Cell Law

HTA licence fees 2009 - 2010

The Human Tissue Authority has recently announced its new licence fees for 2009/10.  The only licence fee to be reduced from the 2008/9 level is that paid by satellite sites of organisations for a post mortem licence (the fee is reduced to £2,000 from £2,100).  All other licence fees payable (for research, public display, post mortem, anatomy and human application) have increased and details can be found here:

 

The Human Tissue Authority is planning to review the licence fee structure during the coming year.

 

Paul

US stem cell research still limited by a Dickey-Wicker

On 9 March 2009, President Obama signed an executive order intended to remove limitations on the Department of Health and Human Services ("HHS") to fund and conduct human embryonic stem cell research. This was described as "an extraordinary medical breakthrough...achieved with the stroke of a pen" by Senator Edward M. Kennedy, the Chairman of the Health, Education, Labor and Pensions Committee in the Senate. There is, however, a fly in the ointment. Scientists seeking federal funding for stem cell research are still faced with a legislative obstacle called the Dickey-Wicker amendment.

Since 1996, the Dickey-Wicker amendment has been attached to every annual appropriations bill for the HHS. It states that "None of the funds made available in this Act may be used for - (1) the creation of a human embryo or embryos for research purposes; or (2) research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death."

President Obama signed the appropriations bill for the fiscal year ending 30 September 2009 on 11 March 2009. Naturally enough, the bill contained the Dickey-Wicker amendment.

So what does this mean for federally-funded stem cell research in the US? Well, President Obama's executive order allowed human stem cell research to be supported and conducted by the HHS "to the extent permitted by law". Thanks to the Dickey-Wicker provisions, it will still be unlawful for federally backed researchers to create their own stem cell lines.  For example, if they wish to create new liver or heart cells for drug testing; they will remain limited to experimenting on existing stem cell lines.    The HHS, through the National Institutes of Health, will be issuing new guidelines on human stem cell research consistent with President Obama's executive order before the end of July.

It should be noted that privately-funded stem cell research does take place in the US, but it is not subject to any government oversight, and Amy Comstock Rick, the President of the Coalition for the Advancement of Medical Research, has argued that the best research in the US benefits from accountability to the HHS and the National Institutes of Health. The New York Times is in support of this view and has carried an editorial calling on Congress to repeal Dickey-Wicker, an amendment passed in 1996 before the full potential of embryonic stem cell research was realized.

It appears the debate about the use of US taxpayers' money for stem cell research has some distance left to run.  To some, however, the issue is irrelevant:  President Obama's announcement has all the significance of raising the speed limit for steam locomotives to 20 miles per hour.  This is because many within the field feel that rapid advances in iPS (induced pluripotent stem) cell technology, notably the recent announcements from Edinburgh and Canada, are tending to marginalise the role of hESC cells. 

Paul and Julian

Redefining Medicine

A new European law is set to accelerate the deployment of highly sophisticated medicinal products based on genes, cells and tissues.   Julian Hitchcock examines the Advanced Therapies Medicinal Products Regulation.

Introduction

As the search for pharmaceutical blockbusters grows more desperate, the law which governs them is expanding to accommodate a new class of product.  From 30 December, the expression, “medicinal product”, will encompass things made using human or animal cells.  Like “gene therapy medicinal products” and “somatic cell medicinal products”, such tissue engineered products (“TEPs”) will fall within a special class; “advanced therapy” medicinal products (“ATMPs”).  Together, they will enjoy a privileged status under European medicines law.

The regulation which will bring about these changes, the Advanced Therapies Medicinal Products Regulation, aims to boost development of personalised, regenerative and nano medicines for the benefit of European patients and industry, while guaranteeing a high level of quality and safety.  The single most important piece of European medicines legislation of the 21^st century and the most revolutionary in its potential, it will apply directly in every state of the Union.

Aims and means

Modern biotechnology has produced so many new genres of medicinal products so quickly that the law has simply failed to keep up.  Products made using tissues such as skin, cartilage or bone have not sat easily within the existing device/medicine framework.  A single product could be classified as device in one state and as a medicinal product in another,- presenting a considerable impediment to anyone seeking to market a tissue engineered product across Europe.  The Regulation resolves this by unifying the classification rules, attempting to make them proof against future technical advances, providing a centralised procedure for authorisation on the European market and adding powerful incentives.  It also recognises that developers are often small and medium sized enterprises and hospitals, rather than large pharmaceutical companies.  However, rather than establishing a new “third pillar” framework for advanced therapies to sit alongside those for devices and medicines, it exploits existing rules and institutions.  Specifically, it amends the Medicinal Products Directive (2001/83) and Regulation on the authorisation and supervision of medical products in the Community (726/2004).  Advanced therapies are, henceforth, medicines.  In many cases, they will also be devices.

 

Defining ATMPs

The ATMP Regulation lays down rules for the authorisation, supervision and pharmacovigilance of gene therapy medicinal products, somatic cell therapy medicinal products and TEPs.  The first two members of the family already being defined, the Regulation’s first job is to define TEPs.  Broadly speaking, they sit between two excluded extremes: cell grafts and devices which lack pharmacological, immunological or metabolic action.

At the root of the old classification problem was the “principle mode of action” rule that separates devices from products.  The Regulation ensures eligibility as a medicinal product, by providing that, even if the device aspect is dominant, the pharmacological, immunological or metabolic action of any viable cells/tissues will be deemed to be the principal mode of action.

The Regulation’s definition of TEP captures products presented as having properties for regenerating, repairing or replacing a human tissue and which contain or consist of cells or tissues: human, animal or both.  TEPs may include additional substances, such as chemicals, scaffolds, matrices and non-viable cells.  However,  products containing no viable cells at all and which do not act principally by pharmacological, immunological or metabolic action are excluded; a sort of “leather exception”.  Crucially, the constituent cells or tissues must be “engineered”.  This means that they are either “subject to substantial manipulations”,- which means rather more than cutting, grinding and various other acts-, or that they are not intended to be used in the same way in the donor as in the recipient.

Where an ATMP is integrated with one or more “medical device” (or  “active implantable medical device” as those terms are defined in relevant directives) and its cell/tissues are either viable or act primarily as a device, it is known as a “combined ATMP” and will be regulated both as a medicine and as the appropriate device.

Finally, the Regulation provides a cascade approach to borderline cases.  If a product could be classified as a TEP or a somatic cell medicinal product, it will be deemed a TEP, but if it could be gene therapy medicinal product then that status will prevail.

Requirements for marketing authorisation

The ATMP is primarily a law of market authorisation.  However, no ATMP will be authorised unless other conditions are met; conditions which are set out in other EU rules.  First, the donation, procurement and testing of cells comprised with the product must accord with the requirements of the Tissue Cell Directive (2004/23).  Second, clinical trials of all ATMPs must be conducted in accordance with the rules which are already applicable to gene therapy and somatic cell therapy medicinal products (Directive 2001/20) and with the Commission’s new good clinical practice guidelines.  Third, products must comply with the GMP Directive (2003/94) and the Commission’s new GMP guidelines for ATMPs.   Fourth, all constituent medical devices and active implantable medical devices of combined ATMPs must comply with the relevant directive (93/42 or 90/385) and the application for authorisation must include a description of the product’s physical characteristics, performance and design methods.

Marketing authorisation procedure

All other modern biomedical products currently regulated at a Community level are subject to a centralised authorisation procedure, involving a single scientific evaluation of the quality, safety and efficacy of the product, carried out to the highest standard by the European Medicines Agency (EMEA).  The Regulation makes this centralised procedure not only possible, but compulsory for ATMPs.

At a stroke, this opens up an entire EU market in ATMPs; a fantastic improvement on the present situation, made all the sweeter for SMEs and hospitals by half price authorisation fees.  In part, however, the requirement for the centralised procedure is an acknowledgment of the scarcity of relevant expertise; expertise which the Regulation concentrates in a new EMEA Committee for Advanced Therapies (“CAT”).  CAT will produce opinions on all applications to market ATMPs, which the EMEA’s Committee for Medicinal Products for Human Use (“CHMP”) must consider before giving approval.

As noted above, combined ATMPs are to be regulated, not only as ATMPs, but as one or more medical device or active implantable medical device. The EMEA makes its final evaluation for authorisation of such combined ATMPs by considering the whole product, with evidence of device conformity.

Post-Authorisation Requirements

Unlike conventional medicinal products, many ATMPs become part of the recipient’s body.  This demands the toughest standards of supervision; for example as regards data needed to demonstrate quality, safety and efficacy.  The traceability requirements introduced pursuant to the Tissue/Cell Directive are extended to ATMPs and bulked up with new Commission guidelines to ensure that the individual product and its starting and raw materials, including all substances coming into contact with the cells or tissues it may contain, can be traced through the sourcing, manufacturing, packaging, storage, transport and delivery to the hospital, institution or private practice where the property is used.  Demands upon the summary of product characteristics, package leaflet and labelling are also cranked up: immediate packaging must bear the unique donation code and product codes required under the Tissue/Cell Directive and, in the case of products intended for autologous use, the unique patient identifier and the statement “For autologous use only”.

Inevitably, pharmacovigilance standards required under the centralised procedure are also elevated; obliging ATMP applicants to provide details of the measures they envisage to ensure the follow-up of efficacy and adverse reactions.   If there is a particular cause for concern, the Commission may, on the EMEA’s advice, require systems to be set up to identify, characterise, prevent or minimise risk.  Alternatively, it can require specific post-marketing studies to be carried out.  However, to ease the burden, the EMEA will advise applicants and marketing authorisation holders on the design of such pharmacovigilance and risk management systems.

Incentives

Carrots are, indeed, a hallmark of the Regulation.  Standard EMEA product evaluation fees are cut by 90% for SMEs,- with a 65% reduction in other cases.  The EMEA will, on request, provide (through CAT) opinions as to whether candidate products fall within the definition of an ATMP.   The price is publication of the recommendations: although the EMEA delete confidential commercial information, many developers will want anonymity too.  SME developers may also submit quality and non-clinical data to the EMEA for scientific evaluation and certification, independent of any application for marketing authorisation.  Certification is not legally binding, but it is hoped that the system will ease applications for clinical trials and marketing authorisation using the same data.  Finally, the Regulation cuts in half the fees for marketing authorisation payable by SMEs and hospitals, provided they can prove that there is particular public health interest in the Community in the ATMP concerned.  The same reduction applies in respect of EMEA fees payable in the first year following the grant of marketing authorisation.

The hospital exemption

Having swept ATMPs into the control of the Medicinal Products Directive, the Regulation then exempts those that are “prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient”.  The manufacture of such products must, nevertheless, comply with the EMEA’s GMP standard and be authorised by the competent authority of the Member State[1], which must also ensure compliance with device legislation, good clinical practice, pharmacovigilance.   The requirements of cell donation, procurement and testing, and the rules as to traceability also continue to apply[2].

The embryo gap

Following bitter debate in the European Parliament, the ATMP Regulation provides a moral opt-out for states whose national legislation prohibits or restricts the use of “any specific type of human or animal cells” or the sale, supply or use of medicinal products containing, consisting of or derived from these cells.  Given the importance of embryos as providers of pluripotent cells, this appears somewhat inconvenient.  However, because the Commission has to publish the relevant legislation of all Member States, it effectively assures an accurate stem cell map for patients and business.  As therapies come on stream, “no” rated states will either mitigate their economic and humanitarian stigma with a glow of self-righteousness or change their tune.

The way forward

The ATMP provides new reasons to invest in regenerative and other advanced therapies.  For European businesses to flourish, however, they must also make headway with equivalent FDA regulations.  Increased transatlantic coordination on GMP matters between the FDA and EU national authorities may add a further economic  boost.   By 30 December 2012, the Commission will publish a progress report on the Regulation, with comprehensive information on each type of ATMP and a review of the scope of the Regulation, especially as regards combined ATMPs.

Julian Hitchcock

November 2008

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[1] In the UK, this is the MHRA.

[2] In the UK, this is the preserve of the HTA.

Men own their frozen sperm

In a recent case, Yearworth and others v North Bristol NHS Trust

, the Court of Appeal announced that developments in medical science now require a re-analysis of the common law's treatment of and approach to the issue of ownership of parts or products of a living human body.

Leading by example, the Court ruled that six men had ownership of sperm that they had ejaculated, but used a new line of reasoning to establish this, rather than relying on the old case law under which ownership of human body parts only existed if the body part had been subject to the exercise of work and skill which had changed its attributes (see Doodeward v Spence (1908) and R v Kelly and Lindsay [1999]).

The six men had all been diagnosed with cancer and, on the advice of the defendant NHS Trust's clinicians, agreed to undergo a course of chemotherapy. Having been told that the treatment might damage their fertility, they agreed to produce samples of semen prior to the start of their treatment on the basis that the hospital would freeze the sperm and store them for possible future use. Unfortunately, after the men had undergone the chemotherapy, the sperm storage system failed, causing the frozen sperm to thaw and (it was presumed by the Court) perish irretrievably.

The Court's rationale behind the decision that the men had ownership of the sperm was as follows:

1. By their bodies, the men alone had generated and ejaculated the sperm;

2. The sole object of the men's ejaculation of the sperm was that, in certain events, it might later be used for their benefit and although the men could not "direct" the use of their sperm, the absence of their ability to direct its use did not derogate from their ownership because, by its provisions for consent, the Human Fertilisation and Embryology Act 1990 ("the Act") preserved the ability of the men to direct that the sperm be not used in a certain way, so their negative control over its use remained absolute;

3. The Act recognised in the men a fundamental feature of ownership, namely that at any time they could require the destruction of the sperm; and

4. No person, whether human or corporate, other than each man had any rights in relation to the sperm produced.

Consequently the NHS Trust could be held liable for the tort of negligence and under the law of bailment when the sperm storage system failed. The law of bailment provided the men with a remedy for psychiatric injury forseeably consequent upon the breach.

It will be interesting to see if this case has a wider application to bodily generated materials (for instance, breast milk), and whether it does spark the re-analysis of living human body ownership called for.

Paul

Challenge to human-animal embryology denied

Challenge to human-animal embryology denied

As a follow up to Chris’s blog in April of this year, the High Court has now ruled that the Christian Legal Centre’s challenge to creating human-animal embryos for research purposes was “totally without merit”.

The Court heard that using human eggs for research purposes was expensive and they were in short supply.  Despite the Christian Legal Centre’s (CLC) arguments that the Human Fertilisation and Embryology Act 1990 (1990 Act) did not allow licensing of human-animal embryos, the Court decided that the Human Fertilisation and Embryology Authority (HFEA) had acted within its powers.

The Human Fertilisation and Embryology Bill 2008, which updates the definition of “embryo” to include hybrid embryos, had already received Royal Assent before the case was heard.  To then allows CLC’s challenge to succeed would have been somewhat ludicrous, knowing that it is Parliament’s intention to allow licences for such research to be granted even if at the time the 1990 Act came into force the hybrid embryo technology was unforeseen.

Bejal

The Embryo Grows Up

With the passage of the Human Fertilisation and Embryology Act 2008, the stem cell community is able to turn to more immediate challenges.  Julian Hitchcock of Mills & Reeve, who is also a Director of the East of England Stem Cell Network, reviews a domain whose time has come.

 

 

Introduction

The new Human Fertilisation and Embryology Act 2008, which reforms the 1990 Act of the same name, changes the law on embryo research rather less than the fuss might suggest.  True, research may now be licensed for purposes of increasing knowledge, not only of serious disease, but of other serious medical conditions; for example, neural trauma or tissue damage.  True, applications may now be founded for the purpose of developing treatments for such conditions; for example, studies into how stem cells transform into particular tissues may lead to methods for repairing and regenerating tissue lost to disease or trauma.  True, the Human Fertilisation and Embryology Authority (“HFEA”) may now grant licences when it is “desirable” to support such research; a purpose which would include the development of non-biological technologies.  Licences to alter the genetic structure of cells forming part of an embryo will also become possible.  These are all quietly significant advances, but the more controversial aspect, the legitimacy of creating embryos using both “animal” and “human” material, had already been accepted by the HFEA.  No, the significance of the new Act is not the enlargement of the research franchise or the statutory tidying-up, but the fact that it could all have been so different.  Precisely because these issues had to run the gauntlet of full-on Parliamentary debate, the 2008 Act provides the highest possible support for an area of immense economic importance: regenerative medicine.

 

 

Embryonomics

One law never changes: things fall apart.  Living longer is no answer: our aging bodies still wear out, surviving on a regime of pharmaceuticals and care.  The cost, already vast, is spiralling and the ratio of economically productive to economically dependent members of society is being turned on its head.  A technology which cured, rather than dosed, conditions such a Alzheimer’s, diabetes and blindness would, therefore, not only alleviate human suffering, but provide a solution of colossal economic significance to individuals, insurers and governments.  Indeed, the state with the most valuable regen patent ownership on its patch could effectively tax all the others.

 

 

It’s not all about embryos.  Many stem cells live in adults, and are of considerable significance, as the recent example of the Bristol windpipe clearly shows.  However, such “adult” cells lack the capacity of embryonically-derived cells to differentiate into any tissue type, for example, nerve cells.  Such “pluripotency” puts a premium upon embryo patents, notably on a group of patents, owned by the Wisconsin Alumni Research Foundation, concerning techniques for isolating human embryonic stem cells and the cells themselves.  WARF’s claims are so broad that, in effect, it guards an embryonic stem cell gateway, collecting royalties from all those who can afford to enter.  While WARF’s US patents were recently certified as valid, following concerted opposition, the corresponding European application was rendered invalid last week by the Enlarged Board of Appeal .  More significantly, however, the ruling expressly does not affect other stem cell patents in Europe.  The many related applications to inventions that do not directly involve the destruction of embryos are unaffected and, having sat on EPO ice for some years, may now proceed in the direction of grant; an ironic shot in the arm if ever there was one.

 

There is, however, a more fundamental problem with stem cell patents: they are just too short.  For all the headlines, the road to market for many therapies is harder and longer than that of any other medicinal product you care to think of.  So long, in fact, that the original patents may have expired by the time anything is sold: hardly a reason to invest in research.  Given the coincidence of economic benefit and investment need, voices within the stem cell community are calling for an international extension of term for therapeutic stem cell inventions.  The embryo squad, of course, will be waiting to do battle.

 

 

Beyond the embryo

Oddly, the entities that inspire so much debate are “embryos” more in law than biology.  Their elevation, following the majority advice of the Warnock Committee, was based upon their inherent human merit; their chimp equivalents remaining with the blastocyst hoi polloi.  The “embryos” from which stem cells are extracted are, therefore, little more than fertilised eggs, whose significance lies in their potential to change into different tissue types and which become useless if, before extraction, they actually do.  If they could develop sufficiently to suffer (which they can’t) they would be worthless.  The prospect of making “embryos” using animal egg shells (to compensate for a shortage of human eggs) added a frisson of Doctor Who to the HFE debate, but the truth is fairly mundane.

 

 

Nevertheless, the “embryo problem” lingers on, leading some to pray that pluripotent cells might be derived from an alternative source.  A year ago, in the midst of the House of Lords debate on the Bill, these prayers were answered by Shinya Yamanaka and James Thomson, using ordinary skin cells.  Lord Alton and his allies, apparently unmoved by a subsequent report that entire human embryos could be made from skin, pounced on the announcement, proposing an amendment that would permit the use of embryos only where the use of such ethics-free cells was impossible.

 

 

Alton’s amendment failed, but “iPS” cells are transforming the domain anyway, by providing a way to bypass WARF in areas such as drug testing and, possibly, in the clinic.  If the requirement of cancer genes to induce pluripotency can be eliminated, companies like Izumibio, which seek dominance in iPS patents, are heading for the money.  Some, however, see Yamanaka as betokening a deeper shift; from cells to the factors which determine their fate.  In the emerging patent landscape, inventions for producing pluripotent cells may wane before processes for transforming one specific cell type into another. Such epigenetic power may lie in relatively small molecules; the stock-in-trade of a business in desperate need of new products and imagination; the pharmaceutical industry.  Indeed, on the very day that the new HFE Act became law, Pfizer launched a new regenerative medicine unit in Cambridge; a development of at least equal significance.  Cambridge is home to the world’s leading epigenetics company, CellCentric, and some of its foremost epigeneticists.

 

 

From ethics to engineering

The drift toward regenerative reality will be brought home this month, with the coming into force of the European Advanced Therapies Regulation, under which tissue engineered products sitting in the gap between cell/tissue grafts and medical devices achieve medicinal product status.  The classification of such products, insofar as there were any, has tended to exercise regulators across Europe, with some states treating them as devices and others as medicinal products.  This was unlikely to enhance the prospects of a young industry with more than enough challenges to face, but the Regulation changes everything: by centralising (under the European Medicines Agency) the marketing authorisation of genetic-, cellular- and tissue engineered products,  discounting fees, offering opinions on whether they fall within the requisite definition, providing scientific advice and support from a newly convened expert committee and to some extent exempting hospitals.  The market scalability, which the Regulation promises, provides a singular boost to the development of increasingly complex products, from windpipes, bladders, joints and jaws to synthetic pancreases and regenerate lung, retina and heart tissue.

 

 

The ethical issues haven’t gone away: the Regulation will be subordinate to national legislation prohibiting or restricting the use of human embryonic stem cells, or the sale, supply or use of medicinal products containing, consisting of or derived from them.  Until advanced therapy products involve embryo-related cells, the European market should remain uniform.  Thereafter, more sophisticated therapies, notably in relation to the nervous system, may only be available in states such as the UK.

 

 

By providing reassurance that moral issues are being handled responsibly, the 2008 Act allows a shift towards the practical, from ethics to engineering, with growing attention to good manufacturing practice and the need for closer transatlantic coordination on regulatory approval.  The problems are mighty and our new laws are bound to date quickly.  Nevertheless, the sense of progress is palpable.

 

 

 

Julian Hitchcock

julian.hitchcock@mills-reeve.com

+44 [0]1223 222545

 

© Mills & Reeve 2008

 

 

Research under the Human Fertilisation and Embryology Act 2008

The new Human Fertilisation and Embryology Act, which entered the statute book on November 13^th, reforms the 1990 Act of the same name so as to extend the subject matter of legitimate in vitro embryo research, and the purposes for which licences may be granted by the Human Fertilisation and Embryology Authority (“HFEA”).

Subject matter

Besides conventional human embryos, it will also be possible to conduct research on “human admixed embryos”; a class which comprises:

·         cytoplasmic hybrids (also known as “cybrids”), which are created by removing the nucleus of an animal egg cell and replacing it with one from a human;

·         true hybrids, which are created by combining human gametes (i.e. egg or sperm) with animal gametes;

·         human transgenic embryos, which are created by introducing animal DNA into one or more cells of a human embryo.  This encompasses both nuclear and mitochondrial DNA; and

·         human animal chimeras, which are created by adding animal cells to a human embryo.  A chimera is an organism comprised of cells from two or more genetically different organisms.  A mouse-mouse chimera might, for example, be made by adding stem cells from a sandy-coloured mouse to the developing embryo of a black mouse.  The resulting mouse is perfectly normal, but remarkable in having two genomes.  In this example, the chimeric mouse might have black and sandy fur.

Licences to alter the genetic structure of cells forming part of an embryo will also become possible.

Purposes of research

The 2008 Act continues to make an important distinction between a project of research and the purpose of that project.  The basic rule remains that use of embryos (or, now, human admixed embryos) must be necessary for the purposes of the proposed research project.  However, because the number of legitimate purposes has been extended, the range of potential research projects has grown.

Under the 2008 Act, research may be licensed for purposes of increasing knowledge, not only of “serious disease”, but also of “other serious medical conditions”; for example, neural trauma or tissue damage.  Applications may also be made for the purpose of developing treatments for such conditions.  For example, studies into how stem cells differentiate into particular tissue types could lead to methods for repairing and regenerating tissue lost to disease or trauma.  Significantly, the HFEA may now grant licences for projects to yield knowledge which it considers to be “capable of being applied for” such purposes.  These might be dubbed “enabling licences”, in that they enable embryos to be used in the development of technologies, which need not be biological,  relevant to laboratory or clinical research.

The new provisions will come into effect with the passage of  a Commencement Order.  We cannot say when this will appear, but know of no obvious reason for its delay.

The great significance of the 2008 Act is less the enlargement of the research franchise or the statutory tidying-up, but the fact that it could all have been so different.  Precisely because these issues ran the gauntlet of full-on Parliamentary debate, the Act provides the highest possible support for the ethically responsible development of regenerative medicine in the United Kingdom.

______________________________________________________________________

This note summarises a complex area of law and cannot be regarded as complete.  For further information, speak to Julian Hitchcock –[44][0]1223 222545, Julian.hitchcock@mills-reeve.com

Stem Cell Windpipe: proof of concept for UK manufacturing

The news reported today, about the creation and implantation of an artificial windpipe, is great for UK stem cell research and demonstrates strongly how important international collaborations are.  An interesting aspect is that the completed organ was constructed off-shore; ie in the UK.  Crucially, it is a wonderful proof of concept of UK cell and tissue manufacturing capacity and its ability to export organs which are actually "autologous"; i.e. made from the patient's own cells.

 

The technology has immense potential to increase the health, wealth and employment of UK citizens.  However, for this potential to be met, the law needs its own "scaffold".  With great good timing, the new European Advanced Therapies Medicinal Products Regulation, which comes into force next month, provides exactly this.  It dramatically opens up a new market in products such as the one used in this European project.

 

Despite recent advances, autologous stem cells cannot yet safely produce the range of tissues which may be derived from embryonically-derived cells; notably, nerve cells.  Under the "moral opt-out" of the ATMP Regulation, national laws concerning particular sorts of cells (essentially embryonic cells) will remain unaffected by overall authorisation to market products in Europe.  As embryo-based therapies come on line, they will not be available in certain territories, with the effect that, for example, therapies in connection with blindness, Alzheimer's and nerve repair, will be unavailable there.  As governments weigh up healthcare costs against the costs of stem cell therapy, we might expect pressure to grow on them to change their laws.

 

Julian

Human Tissue Authority Consultation on Codes of Practice

On 1 August, the Human Tissue Authority (HTA) launched a public consultation on its revised Codes of Practice. The Codes relate to the removal, storage, use and disposal of human tissue and organs.  Their aim is to give practical guidance and lay down standards.

Besides revisions to existing Codes, the consultation includes a new Code on research (Code 9).  This is directed at all those who store human tissue for research.  It covers areas the licensing and consent requirements for both living and deceased donors, as well as provisions governing the use of cell lines and stem cells, including their use in clinical trials.

Another newcomer, first published in May, is Code 8.  It concerns the import and export of human bodies, body parts and tissue.  Code 8 is not under consultation at this stage.

Failure to comply with a codes of practice is not of itself a criminal offence, but the non-compliant act may be an offence under the Human Tissue act 2004.   Even if there is no offence, non-compliance with a Code may be taken into account when reviewing licences.

Comments are welcome on any part of the draft Codes, but the HTA has asked some specific questions including:

• whether the codes clear and comprehensible;
• whether the codes provide a broad framework of guidance rather than a detailed prescription;
• whether there is a clear enough distinction between what must be done and what is good practice; and
• whether the examples of best practice are helpful in illustrating the guidance.

The consultation may be completed on-line.  Visit the Human Tissue Authority website (www.hta.gov.uk) for more details, or click here.  The consultation closes on 14 November 2008

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MHRA Public Consultation on Advanced Therapy Medicinal Products

The Medicines and Healthcare products Regulatory Agency (MHRA) has launched a public consultation to gain public and industry input on the UK’s “hospital exemption” scheme under the 2007 European Advanced Therapy Medicinal Products Regulation. The MHRA is also consulting on changes to the “Specials” regime in connection with Advanced Therapy Medicinal Products.

What is an ATMP and why is it important?

An Advanced Therapy Medicinal Product (ATMP) is one of, or a combination, of a “gene therapy medicinal product”, a “somatic cell therapy medicinal product” and a “tissue engineered product”. The Regulation sweeps all these sophisticated products into a European legal regime that is primarily concerned with pharmaceutical products; that of the 2001 Medicinal Products Directive. However, the scientific, regulatory and economic issues concerning ATMPs mean introduce issues which go far beyond those which are relevant to conventional pharmaceutical products, or even biosimilars. One effect of the Regulation is therefore to make significant amendments to the Medicinal Products Directive.

The “hospital exemption”

As science accelerates into the future, the law which regulates it is often left languishing in its tail lights. The exemption under Article 28 (2) of the ATMP Regulation aims to provide some flexibility from general regulatory requirements so as to accommodate small scale and developmental research in hospitals.

Under the Regulation, there is an exemption for ATMPs which are prepared on a non routine basis and used within the same Member State in a hospital under the professional responsibility of a medical practitioner in order to comply with an individual prescription for an individual patient.

The hospital exemption applies only to ATMPs prepared on non-routine basis and used within the same Member State, according to specific quality standards and used in a hospital under the professional responsibility of a medical practitioner in order to comply with individual prescription for a specific patient.

ATMP manufacturers must be authorised by the competent authority of the relevant Member State: in the UK, this is the MHRA. As such, the MHRA is required to “ensure that national traceability and pharmacovigilance requirements as well as the specific quality standards…equivalent to those provided for at Community level” are met.

When the Regulation comes into force at the end of this year, applications for marketing authorisations for ATMPs will be brought under a centralised procedure in which a centralised European authorisation is granted by the European Commission following assessment by the European Medicines Agency (“EMEA”). Under the exemption, therefore, traceability and pharmacovigilance need to be equivalent to ATMPs for which a centralised marketing authorisation would be granted by the European Medical Agency.

The “Specials” scheme

“Specials” are unlicensed medicinal products ordered and used by an authorised healthcare professional to meet the special needs of specific patients, supplied in response to a bona fide unsolicited order. They are permitted, as a derogation from the general law on medicinal products, by Article 5(1) of the Medicinal Products Directive. As such, the “Specials” scheme is similar to, but distinct from, the “hospital exemption”. Specials that are not ATMPs will not be affected by the new proposals.

The MHRA’s oproposals for the hospital exemption and specials scheme

Although Regulations are directly effective in each Member State (i.e. they need no implementing legislation), states are required to implement the hospital exemption using domestic arrangements. In the UK, responsibility is again placed on the shoulders of the MHRA. It is therefore consulting stakeholders to formulate how best to implement the exemption here.  Here are some of its proposals.

Good Manufacturing Practice (“GMP”) – GMP plays an important role in the hospital exemption, as the ATMPs must be manufactured to a particular standard under licence from the MHRA. The role of the MHRA would be granting manufacturer’s licences for unlicensed products and inspection for compliance with GMP standards.

Pharmacovigilence – It is proposed that the pharmacovigilence requirements for the hospital exemption would cover notification of adverse reactions. It may provide the MHRA with the ability to ask for a risk management plan. Such a request may be made at the time the manufacturer seeks a licence from the MHRA.

Traceability – It is proposed that there must be traceable records of donors to the point of dispatch to the organisation using the ATMPs. The end user would be required to keep records of the receipt of the materials until its destruction.

Patient information/labelling/advertising – The proposals are aimed to reflect the potentially high risk nature of ATMPs.

Ethical issues – It is proposed that, provided that the treatment does not involve xenotranplantation, it would not require the approval of a research ethics committee. Clinical ethical issues would be governed by the particular NHS trusts’ clinical governance arrangements. The Gene Therapy Advisory Committee (“GTAC”) may also be called upon to provide ethical advice to medical practitioners on the use of gene therapy and stem cell-derived products.

Additional requirements – The Regulation sets minimum standards, but Member States may set a higher bar. The MHRA suggests that the test for such additional requirements would be if the measure was:

• necessary to protect the public,
• consistent with the purpose of the hospital exemption
• necessary on the grounds of ensuring clarity of the regulatory arrangements

What Next?

The ATMP Regulation enters into force on 30 December 2008. It is envisaged that the exemption will be implemented on the same date.

The deadline to submit a response to the consultation is 15 October 2008.