical industry that contributes significantly to the UK economy;

A comparatively strong scientific research base; An impressive record of pharmaceutical innovation; A relatively rapid regulatory process for medicines compared to other countries; and Relatively slow uptake of medicines by prescribers

There are not enough trained medical researchers in the UK. This means there are too few individuals who can organise clinical trials or take part in a reviewing or

implementation capacity.

 There is a shortage of appropriately trained clinical investigators in the UK, and this reflects lack of investment in clinical research and problems with clinical training pathways.

Specialist facilities are also lacking. There are very few centres in which paediatric

clinical trials may be effectively conducted, for example. This will become more relevant following the introduction of a new European Regulation on Paediatric Medicines in 2006, which will require more medicines to be licensed for use in children.

Medicines licensing

Drug approval and licensing systems worldwide are based on detailed requirements and elaborate processes, the scope of which is constantly changing. However, the core elements of drug control remain essentially unchanged.

 The executive arm of the UK Licensing Authority is the Medicines and Healthcare

products Regulatory Agency (MHRA), which is also responsible for approving clinical trials48. The MHRA is assisted by the Committee on the Safety of Medicines (CSM), and the Medicines Commission. These latter two organisations are due to be merged into one over-arching body, the Commission for Human Medicines. Medicines may be licensed for use in the UK either on a national basis (directly through the MHRA), through centralised approval system of the European Medicines Agency (EMEA) or through a procedure for ‘mutual recognition’. Under the centralised scheme, companies apply for a licence directly to the EMEA. The centralised approval system is already compulsory for biotechnology products and has expanded in scope to cover drugs for AIDS, cancer,  neurodegenerative diseases and diabetes. Alternatively, a company may designate one EU

country to approve a drug licensing application, and then receive marketing authorisation in various EU countries, provided these other countries agree. Under this ‘mutual recognition’ procedure, all EU countries in which marketing permission is sought receive the full drug licence application, and any objections are considered and resolved through EMEA’s oversight body, the Committee on Human Medicinal Products (CHMP). Details for the arrangements for medicines licensing, regulation and post-licensing surveillance are discussed in Part 5.

Once licensed, the drug itself is under patent protection for 10 years, although in

certain circumstances this may be extended. Once the period of patent protection has expired, the originating company is deemed to have been rewarded for risks of innovation and generic versions of the drug may enter the market. A generic medicine contains the same active ingredients as an original product that has been researched and developed by a pharmaceutical company. Regulatory standards for safety and efficacy are the same for generic medicines as for branded products and marketing authorisation must be obtained from the MHRA before the drug is allowed on to the market. Additional clinical data is not required. The manufacturers of generic medicines need prove only that their products are effectively identical to the original branded product, implying that they have identical effects on patients.

Post-licensing evaluation, including value for money assessments

.The initial marketing authorisation lasts for five years, at which time the company must apply to the MHRA for a further, essentially permanent, licence if it wishes the product to remain on the market. The legal criteria for re-licensing are the same as those for the original assessment (safety, efficacy and quality) but in reality scrutiny is much less stringent and would rarely involve the CSM. Efficacy is rarely considered. There is no specific policy regarding the continuing evaluation and safety assessment of medicines.

The MHRA is also charged with conducting more general post-marketing surveillance. This may involve scrutiny of Phase IV trials, which include patients in a more typical setting, as well as monitoring published medical literature and evaluation of spontaneous reports of suspected adverse drug reactions (ADRs.

Legislation requires that pharmaceutical companies must provide information on their products on request from healthcare professionals. This obligation continues once medicines come off-patent and does not apply to generic companies. Large companies in the UK may each receive 15–30,000 requests for information annually. As an example,  Pfizer, the largest supplier of prescription medicines to the NHS, pays over Ł1 million annually to cover the cost of providing this information service.51 Information to prescribers A Summary of Product Characteristics (SPC) is issued to prescribers and other healthcare professionals for every new drug. The detail of content, style, layout and format are closely defined and approval is part of the licensing process.

The British National Formulary (BNF), which is published biannually, also provides information to prescribers. The BNF is published jointly by the British Medical Association  (BMA) and the Royal Pharmaceutical Society of Great Britain (RPSGB). It provides information on the prescription, dispensing, administration and cost of medicines.

A range of alternative sources of independent information is available, including the Drug and Therapeutics Bulletin (DTB) that is published by Which? and distributed by the Department of Health to all doctors,52 the Cochrane Collaboration and the James Lind Library. Medical journals provide a variety of specialist and non-specialist data relating to clinical trials or basic scientific studies. Industry produced or sponsored information is also provided to prescribers, in the form of journal supplements, reprints and other literature.

Information to patients

Patient Information Leaflets (PILs), which are legally required documents written in accordance with EU regulations and approved by the MHRA, are printed and distributed alongside medicines by pharmaceutical companies to inform patients of how to take their medicine most effectively and to warn them of possible risks and side-effects. Like the SPC,  they are approved as part of the licensing process; however, the regulations are not so prescriptive for PILs, allowing limited variation in their content and appearance. The PIL must correspond to the SPC. In response to long-standing criticisms, the MHRA set up a Patient Information Working Group in 2003, to review the design, content and utility of PILs. The work of this group is continuing In addition to the PIL, patients (and carers) may receive industry-produced pamphlets or written instructions through their doctor or other healthcare professional. Patients can also access large amounts of information and promotional material on the Internet.

The Department provides a grant to cover this service.

Professional and patient education

Doctors are required to continue their education after they have qualified by taking

part in accredited activities. These may take the form of attendance at training days or workshops. Industry funds over half of all postgraduate education and training for doctors in the UK, often meeting the travel and accommodation costs of attendance. The pharmaceutical industry also funds a significant amount of training for nurses. In 2003, for instance, GSK funded 235 nursing diplomas in respiratory disease management and 199 diplomas in diabetes management.

Education for patients is provided in a variety of ways, including disease awareness campaigns, which are discussed in detail in Part 8. Such campaigns are designed to increase awareness among the general public of particular conditions that may be under-reported or under-diagnosed and to encourage people to seek treatment. Often, such campaigns are sponsored by a drug company and may bear a company’s logo; they may be also endorsedby a charity or patient organisation and/or supported by a celebrity.

Guidelines for disease awareness campaigns, developed jointly between the MHRA and the ABPI, were published in April 2003. The guidelines state that educational materials may highlight the availability of treatment but may not focus on, or name, any single intervention.

The promotion of drugs

Worldwide, there has been a marked trend to substantially increased expenditure on marketing. In the US, major pharmaceutical companies spend of the order of 24% to 33% of sales on marketing, about twice as much as on R&D.55 Exact comparisons are complicated because of uncertainties about the dividing line/overlap between marketing and related activities, notably provision of drug information and professional education programmes. We have not been presented with UK figures, but direct promotional expenditure in this country is proportionately lower than in most European countries, reflecting the dominance of the NHS as the major drug purchaser and the terms of the Pharmaceutical Price Regulation Scheme (PPRS),  Prescription-only medicines may be promoted only to healthcare professionals, except in very specific cases such as Government-endorsed vaccination programmes. Promotion to prescribers may take many forms:

a) Drug company representatives. Approximately. 8,000 drug company representatives operate in the UK and play an important role in information provision and medicines. 

b) Sponsored attendance at industry-organised events or medical conferences. Travel and accommodation costs are often met by the company. Other forms of hospitality are also provided.

c) Journal articles and supplements supporting use of the company’s drug. These are distributed free to prescribers and are available at conferences and on the Internet.

d) Direct advertising. Advertisements are placed in medical journals and magazines.

Direct mailing to healthcare professionals often takes the form of informing prescribers of changes in drug delivery systems or the availability of new drug formulations.

Approximately 80% of medicines advertising is aimed at doctors, with an increasing amount targeting nurses with new prescribing powers

Public relations and marketing agencies are often used by the pharmaceutical industry to assist with the promotional activities described above. ‘Medical communications’ play an important role in the marketing of medicines. The main aim is to improve sales figures and there are dedicated agencies that often form part of enormous, multinational PR and communications companies, such as Ogilvy, Burson-Marsteller, Edelman and Ketchum.

Medical communications agencies may be involved in all or some of the following:

a) Pre-marketing of drugs;

b) Identification of disease areas;

c) Disease awareness campaigns;

d) Consumer education and marketing;

e) Publications and papers;

f) Conferences, meetings and hospitality;

g) ‘Product lifecycle management’;

h) Regulatory and policy issues;

i) Grassroots communications;

j) Key opinion leader development; and

k) The production of ‘educational’ materials aimed at prescribers.

A critical element of the work of medical communications companies is the

recruitment and training of key opinion leaders (KOLs), who are usually ‘authoritative

third parties’ such as physicians at the top of their field. These individuals may be paid to

speak and write on behalf of the sponsoring pharmaceutical company.

 Increasingly creative methods are used in the promotion of drugs by Industry. Which?

cited a financial donation made by the manufacturers of Cipralex (escitalopram, an

antidepressant manufactured by Eli Lilly) to Depression Alliance when GPs completed and

returned a feedback leaflet relating to their drug58 and a spoof Mr Man book (‘Mr Sneeze’)

that was sponsored by a drug company and carried information about its anti-allergy

product.

The direct advertising of prescription drugs to patients is prohibited. Direct-to-

consumer advertising (DTCA) of prescription-only medicines is permitted only in the US

and New Zealand. Moves towards extending DTCA to Europe proposed by the European

Commission were quashed by the European Parliament in October 2002 by a majority of

494 to 42. Only over-the-counter (OTC) medicines may be advertised to the UK general

public. The Medicines (Advertising) Regulations 1994, amended in 1999, govern the

advertising of these medicines. There are specific regulations relating to promotional

methods that could lead to the unnecessary or excessive use of medicines.

85. Complaints regarding advertising material are handled by a variety of bodies. The

Proprietary Association of Great Britain (for OTC medicines), the Prescription Medicines

Code of Practice Authority (PMCPA, for prescription-only drugs) and the Advertising

Standards Authority operate as self-regulatory schemes and take responsibility for

handling advertising complaints alongside the MHRA. Corrective statements are rarely

mandatory, although a recent increase in the number of such statements required by the

MHRA has been observed.

A number of processes are in place to control the research, marketing and promotional

activities of the UK pharmaceutical industry. These include:

a) International standards of good clinical practice (GCP) in research;

b) Research Ethics Committees;

c) Medicines licensing regulation;

d) Post-marketing safety surveillance and drug evaluation; and

e) Cost assessment.

Orphan drugs

In order to increase rates of research into areas of serious disease that affect relatively

few people (and therefore might be expected to have low market value) the US Orphan

Drugs Act was passed in 1983 in the US and its principles were adopted in the European

Orphan Drugs Act in 2000. Incentives to develop orphan drugs include intellectual

property protection and 11-year market exclusivity.

A number of criticisms have been levelled against the current system for encouraging

the development of orphan drugs. The lack of competition drives up orphan drug prices

and this may have important economic implications for PCTs and other healthcare

providers. An example of this is nitric oxide, which was available for years and, unlicensed,

cost very little (it cost approximately Ł2,000 to supply a neo-natal unit with nitric oxide for

one year71). Two clinical trials proved the benefit of inhaled nitric oxide and it was

approved and received a patent in the US and EU on this basis.72 Since licensing, nitric

oxide now costs many times more (it was estimated that supply of nitric oxide for the same

neo-natal unit would now cost over Ł63,000 per year).

Some drugs marketed as Orphan Drugs may have required little research input. The

quality of clinical trials of Orphan Drugs has been questioned. In addition, innovation in a

particular area may be reduced once a single product is available, due to market exclusivity.

The National Institute for Clinical Excellence

The uptake of novel drugs, an issue of great importance to the industry, is partially

determined by NICE. The Institute issues guidance about the use of both old and new

medicines and procedures. Guidance is of four main forms:

a) Technology appraisals: recommendations on the use of new and existing medicines

and other treatments (devices, surgical and other procedures, diagnostic techniques

and health promotion methods);

b) Clinical guidelines: recommendations on the appropriate treatment and care of

patients with specific diseases and conditions, such as diabetes and schizophrenia;

c) Cancer service guidance: recommendations on arrangements for the organisation and

delivery of services for people with cancer; and

d) Interventional procedures: guidance about whether interventional procedures used for

diagnosis and treatment are safe enough and work well enough for routine use. An

interventional procedure is one used for diagnosis or treatment that involves making a

cut or hole in the body, entry into a body cavity or using electromagnetic radiation

(including X-rays or lasers) and ultrasound.

NICE currenty publishes around 25 technology appraisals, 12 clinical guidelines and

60 pieces of interventional procedures guidance each year. Of the 25 technology appraisals,

not all are for new drugs; they can also be reviews of non-drug treatments, re-reviews or

reviews of medicines licensed several years ago. This means that a minority of new drugs

approved by the MHRA are subsequently subject to NICE scrutiny. The Department of

Health asks the Institute to look at particular drugs and devices only where the availability

of the drug or device varies across England and Wales or where there is confusion or

uncertainty over its value.

The pharmaceutical industry has some say in the selection of topics for appraisal.

Drug companies provide information to the National Horizon Scanning Centre on the

development of new pharmaceutical products and their licensing position and have one

seat on the Advisory Committee on Topic Selection (ACTS), which assesses proposals for

work topics for NICE against published criteria. The Joint Planning Group, which

considers ACTS’ proposals and advises Ministers, who take final decisions on NICE’s work

programme, does not include the pharmaceutical industry in its membership. NICE’s

approach to engaging with the pharmaceutical industry in the development of its

technology appraisals and clinical guidelines is as follows:

a) NICE drafts a written consultation on the scope for a technology appraisal or a clinical

guideline.

b) NICE invites relevant members of the pharmaceutical industry, alongside the other

stakeholders, to a meeting at the start of the development of a piece of guidance to

discuss the scope, the approach to assembling the evidence base, and the key issues that

will be addressed during the development of the guidance.

c) NICE consults on the evidence to be used by the advisory body and all stakeholders are

given the opportunity to supplement the evidence base. Ultimately, the evidence that is

taken account of is a matter for the advisory body, which sets out the rationale for the

use or otherwise of the evidence submitted by all stakeholders.

d) The advisory body prepares a written consultation on the draft recommendations, on

two occasions during the development of a clinical guideline (where there is no appeal

stage), and on one occasion during the development of technology appraisal guidance

(where there is an appeal stage). Comments received from the pharmaceutical industry

on draft documents, in common with responses from other stakeholders, are posted on

the Institute’s website.

e) In the technology appraisal programme the relevant pharmaceutical company,

alongside other stakeholders, has the opportunity to submit an appeal on the grounds

that the Institute has exceeded its powers or has failed to follow its process, or that the

guidance is perverse.

The Pharmaceutical Price Regulation Scheme

The Pharmaceutical Price Regulation Scheme (PPRS) is a mechanism for determining

the profit made by drug companies through the sales of their medicines to the NHS.73

Details of the Scheme, which has been running since 1956 (when it was known as the

Voluntary Price Regulation Scheme) are negotiated periodically by the Department of

Health and the ABPI. The present Scheme came into force on 1 January 2005 and, unless

either side withdraws beforehand, will continue until at least 2010. The overall objectives of

the PPRS are to:

Secure the provision of safe and effective medicines for the NHS at reasonable prices;

Promote a strong and profitable industry capable of such sustained research and

development expenditure as should lead to the future availability of new and improved

medicines; and

Encourage the efficient and competitive development and supply of medicines to

pharmaceutical markets in this and other countries.

The PPRS, which applies only to companies supplying licensed brand name products

to the NHS, indirectly controls drug prices. Although it nominally applies to all such drug

suppliers, only those companies with sales each year to the NHS of more than Ł25 million

become involved in detailed negotiations. Sales by the 44 companies currently involved at

this level account for 94% of the total amount the NHS spends on purchasing brand name

products.

Through the Scheme, each year individual companies are set a level of return on

capital (ROC; the amount of money they can earn through sales to the NHS). Once this

profit target has been agreed, it is for the company to adjust the prices of its portfolio to

reach that target. Companies are required to reimburse the NHS when their returns are

above target, and may increase their prices when returns are below target.

Target ROCs are set in advance, so the profit actually achieved may differ from that

predicted. To take this into account, margins of tolerance (MOTs) are built into the PPRS

such that reimbursement is not required until returns are over 140% of the ROC target,

and price rises not permitted until returns are less than 40% of the ROC target. Increasing

the prices of established drugs is not encouraged, so companies generally aim to reach their

ROC targets by charging high prices for their drugs at the time of launch or by broadening

their sales base.

In order to set the ROC target, each year the company submits details of its business

in an annual financial return (AFR). One section of the AFR seeks information on the

company's fixed assets (which includes the historic cost of the company's UK sites, land,

buildings, plant and machinery). The profit the company is allowed is then calculated as

21% of the fixed asset figure, which, with the MOT, may rise to 29.4% of the fixed assets.

118. Also included in the determination of the final ROC are allowances for the company's

spend on R&D, marketing and the provision of information. For R&D, the allowance is

 equivalent to up to 28% of the company's sales to the NHS, and in this figure provision is

made for each new drug introduced. For drug promotion, the figure is 4% of sales, and to

this is added further allowances depending on the number of drugs available. For

providing information, the allowance is again equivalent to 4% of sales to the NHS.

By determining company profit margins allowed against the sale of medicines to the

NHS, and by incorporating into these margins allowances for R&D, innovation, drug

promotion and the provision of information, the PPRS provides a key mechanism by

which the Department can act as the UK-based industry's sponsor.

The price of generic medicines is not controlled by the PPRS but, since August 2000,

the main generics used in the community have been subject to a statutory maximum price

scheme. This cap on prices was introduced following ‘turbulence’ and alleged price-fixing

in the generics market that led to substantial prices increases in 1999/2000.

Drug and Therapeutics Committees

Local NHS measures may also be in place to control the activities of the

pharmaceutical industry. Drug and Therapeutics Committees (also known as Use of

Medicines Committees), which operate in local hospital Trusts, address prescribing and

medicines use across the Trust, including affiliated primary care trusts (PCTs). Their

guidance may be stricter than that of NICE. [See boxed text in Part 6 for an example of a

Drug and Therapeutics Committee.]

There are also Area Prescribing Committees, which operate across health authorities

and aim to ensure appropriate medicines use across the primary and secondary care

boundary. In addition, there are prescribing advisers, usually pharmacists, who are

employed by Strategic Health Authorities and PCTs, and work to encourage rational and

cost-effective prescribing in primary care. According to the Department of Health, over

1,200 prescribing advisers are now in place in England and Wales.74 This works out at an

average of fewer than four per PCT.

Professional bodies

The core guidance booklet published by the General Medical Council (GMC), Good

Medical Practice, warns doctors against “involvement in any relationships with

pharmaceutical or other companies which could raise, or be seen to raise, a conflict of

interests”.75 The GMC states that this is intended to cover matters such as accepting any

kind of substantial hospitality or gifts from pharmaceutical companies. According to Good

Medical Practice, doctors must be honest about any financial or commercial interests they

have in pharmaceutical companies and ensure that those interests do not affect their

independent judgement in providing and arranging patient care. No mention is made of

guidelines for medically qualified doctors working within the industry but the GMC is

reported to be working with Faculty of Pharmaceutical Medicine to set standards for

. The World Medical Association also issued guidelines in October 2004 on the relationship between doctors and commercial enterprises, with particular reference to the disclosure of interests in the context of

research, conference attendance, gifts and affiliations.

Other professional bodies, such as the Royal College of Nursing (RCN), Royal College

of General Practitioners (RCGP) and National Pharmaceutical Association (NPA), may

have individual policies in place regarding funding received from the pharmaceutical

industry. For example, the RCGP, which received 3% of its annual income from the

industry in the 2003–2004 financial year, stated:

The College has strict guidelines on accepting money from any sponsor, in order to

ensure that the sponsor has no direct influence on the educational content of an

event or conference.Although the GMC pointed out that, “complaints about doctors asking for or

accepting inappropriate fees or hospitality” from pharmaceutical companies are unusual,

we have not heard of any standard policies in place among professional organisations

governing the interaction between industry and their members. There is no centrally held

register of personal or financial interests in the pharmaceutical industry. The RCN, which

receives approximately 30% of its annual sponsorship income from the pharmaceutical

industry, stated that individual contact between nurses and drug company representatives

does not involve the College:

Nurses can get offered the opportunity to negotiate payment of expenses for further

training directly with company representatives without reference, support or the

knowledge of the RCN. In these situations the RCN is not in any way involved, and

does not attempt to regulate.

The industry’s codes of practice

The industry has its own arrangements for regulating the sales and marketing

activities of its companies. This is largely achieved through the Code of Practice of the

ABPI.81 The Medicines Act and related EU legislation requires Ministers to exercise

oversight of these activities. All aspects of the promotion of medicines, including

advertisements, representatives’ activities, meetings, the provision of education and

hospitality and the provision of medical information by the industry are subject to self-

regulation through the Code. The ABPI states that the industry “works well within self-

regulation”.

History

The earliest drugstores date to the Middle Ages. The first known drugstore was opened by Arabian pharmacists in Baghdad in 754, and many more soon began operating throughout the medieval Islamic world and eventually medieval Europe. By the 19th century, many of the drugstores in Europe and North America had eventually developed into larger pharmaceutical companies.

Most of today's major pharmaceutical companies were founded in the late 19th and early 20th centuries. Key discoveries of the 1920s and 1930s, such as insulin and penicillin, became mass-manufactured and distributed. Switzerland, Germany and Italy had particularly strong industries, with the UK, US, Belgium and the Netherlands following suit.

Legislation was enacted to test and approve drugs and to require appropriate labeling. Prescription and non-prescription drugs became legally distinguished from one another as the pharmaceutical industry matured. The industry got underway in earnest from the 1950s, due to the development of systematic scientific approaches, understanding of human biology (including DNA) and sophisticated manufacturing techniques.

Numerous new drugs were developed during the 1950s and mass-produced and marketed through the 1960s. These included the first oral contraceptive, "The Pill", Cortisone, blood-pressure drugs and other heart medications. MAO Inhibitors, chlorpromazine (Thorazine), Haldol (Haloperidol) and the tranquilizers ushered in the age of psychiatric medication.Valium (diazepam), discovered in 1960, was marketed from 1963 and rapidly became the most prescribed drug in history, prior to controversy over dependency and habituation.

Attempts were made to increase regulation and to limit financial links between companies and prescribing physicians, including by the relatively new U.S. Food and Drug Administration (FDA). Such calls increased in the 1960s after the thalidomide tragedy came to light, in which the use of a new anti-emetic in pregnant women caused severe birth defects. In 1964, the World Medical Association issued its Declaration of Helsinki, which set standards for clinical research and demanded that subjects give their informed consent before enrolling in an experiment. Pharmaceutical companies became required to prove efficacy in clinical trials before marketing drugs.

The industry remained relatively small scale until the 1970s when it began to expand to a greater rate.[citation needed] Legislation allowing for strong patents, to cover both the process of manufacture and the specific products, came in to force in most countries. By the mid-1980s, small biotechnology firms were struggling for survival, which led to the formation of mutually beneficial partnerships with large pharmaceutical companies and a host of corporate buyouts of the smaller firms. Pharmaceutical manufacturing became concentrated, with a few large companies holding a dominant position throughout the world and with a few companies producing medicines within each country.

The pharmaceutical industry entered the 1980s pressured by economics and a host of new regulations, both safety and environmental, but also transformed by new DNA chemistries and new technologies for analysis and computation.[citation needed] Drugs for heart disease and for AIDS were a feature of the 1980s, involving challenges to regulatory bodies and a faster approval process.

Managed care and Health maintenance organizations (HMOs) spread during the 1980s as part of an effort to contain rising medical costs, and the development of preventative and maintenance medications became more important. A new business atmosphere became institutionalized in the 1990s, characterized by mergers and takeovers, and by a dramatic increase in the use of contract research organizations for clinical development and even for basic R&D. The pharmaceutical industry confronted a new business climate and new regulations, born in part from dealing with world market forces and protests by activists in developing countries. Animal Rights activism was also a challenge.

Marketing changed dramatically in the 1990s. The Internet made possible the direct purchase of medicines by drug consumers and of raw materials by drug producers, transforming the nature of business. In the US, Direct-to-consumer advertising proliferated on radio and TV because of new FDA regulations in 1997 that liberalized requirements for the presentation of risks. The new antidepressants, the SSRIs, notably Fluoxetine (Prozac), rapidly became bestsellers and marketed for additional disorders. In the United States as of 2012, the industry spent about 1.3 percent of its revenue on research vs. about 25 percent on marketing.

Drug development progressed from a hit-and-miss approach to rational drug discovery in both laboratory design and natural-product surveys. Demand for nutritional supplements and so-called alternative medicines created new opportunities and increased competition in the industry. Controversies emerged around adverse effects, notably regarding Vioxx in the US, and marketing tactics. Pharmaceutical companies became increasingly accused of disease mongering or over-medicalizing personal or social problems.

Research and development

Drug discovery is the process by which potential drugs are discovered or designed. In the past most drugs have been discovered either by isolating the active ingredient from traditional remedies or by serendipitous discovery. Modern biotechnology often focuses on understanding the metabolic pathways related to a disease state or pathogen, and manipulating these pathways using molecular biology or biochemistry. A great deal of early-stage drug discovery has traditionally been carried out by universities and research institutions. Public funding accounts for 80% of the amount spent on basic research for new drugs and vaccines in the United States.

Drug development refers to activities undertaken after a compound is identified as a potential drug in order to establish its suitability as a medication. Objectives of drug development are to determine appropriate Formulation and Dosing, as well as to establish safety. Research in these areas generally includes a combination of in vitro studies, in vivostudies, and clinical trials. The amount of capital required for late stage development has made it a historical strength of the larger pharmaceutical companies.

Often, large multinational corporations exhibit vertical integration, participating in a broad range of drug discovery and development, manufacturing and quality control, marketing, sales, and distribution. Smaller organizations, on the other hand, often focus on a specific aspect such as discovering drug candidates or developing formulations. Often, collaborative agreements between research organizations and large pharmaceutical companies are formed to explore the potential of new drug substances.

The cost of innovation

Drug companies are like other companies in that they manufacture products that must be sold for a profit in order for the company to survive and grow. They are different from some companies because the drug business is very risky. For instance, only one out of every ten thousand discovered compounds actually becomes an approved drug for sale. Much expense is incurred in the early phases of development of compounds that will not become approved drugs. In addition, it takes about 7 to 10 years and only 3 out of every 20 approved drugs bring in sufficient revenue to cover their developmental costs, and only 1 out of every 3 approved drugs generates enough money to cover the development costs of previous failures. This means that for a drug company to survive, it needs to discover a blockbuster (billion-dollar drug) every few years.

Drug discovery and development is very expensive; of all compounds investigated for use in humans only a small fraction are eventually approved in most nations by government appointed medical institutions or boards, who have to approve new drugs before they can be marketed in those countries. In 2010 18 NMEs (New Molecular Entities) were approved and three biologics by the FDA, or 21 in total, which is down from 26 in 2009 and 24 in 2008. On the other hand, there were only 18 approvals in total in 2007 and 22 back in 2006. Since 2001, the Center for Drug Evaluation and Research has averaged 22.9 approvals a year.  This approval comes only after heavy investment in pre-clinical development andclinical trials, as well as a commitment to ongoing safety monitoring. Drugs which fail part-way through this process often incur large costs, while generating no revenue in return. If the cost of these failed drugs is taken into account, the cost of developing a successful new drug (New chemical entity or NCE), has been estimated at about 1.3 billion USD[8](not including marketing expenses). Professors Light and Lexchin reported in 2012, however, that the rate of approval for new drugs has been a relatively stable average rate of 15 to 25 for decades.

Industry-wide research and investment reached a record $65.3 billion in 2009.[9] While the cost of research in the U.S. was about $34.2 billion between 1995 and 2010, revenues rose faster (revenues rose by $200.4 billion in that time).

A study by the consulting firm Bain & Company reported that the cost for discovering, developing and launching (which factored in marketing and other business expenses) a new drug (along with the prospective drugs that fail) rose over a five-year period to nearly $1.7 billion in 2003.

These estimates also take into account the opportunity cost of investing capital many years before revenues are realized (see Time-value of money). Because of the very long time needed for discovery, development, and approval of pharmaceuticals, these costs can accumulate to nearly half the total expense. Some approved drugs, such as those based on re-formulation of an existing active ingredient (also referred to as Line-extensions) are much less expensive to develop.

Calculations and claims in this area are controversial because of the implications for regulation and subsidization of the industry through tax credits and federally funded research grants.

"Me-too" drugs

Competition between pharmaceutical companies has resulted in "me-too" drugs, which are defined as chemically-similar compounds or compounds with the same mechanism of action as an existing, approved chemical entity. Critics of the pharma industry suggest that "me-too" drugs are only brought to market because their development is cheaper and less risky than drugs with a novel mechanism of action. However, proponents point to the cost benefits of market competition between similar drugs. In addition, it may take 10 or more years for a drug to go from discovery to FDA approval, and if a new clinical pathway is discovered, multiple companies often will simultaneously develop a drug treatment within this pathway, leading to several similar drugs arriving on the market within a short period of time. This is why some suggest that much of the “me-too” drug phenomenon is actually a result of independent parallel research at rival companies.

Controversy over commercial ties and unfavorable studies

Due to repeated accusations and findings that some clinical trials conducted or funded by pharmaceutical companies may report only positive results for the preferred medication, the industry has been looked at much more closely by independent groups and government agencies.

In response to specific cases in which unfavorable data from pharmaceutical company-sponsored research was not published, the Pharmaceutical Research and Manufacturers of America have published new guidelines urging companies to report all findings and limit the financial involvement in drug companies of researchers.[18] US congress signed into law a bill which requires phase II and phase III clinical trials to be registered by the sponsor on the clinical trials.gov website run by the NIH.

Drug researchers not directly employed by pharmaceutical companies often look to companies for grants, and companies often look to researchers for studies that will make their products look favorable. Sponsored researchers are rewarded by drug companies, for example with support for their conference/symposium costs. Lecture scripts and even journal articles presented by academic researchers may actually be 'ghost-written' by pharmaceutical companies.[20] Some researchers who have tried to reveal ethical issues with clinical trials or who tried to publish papers that show harmful effects of new drugs or cheaper alternatives have been threatened by drug companies with lawsuits.

Product approval in the US

In the United States, new pharmaceutical products must be approved by the Food and Drug Administration (FDA) as being both safe and effective. This process generally involves submission of an Investigational new drug filing with sufficient pre-clinical data to support proceeding with human trials. Following IND approval, three phases of progressively larger human clinical trials may be conducted. Phase I generally studies toxicity using healthy volunteers. Phase II can include Pharmacokinetics and Dosing in patients, and Phase III is a very large study of efficacy in the intended patient population. Following the successful completion of phase III testing, a New Drug Application is submitted to the FDA. The FDA review the data and if the product is seen as having a positive benefit-risk assessment, approval to market the product in the US is granted.

A fourth phase of post-approval surveillance is also often required due to the fact that even the largest clinical trials cannot effectively predict the prevalence of rare side-effects. Post-marketing surveillance ensures that after marketing the safety of a drug is monitored closely. In certain instances, its indication may need to be limited to particular patient groups, and in others the substance is withdrawn from the market completely. Questions continue to be raised regarding the standard of both the initial approval process, and subsequent changes to product labeling (it may take many months for a change identified in post-approval surveillance to be reflected in product labeling) and this is an area where congress is active.

The FDA provides information about approved drugs at the Orange Book site.

Orphan drugs

There are special rules for certain rare diseases ("orphan diseases") involving fewer than 200,000 patients in the United States, or larger populations in certain circumstances. [26]Because medical research and development of drugs to treat such diseases is financially disadvantageous, companies that do so are rewarded with tax reductions, fee waivers, andmarket exclusivity on that drug for a limited time (seven years), regardless of whether the drug is protected by patents.

Legal issues

Where pharmaceutics have been shown to cause side-effects, civil action has occurred, especially in countries where tort payouts are likely to be large. The top 20 pharmaceutical cases account for over $16 billion in recoveries. Due to high-profile cases leading to large compensations, most pharmaceutical companies endorse tort reform. Recent controversies have involved Vioxx and SSRI antidepressants.

Pharmaceutical fraud

Pharmaceutical fraud involves activities that result in false claims to insurers or programs such as Medicare in the United States or equivalent state programs for financial gain to a pharmaceutical company. There are several different schemesused to defraud the health care system which are particular to the pharmaceutical industry. These include: Good Manufacturing Practice (GMP) Violations, Off Label Marketing, Best Price Fraud, CME Fraud, Medicaid Price Reporting, and Manufactured Compound Drugs. The Federal Bureau of Investigation (FBI) estimates that health care fraud costs American taxpayers $60 billion a year. Of this amount $2.5 billion was recovered through False Claims Act cases in FY 2010. Examples of fraud cases include the GlaxoSmithKline $3 billion settlement, Pfizer $2.3 billion settlement and Merk $650 million settlement. Damages from fraud can be recovered by use of the False Claims Act, most commonly under the qui tam provisions which rewards an individual for being a "whistleblower", or relator (law).

Antipsychotic drugs are now the top-selling class of pharmaceuticals in America, generating annual revenue of about $14.6 billion. Every major company selling the drugs — Bristol-Myers Squibb, Eli Lilly, Pfizer, AstraZeneca and Johnson & Johnson — has either settled recent government cases, under the False Claims Act, for hundreds of millions of dollars or is currently under investigation for possible health care fraud. Following charges of illegal marketing, two of the settlements set records last year for the largest criminal fines ever imposed on corporations. One involved Eli Lilly’s antipsychotic Zyprexa, and the other involved Bextra. In the Bextra case, the government also charged Pfizer with illegally marketing another antipsychotic, Geodon; Pfizer settled that part of the claim for $301 million, without admitting any wrongdoing.

The following is a list of the four largest settlements reached with pharmaceutical companies from 1991 to 2012, rank ordered by the size of the total settlement. Legal claims against the pharmaceutical industry have varied widely over the past two decades, including Medicare and Medicaid fraud, off-label promotion, and inadequate manufacturing practices.

Product approval elsewhere

In many non-US western countries a 'fourth hurdle' of cost effectiveness analysis has developed before new technologies can be provided. This focuses on the efficiency (in terms of the cost per QALY) of the technologies in question rather than their efficacy. In England NICE approval requires technologies be made available by the NHS, whilst similar arrangements exist with the Scottish Medicines Consortium in Scotland and the Pharmaceutical Benefits Advisory Committee in Australia. A product must pass the threshold for cost-effectiveness if it is to be approved. Treatments must represent 'value for money' and a net benefit to society. There is much speculation[42] that a NICE style framework may be implemented in the USA in an attempt to decrease Medicare and Medicaid spending by balancing benefits to patients versus profits for the medical industry.

In the UK, the British National Formulary is the core guide for pharmacists and clinicians.

Industry revenues

For the first time ever, in 2006, global spending on prescription drugs topped $643 billion, even as growth slowed somewhat in Europe and North America. The United States accounts for almost half of the global pharmaceutical market, with $289 billion in annual sales followed by the EU and Japan.(pdf) Emerging markets such as China, Russia, South Korea and Mexico outpaced that market, growing a huge 81 percent.

US profit growth was maintained even whilst other top industries saw little or no growth. Despite this, "..the pharmaceutical industry is — and has been for years — the most profitable of all businesses in the U.S. In the annual Fortune 500 survey, the pharmaceutical industry topped the list of the most profitable industries, with a return of 17% on revenue."

Pfizer's cholesterol pill Lipitor remains a best-selling drug world wide. Its annual sales were $12.9 billion, more than twice as much as its closest competitors: Plavix, the blood thinner from Bristol-Myers Squibb and Sanofi-Aventis; Nexium, the heartburn pill from AstraZeneca; and Advair, the asthma inhaler from GlaxoSmithKline.

IMS Health publishes an analysis of trends expected in the pharmaceutical industry in 2007, including increasing profits in most sectors despite loss of some patents, and new 'blockbuster' drugs on the horizon.

Teradata Magazine predicted that by 2007, $40 billion in U.S. sales could be lost at the top 10 pharmaceutical companies as a result of slowdown in R&D innovation and the expiry of patents on major products, with 19 blockbuster drugs losing patent.

Market leaders in terms of healthcare revenue

The following is a list of the 20 largest pharmaceutical and biotech companies ranked by healthcare revenue. Some companies (e.g., Bayer, Johnson and Johnson and Procter & Gamble) have additional revenue not included here. The phrase Big Pharma is often used to refer to companies with revenue in excess of $3 billion, and/or R&D expenditure in excess of $500 million.

Patents and generics

Depending on a number of considerations, a company may apply for and be granted a patent for the drug, or the process of producing the drug, granting exclusivity rights typically for about 20 years.  However, only after rigorous study and testing, which takes 10 to 15 years on average, will governmental authorities grant permission for the company to market and sell the drug. Patent protection enables the owner of the patent to recover the costs of research and development through high profit margins for the branded drug. When the patent protection for the drug expires, a generic drug is usually developed and sold by a competing company. The development and approval of generics is less expensive, allowing them to be sold at a lower price. Often the owner of the branded drug will introduce a generic version before the patent expires in order to get a head start in the generic market.[52] Restructuring has therefore become routine, driven by the patent expiration of products launched during the industry's 'golden era' in the 1990s and companies' failure to develop sufficient new blockbuster products to replace lost revenues.

In 2003 the United States enacted the Medicare Prescription Drug, Improvement, and Modernization Act (MMA), a program to provide prescription drug benefits to the elderly anddisabled. This program is a component of Medicare (United States) and is known as Medicare Part D. This program, set to begin in January 2006, will significantly alter the revenue models for pharmaceutical companies. Revenues from the program are expected to be $724 billion between 2006 and 2015.

Pharmaceuticals developed by biotechnological processes often must be injected in a physician's office rather than be delivered in the form of a capsule taken orally. Medicare payments for these drugs are usually made through Medicare Part B (physician office) rather than Part D (prescription drug plan).

Mergers, acquisitions, and co-marketing of drugs

A merger, acquisition, or co-marketing deal between pharmaceutical companies may occur as a result of complementary capabilities between them. A small biotechnologycompany might have a new drug but no sales or marketing capability. Conversely, a large pharmaceutical company might have unused capacity in a large sales force due to a gap in the company pipeline of new products. It may be in both companies' interest to enter into a deal to capitalize on the synergy between the companies.

Prescriptions

In the U.S., prescriptions have increased over the past decade to 3.4 billion annually, a 61 percent increase. Retail sales of prescription drugs jumped 250 percent from $72 billion to $250 billion, while the average price of prescriptions has more than doubled from $30 to $68.

Retail prescription drug sales 1995 to 2006 PDF from www.census.gov

Publications

The drug company Merck & Co. publishes the Merck Manual of Diagnosis and Therapy, the world's best-selling medical textbook, and the Merck Index, a collection of information about chemical compounds.

Marketing

Pharmaceutical companies commonly spend a large amount on advertising, marketing and lobbying. In the US, drug companies spend $19 billion a year on promotions. Advertising is common in healthcare journals as well as through more mainstream media routes. In some countries, notably the US, they are allowed to advertise directly to the general public. Pharmaceutical companies generally employ sales people (often called 'drug reps' or, an older term, 'detail men') to market directly and personally to physicians and other healthcare providers. In some countries, notably the US, pharmaceutical companies also employ lobbyists to influence politicians. Marketing of prescription drugs in the US is regulated by the federalPrescription Drug Marketing Act of 1987.

To healthcare professionals

Currently, there are approximately 81,000 pharmaceutical sales representatives in the United Statespursuing some 830,000 pharmaceutical prescribers. A pharmaceutical representative will often try to see a given physician every few weeks. Representatives often have a call list of about 200-300 physicians with 120-180 targets that should be visited in 1-2 or 3 week cycle. The number of pharmaceutical sales reps has been shrinking between 2008 and 2010, an estimated 30% industry wide reduction has occurred and current estimates are there may only be 60,000 pharmaceutical sales reps in the United States.

To insurance and public health bodies

Private insurance or public health bodies (e.g. the NHS in the UK) decide which drugs to pay for, and restrict the drugs that can be prescribed through the use of formularies. Public and private insurers restrict the brands, types and number of drugs that they will cover. Not only can the insurer affect drug sales by including or excluding a particular drug from a formulary, they can affect sales by tiering or placing bureaucratic hurdles to prescribing certain drugs as well. In January 2006, the U.S. instituted a new public prescription drug plan through its Medicare program known as Medicare Part D. This program engages private insurers to negotiate with pharmaceutical companies for the placement of drugs on tiered formularies.

To retail pharmacies and stores

Commercial stores and pharmacies are a major target of non-prescription sales and marketing for pharmaceutical companies.

Direct to consumer advertising

Since the 1980s new methods of marketing for prescription drugs to consumers have become important. Direct-to-consumer media advertising was legalised in the FDA Guidance for Industry on Consumer-Directed Broadcast Advertisements.

Internationally, many pharmaceutical companies market directly to the consumer rather than going through a conventional retail sales channel. For example, Japan-based Kenricomarkets largely through its company website.

Controversy about drug marketing and lobbying

There has been increasing controversy surrounding pharmaceutical marketing and influence. There have been accusations and findings of influence on doctors and other health professionals through drug reps, including the constant provision of marketing 'gifts' and biased information to health professionals; highly prevalent advertising in journals and conferences; funding independent healthcare organizations and health promotion campaigns; lobbying physicians and politicians (more than any other industry in the US); sponsorship of medical schools or nurse training; sponsorship of continuing educational events, with influence on the curriculum; and hiring physicians as paid consultants on medical advisory boards.

To help ensure the status quo on U.S. drug regulation and pricing, the pharmaceutical industry has thousands of lobbyists in Washington, DC that lobby Congress and protect their interests. The pharmaceutical industry spent $855 million, more than any other industry, on lobbying activities from 1998 to 2006, according to the non-partisan Center for Public Integrity.

Some advocacy groups, such as No Free Lunch, have criticized the effect of drug marketing to physicians because they say it biases physicians to prescribe the marketed drugs even when others might be cheaper or better for the patient.

There have been related accusations of disease mongering (over-medicalising) to expand the market for medications. An inaugural conference on that subject took place in Australia in 2006. In 2009, the Government-funded National Prescribing Service launched the "Finding Evidence - Recognising Hype" program, aimed at educating GPs on methods for independent drug analysis.

A 2005 review by a special committee of the UK government came to all the above conclusions in a European Union contextwhilst also highlighting the contributions and needs of the industry.

There is also huge concern about the influence of the pharmaceutical industry on the scientific process. Meta-analyses have shown that studies sponsored by pharmaceutical companies are several times more likely to report positive results, and if a drug company employee is involved (as is often the case, often multiple employees as co-authors and helped by contracted marketing companies) the effect is even larger. Influence has also extended to the training of doctors and nurses in medical schools, which is being fought.

It has been argued that the design of the Diagnostic and Statistical Manual of Mental Disorders and the expansion of the criteria represents an increasing medicalization of human nature, or "disease mongering", driven by drug company influence on psychiatry.[68] The potential for direct conflict of interest has been raised, partly because roughly half the authors who selected and defined the DSM-IV psychiatric disorders had or previously had financial relationships with the pharmaceutical industry.[69] The president of the organization that designs and publishes the DSM, the American Psychiatric Association, recently acknowledged that in general American psychiatry has "allowed the biopsychosocial model to become the bio-bio-bio model" and routinely accepted "kickbacks and bribes" from pharmaceutical companies.[70]

Developing world

The role of pharmaceutical companies in the developing world is a matter of some debate, ranging from those highlighting the aid provided to the developing world, to those critical of the use of the poorest in human clinical trials, often without adequate protections, particularly in states lacking a strong rule of law. Other criticisms include an alleged reluctance of the industry to invest in treatments of diseases in less economically advanced countries, such as malaria; Criticism for the price of patented AIDS medication, which could limit therapeutic options for patients in the Third World, where most of the AIDS infected people are living. However, a better policy of price discrimination would benefit to both patients and companies.

In September 2008 the Open Source Drug Discovery Network was launched in India to combat infectious diseases common to developing countries.

Patents

Patents have been criticized in the developing world, as they are thought to reduce access to existing medicines. However, without the financial incentive of patents, future innovation of medicines is discouraged. Reconciling patents and universal access to medicine would require an efficient international policy of price discrimination. Moreover, under the TRIPS agreement of the World Trade Organization, countries must allow pharmaceutical products to be patented. In 2001, the WTO adopted the Doha Declaration, which indicates that the TRIPS agreement should be read with the goals of public health in mind, and allows some methods for circumventing pharmaceutical monopolies: via compulsory licensing or parallel imports, even before patent expiration.

In March 2001, 40 multi-national pharmaceutical companies brought litigation against South Africa for its Medicines Act, which allowed the generic production of antiretroviral drugs (ARVs) for treating HIV, despite the fact that these drugs were on-patent. HIV was and is an epidemic in South Africa, and ARVs at the time cost between 10,000 and 15,000 USD per patient per year. This was unaffordable for most South African citizens, and so the South African government committed to providing ARVs at prices closer to what people could afford. To do so, they would need to ignore the patents on drugs and produce generics within the country (using a compulsory license), or import them from abroad. The Indian pharmaceutical company Cipla audaciously offered to make the drugs at 350 USD per patient per year, roughly 1/40th of the lowest price available from a patent holder, which stunned the world community. After massive international protest in favour of public health rights (including the collection of 250,000 signatures by MSF), the governments of several developed countries (including The Netherlands, Germany, France, and later the US) backed the South African government, and the case was dropped in April of that year.

Charitable programmes

Charitable programs and drug discovery & development efforts are routinely undertaken by pharmaceutical companies. Some examples include:

"Merck's Gift," wherein billions of River Blindness drugs were donated in Africa 

Pfizer's gift of free/discounted fluconazole and other drugs for AIDS in South Africa

GSK's commitment to give free albendazole tablets to the WHO for, and until, the elimination of lymphatic filariasis worldwide.

In 2006, Novartis committed USD 755 million in corporate citizenship initiatives around the world, particularly focusing on improved access to medicines in the developing world through its Access to Medicine projects, including donations of medicines to patients affected by leprosy, tuberculosis, and malaria; Glivec patient assistance programmes; and relief to support major humanitarian organisations with emergency medical needs.

However, some NGOs such as Médecins Sans Frontières do not routinely accept corporate donations of medicines. More precisely, they do not become reliant on such supplies of medicines because the supply is dependent upon the fluid, profit-driven charities of said pharmaceutical companies, and thus may dry up during a critical or otherwise important time. The book An Imperfect Offering: Humanitarian Action for the 21st Century by ex-MSF president James Orbinski describes this in detail.

Pharmaceutical industry in popular culture

As for many other major industries since the middle of the twentieth century, the pharmaceutical industry has been portrayed as a global shadowy force in numerous western fiction works. Notorious films such as The Fugitive (1993) and Resident evil and novels/films such as The Constant Gardener characterize this trend.

Industry associations

European Confederation of Pharmaceutical Entrepreneurs (EUCOPE)

Drug Information Association (DIA)

[[European Generic Medicines Association]] (EGA)

European Federation of Pharmaceutical Industries and Associations (EFPIA)

European Pharmaceutical Market Research Association (EphMRA)

International Federation of Pharmaceutical Manufacturers and Associations (IFPMA)

Japan Pharmaceutical Manufacturers Association (JPMA)

New York Health Products Council (NYHPC)

Pharmaceutical Research and Manufacturers of America (PhRMA)

Irish Pharmaceutical Healthcare Association (IPHA)

Pharmaceutical industry in the United Kingdom

The pharmaceutical industry in the United Kingdom directly employs around 72,000 people and in 2007 contributed £8.4 billion to the UK's GDP and invested a total of £3.9 billion in research and development.^[1][2] In 2007 exports of pharmaceutical products from the UK totalled £14.6 billion, creating a trade surplus in pharmaceutical products of £4.3 billion.^[

The UK is home to GlaxoSmithKline and AstraZeneca, respectively the world's fifth- and sixth-largest pharmaceutical companies measured by 2009 market share. Foreign companies with a major presence in the UK pharmaceutical industry include Pfizer, whose only research hub outside of the United States is based in Sandwich, Kent, Novartis,^[ Hoffmann–La Roche and Eisai. One in five of the world's biggest-selling prescription drugs were developed in the UK.

History

19th century

In 1842 Thomas Beecham established the Beecham's Pills laxative business, which would later become the Beecham Group. By 1851 UK-based patent medicine companies had combined domestic revenues of around £250,000.^[9] Beecham opened Britain's first modern drugs factory in St Helens in 1859. Henry Wellcome and Silas Burroughs formed a partnership in September 1880, and established an office in Snow Hill in Central London. The London Wholesale Drug and Chemical Protection Society was formed in 1867, which became the Drug Club in 1891, the forerunner of the present-day Association of the British Pharmaceutical Industry. In 1883 Burroughs Wellcome & Co. opened their first factory, at Bell Lane Wharf in Wandsworth, utilising compressed medicine tablet-making machinery acquired from Wyeth of the United States.^[10] Burroughs Wellcome & Co. established its first overseas branch in Sydney in 1898.

20th century

The Glaxo department of Joseph Nathan and Co was established in London in 1908.^[ Glaxo Laboratories Ltd absorbed Joseph Nathan and Co in 1947 and was listed on the London Stock Exchange in the same year. In order to satisfy regulations then in place in the UK on the importation of medicines, Pfizer established a compounding operation in Folkstone, Kent in Autumn 1952. Pfizer acquired an 80 acre site on the outskirts of Sandwich in 1954 to enable the expansion of its Kent-based activities.^[12] Glaxo acquired Allen and Hanburys Ltd. in 1958. In 1981 the bacterial infection treatment Augmentin (amoxicillin/clavulanate potassium) was launched by Beecham; the anti-ulcer treatment Zantac (ranitidine) was launched by Glaxo; and the antiviral herpes treatment Zovirax (aciclovir) was launched by Wellcome.

In 1991 SmithKline Beecham launched Seroxat/Paxil (paroxetine hydrochloride). In June 1993 Imperial Chemical Industries demerged its pharmaceuticals and agrochemicalsbusinesses, forming Zeneca Group plc. In 1995 Glaxo opened a major research and development facility in Stevenage, constructed at a cost of £700 million. In March 1995 the £9 billion acquisition of Wellcome by Glaxo was completed, forming Glaxo Wellcome, in what was the largest merger in UK corporate history to date. BASF completed the acquisition of the pharmaceutical division of The Boots Company in April 1995.^[16] In 1997 SmithKline Beecham opened a major new research centre at New Frontiers Science Park in Harlow, Essex.^[ In 1999 Zeneca Group plc and Sweden-based Astra AB merged to form AstraZeneca plc.^[ Glaxo Wellcome and SmithKline Beecham announced their intention to merge in January 2000, with the merger completing in December of that year, forming GlaxoSmithKline plc.

21st century

In February 2001 the Novartis Respiratory Research Centre, the largest single-site respiratory research centre in the world, opened in Horsham. In May 2006 AstraZeneca agreed to buy Cambridge Antibody Technology, then the largest UK-based biotechnology company, for £702 million. In April 2007 AstraZeneca agreed to acquire the U.S.-based biotechnology company MedImmune for $15.6 billion. In April 2009 GlaxoSmithKline agreed to acquire Stiefel Laboratories, then the world's largest independent dermatology company, for US$3.6 billion. In June 2009 Eisai opened a major new research and development and manufacturing facility in Hatfield, constructed at a cost of over £100 million. In November 2009 GlaxoSmithKline and Pfizer combined their respective AIDS divisions into one London-based company, ViiV Healthcare. On 1 February 2011 Pfizer announced that it would be closing its entire research and development facility at Sandwich, Kent within 18-24 months with the loss of 2,400 jobs, as part of a company-wide plan to reduce its spending on research and development.

Research and development

The current world headquarters of GlaxoSmithKline in Brentford, London

In 2007 the UK had the third-highest share of global pharmaceutical R&D expenditure of any nation, with 9% of the total, behind the United States (49%) and Japan (15%).The UK has the largest pharmaceutical R&D expenditure of any European nation, accounting for 23% of the total; followed by France (20%), Germany (19%), and Switzerland (11%).

Top 25 UK investors in pharmaceuticals & biotechnology R&D - 2009/10^[]
	Company^a	R&D spending^b(£m)
1	GlaxoSmithKline	3,629.00
2	AstraZeneca	2,745.68
3	Shire	346.71
4	Pfizer UK	325.66
5	Roche Products	208.44
6	Eisai Europe	151.13
7	Eli Lilly and Company	130.21
8	Amgen	127.06
9	Merial	102.42
10	Novartis Pharmaceuticals	90.27
11	John Wyeth & Brother	60.33
12	Bristol-Myers Squibb	55.49
13	Janssen-Cilag	54.37
14	PowderMed	45.57
15	Aventis Pharma	44.92
16	Allergan	37.40
17	Organon Laboratories	36.78
18	Vectura	36.40
19	Antisoma	35.77
20	Boehringer Ingelheim	29.29
21	Genus	28.60
22	BTG	27.00
23	Servier R&D	25.10
24	Ipsen Developments	23.97
25	Renovo	18.07

http://www.egagenerics.com/

Present Simple Tense

I sing

How do we make the Present Simple Tense?

subject	+	auxiliary verb	+	main verb
		do		base

There are three important exceptions:

1. For positive sentences, we do not normally use the auxiliary.

2. For the 3rd person singular (he, she, it), we add s to the main verb or es to the auxiliary.

3. For the verb to be, we do not use an auxiliary, even for questions and negatives.

Look at these examples with the main verb like:

	subject	auxiliary verb		main verb
+	I, you, we, they			like	coffee.
	He, she, it			likes	coffee.
-	I, you, we, they	do	not	like	coffee.
	He, she, it	does	not	like	coffee.
?	Do	I, you, we, they		like	coffee?
	Does	he, she, it		like	coffee?

Look at these examples with the main verb be. Notice that there is no auxiliary:

	subject	main verb
+	I	am		French.
	You, we, they	are		French.
	He, she, it	is		French.
-	I	am	not	old.
	You, we, they	are	not	old.
	He, she, it	is	not	old.
?	Am	I		late?
	Are	you, we, they		late?
	Is	he, she, it		late?

How do we use the Present Simple Tense?

We use the present simple tense when:

• the action is general
• the action happens all the time, or habitually, in the past, present and future
• the action is not only happening now
• the statement is always true

John drives a taxi.
past	present	future
It is John's job to drive a taxi. He does it every day. Past, present and future.

Look at these examples:

• I live in New York.
• The Moon goes round the Earth.
• John drives a taxi.
• He does not drive a bus.
• We meet every Thursday.
• We do not work at night.
• Do you play football?

Note that with the verb to be, we can also use the present simple tense for situations that are not general. We can use the present simple tense to talk about now. Look at these examples of the verb "to be" in the present simple tense - some of them are general, some of them are now:

Am I right? Tara is not at home. You are happy.
past	present	future
The situation is now.

I am not fat. Why are you so beautiful? Ram is tall.
past	present	future
The situation is general. Past, present and future.

Present Continuous

am/is/are + present participle]

Examples:

• You are watching TV.
• Are you watching TV?
• You are not watching TV.

Complete List of Present Continuous Forms

USE 1 Now

Use the Present Continuous with Normal Verbs to express the idea that something is happening now, at this very moment. It can also be used to show that something is not happening now.

Examples:

• You are learning English now.
• You are not swimming now.
• Are you sleeping?
• I am sitting.
• I am not standing.
• Is he sitting or standing?
• They are reading their books.
• They are not watching television.
• What are you doing?
• Why aren't you doing your homework?

USE 2 Longer Actions in Progress Now

In English, "now" can mean: this second, today, this month, this year, this century, and so on. Sometimes, we use the Present Continuous to say that we are in the process of doing a longer action which is in progress; however, we might not be doing it at this exact second.

Examples: (All of these sentences can be said while eating dinner in a restaurant.)

• I am studying to become a doctor.
• I am not studying to become a dentist.
• I am reading the book Tom Sawyer.
• I am not reading any books right now.
• Are you working on any special projects at work?
• Aren't you teaching at the university now?

USE 3 Near Future

Sometimes, speakers use the Present Continuous to indicate that something will or will not happen in the near future.

Examples:

• I am meeting some friends after work.
• I am not going to the party tonight.
• Is he visiting his parents next weekend?
• Isn't he coming with us tonight?

USE 4 Repetition and Irritation with "Always"

The Present Continuous with words such as "always" or "constantly" expresses the idea that something irritating or shocking often happens. Notice that the meaning is like Simple Present, but with negative emotion. Remember to put the words "always" or "constantly" between "be" and "verb+ing."

Examples:

• She is always coming to class late.
• He is constantly talking. I wish he would shut up.
• I don't like them because they are always complaining.

REMEMBER Non-Continuous Verbs/ Mixed Verbs

It is important to remember that Non-Continuous Verbs cannot be used in any continuous tenses. Also, certain non-continuous meanings for Mixed Verbs cannot be used in continuous tenses. Instead of using Present Continuous with these verbs, you must use Simple Present.

Examples:

• She is loving this chocolate ice cream. Not Correct
• She loves this chocolate ice cream. Correct

ADVERB PLACEMENT

The examples below show the placement for grammar adverbs such as: always, only, never, ever, still, just, etc.

Examples:

• You are still watching TV.
• Are you still watching TV?

ACTIVE / PASSIVE

Examples:

• Right now, Tom is writing the letter. Active
• Right now, the letter is being written by Tom. Passive

Simple Past

 [VERB+ed] or irregular verbs

Examples:

• You called Debbie.
• Did you call Debbie?
• You did not call Debbie.

USE 1 Completed Action in the Past

Use the Simple Past to express the idea that an action started and finished at a specific time in the past. Sometimes, the speaker may not actually mention the specific time, but they do have one specific time in mind.

Examples:

• I saw a movie yesterday.
• I didn't see a play yesterday.
• Last year, I traveled to Japan.
• Last year, I didn't travel to Korea.
• Did you have dinner last night?
• She washed her car.
• He didn't wash his car.

USE 2 A Series of Completed Actions

We use the Simple Past to list a series of completed actions in the past. These actions happen 1st, 2nd, 3rd, 4th, and so on.

Examples:

• I finished work, walked to the beach, and found a nice place to swim.
• He arrived from the airport at 8:00, checked into the hotel at 9:00, and met the others at 10:00.
• Did you add flour, pour in the milk, and then add the eggs?

USE 3 Duration in Past

The Simple Past can be used with a duration which starts and stops in the past. A duration is a longer action often indicated by expressions such as: for two years, for five minutes, all day, all year, etc.

Examples:

• I lived in Brazil for two years.
• Shauna studied Japanese for five years.
• They sat at the beach all day.
• They did not stay at the party the entire time.
• We talked on the phone for thirty minutes.
• A: How long did you wait for them?
  B: We waited for one hour.

USE 4 Habits in the Past

The Simple Past can also be used to describe a habit which stopped in the past. It can have the same meaning as "used to." To make it clear that we are talking about a habit, we often add expressions such as: always, often, usually, never, when I was a child, when I was younger, etc.

Examples:

• I studied French when I was a child.
• He played the violin.
• He didn't play the piano.
• Did you play a musical instrument when you were a kid?
• She worked at the movie theater after school.
• They never went to school, they always skipped class.

USE 5 Past Facts or Generalizations

The Simple Past can also be used to describe past facts or generalizations which are no longer true. As in USE 4 above, this use of the Simple Past is quite similar to the expression "used to."

Examples:

• She was shy as a child, but now she is very outgoing.
• He didn't like tomatoes before.
• Did you live in Texas when you were a kid?
• People paid much more to make cell phone calls in the past.

IMPORTANT When-Clauses Happen First

Clauses are groups of words which have meaning but are often not complete sentences. Some clauses begin with the word "when" such as "when I dropped my pen..." or "when class began..." These clauses are called when-clauses, and they are very important. The examples below contain when-clauses.

Examples:

• When I paid her one dollar, she answered my question.
• She answered my question when I paid her one dollar.

When-clauses are important because they always happen first when both clauses are in the Simple Past. Both of the examples above mean the same thing: first, I paid her one dollar, and then, she answered my question. It is not important whether "when I paid her one dollar" is at the beginning of the sentence or at the end of the sentence. However, the example below has a different meaning. First, she answered my question, and then, I paid her one dollar.

Example:

• I paid her one dollar when she answered my question.

ADVERB PLACEMENT

The examples below show the placement for grammar adverbs such as: always, only, never, ever, still, just, etc.

Examples:

• You just called Debbie.
• Did you just call Debbie?

ACTIVE / PASSIVE

Examples:

• Tom repaired the car. Active
• The car was repaired by Tom. Passive

Past Continuous

FORM

[was/were + present participle]

Examples:

• You were studying when she called.
• Were you studying when she called?
• You were not studying when she called.

USE 1 Interrupted Action in the Past

Use the Past Continuous to indicate that a longer action in the past was interrupted. The interruption is usually a shorter action in the Simple Past. Remember this can be a real interruption or just an interruption in time.

Examples:

• I was watching TV when she called.
• When the phone rang, she was writing a letter.
• While we were having the picnic, it started to rain.
• What were you doing when the earthquake started?
• I was listening to my iPod, so I didn't hear the fire alarm.
• You were not listening to me when I told you to turn the oven off.
• While John was sleeping last night, someone stole his car.
• Sammy was waiting for us when we got off the plane.
• While I was writing the email, the computer suddenly went off.
• A: What were you doing when you broke your leg?
  B: I was snowboarding.

USE 2 Specific Time as an Interruption

In USE 1, described above, the Past Continuous is interrupted by a shorter action in the Simple Past. However, you can also use a specific time as an interruption.

Examples:

• Last night at 6 PM, I was eating dinner.
• At midnight, we were still driving through the desert.
• Yesterday at this time, I was sitting at my desk at work.

IMPORTANT

In the Simple Past, a specific time is used to show when an action began or finished. In the Past Continuous, a specific time only interrupts the action.

Examples:

• Last night at 6 PM, I ate dinner.
  I started eating at 6 PM.
• Last night at 6 PM, I was eating dinner.
  I started earlier; and at 6 PM, I was in the process of eating dinner.

USE 3 Parallel Actions

When you use the Past Continuous with two actions in the same sentence, it expresses the idea that both actions were happening at the same time. The actions are parallel.

Examples:

• I was studying while he was making dinner.
• While Ellen was reading, Tim was watching television.
• Were you listening while he was talking?
• I wasn't paying attention while I was writing the letter, so I made several mistakes.
• What were you doing while you were waiting?
• Thomas wasn't working, and I wasn't working either.
• They were eating dinner, discussing their plans, and having a good time.

USE 4 Atmosphere

In English, we often use a series of parallel actions to describe the atmosphere at a particular time in the past.

Example:

• When I walked into the office, several people were busily typing, some were talking on the phones, the boss was yelling directions, and customers were waiting to be helped. One customer was yelling at a secretary and waving his hands. Others were complaining to each other about the bad service.

USE 5 Repetition and Irritation with "Always"

The Past Continuous with words such as "always" or "constantly" expresses the idea that something irritating or shocking often happened in the past. The concept is very similar to the expression "used to" but with negative emotion. Remember to put the words "always" or "constantly" between "be" and "verb+ing."

Examples:

• She was always coming to class late.
• He was constantly talking. He annoyed everyone.
• I didn't like them because they were always complaining.

While vs. When

Clauses are groups of words which have meaning, but are often not complete sentences. Some clauses begin with the word "when" such as "when she called" or "when it bit me." Other clauses begin with "while" such as "while she was sleeping" and "while he was surfing." When you talk about things in the past, "when" is most often followed by the verb tense Simple Past, whereas "while" is usually followed by Past Continuous. "While" expresses the idea of "during that time." Study the examples below. They have similar meanings, but they emphasize different parts of the sentence.

Examples:

• I was studying when she called.
• While I was studying, she called.

REMEMBER Non-Continuous Verbs / Mixed Verbs

It is important to remember that Non-Continuous Verbs cannot be used in any continuous tenses. Also, certain non-continuous meanings for Mixed Verbs cannot be used in continuous tenses. Instead of using Past Continuous with these verbs, you must use Simple Past.

Examples:

• Jane was being at my house when you arrived. Not Correct
• Jane was at my house when you arrived. Correct

ADVERB PLACEMENT

The examples below show the placement for grammar adverbs such as: always, only, never, ever, still, just, etc.

Examples:

• You were just studying when she called.
• Were you just studying when she called?

ACTIVE / PASSIVE

Examples:

• The salesman was helping the customer when the thief came into the store. Active
• The customer was being helped by the salesman when the thief came into the store. Passive

Present Perfect

FORM

[has/have + past participle]

Examples:

• You have seen that movie many times.
• Have you seen that movie many times?
• You have not seen that movie many times.

USE 1 Unspecified Time Before Now

We use the Present Perfect to say that an action happened at an unspecified time before now. The exact time is not important. You CANNOT use the Present Perfect with specific time expressions such as: yesterday, one year ago, last week, when I was a child, when I lived in Japan, at that moment, that day, one day, etc. We CAN use the Present Perfect with unspecific expressions such as: ever, never, once, many times, several times, before, so far, already, yet, etc.

Examples:

• I have seen that movie twenty times.
• I think I have met him once before.
• There have been many earthquakes in California.
• People have traveled to the Moon.
• People have not traveled to Mars.
• Have you read the book yet?
• Nobody has ever climbed that mountain.
• A: Has there ever been a war in the United States?
  B: Yes, there has been a war in the United States.

How Do You Actually Use the Present Perfect?

The concept of "unspecified time" can be very confusing to English learners. It is best to associate Present Perfect with the following topics:

TOPIC 1 Experience

You can use the Present Perfect to describe your experience. It is like saying, "I have the experience of..." You can also use this tense to say that you have never had a certain experience. The Present Perfect is NOT used to describe a specific event.

Examples:

• I have been to France.
  This sentence means that you have had the experience of being in France. Maybe you have been there once, or several times.
• I have been to France three times.
  You can add the number of times at the end of the sentence.
• I have never been to France.
  This sentence means that you have not had the experience of going to France.
• I think I have seen that movie before.
• He has never traveled by train.
• Joan has studied two foreign languages.
• A: Have you ever met him?
  B: No, I have not met him.

TOPIC 2 Change Over Time

We often use the Present Perfect to talk about change that has happened over a period of time.

Examples:

• You have grown since the last time I saw you.
• The government has become more interested in arts education.
• Japanese has become one of the most popular courses at the university since the Asian studies program was established.
• My English has really improved since I moved to Australia.

TOPIC 3 Accomplishments

We often use the Present Perfect to list the accomplishments of individuals and humanity. You cannot mention a specific time.

Examples:

• Man has walked on the Moon.
• Our son has learned how to read.
• Doctors have cured many deadly diseases.
• Scientists have split the atom.

TOPIC 4 An Uncompleted Action You Are Expecting

We often use the Present Perfect to say that an action which we expected has not happened. Using the Present Perfect suggests that we are still waiting for the action to happen.

Examples:

• James has not finished his homework yet.
• Susan hasn't mastered Japanese, but she can communicate.
• Bill has still not arrived.
• The rain hasn't stopped.

TOPIC 5 Multiple Actions at Different Times

We also use the Present Perfect to talk about several different actions which have occurred in the past at different times. Present Perfect suggests the process is not complete and more actions are possible.

Examples:

• The army has attacked that city five times.
• I have had four quizzes and five tests so far this semester.
• We have had many major problems while working on this project.
• She has talked to several specialists about her problem, but nobody knows why she is sick.

Time Expressions with Present Perfect

When we use the Present Perfect it means that something has happened at some point in our lives before now. Remember, the exact time the action happened is not important.

Sometimes, we want to limit the time we are looking in for an experience. We can do this with expressions such as: in the last week, in the last year, this week, this month, so far, up to now, etc.

Examples:

• Have you been to Mexico in the last year?
• I have seen that movie six times in the last month.
• They have had three tests in the last week.
• She graduated from university less than three years ago. She has worked for three different companies so far.
• My car has broken down three times this week.

NOTICE

"Last year" and "in the last year" are very different in meaning. "Last year" means the year before now, and it is considered a specific time which requires Simple Past. "In the last year" means from 365 days ago until now. It is not considered a specific time, so it requires Present Perfect.

Examples:

• I went to Mexico last year.
  I went to Mexico in the calendar year before this one.
• I have been to Mexico in the last year.
  I have been to Mexico at least once at some point between 365 days ago and now.

USE 2 Duration From the Past Until Now (Non-Continuous Verbs)

With Non-Continuous Verbs and non-continuous uses of Mixed Verbs, we use the Present Perfect to show that something started in the past and has continued up until now. "For five minutes," "for two weeks," and "since Tuesday" are all durations which can be used with the Present Perfect.

Examples:

• I have had a cold for two weeks.
• She has been in England for six months.
• Mary has loved chocolate since she was a little girl.

Although the above use of Present Perfect is normally limited to Non-Continuous Verbs and non-continuous uses of Mixed Verbs, the words "live," "work," "teach," and "study" are sometimes used in this way even though they are NOT Non-Continuous Verbs.

ADVERB PLACEMENT

The examples below show the placement for grammar adverbs such as: always, only, never, ever, still, just, etc.

Examples:

• You have only seen that movie one time.
• Have you only seen that movie one time?

ACTIVE / PASSIVE

Examples:

• Many tourists have visited that castle. Active
• That castle has been visited by many tourists. Passive

Present Perfect Continuous

 [has/have + been + present participle]

Examples:

• You have been waiting here for two hours.
• Have you been waiting here for two hours?
• You have not been waiting here for two hours.

USE 1 Duration from the Past Until Now

We use the Present Perfect Continuous to show that something started in the past and has continued up until now. "For five minutes," "for two weeks," and "since Tuesday" are all durations which can be used with the Present Perfect Continuous.

Examples:

• They have been talking for the last hour.
• She has been working at that company for three years.
• What have you been doing for the last 30 minutes?
• James has been teaching at the university since June.
• We have been waiting here for over two hours!
• Why has Nancy not been taking her medicine for the last three days?

USE 2 Recently, Lately

You can also use the Present Perfect Continuous WITHOUT a duration such as "for two weeks." Without the duration, the tense has a more general meaning of "lately." We often use the words "lately" or "recently" to emphasize this meaning.

Examples:

• Recently, I have been feeling really tired.
• She has been watching too much television lately.
• Have you been exercising lately?
• Mary has been feeling a little depressed.
• Lisa has not been practicing her English.
• What have you been doing?

IMPORTANT

Remember that the Present Perfect Continuous has the meaning of "lately" or "recently." If you use the Present Perfect Continuous in a question such as "Have you been feeling alright?", it can suggest that the person looks sick or unhealthy. A question such as "Have you been smoking?" can suggest that you smell the smoke on the person. Using this tense in a question suggests you can see, smell, hear or feel the results of the action. It is possible to insult someone by using this tense incorrectly.

REMEMBER Non-Continuous Verbs/ Mixed Verbs

It is important to remember that Non-Continuous Verbs cannot be used in any continuous tenses. Also, certain non-continuous meanings for Mixed Verbs cannot be used in continuous tenses. Instead of using Present Perfect Continuous with these verbs, you must use Present Perfect.

Examples:

• Sam has been having his car for two years. Not Correct
• Sam has had his car for two years. Correct

ADVERB PLACEMENT

The examples below show the placement for grammar adverbs such as: always, only, never, ever, still, just, etc.

Examples:

• You have only been waiting here for one hour.
• Have you only been waiting here for one hour?

ACTIVE / PASSIVE

Examples:

• Recently, John has been doing the work. Active
• Recently, the work has been being done by John. Passive

NOTE: Present Perfect Continuous is less commonly used in its passive form.

Past Perfect

FORM

[had + past participle]

Examples:

• You had studied English before you moved to New York.
• Had you studied English before you moved to New York?
• You had not studied English before you moved to New York.

USE 1 Completed Action Before Something in the Past

The Past Perfect expresses the idea that something occurred before another action in the past. It can also show that something happened before a specific time in the past.

Examples:

• I had never seen such a beautiful beach before I went to Kauai.
• I did not have any money because I had lost my wallet.
• Tony knew Istanbul so well because he had visited the city several times.
• Had Susan ever studied Thai before she moved to Thailand?
• She only understood the movie because she had read the book.
• Kristine had never been to an opera before last night.
• We were not able to get a hotel room because we had not booked in advance.
• A: Had you ever visited the U.S. before your trip in 2006?
  B: Yes, I had been to the U.S. once before.

USE 2 Duration Before Something in the Past (Non-Continuous Verbs)

With Non-Continuous Verbs and some non-continuous uses of Mixed Verbs, we use the Past Perfect to show that something started in the past and continued up until another action in the past.

Examples:

• We had had that car for ten years before it broke down.
• By the time Alex finished his studies, he had been in London for over eight years.
• They felt bad about selling the house because they had owned it for more than forty years.

Although the above use of Past Perfect is normally limited to Non-Continuous Verbs and non-continuous uses of Mixed Verbs, the words "live," "work," "teach," and "study" are sometimes used in this way even though they are NOT Non-Continuous Verbs.

IMPORTANT Specific Times with the Past Perfect

Unlike with the Present Perfect, it is possible to use specific time words or phrases with the Past Perfect. Although this is possible, it is usually not necessary.

Example:

• She had visited her Japanese relatives once in 1993 before she moved in with them in 1996.

MOREOVER

If the Past Perfect action did occur at a specific time, the Simple Past can be used instead of the Past Perfect when "before" or "after" is used in the sentence. The words "before" and "after" actually tell you what happens first, so the Past Perfect is optional. For this reason, both sentences below are correct.

Examples:

• She had visited her Japanese relatives once in 1993 before she moved in with them in 1996.
• She visited her Japanese relatives once in 1993 before she moved in with them in 1996.

HOWEVER

If the Past Perfect is not referring to an action at a specific time, Past Perfect is not optional. Compare the examples below. Here Past Perfect is referring to a lack of experience rather than an action at a specific time. For this reason, Simple Past cannot be used.

Examples:

• She never saw a bear before she moved to Alaska. Not Correct
• She had never seen a bear before she moved to Alaska. Correct

ADVERB PLACEMENT

The examples below show the placement for grammar adverbs such as: always, only, never, ever, still, just, etc.

Examples:

• You had previously studied English before you moved to New York.
• Had you previously studied English before you moved to New York?

ACTIVE / PASSIVE

Examples:

• George had repaired many cars before he received his mechanic's license. Active
• Many cars had been repaired by George before he received his mechanic's license. Passive

Past Perfect Continuous

FORM

[had been + present participle]

Examples:

• You had been waiting there for more than two hours when she finally arrived.
• Had you been waiting there for more than two hours when she finally arrived?
• You had not been waiting there for more than two hours when she finally arrived.

USE 1 Duration Before Something in the Past

We use the Past Perfect Continuous to show that something started in the past and continued up until another time in the past. "For five minutes" and "for two weeks" are both durations which can be used with the Past Perfect Continuous. Notice that this is related to the Present Perfect Continuous; however, the duration does not continue until now, it stops before something else in the past.

Examples:

• They had been talking for over an hour before Tony arrived.
• She had been working at that company for three years when it went out of business.
• How long had you been waiting to get on the bus?
• Mike wanted to sit down because he had been standing all day at work.
• James had been teaching at the university for more than a year before he left for Asia.
• A: How long had you been studying Turkish before you moved to Ankara?
  B: I had not been studying Turkish very long.

USE 2 Cause of Something in the Past

Using the Past Perfect Continuous before another action in the past is a good way to show cause and effect.

Examples:

• Jason was tired because he had been jogging.
• Sam gained weight because he had been overeating.
• Betty failed the final test because she had not been attending class.

Past Continuous vs. Past Perfect Continuous

If you do not include a duration such as "for five minutes," "for two weeks" or "since Friday," many English speakers choose to use the Past Continuous rather than the Past Perfect Continuous. Be careful because this can change the meaning of the sentence. Past Continuous emphasizes interrupted actions, whereas Past Perfect Continuous emphasizes a duration of time before something in the past. Study the examples below to understand the difference.

Examples:

• He was tired because he was exercising so hard.
  This sentence emphasizes that he was tired because he was exercising at that exact moment.
• He was tired because he had been exercising so hard.
  This sentence emphasizes that he was tired because he had been exercising over a period of time. It is possible that he was still exercising at that moment OR that he had just finished.

REMEMBER Non-Continuous Verbs / Mixed Verbs

It is important to remember that Non-Continuous Verbs cannot be used in any continuous tenses. Also, certain non-continuous meanings for Mixed Verbs cannot be used in continuous tenses. Instead of using Past Perfect Continuous with these verbs, you must use Past Perfect.

Examples:

• The motorcycle had been belonging to George for years before Tina bought it. Not Correct
• The motorcycle had belonged to George for years before Tina bought it. Correct

ADVERB PLACEMENT

The examples below show the placement for grammar adverbs such as: always, only, never, ever, still, just, etc.

Examples:

• You had only been waiting there for a few minutes when she arrived.
• Had you only been waiting there for a few minutes when she arrived?

ACTIVE / PASSIVE

Examples:

• Chef Jones had been preparing the restaurant's fantastic dinners for two years before he moved to Paris. Active
• The restaurant's fantastic dinners had been being prepared by Chef Jones for two years before he moved to Paris. Passive

NOTE: Passive forms of the Past Perfect Continuous are not common.

Simple Future

Simple Future has two different forms in English: "will" and "be going to." Although the two forms can sometimes be used interchangeably, they often express two very different meanings. These different meanings might seem too abstract at first, but with time and practice, the differences will become clear. Both "will" and "be going to" refer to a specific time in the future.

FORM Will

[will + verb]

Examples:

• You will help him later.
• Will you help him later?
• You will not help him later.

FORM Be Going To

[am/is/are + going to + verb]

Examples:

• You are going to meet Jane tonight.
• Are you going to meet Jane tonight?
• You are not going to meet Jane tonight.

USE 1 "Will" to Express a Voluntary Action

"Will" often suggests that a speaker will do something voluntarily. A voluntary action is one the speaker offers to do for someone else. Often, we use "will" to respond to someone else's complaint or request for help. We also use "will" when we request that someone help us or volunteer to do something for us. Similarly, we use "will not" or "won't" when we refuse to voluntarily do something.

Examples:

• I will send you the information when I get it.
• I will translate the email, so Mr. Smith can read it.
• Will you help me move this heavy table?
• Will you make dinner?
• I will not do your homework for you.
• I won't do all the housework myself!
• A: I'm really hungry.
  B: I'll make some sandwiches.
• A: I'm so tired. I'm about to fall asleep.
  B: I'll get you some coffee.
• A: The phone is ringing.
  B: I'll get it.

USE 2 "Will" to Express a Promise

"Will" is usually used in promises.

Examples:

• I will call you when I arrive.
• If I am elected President of the United States, I will make sure everyone has access to inexpensive health insurance.
• I promise I will not tell him about the surprise party.
• Don't worry, I'll be careful.
• I won't tell anyone your secret.

USE 3 "Be going to" to Express a Plan

"Be going to" expresses that something is a plan. It expresses the idea that a person intends to do something in the future. It does not matter whether the plan is realistic or not.

Examples:

• He is going to spend his vacation in Hawaii.
• She is not going to spend her vacation in Hawaii.
• A: When are we going to meet each other tonight?
  B: We are going to meet at 6 PM.
• I'm going to be an actor when I grow up.
• Michelle is going to begin medical school next year.
• They are going to drive all the way to Alaska.
• Who are you going to invite to the party?
• A: Who is going to make John's birthday cake?
  B: Sue is going to make John's birthday cake.

USE 4 "Will" or "Be Going to" to Express a Prediction

Both "will" and "be going to" can express the idea of a general prediction about the future. Predictions are guesses about what might happen in the future. In "prediction" sentences, the subject usually has little control over the future and therefore USES 1-3 do not apply. In the following examples, there is no difference in meaning.

Examples:

• The year 2222 will be a very interesting year.
• The year 2222 is going to be a very interesting year.

• John Smith will be the next President.
• John Smith is going to be the next President.

• The movie "Zenith" will win several Academy Awards.
• The movie "Zenith" is going to win several Academy Awards.

IMPORTANT

In the Simple Future, it is not always clear which USE the speaker has in mind. Often, there is more than one way to interpret a sentence's meaning.

No Future in Time Clauses

Like all future forms, the Simple Future cannot be used in clauses beginning with time expressions such as: when, while, before, after, by the time, as soon as, if, unless, etc. Instead of Simple Future, Simple Present is used.

Examples:

• When you will arrive tonight, we will go out for dinner. Not Correct
• When you arrive tonight, we will go out for dinner. Correct

ADVERB PLACEMENT

The examples below show the placement for grammar adverbs such as: always, only, never, ever, still, just, etc.

Examples:

• You will never help him.
• Will you ever help him?

• You are never going to meet Jane.
• Are you ever going to meet Jane?

ACTIVE / PASSIVE

Examples:

• John will finish the work by 5:00 PM. Active
• The work will be finished by 5:00 PM. Passive

• Sally is going to make a beautiful dinner tonight. Active
• A beautiful dinner is going to be made by Sally tonight. Passive

Future Continuous

Future Continuous has two different forms: "will be doing " and "be going to be doing." Unlike Simple Future forms, Future Continuous forms are usually interchangeable.

FORM Future Continuous with "Will"

[will be + present participle]

Examples:

• You will be waiting for her when her plane arrives tonight.
• Will you be waiting for her when her plane arrives tonight?
• You will not be waiting for her when her plane arrives tonight.

FORM Future Continuous with "Be Going To "

[am/is/are + going to be + present participle]

Examples:

• You are going to be waiting for her when her plane arrives tonight.
• Are you going to be waiting for her when her plane arrives tonight?
• You are not going to be waiting for her when her plane arrives tonight.

REMEMBER: It is possible to use either "will" or "be going to" to create the Future Continuous with little difference in meaning.

USE 1 Interrupted Action in the Future

Use the Future Continuous to indicate that a longer action in the future will be interrupted by a shorter action in the future. Remember this can be a real interruption or just an interruption in time.

Examples:

• I will be watching TV when she arrives tonight.
• I will be waiting for you when your bus arrives.
• I am going to be staying at the Madison Hotel, if anything happens and you need to contact me.
• He will be studying at the library tonight, so he will not see Jennifer when she arrives.

Notice in the examples above that the interruptions (marked in italics) are in Simple Present rather than Simple Future. This is because the interruptions are in time clauses, and you cannot use future tenses in time clauses.

USE 2 Specific Time as an Interruption in the Future

In USE 1, described above, the Future Continuous is interrupted by a short action in the future. In addition to using short actions as interruptions, you can also use a specific time as an interruption.

Examples:

• Tonight at 6 PM, I am going to be eating dinner.
  I will be in the process of eating dinner.
• At midnight tonight, we will still be driving through the desert.
  We will be in the process of driving through the desert.

REMEMBER

In the Simple Future, a specific time is used to show the time an action will begin or end. In the Future Continuous, a specific time interrupts the action.

Examples:

• Tonight at 6 PM, I am going to eat dinner.
  I am going to start eating at 6 PM.
• Tonight at 6 PM, I am going to be eating dinner.
  I am going to start earlier and I will be in the process of eating dinner at 6 PM.

USE 3 Parallel Actions in the Future

When you use the Future Continuous with two actions in the same sentence, it expresses the idea that both actions will be happening at the same time. The actions are parallel.

Examples:

• I am going to be studying and he is going to be making dinner.
• Tonight, they will be eating dinner, discussing their plans, and having a good time.
• While Ellen is reading, Tim will be watching television.
  Notice "is reading" because of the time clause containing "while."

USE 4 Atmosphere in the Future

In English, we often use a series of Parallel Actions to describe atmosphere at a specific point in the future.

Example:

• When I arrive at the party, everybody is going to be celebrating. Some will be dancing. Others are going to be talking. A few people will be eating pizza, and several people are going to be drinking beer. They always do the same thing.

REMEMBER No Future in Time Clauses

Like all future tenses, the Future Continuous cannot be used in clauses beginning with time expressions such as: when, while, before, after, by the time, as soon as, if, unless, etc. Instead of Future Continuous, Present Continuous is used.

Examples:

• While I am going to be finishing my homework, she is going to make dinner. Not Correct
• While I am finishing my homework, she is going to make dinner. Correct

AND REMEMBER Non-Continuous Verbs / Mixed Verbs

It is important to remember that Non-Continuous Verbs cannot be used in any continuous tenses. Also, certain non-continuous meanings for Mixed Verbs cannot be used in continuous tenses. Instead of using Future Continuous with these verbs, you must use Simple Future.

Examples:

• Jane will be being at my house when you arrive. Not Correct
• Jane will be at my house when you arrive. Correct

ADVERB PLACEMENT

The examples below show the placement for grammar adverbs such as: always, only, never, ever, still, just, etc.

Examples:

• You will still be waiting for her when her plane arrives.
• Will you still be waiting for her when her plane arrives?

• You are still going to be waiting for her when her plane arrives.
• Are you still going to be waiting for her when her plane arrives?

ACTIVE / PASSIVE

Examples:

• At 8:00 PM tonight, John will be washing the dishes. Active
• At 8:00 PM tonight, the dishes will be being washed by John. Passive

• At 8:00 PM tonight, John is going to be washing the dishes. Active
• At 8:00 PM tonight, the dishes are going to be being washed by John. Passive

NOTE: Passive forms of the Future Continuous are not common.

Future Perfect

Future Perfect has two different forms: "will have done" and "be going to have done." Unlike Simple Future forms, Future Perfect forms are usually interchangeable.

FORM Future Perfect with "Will"

[will have + past participle]

Examples:

• You will have perfected your English by the time you come back from the U.S.
• Will you have perfected your English by the time you come back from the U.S.?
• You will not have perfected your English by the time you come back from the U.S.

FORM Future Perfect with "Be Going To"

[am/is/are + going to have + past participle]

Examples:

• You are going to have perfected your English by the time you come back from the U.S.
• Are you going to have perfected your English by the time you come back from the U.S.?
• You are not going to have perfected your English by the time you come back from the U.S.

NOTE: It is possible to use either "will" or "be going to" to create the Future Perfect with little or no difference in meaning.

Complete List of Future Perfect Forms

USE 1 Completed Action Before Something in the Future

The Future Perfect expresses the idea that something will occur before another action in the future. It can also show that something will happen before a specific time in the future.

Examples:

• By next November, I will have received my promotion.
• By the time he gets home, she is going to have cleaned the entire house.
• I am not going to have finished this test by 3 o'clock.
• Will she have learned enough Chinese to communicate before she moves to Beijing?
• Sam is probably going to have completed the proposal by the time he leaves this afternoon.
• By the time I finish this course, I will have taken ten tests.
• How many countries are you going to have visited by the time you turn 50?

Notice in the examples above that the reference points (marked in italics) are in Simple Present rather than Simple Future. This is because the interruptions are in time clauses, and you cannot use future tenses in time clauses.

USE 2 Duration Before Something in the Future (Non-Continuous Verbs)

With Non-Continuous Verbs and some non-continuous uses of Mixed Verbs, we use the Future Perfect to show that something will continue up until another action in the future.

Examples:

• I will have been in London for six months by the time I leave.
• By Monday, Susan is going to have had my book for a week.

Although the above use of Future Perfect is normally limited to Non-Continuous Verbs and non-continuous uses of Mixed Verbs, the words "live," "work," "teach," and "study" are sometimes used in this way even though they are NOT Non-Continuous Verbs.

REMEMBER No Future in Time Clauses

Like all future forms, the Future Perfect cannot be used in clauses beginning with time expressions such as: when, while, before, after, by the time, as soon as, if, unless, etc. Instead of Future Perfect, Present Perfect is used.

Examples:

• I am going to see a movie when I will have finished my homework. Not Correct
• I am going to see a movie when I have finished my homework. Correct

ADVERB PLACEMENT

The examples below show the placement for grammar adverbs such as: always, only, never, ever, still, just, etc.

Examples:

• You will only have learned a few words.
• Will you only have learned a few words?

• You are only going to have learned a few words.
• Are you only going to have learned a few words?

ACTIVE / PASSIVE

Examples:

• They will have completed the project before the deadline. Active
• The project will have been completed before the deadline. Passive

• They are going to have completed the project before the deadline. Active
• The project is going to have been completed before the deadline. Passive

Future Perfect Continuous

Future Perfect Continuous has two different forms: "will have been doing " and "be going to have been doing." Unlike Simple Future forms, Future Perfect Continuous forms are usually interchangeable.

FORM Future Perfect Continuous with "Will"

[will have been + present participle]

Examples:

• You will have been waiting for more than two hours when her plane finally arrives.
• Will you have been waiting for more than two hours when her plane finally arrives?
• You will not have been waiting for more than two hours when her plane finally arrives.

FORM Future Perfect Continuous with "Be Going To"

[am/is/are + going to have been + present participle]

Examples:

• You are going to have been waiting for more than two hours when her plane finally arrives.
• Are you going to have been waiting for more than two hours when her plane finally arrives?
• You are not going to have been waiting for more than two hours when her plane finally arrives.

NOTE: It is possible to use either "will" or "be going to" to create the Future Perfect Continuous with little or no difference in meaning.

USE 1 Duration Before Something in the Future

We use the Future Perfect Continuous to show that something will continue up until a particular event or time in the future. "For five minutes," "for two weeks," and "since Friday" are all durations which can be used with the Future Perfect Continuous. Notice that this is related to the Present Perfect Continuous and the Past Perfect Continuous; however, with Future Perfect Continuous, the duration stops at or before a reference point in the future.

Examples:

• They will have been talking for over an hour by the time Thomas arrives.
• She is going to have been working at that company for three years when it finally closes.
• James will have been teaching at the university for more than a year by the time he leaves for Asia.
• How long will you have been studying when you graduate?
• We are going to have been driving for over three days straight when we get to Anchorage.
• A: When you finish your English course, will you have been living in New Zealand for over a year?
  B: No, I will not have been living here that long.

Notice in the examples above that the reference points (marked in italics) are in Simple Present rather than Simple Future. This is because these future events are in time clauses, and you cannot use future tenses in time clauses.

USE 2 Cause of Something in the Future

Using the Future Perfect Continuous before another action in the future is a good way to show cause and effect.

Examples:

• Jason will be tired when he gets home because he will have been jogging for over an hour.
• Claudia's English will be perfect when she returns to Germany because she is going to have been studying English in the United States for over two years.

Future Continuous vs. Future Perfect Continuous

If you do not include a duration such as "for five minutes," "for two weeks" or "since Friday," many English speakers choose to use the Future Continuous rather than the Future Perfect Continuous. Be careful because this can change the meaning of the sentence. Future Continuous emphasizes interrupted actions, whereas Future Perfect Continuous emphasizes a duration of time before something in the future. Study the examples below to understand the difference.

Examples:

• He will be tired because he will be exercising so hard.
  This sentence emphasizes that he will be tired because he will be exercising at that exact moment in the future.
• He will be tired because he will have been exercising so hard.
  This sentence emphasizes that he will be tired because he will have been exercising for a period of time. It is possible that he will still be exercising at that moment OR that he will just have finished.

REMEMBER No Future in Time Clauses

Like all future forms, the Future Perfect Continuous cannot be used in clauses beginning with time expressions such as: when, while, before, after, by the time, as soon as, if, unless, etc. Instead of Future Perfect Continuous, Present Perfect Continuous is used.

Examples:

• You won't get a promotion until you will have been working here as long as Tim. Not Correct
• You won't get a promotion until you have been working here as long as Tim. Correct

AND REMEMBER Non-Continuous Verbs / Mixed Verbs

It is important to remember that Non-Continuous Verbs cannot be used in any continuous tenses. Also, certain non-continuous meanings for Mixed Verbs cannot be used in continuous tenses. Instead of using Future Perfect Continuous with these verbs, you must use Future Perfect .

Examples:

• Ned will have been having his driver's license for over two years. Not Correct
• Ned will have had his driver's license for over two years. Correct

ADVERB PLACEMENT

The examples below show the placement for grammar adverbs such as: always, only, never, ever, still, just, etc.

Examples:

• You will only have been waiting for a few minutes when her plane arrives.
• Will you only have been waiting for a few minutes when her plane arrives?

• You are only going to have been waiting for a few minutes when her plane arrives.
• Are you only going to have been waiting for a few minutes when her plane arrives?

ACTIVE / PASSIVE

Examples:

• The famous artist will have been painting the mural for over six months by the time it is finished. Active
• The mural will have been being painted by the famous artist for over six months by the time it is finished. Passive

• The famous artist is going to have been painting the mural for over six months by the time it is finished. Active
• The mural is going to have been being painted by the famous artist for over six months by the time it is finished. Passive

NOTE: Passive forms of the Future Perfect Continuous are not common.

Common English Irregular Verb List

Base Form	Past Simple	Past Participle	3rd Person Singular	Present Participle / Gerund
Abide	Abode/Abided	Abode/Abided/Abidden	Abides	Abiding
Alight	Alit/Alighted	Alit/Alighted	Alights	Alighting
Arise	Arose	Arisen	Arises	Arising
Awake	Awoke	Awoken	Awakes	Awaking
Be	Was/Were	Been	Is	Being
Bear	Bore	Born/Borne	Bears	Bearing
Beat	Beat	Beaten	Beats	Beating
Become	Became	Become	Becomes	Becoming
Begin	Began	Begun	Begins	Beginning
Behold	Beheld	Beheld	Beholds	Beholding
Bend	Bent	Bent	Bends	Bending
Bet	Bet	Bet	Bets	Betting
Bid	Bade	Bidden	Bids	Bidding
Bid	Bid	Bid	Bids	Bidding
Bind	Bound	Bound	Binds	Binding
Bite	Bit	Bitten	Bites	Biting
Bleed	Bled	Bled	Bleeds	Bleeding
Blow	Blew	Blown	Blows	Blowing
Break	Broke	Broken	Breaks	Breaking
Breed	Bred	Bred	Breeds	Breeding
Bring	Brought	Brought	Brings	Bringing
Broadcast	Broadcast/Broadcasted	Broadcast/Broadcasted	Broadcasts	Broadcasting
Build	Built	Built	Builds	Building
Burn	Burnt/Burned	Burnt/Burned	Burns	Burning
Burst	Burst	Burst	Bursts	Bursting
Bust	Bust	Bust	Busts	Busting
Buy	Bought	Bought	Buys	Buying
Cast	Cast	Cast	Casts	Casting
Catch	Caught	Caught	Catches	Catching
Choose	Chose	Chosen	Chooses	Choosing
Clap	Clapped/Clapt	Clapped/Clapt	Claps	Clapping
Cling	Clung	Clung	Clings	Clinging
Clothe	Clad/Clothed	Clad/Clothed	Clothes	Clothing
Come	Came	Come	Comes	Coming
Cost	Cost	Cost	Costs	Costing
Creep	Crept	Crept	Creeps	Creeping
Cut	Cut	Cut	Cuts	Cutting
Dare	Dared/Durst	Dared	Dares	Daring
Deal	Dealt	Dealt	Deals	Dealing
Dig	Dug	Dug	Digs	Digging
Dive	Dived/Dove	Dived	Dives	Diving
Do	Did	Done	Does	Doing
Draw	Drew	Drawn	Draws	Drawing
Dream	Dreamt/Dreamed	Dreamt/Dreamed	Dreams	Dreaming
Drink	Drank	Drunk	Drinks	Drinking
Drive	Drove	Driven	Drives	Driving
Dwell	Dwelt	Dwelt	Dwells	Dwelling
Eat	Ate	Eaten	Eats	Eating
Fall	Fell	Fallen	Falls	Falling
Feed	Fed	Fed	Feeds	Feeding
Feel	Felt	Felt	Feels	Feeling
Fight	Fought	Fought	Fights	Fighting
Find	Found	Found	Finds	Finding
Fit	Fit/Fitted	Fit/Fitted	Fits	Fitting
Flee	Fled	Fled	Flees	Fleeing
Fling	Flung	Flung	Flings	Flinging
Fly	Flew	Flown	Flies	Flying
Forbid	Forbade/Forbad	Forbidden	Forbids	Forbidding
Forecast	Forecast/Forecasted	Forecast/Forecasted	Forecasts	Forecasting
Foresee	Foresaw	Foreseen	Foresees	Foreseeing
Foretell	Foretold	Foretold	Foretells	Foretelling
Forget	Forgot	Forgotten	Forgets	Foregetting
Forgive	Forgave	Forgiven	Forgives	Forgiving
Forsake	Forsook	Forsaken	Forsakes	Forsaking
Freeze	Froze	Frozen	Freezes	Freezing
Frostbite	Frostbit	Frostbitten	Frostbites	Frostbiting
Get	Got	Got/Gotten	Gets	Getting
Give	Gave	Given	Gives	Giving
Go	Went	Gone/Been	Goes	Going
Grind	Ground	Ground	Grinds	Grinding
Grow	Grew	Grown	Grows	Growing
Handwrite	Handwrote	Handwritten	Handwrites	Handwriting
Hang	Hung/Hanged	Hung/Hanged	Hangs	Hanging
Have	Had	Had	Has	Having
Hear	Heard	Heard	Hears	Hearing
Hide	Hid	Hidden	Hides	Hiding
Hit	Hit	Hit	Hits	Hitting
Hold	Held	Held	Holds	Holding
Hurt	Hurt	Hurt	Hurts	Hurting
Inlay	Inlaid	Inlaid	Inlays	Inlaying
Input	Input/Inputted	Input/Inputted	Inputs	Inputting
Interlay	Interlaid	Interlaid	Interlays	Interlaying
Keep	Kept	Kept	Keeps	Keeping
Kneel	Knelt/Kneeled	Knelt/Kneeled	Kneels	Kneeling
Knit	Knit/Knitted	Knit/Knitted	Knits	Knitting
Know	Knew	Known	Knows	Knowing
Lay	Laid	Laid	Lays	laying
Lead	Led	Led	Leads	Leading
Lean	Leant/Leaned	Leant/Leaned	Leans	Leaning
Leap	Leapt/Leaped	Leapt/Leaped	Leaps	Leaping
Learn	Learnt/Learned	Learnt/Learned	Learns	Learning
Leave	Left	Left	Leaves	Leaving
Lend	Lent	Lent	Lends	Lending
Let	Let	Let	Lets	Letting
Lie	Lay	Lain	Lies	Lying
Light	Lit	Lit	Lights	Lighting
Lose	Lost	Lost	Loses	Losing
Make	Made	Made	Makes	Making
Mean	Meant	Meant	Means	Meaning
Meet	Met	Met	Meets	Meeting
Melt	Melted	Molten/Melted	Melts	Melting
Mislead	Misled	Misled	Misleads	Misleading
Mistake	Mistook	Mistaken	Mistakes	Mistaking
Misunderstand	Misunderstood	Misunderstood	Misunderstands	Misunderstanding
Miswed	Miswed/Miswedded	Miswed/Miswedded	Misweds	Miswedding
Mow	Mowed	Mown	Mows	Mowing
Overdraw	Overdrew	Overdrawn	Overdraws	Overdrawing
Overhear	Overheard	Overheard	Overhears	Overhearing
Overtake	Overtook	Overtaken	Overtakes	Overtaking
Pay	Paid	Paid	Pays	Paying
Preset	Preset	Preset	Presets	Presetting
Prove	Proved	Proven/Proved	Proves	Proving
Put	Put	Put	Puts	Putting
Quit	Quit	Quit	Quits	Quitting
Re-prove	Re-proved	Re-proven/Re-proved	Re-proves	Re-proving
Read	Read	Read	Reads	Reading
Rid	Rid/Ridded	Rid/Ridded	Rids	Ridding
Ride	Rode	Ridden	Rides	Riding
Ring	Rang	Rung	Rings	Ringing
Rise	Rose	Risen	Rises	Rising
Rive	Rived	Riven/Rived	Rives	Riving
Run	Ran	Run	Runs	Running
Saw	Sawed	Sawn/Sawed	Saws	Sawing
Say	Said	Said	Says	Saying
See	Saw	Seen	Sees	Seeing
Seek	Sought	Sought	Seeks	Seeking
Sell	Sold	Sold	Sells	Selling
Send	Sent	Sent	Sends	Sending
Set	Set	Set	Sets	Setting
Sew	Sewed	Sewn/Sewed	Sews	Sewing
Shake	Shook	Shaken	Shakes	Shaking
Shave	Shaved	Shaven/Shaved	Shaves	Shaving
Shear	Shore/Sheared	Shorn/Sheared	Shears	Shearing
Shed	Shed	Shed	Sheds	Shedding
Shine	Shone	Shone	Shines	Shining
Shoe	Shod	Shod	Shoes	Shoeing
Shoot	Shot	Shot	Shoots	Shooting
Show	Showed	Shown	Shows	Showing
Shrink	Shrank	Shrunk	Shrinks	Shrinking
Shut	Shut	Shut	Shuts	Shutting
Sing	Sang	Sung	Sings	Singing
Sink	Sank	Sunk	Sinks	Sinking
Sit	Sat	Sat	Sits	Sitting
Slay	Slew	Slain	Slays	Slaying
Sleep	Slept	Slept	Sleeps	Sleeping
Slide	Slid	Slid/Slidden	Slides	Sliding
Sling	Slung	Slung	Slings	Slinging
Slink	Slunk	Slunk	Slinks	Slinking
Slit	Slit	Slit	Slits	Slitting
Smell	Smelt/Smelled	Smelt/Smelled	Smells	Smelling
Sneak	Sneaked/Snuck	Sneaked/Snuck	Sneaks	Sneaking
Soothsay	Soothsaid	Soothsaid	Soothsays	Soothsaying
Sow	Sowed	Sown	Sows	Sowing
Speak	Spoke	Spoken	Speaks	Speaking
Speed	Sped/Speeded	Sped/Speeded	Speeds	Speeding
Spell	Spelt/Spelled	Spelt/Spelled	Spells	Spelling
Spend	Spent	Spent	Spends	Spending
Spill	Spilt/Spilled	Spilt/Spilled	Spills	Spilling
Spin	Span/Spun	Spun	Spins	Spinning
Spit	Spat/Spit	Spat/Spit	Spits	Spitting
Split	Split	Split	Splits	Splitting
Spoil	Spoilt/Spoiled	Spoilt/Spoiled	Spoils	Spoiling
Spread	Spread	Spread	Spreads	Spreading
Spring	Sprang	Sprung	Springs	Springing
Stand	Stood	Stood	Stands	Standing
Steal	Stole	Stolen	Steals	Stealing
Stick	Stuck	Stuck	Sticks	Sticking
Sting	Stung	Stung	Stings	Stinging
Stink	Stank	Stunk	Stinks	Stinking
Stride	Strode/Strided	Stridden	Strides	Striding
Strike	Struck	Struck/Stricken	Strikes	Striking
String	Strung	Strung	Strings	Stringing
Strip	Stript/Stripped	Stript/Stripped	Strips	Stripping
Strive	Strove	Striven	Strives	Striving
Sublet	Sublet	Sublet	Sublets	Subletting
Sunburn	Sunburned/Sunburnt	Sunburned/Sunburnt	Sunburns	Sunburning
Swear	Swore	Sworn	Swears	Swearing
Sweat	Sweat/Sweated	Sweat/Sweated	Sweats	Sweating
Sweep	Swept/Sweeped	Swept/Sweeped	Sweeps	Sweeping
Swell	Swelled	Swollen	Swells	Swelling
Swim	Swam	Swum	Swims	Swimming
Swing	Swung	Swung	Swings	Swinging
Take	Took	Taken	Takes	Taking
Teach	Taught	Taught	Teaches	Teaching
Tear	Tore	Torn	Tears	Tearing
Tell	Told	Told	Tells	Telling
Think	Thought	Thought	Thinks	Thinking
Thrive	Throve/Thrived	Thriven/Thrived	Thrives	Thriving
Throw	Threw	Thrown	Throws	Throwing
Thrust	Thrust	Thrust	Thrusts	Thrusting
Tread	Trod	Trodden	Treads	Treading
Undergo	Underwent	Undergone	Undergoes	Undergoing
Understand	Understood	Understood	Understands	Understanding
Undertake	Undertook	Undertaken	Undertakes	Undertaking
Upset	Upset	Upset	Upsets	Upsetting
Vex	Vext/Vexed	Vext/Vexed	Vexes	Vexing
Wake	Woke	Woken	Wakes	Waking
Wear	Wore	Worn	Wears	Wearing
Weave	Wove	Woven	Weaves	Weaving
Wed	Wed/Wedded	Wed/Wedded	Weds	Wedding
Weep	Wept	Wept	Weeps	Weeping
Wend	Wended/Went	Wended/Went	Wends	Wending
Wet	Wet/Wetted	Wet/Wetted	Wets	Wetting
Win	Won	Won	Wins	Winning
Wind	Wound	Wound	Winds	Winding
Withdraw	Withdrew	Withdrawn	Withdraws	Withdrawing
Withhold	Withheld	Withheld	Withholds	Withholding
Withstand	Withstood	Withstood	Withstands	Withstanding
Wring	Wrung	Wrung	Wrings	Wringing
Write	Wrote	Written	Writes	Writing
Zinc	Zinced/Zincked	Zinced/Zincked	Zincs/Zincks	Zincking

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