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Regulation of Follow-on BiologicsIn brief: Partner Sarah Matheson (view CV) and Articled Clerk Adel Mohamed provide a brief overview of follow-on biologics and the regulatory frameworks in the United States of America, Europe and Australia established to regulate this emerging class of therapeutic products. IntroductionPatent protection is expiring on the first biopharmaceutical products and several generic manufacturers are gearing up to move into this new marketplace. There are unresolved legal issues implicated in the discussion of whether and how to approve 'follow-on biologics' (FOBs) for medical use. Foreign regulators such as the United States Food and Drug Administration (FDA) have stated that the generic drug approval pathway is not appropriate for complex biologics. This article briefly explores the regulatory framework for FOBs in the US, Europe and Australia.
What are follow-on biologics?Pharmaceutical treatments include drugs that are manufactured via chemical or biological processes. Chemically manufactured drugs (eg, paracetamol) tend to be small molecule drugs that can be administered orally and work in the body within cells. In contrast, biologically manufactured drugs (eg, insulin), or biologics, are much larger and more complex compounds that tend to have activity in the blood stream or on the surface of cells. Biologics constitute many of the latest breakthrough medical therapies for serious and life threatening illnesses, such as cancer, multiple sclerosis, diabetes and HIV/AIDS. A generic drug generally has the same active ingredient as that of the innovator's drug, but may or may not have the same composition of inactive ingredients. A generic with the same active ingredient is generally designated as therapeutically interchangeable with the innovator drug. Similarly a FOB generally refers to a biologically manufactured drug that is comparable to a novel, previously approved biologic. However, an FOB is not the same as a generic drug is to a chemically manufactured drug. Biologics that serve the same function may have differences in their structural organisation (ie, folding of proteins) that may lead to variances in biological activity. Differing structural organisation results where the manufacturing process used to develop the FOB is different to the manufacturing process used to develop the innovator biologic. Owing to the differences that can exist between FOBs and innovator biologics, the generic drug approval pathway is not considered appropriate for complex biologics.
Regulatory frameworksUnited States The United States Senate Health, Education, Labor and Pensions Committee has passed a Bill regulating the authorisation of FOBs. The Bill, known as the Biologic Price Competition and Innovation Act, grants the FDA authority to approve FOBs under a two tiered system. The first tier involves a finding from the FDA that a FOB is 'biosimilar' to an innovator biologic and the second tier involves a finding that the FOB is 'interchangeable' with the innovator biologic. A finding of biosimilarity would allow a FOB to be sold in the US and a finding of interchangeability would permit pharmacies to substitute a prescription for a innovator biologic with that of the interchangeable FOB without the need for a healthcare provider's approval. Accordingly interchangeability is likely to be preferred by manufacturers of FOBs because competition with biologic innovators is concentrated on price. The Bill also proposes to grant 12 years of market exclusivity for an innovator biologic and one year of market exclusivity for the first interchangeable FOB to be approved. In order for a finding of biosimilarity to be made, the Bill requires an applicant to demonstrate the absence of clinically meaningful differences in safety, purity and potency between its biosimilar product and the innovator biologic. The demonstration needs to include analytical data, animal testing and at least one clinical study, unless the FDA determines that this requirement is unnecessary. Where a finding of interchangeability is sought, the applicant is required to provide evidence that the biosimilar product produces the same clinical result as the brand product in any patient and presents no additional risk in terms of safety or diminished efficacy if a patient changes between products. The legislation also outlines a process for resolving disputes concerning patents that a FOB may infringe. Initially the FOB applicant and the innovator company are required to identify the patents at issue and offer their opinions as to validity. The two parties must then agree to a list of patents to be litigated first or exchange lists and the innovator company is given 30 days within which to sue the FOB applicant. If a court decides that a patent is valid and was or will be infringed by a FOB before the 12 year exclusivity period has ended, the court must make orders that the patent not be infringed for the period that exclusivity is granted. Where a patent had been identified but not included in the initial litigation, the FOB applicant is required to give the innovator company 180 days' notice before it launches its product, thereby allowing the innovator company a period of time in which to seek an interlocutory injunction to prevent launch. Europe In Europe FOBs are known as 'biosimilars'. The European Medicines Agency (EMEA) has published a set of guidelines on similar biological medicinal products that distinguishes between biosimilar products and generics. The guidelines came into effect on 1 June 2006. The EMEA also published two new concept papers. The first is a concept paper on comparability of biotechnology-derived medicinal products after a change in the manufacturing process (non-clinical and clinical issues). The second is a concept paper on immunogenicity assessment of therapeutic proteins. The EMEA system requires extensive testing before approval. In particular where there are safety and efficacy differences between the biosimilar product and the innovator biologic, the EMEA has said that any 'differences between the similar biological medicinal product and the reference (innovator) medicinal product will have to be justified by appropriate studies on a cases-by-case basis'. The EMEA has indicated that such studies should typically include clinical trials. Further, owing to the potential for immunogeniticity problems to arise, the EMEA requires that biosimilar products undergo post-marketing monitoring akin to that required for innovator biologics. Australia The Therapeutic Goods Administration (TGA) in Australia has adopted the EMEA guidelines on similar biological medicinal products and are titled Similar biological medicinal products. The TGA was the first regulatory agency amongst the agencies discussed in this article to approve Omnitrope, a 'follow-on' human growth hormone. At the time of approval the TGA had not adopted the EMEA guidelines and operated on the basis that therapeutic products should not, for the purposes of regulatory approval, be characterised according to the way they are derived.
ConclusionThere is a consesus in the view that FOBs should not be regulated in the same way as traditional generic pharmaceuticals. The regulatory frameworks discussed above indicate that applications for regulatory approval of FOBs need to be supported with independent safety and efficacy data. However, there is no uniform view as to the exact requirements for regulatory approval of a FOB. The regulation of FOBs are likely to evolve as technology evolves and techniques for assessing safety and efficacy of biologics are refined.. For further information contact Sarah Matheson
Company newsIn brief: Regular news from the biotech industry.
GSK to supply pandemic flu vaccine to the UK16 August – In one of the largest contracts it has signed to date for its adjuvanted pandemic flu vaccine, GlaxoSmithKline (GSK) have entered into an agreement with the UK Government to provide its pandemic influenza vaccine in the event of a flu pandemic. As part of an Advance Supply Agreement, GSK has committed to make the necessary preparations to supply its pandemic influenza vaccine as soon as possible after a pandemic outbreak has been declared. Professor John Oxford, Professor of Virology, Queen Mary's School of Medicine, St Bartholomew's and the Royal London hospitals said: 'This announcement by the UK Government is very good news. The World Health Organisation and experts across the globe agree that an influenza pandemic is likely to occur, but cannot predict when. Despite this uncertainty, there is still the opportunity to be thoroughly prepared. This agreement is part of the preparation needed to protect the UK population when an influenza pandemic eventually strikes.' [Source: Company announcement] MedImmune licenses reverse genetics IP to Novartis23 August – MedImmune has announced that it has licensed its proprietary reverse genetics intellectual property to Novartis to support the development and construction of new vaccine strains to produce inactivated human seasonal, pre-pandemic and pandemic influenza vaccines. Reverse genetics is a method by which viruses such as influenza can be generated from segments of DNA. MedImmune will receive an upfront payment and royalties on certain vaccine stockpiles or sales of other influenza products developed using the reverse genetics technology. [Source: Company announcement] Phylogica enters the anti-microbial field with Dynamic Microbials24 August – Australian biotech Phylogica announced that it has entered into an agreement with Perth company Dynamic Microbials to license anti-microbial applications of its proprietary Phylomer peptide technology. Based on the results of a technical evaluation, Phylogica will grant a licence to Dynamic to develop anti-microbial drugs. Dynamic will have exclusive rights to develop anti-microbial drugs for human applications in defined fields and non-exclusive rights for human anti-viral applications. In return Phylogica will receive an equity position in Dynamic, together with a royalty on direct sales of products and a percentage of commercialisation income. The initial technical evaluation involved the generation of potent Phylomer peptides against Acinetobacter Baumanii, a bacteria that is the cause of a number of hospital-acquired infections which has shown antibiotic resistance in an increasing number of cases. [Source: Company announcement] Pfizer appoints new CFO22 August – Pfizer has announced the appointment of Frank D'Amelio, currently Senior Executive Vice President at Alcatel-Lucent, as Pfizer's new Senior Vice President and Chief Financial Officer effective in mid-September. Mr D'Amelio will have responsibility for all aspects of the company's finances, including treasury, tax, the controller's division and investor development and will report to Pfizer Chairman and CEO Jeff Kindler. Mr D'Amelio succeeds Alan Levin, whose resignation from Pfizer was announced in May. Mr Kindler said that Pfizer 'are very pleased that an executive with Frank's skills, integrity, global experience and proven leadership is joining our management team. Through almost three decades at AT&T, Lucent and Alcatel-Lucent in both operating and financial roles, Frank was a senior executive in global companies undergoing the kind of rapid and complex changes we have undertaken at Pfizer in response to our own rapidly changing markets.' [Source: Company announcement] Progen engages Quintiles to assist with clinical trials16 August – Australian company Progen Pharmaceuticals announced it has executed an agreement with the world's largest Contract Research Organisation, Quintiles, to utilise their services for a number of clinical development-related projects. This agreement includes the execution of the Phase 3 clinical trial of anti-cancer drug PI-88 for the treatment of primary liver cancer (hepatocellular carcinoma). Quintiles, which has over 18,000 employees, operates directly in each of the 14 North American, European and Asian countries where Progen will be conducting the Phase III PI-88 trial. [Source: Company announcement] pSivida and Alimera begin pharmacokinetic study for Medidur22 August – ASX listed bio-nanotech pSivida and Alimera Sciences, a privately held US ophthalmic pharmaceutical company, have announced that enrollment has begun for the first human pharmacokinetic study of fluocinolone acetonide (FA) in Medidur, the companies' investigational product for the treatment of diabetic macular edema (DME). Medidur is a tiny insert, injected intra-vitreally, which is being studied as a way to deliver a very low dose of FA, a corticosteroid, to the retina for up to three years as a treatment for DME. Alimera Sciences and pSivida Limited have a worldwide agreement to co-develop and market the Medidur insert for the use of the FA study to treat DME. The agreement also includes the option to identify other compounds for ophthalmic diseases. Medidur FA is currently in a Phase III global clinical trial that will follow approximately 900 patients in the US, Canada, Europe and India for three years with safety and efficacy assessed at two years. The pharmacokinetic study is designed to support the Phase III trial by providing pharmacokinetic/pharmacodynamic correlation data from DME patients. [Source: Company announcement] Roche extends Ventana offer21 August – Roche has extended by four weeks its offer to acquire all of the outstanding common shares of tissue-based diagnostics company Ventana Medical Systems at US$75 per share. The offer will now close on September 20. All other terms and conditions of the original June 27 tender offer remain unchanged. In response to the extension Ventana issued the following statement: 'We remain steadfast in our position that Roche's offer is wholly inadequate and our Board of Directors continues to recommend that stockholders not tender any of their shares to Roche. Roche's offer remains significantly below our current stock price, even with the recent tumultuous market conditions, proving that the market agrees that the offer fails to reflect the inherent value of the Company, its steady growth momentum, and the magnitude of the synergies that would be unlocked in a combination with Roche. Ventana is an extraordinary company which, given the increasing focus on and significant value of companion diagnostics to pharmaceutical companies, is uniquely poised to benefit from the potential in the future of personalized medicine.' [Source: Company announcement]
BioTip: Recording an interest on the Patents RegisterAustralia and many other jurisdictions have a Patents Register to record various particulars in relation to pending or granted patent rights. Particulars typically recorded include: title of the invention; listing of inventor/s and applicant/s; filing date and priority date/s; status, including renewal status; and several other particulars. It is also possible for third party interests to be recorded on the Register including, for example, entitlement as mortgagee, licensee or otherwise to an interest in the patent/application, and a transfer or a share in such an entitlement. Third parties with an interest in a patent/application should seek to have that interest recorded on the Register so that anyone considering dealing with the patent/application will have notice of that interest by inspecting the Register.
EventsInformation on the latest conferences See conferences in: September | October | November BIO Korea 2007 NEW – What Are United
Nations Millennium Development Goals? What is BioVision? BIO Japan
2007 Australian Bioscience and Scientific Industry Delegation to Hong Kong
NEW – 2007 BIO InvestorForum AusBiotech 2007 National Conference &
Business Partnering & Investment Forum Pharma Partnering Event – One-to-One License
Meetings Asian Patent Attorneys Association (APPA) Annual
Meeting As active members of APAA, we look forward to attending what promises to be a very enjoyable and rewarding conference and, of course, to meeting many of our clients and contacts there. If you are planning to attend this meeting, please do take the opportunity to come and visit us in our Sydney or Melbourne office while you are in Australia. Let us know by getting in touch with Dr Trevor Davies (contact details below).
For further information, please contact:
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