When a patent runs out on a parent conventional medicine, any other company can start to produce and distribute it as a so-called generic medicine or drug. A drug is the active constituent of a medicine. Generic prescribing is encouraged by the national health service because, in general, generic drugs are substantially cheaper than the originally marketed parent drug. That is because companies that market generic drugs do not have to conduct the research that led to the discovery of the parent drug, thus avoiding expensive clinical trials to establish its safety and efficacy in human use.
Today, more than 200 drugs are produced by the biotechnology industry, in living cells or in reaction vessels using gene technology, to treat various cancers, AIDS, neurological disorders, heart disease, diabetes and rare genetic diseases. Those so-called biopharmaceuticals, or biological drugs, benefit about 325 million people worldwide. The biopharmaceutical industry is an essential component of the British biotechnology industry in general. So far, the patents have run out on five of the parent branded biological drugs, but that number will increase significantly in the next few years.
Whereas generic copies of branded conventional drugs, prepared by conventional chemical synthesis, are relatively easy to produce and purify for human consumption, the same is not true for biological drugs, which are extremely complicated chemical molecules compared with most conventional drugs, and are mainly of protein origin. Proteins are very large molecules. They can kink, fold up and even get twisted, which can result in what can be compared with a tangled ball of wool, containing cavities in which other, smaller molecules can sit. There can be interactions between the different parts of those complex protein molecules that can facilitate this tangling of the complex molecule and even interactions between one tangled molecule and another.
When another biotechnology company produces one of those biological drugs, using a process different from that used by the company that discovered the parent drug—and invariably using a different cell line—the resulting tangled molecule will not be quite the same as the parent one. Thus, copies of biological drugs are not identical to the parent drug and are called biosimilars. For their use as drugs, we have to be sure that biosimilar drugs are as close in structure to the parent drug as possible. Otherwise their clinical profile, including safety and efficacy, will be different.
A particular characteristic of proteins is their ability to produce antibodies and a possible immune response. The time of onset of antibodies is months rather than days or weeks—normally between nine and 14 months for an erythropoietin, or EPO, for example. The parent biological drug will have been through extensive and expensive clinical trials to ensure its safety and clinical efficacy in as many patients as possible. It is important to establish that the biosimilar copy has the same safety profile and clinical efficacy.
For most biosimilar drugs, extensive clinical trials will be necessary to establish the drug in the marketplace, although in most cases they will not be as extensive as those for the parent drug. A biosimilar drug costs in the region of £5 million to £20 million to develop, compared with £500,000 to £1 million for a generic drug, with a timeline similar to the development of the parent biological drug. Savings to the NHS will be in the region of 10 to 20 per cent. However, because biological drugs are more expensive than conventional drugs, that could be a considerable overall saving to the NHS.
At present, biological drugs are mainly used in a hospital setting, but it is expected that they will be prescribed in future by general practitioners and dispensed by community pharmacists. Currently used biological drugs include insulins, interferons, recombinant factor VIII, erythropoietins, growth hormones and granulocyte colony-stimulating factors, or G-CSF. Erythropoietins are used to treat the radiation-induced anaemia suffered by many cancer patients and to treat anaemia caused by chronic kidney disease. They are made in Chinese hamster ovaries. G-CSF is a hormone that stimulates white blood cell production and its use allows the dose of a chemotherapeutic agent to be increased.
Whereas approval for generic drugs is the responsibility of each member state, the European Medicines Agency, or EMEA, is responsible for approving biosimilar drugs throughout the European Union. The term biosimilar drug is preferred by both the EMEA and the Medicines and Healthcare Products Regulatory Agency, the MHRA, as distinct from the term biogeneric drug, which some manufacturers would prefer to use. By October 2007, eight biosimilar drugs had been approved by the EMEA.
We recommended that biological drugs, whether the parent drug or a biosimilar, should be prescribed by the doctor and dispensed by a pharmacist only by their brand names, not by their international non-proprietary names, or INNs. It is preferable, in our opinion, for a patient to be established on one biological drug by their doctor and for the patient to remain on that drug for the duration of their treatment unless adverse drug reactions are noticed. Several countries, including France, Spain, the Netherlands and Norway, have already introduced legislation and measures to prevent automatic substitution of biological drugs.
We recommended that an urgent ban on substitution should be put in place in the UK until effective safeguards can be relied on. With the existing pharmacovigilance systems, it may not be possible to distinguish accurately or trace precisely the product dispensed by the pharmacist to the patient should they suffer an adverse drug reaction. The European Commission responsible for pharmaceuticals has written to all regulatory agencies in member countries outlining a need to improve their pharmacovigilance systems in order to ensure that the arrival of biosimilar drugs such as the erythropoietins are monitored closely for adverse drug reactions.
A problem being addressed by regulators such as the World Health Organisation is the nomenclature of biosimilar drugs in order that an adverse drug reaction can be attributed to the right biosimilar product, its manufacturer and even the right batch number. Up to eight erythropoietic agents are now in existence. Until recently, only one was in use—epoetin alpha—which comes as a formulation under the brand name Eprex. There are now three different versions of epoetin alpha alone. The European Commission has approved four other formulations: erythropoietin beta; Darbepoietin; Mircera, which is a pegylated formulation; and erythropoietin delta. Other formulations are pending approval. Obviously, it is important that a nomenclature system is established which allows professionals and patients to differentiate between different versions of what is essentially the same drug.
The MHRA's black triangle symbol is applied to drugs that are new to the market and denotes a product that should be intensively monitored for adverse drug reactions by the MHRA and the Commission on Human Medicines, and to confirm the risk-benefit profile. We recommended that a black triangle symbol should be applied to all biosimilar drugs and that, at two-year or other periodic review, that symbol should remain unless the safety evidence is clear that it can be removed.
The British National Formulary—the BNF—provides doctors with information on prescribing drugs and on their pharmacology. We recommended that the BNF should flag biosimilar drugs with a black triangle and emphasised that clinician choice should be exercised in prescribing them. I am pleased to report that the BNF acted on this recommendation last month.
It is even more important for biosimilars that pharmacovigilance is strengthened, as well as the yellow card scheme for reporting adverse drug reactions that the patient may suffer. There has been criticism of the effectiveness of the current voluntary yellow card scheme, under-reporting being a serious concern, and the MHRA is committed to increasing overall reporting of adverse drug reactions. I understand that an expert group of the Commission on Human Medicines is advising on this issue at the present time.
An example of the possible risks that can arise from prescribing biosimilar drugs arose in the use of erythropoietins. A small change in the manufacturing process used by one company caused a significant and major adverse drug reaction known as pure red cell aplasia, which is a type of anaemia affecting the precursors to red blood cells but not to white blood cells. The bone marrow of a patient with this condition, which is an auto-immune disease, stops producing red blood cells. The company picked up that adverse drug reaction through its post-marketing surveillance, it acted responsibly, and it traced and arranged treatment for the patients who had received the affected batch of product all around the world.
The summary of medicinal product characteristics, product packaging and patient information leaflet should include details of biosimilar formulation and manufacture for all biosimilar drugs, and reference should be made to the possible dangers of substitution of those products. That should provide clinicians, pharmacists and patients with clear information on biosimilar drugs and the added importance of reporting adverse drug reactions.
We have recommended that Government agencies begin a consultation period with all professional organisations that represent clinicians, nurses and others, especially the royal colleges, which are involved in the purchasing and prescribing of biosimilar drugs. Those organisations, in turn, should be tasked with educating their memberships. A publicity campaign should be launched to raise public awareness of the risks of the substitution of biological drugs, and patients should be actively encouraged to monitor and report to their doctor any adverse drug reactions that they may experience.
Knowledge about biosimilar drugs is extremely limited among the general public, which is one reason why I applied for this Adjournment debate. I hope that it will help to raise awareness of this subject, particularly among parliamentarians. The International Alliance of Patients Organisations has launched an educational programme on biosimilar drugs to help patient organisations make informed judgments on their value and on the scientific, social, ethical and economic issues involved. The use of such products is low at this time and few—although perhaps serious—adverse drug reactions will be reported in the initial stages of their use. Therefore, we have recommended that a European-wide database should be established to audit adverse drug reactions that may be associated with biosimilar drugs.
Finally, we have also recommended that our findings on biosimilar drugs should be made available to the relevant authorities in the devolved nations of this country.
In conclusion, I hope that I have demonstrated that biosimilar drugs must not be regarded by Governments as equivalent products to generic drugs, and that we need to establish different monitoring regimes to ensure patient safety in their use. It is a privilege that my right hon. Friend the Minister of State is here this evening and I look forward to her response.
I congratulate my hon. Friend Dr. Iddon on securing tonight's Adjournment debate. The depth and breadth of his knowledge on this important subject are clear. I am grateful to him for sending me a copy of his panel's report, and I look forward to discussing it with him in due course.
I welcome the opportunity to clarify the general regulatory position on biosimilar medicines—a regulatory framework that already delivers much of what is suggested in the report. Biotechnology is an important and growing field within modern medicine, and the United Kingdom is home to an innovative biotechnology industry that makes a significant contribution to the development of new medicines, to the economy as a whole and to the research capacity of this country.
My hon. Friend gave examples of biological medicines that help in the treatment of some very serious diseases. They make a crucial contribution to modern health care. Innovative medicines benefit from a period of data protection, but when they reach patent expiry, generic copies—biosimilar medicines—are allowed by law. Properly licensed biosimilar medicines increase the number of such drugs available to patients and clinicians. Biosimilar medicines are manufactured following the same robust quality standards as for all other medicines but, as my hon. Friend pointed out, the complex nature of biological medicines requires careful testing and specialised control of production processes. Owing to the complex method of production of biological medicines, the active substance may differ slightly from the biological reference and the biosimilar medicine.
It is important that those additional factors are fully taken into account when biosimilar medicines are manufactured and assessed. That is why special European regulations are in place to ensure that biosimilar manufacturers supply comprehensive data to regulators to demonstrate the safety, quality and efficacy of the product and its similarity to the original reference medicinal product. Regulatory authorities also perform periodic inspections of the manufacturing process.
I note my hon. Friend's concerns about best practice guidance to promote brand prescribing and prevent automatic substitution of biosimilar medicines by pharmacies, and the use of the black triangle notification in the British National Formulary—the BNF. I agree that it is important that those procedures are designed to safeguard best practice and offer proper patient protection. Several initiatives are under way to ensure that we can effectively monitor the safety of the biosimilar products on the market.
We are working with other European regulatory authorities to ensure that health professionals who report adverse reactions to biosimilar products know that they should provide the brand name and batch number of the suspected product. We are also making it clear that marketing authorisation holders and regulatory authorities throughout the EU should directly contact reporters for that information if it is not provided in the initial report.
It is the existing policy and current practice of the Medicines and Healthcare products Regulatory Agency to apply the black triangle symbol to all new medicinal products, including biosimilar medicines, for the first two years of marketing. The symbol denotes intensive monitoring of the new product and encourages reporting of all suspected adverse reactions through the yellow card scheme. After two years, the product's safety profile is reviewed and decisions are made about whether the intensive monitoring can be lifted.
My hon. Friend raised concerns this evening about the under-use of the yellow card scheme for reporting adverse reactions. The MHRA works continuously to increase the number of reports received through the schemes from patients and health care professionals. There has recently been a promotion in community pharmacies to raise awareness of the yellow card scheme among medicine users. The MHRA has just launched an updated online reporting form, which makes it easier and quicker to submit reports of suspected adverse reactions.
Biosimilar medicines are not identical copies of reference products, and therefore subtle differences may exist which may make a difference to their effect or side effects when taken by patients. It is preferable that, when such products are prescribed, they should be clearly identified and prescribed by brand name to ensure that the patient receives the exact product prescribed and that its safety in use can be properly monitored.
The MHRA encourages companies that manufacture biosimilar medicines to give them a brand name so that there is no possibility of the pharmacist substituting another biosimilar product when dispensing a prescription. I note my hon. Friend's concern that pharmacists may automatically substitute biosimilar medicines for prescribed, branded products. It is important to stress that UK medicines legislation does not allow such substitution of a named brand product with any other without first agreeing that with the prescriber. There is no concrete evidence that substitution is happening. If my hon. Friend has any, or it is in his report, I would be interested in considering it.
The Royal Pharmaceutical Society of Great Britain advises pharmacists that, except in an emergency, a specifically named innovator biological medicine should not be substituted with any other biosimilar medicine without the approval of the patient, carer, prescriber and, in the case of hospital drugs, the therapeutics committee or in line with other, similar, locally agreed protocols.
The February edition of the MHRA bulletin for health professionals, "Drug Safety Update", carried an article on biosimilar products. The article emphasised that it is good practice to prescribe biological products using the brand name, to ensure that a substitution of a biosimilar product by the pharmacist does not occur. The article also highlighted the need for reporters to use a specific brand name when reporting an adverse reaction to a biological product, to ensure that the reaction is assigned to the appropriate product.
I hope that that briefly explains the general regulatory provisions. As my hon. Friend said at the beginning of his contribution, he chaired a panel considering the measures and a report has now been produced. The issue is vital. I look forward to discussions in due course with representatives of the panel and my right hon.—or rather, my hon. Friend, whom I nearly promoted—on the contents of that report and any further action that should be necessary.
Question put and agreed to.
Adjourned accordingly at nine minutes to Eight o'clock.