Australia’s Therapeutic Goods Administration has issued an update on its overhaul of the regulatory framework for complementary medicines — also known as ‘traditional’ or ‘alternative’ medicines including vitamins, minerals, herbal, aromatherapy and homeopathic products. With these reforms the TGA aims to improve public confidence in the safety and quality of these medicines.

At the moment the regulator is consulting on Part C of the proposed new Australian regulatory guidelines for complementary medicines (ARGCM) regarding evaluation of complementary medicine substances for use in listed medicines. Comments are due by 14 May 2013.

The TGA plans to launch another consultation on the registration process for complementary medicines (Part D) in May/June 2013.

It has already sought public comment on Part A, which provides an overview of the regulatory framework for therapeutic goods in Australia, and Part B, which covers the regulation of ‘low-risk’ complementary medicines. Once all feedback has been received, the ARGCM parts will be consolidated into a final revised document, replacing the existing Parts I-V, which were first published in 2001.

The TGA also held a consultation on permitted (coded) indications, which closed on 15 March 2013.

A table with all the reform timeframes and developments can be found here.

Regulatory convergence with New Zealand under ANZTPA?

Although Australia and New Zealand have once again begun working towards a joint regulatory framework for therapeutic products, New Zealand is introducing a separate scheme to regulate ‘natural health products’. In fact, a second reading of the proposed Natural Health and Supplementary Products Bill took place in New Zealand’s Parliament on 20^th March.

The bill would create a Natural Health and Supplementary Products Regulatory Authority to oversee the pre-market notification, but not pre-approval, of products. To bring a product to market a ‘notifier’ would have to:

• tell the authority what the product contains; the ingredients would have to consist solely of substances from an open-ended list of permitted ingredients
• have either scientific evidence or evidence of traditional use to back up any claims of health benefit being made for the product (the regulator will publish a list of conditions that sellers will be able to make claims about)

A list of forbidden ingredients that will include prescription medicines and controlled drugs will also be published.

One of the main reasons that the first attempt at creating an Australia New Zealand Therapeutic Products Authority (ANZTPA) broke down in 2007 was because stakeholders in New Zealand were opposed to having a pharmaceutical-style regulatory regime imposed on the complementary medicines sector.

When the ANZTPA has been in place for five years, New Zealand will re-evaluate whether it would be better to include the regulation of natural health products under the joint system.

I never expected a dog show to be the inspiration for my next post, but nevertheless, that is exactly what has happened. When I switched on the TV recently, I was presented with Daisy the medical detection dog (MDD), a retriever who can sniff out cancer with striking reliability.

Can a dog be CE marked?

Being regulatory minded, I wondered whether Daisy and other MDDs were actually being used in the clinical setting and if so, were they regulated as traditional diagnostics? It seems a ridiculous question ‒ after all, how can a dog be CE marked? I still felt compelled to look into it, so I contacted the Medicines and Healthcare products Regulatory Agency, the UK regulatory authority for medical (in vitro) diagnostic tests. An MHRA spokesperson said: “[I] am sure these dogs would not come under our regulation. This is not something that I am aware has come to us in the past… [it] is not something we are looking at.”

Likewise, when asked whether these dogs were being used in the National Health Service, a Department of Health spokesperson told me: “I’m afraid this is not something that NICE [the National Institute for Health and Care Excellence] is involved in.  As you know, NICE produces guidance, standards and information on health and social care.”

The science behind the sniffers

The science behind the dogs’ ability to detect the odour of cancer is believed to be linked to Volatile Organic Compounds produced by malignant cells, according to Medical Detection Dogs (aka Cancer and Bio-detection Dogs), the charity that trains the dogs and carries out research with them. “It has been established that during tumour growth protein changes in these cells which leads to peroxidation of the cell membrane components and this produces Volatiles that can be detected in the headspace of the cells,” the charity explains.

Where do we go from here?

In an interview with the BBC, Medical Detection Dogs chief executive Dr Claire Guest said that the research is at a very early stage and the next step would be a clinical trial with samples from local hospitals. She suggested that understanding how the dogs are able to detect the disease could pave the way for the development of an ‘electronic nose’ in future.

The charity was unavailable for comment in this post, but it has previously said that it has been trying to get government funding for some time now, with no success. Perhaps this is because it would be impossible to regulate these as ‘diagnostics’ in the traditional sense. It would be a shame that such a promising potential for early cancer diagnosis may never get off the ground due to regulatory limitations, especially when it could lead to technology that could easily carry a CE mark.

The Italian Medicines Agency, AIFA, is enhancing its scientific and regulatory activities by establishing six new advisory committees covering major therapeutic areas.

The committees will contribute to the work of the agency’s technical scientific commission (CTS) and its pricing and reimbursement committee (CPR) by carrying out evaluations and providing opinions on regulatory and scientific matters.

Conflicts of interest considered

AIFA notes that it has followed conflict-of-interest rules in establishing the committees, which will each be comprised of seven members (maximum) who are leading clinical experts in their fields. The therapeutic areas are:

• Cardiology
• Neuroscience
• Endocrinology
• Paediatrics
• Primary care
• Oncology

To contain costs and streamline procedures, the committees will generally hold their meetings via video conference; only on occasions of particular importance will meetings take place at AIFA headquarters.

The UK complementary medicines sector could take a hit from critics such as The Nightingale Collaboration following recent cases involving product contamination and misleading advertising.

Contaminated Chinese medicines

The UK medicines regulator, the MHRA, has issued a warning about several Chinese herbal medicinal products that were found to contain heavy metals:

• [W.S.] Tian Ma Toutong Wan, promoted for relieving headaches
• Shi Hu Ye Guang Wan (Ye Guang Wan) and Nai Chang Ming Yan Pills (Ming Yan Pills), promoted for improving vision in adults
• [Fung Shing Pai] Tian-Ma Wan, promoted for relieving arthritic symptoms and headaches
• Bak Foong Pills, promoted for relieving menstrual discomfort

The agency advised consumers not to use the medicines after the Hong Kong Department of Health warned that specific batches contained excessive levels of lead or mercury, which can pose serious health risks if ingested. The MHRA noted that Tian Ma Toutong Wan also contains Aconitum, a herbal ingredient that is prohibited for internal use in the UK.

This follows an MHRA announcement in January that a number of “natural” slimming products labelled in English and Chinese contained sibutramine, which was withdrawn from the EU market in 2010 due to the increased risk of heart attacks and strokes.

Homeopathic remedies advertised as ‘vaccines’

Earlier this year, the MHRA ordered homeopathic pharmacies Ainsworths and Helios to stop advertising a number of their products as alternative treatments to proven conventional vaccines. The agency also sent a warning letter to Homeoforce, which was selling similar products.

The issue was uncovered in an investigation by BBC Inside Out South West, which was followed by a BBC News article on the matter. According to the article, the pharmacies were selling vials of pills labelled Meningitis Vac Hib, Measles Vaccine, Rubella Vaccine, Pertussin and Pertussis (Whooping Cough) Vaccine.

The inclusion of patients in drug development and regulatory decision making has been steadily increasing over the past several years. Various initiatives have come from a range of stakeholders including regulators, pharma companies and academia. This has been a progressive step in the right direction, but there are many people (most notably, patients!) who believe that even more needs to be done to actively engage patients in all stages of drug development so they can truly benefit from the medicines they take.

One could say that health technology assessment (HTA) bodies, in their push for patient-based evidence, have been the impetus for change. HTA bodies inform decision makers on whether new drugs should be made available in healthcare systems; however, they are often lambasted for creating obstacles to market access. This is because once a medicine is approved for marketing, HTA bodies – more often than not – seek additional evidence that the drug will really provide value to patients before they will recommend its reimbursement on national healthcare systems.

It’s difficult to obtain all the data these HTA bodies are looking for from clinical studies because, by their very nature, the studies are not carried out in a “real-world” healthcare setting. Hence, they seek real-world evidence from sources including observational studies, databases, registries and patient-reported outcome measures, which traditionally have not been part of the drug approval process.

This gap between the data regulators use to approve a product for marketing and that which HTA bodies need in order to recommend the go-ahead for reimbursement  delays patient access to innovative products and increases costs for pharma companies…resulting in criticism from all corners.

Convergence of thinking as regulators realise that patients are the key

Finding a way to resolve this disconnect between the evidence needed for a drug’s approval and reimbursement has become a HUGE issue. Nobody is benefitting from the status quo, least of all the patients. To address this, regulators worldwide are inching their way towards a more “HTA” way of thinking in terms of the need for real-world evidence, and they recognise that this comes largely from an increased focus on the end users themselves. In some countries, patient involvement in the drug development and approval process is even being mandated by legislation.

In the US, for example, the Prescription Drug User Fee Act (PDUFA V), which was reauthorised last July as part of the Food and Drug Administration Safety and Innovation Act (FDASIA), explicitly states that the health secretary “shall develop and implement strategies to solicit the views of patients during the medical product development process and consider the perspectives of patients during regulatory discussions”. Under PDUFA V, the FDA has also committed to providing “a more systematic and expansive approach” to involving patients in the drug review process. To this end, the agency has, among other actions, launched the Patient-Focused Drug Development initiative to get input from patients on specific diseases where little is known about the burden of the disease or where outcome measures to determine benefit are lacking.

Moreover, the President’s Council of Advisors on Science and Technology (PCAST) emphasises that patients should play a central role in drug development and evaluation. For example, in its September 2012 Report to the President on Propelling Innovation in Drug Discovery, Development, and Evaluation, PCAST calls for patient involvement in a new Partnership to Accelerate Therapeutics aimed at promoting “innovation and improvement in the discovery, development, and evaluation of new medicines for important public health needs”.

A senior official at Health Canada recently told me that Canadian lawmakers will also be focusing squarely on the patient as they overhaul the entire legislative framework for pharmaceuticals, beginning with the new approval pathway for orphan drugs. As for Health Canada itself, the regulator is listening to patients more than ever to ensure drug reviewers consider “clinically meaningful” evidence of a drug’s benefits and harms (they are phasing out the term “risk”) – it’s all about being socially responsible, the official explained.

The European Medicines Agency (EMA) already includes patient representatives in certain scientific committee meetings, but the agency acknowledges that it needs to do more. In its Roadmap to 2015, the EMA says that one of its main objectives is to improve the decision-making process by taking into account patient experience. This is expected to help optimise the safe and rational use of medicines.

The European Commission is also keen to make sure patients are well informed so they can have a voice in drug development and eventual commercialisation. One example of its efforts in this regard is the European Patients’ Academy on Therapeutic Innovation (EUPATI), a project the Commission is funding along with the European pharmaceutical industry federation, EFPIA. Under the patient-led initiative, which runs from 2012-2017, a 29-member consortium will develop training courses, educational material and an online public library that will empower patients to engage more effectively in the development and approval of new treatments.

The theme of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 18^th Annual International Meeting bears testimony to this trend. “Patient-Centered Outcomes: Focusing on the Patient” is scheduled for 18-22 May 2013 in New Orleans, LA, USA, and will feature three plenary sessions:

• Finding the patient in health research and policy
• Finding the patient in the drug development process
• Assessing the evidence for better patient care: A health care decision-maker toolkit

The programme for the first plenary states: The new buzz words are ‘patient-centered’ and ‘patient-focused’. Why is the focus on the patient? Why wasn’t the focus on the patient before now?

That is precisely what I’d like to know, too.

Three new papers published by the Global Medical Technology Alliance highlight how the industry’s challenges are different to those facing the pharmaceutical industry.

• HTA Position Paper: explains why applying health technology assessment to medical devices is difficult and why adopting a pharmaceutical paradigm, based on an expectation of multiple randomised controlled trials being available at the time of launch, may lead to restrictions on access to many new medical technologies; calls on HTA bodies to recognise a device-specific assessment paradigm.
• Differences between medical devices and drugs: a table that compares medical devices, in vitro diagnostics (IVDs) and drugs with regard to, for example, product development and intellectual property concerns.
• Patents for Medical Devices and Pharmaceuticals – Summary of Key Differences: published in response to numerous requests about how patents are applied to medical devices and the differences in their use as compared with pharmaceuticals.

The GMTA represents more than 20 national and regional medical technology associations whose members supply over 85% of the medical devices and diagnostics purchased annually around the world. Among other objectives, it develops and disseminates information on international medical technology policies and issues. It also co-ordinates common policy positions for effective representation of the medical technology industry at a global level.

Europe’s Innovative Medicines Initiative Joint Undertaking (IMI JU) recently announced that it intends to set aside up to €8 million to fund a three-year public-private research project on incorporating real-life clinical data into drug development. In a webinar on 2^nd August, GlaxoSmithKline’s Chris Chinn explained why this research is sorely needed.

There is a “significant level of uncertainty around the development of medicines”, he said, particularly during the periods just before and just after marketing authorisation when there is a “critical point of interdependency” between the company and the regulator. These uncertainties are both operational and analytical in nature.

Mr Chinn said that the aim is not to challenge the evidence required of sponsors, but to increase the value and quality of that evidence – real-world evidence – to introduce more certainty into the R&D decision-making process when considering alternative development strategies and regulatory approval options.

Key objectives of the project are:

• Improving the quality of information available to inform both benefit-risk and real-world effectiveness at critical points in the assessments of medicines
• Guiding how and when relative effectiveness research can be incorporated into R&D drug development plans
• Increasing the confidence that Health Technology Assessment (HTA) bodies and other decision makers have in the assessment of the value of new medicines, and the consistency of decisions affecting patient access
• Bringing together insights from/provide a scientific platform for related initiatives in EU and US
• Creating a greater understanding in R&D of the importance of relative effectiveness in defining the ultimate value of new medicines to patients and providers
• Identifying and overcoming operational difficulties associated with generating evidence of relative effectiveness before launch
• Improving the scientific basis of discussions/decisions between industry, regulatory authorities, and HTA and reimbursement agencies on: reasonable expectations for evidence available at launch; the robustness of predictive models; and the value of further evidence collected after launch

For this project a multi-disciplinary grouping will be required to enable effective communication between key stakeholder groups (international academia, regulatory agencies, HTA bodies, reimbursement agencies, healthcare budget holders, and patient groups). Moreover, it should be pan-European in nature to ensure frameworks and procedures developed through the course of the project are relevant for a broad range of European countries.

Expressions of interest for this project (Stage 1 of the IMI’s 7^th Call 2012) are due by 9 October 2012. See http://www.imi.europa.eu/content/stage-1-5 for full details. At Stage 1, applicant consortia may include research organisations, universities, small and medium sized enterprises (SMEs), patient organisations, and any legal entity which is not a pharmaceutical company that is a member of the European Federation of Pharmaceutical Industries and Associations (Efpia).

The IMI JU is a pan-European public-private partnership between the European Commission and Efpia aimed at driving (pre-competitive) collaboration between all relevant stakeholders. The goal is to introduce a co-ordinated approach to overcoming identified research bottlenecks in the drug development process.

Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) is working to improve the speed and efficiency of its review systems. One way it is doing this is via its new Science Board, which met for the first time on 18^th June and is due to hold its second meeting on 31^st July.

At the inaugural meeting, the board set up several subcommittees in the following areas:

• pharmaceuticals
• medical devices
• biotechnology
• cellular and tissue-based products (regenerative medicinal products)

The board was established in May 2012 as a high-level consultative body comprised of external experts from the medical, dental, pharmaceutical and engineering fields. In line with its focus on regulatory science, the PMDA hopes that closer collaboration with the academia and healthcare professionals who make up the board will help PMDA reviewers keep up with the latest scientific and technological advances. This, the PMDA hopes, will ensure they can “provide sound advice and guidance” quickly and efficiently.

Tatsuro Irimura, a professor at the University of Tokyo’s Faculty of Pharmaceutical Science, chairs the board; Kazuhiko Yamamoto, a professor at the university’s Graduate School of Medicine and Faculty of Medicine, is vice-chair.

The creation of the board is part of the PMDA’s Five-year Strategy for Medical Innovations, which aims among other things to increase the number of reviewers and safety staff (including those responsible for regenerative medicinal products).

Japan has been under mounting pressure from other countries to eliminate its “drug lag”, ie its approval of new drugs is several years behind that of other countries.

Well, it’s final: The Anti-Counterfeiting Trade Agreement, ACTA, has been rejected by the European Parliament in a 478-39 vote (with 165 abstentions). A statement by Parliament said: “While debating [on] whether to give its consent to ACTA, Parliament experienced unprecedented direct lobbying by thousands of EU citizens who called on it to reject ACTA, in street demonstrations, e-mails to MEPs and calls to their offices. Parliament also received a petition, signed by 2.8 million citizens worldwide, urging it to reject the agreement.” It will be interesting to see whether this latest development renders invalid the outstanding Court of Justice case on ACTA’s compatibility with EU law.

Separately, in a first reading on 3^rd July, Parliament voted in favour of a proposed EU regulation on customs enforcement of intellectual property rights, meaning the draft legislation now goes to the Council for a first reading. When finalised, the legislation will revise Regulation (EC) 1383/2003 in order to strengthen the enforcement of IPR by customs authorities as well as to improve legal clarity, adapting the provisions of the regulation to new developments.

See Parliament’s vote on EU patent law delayed, but IPR law and ACTA remain on agenda for more information on these topics.

The European Parliament’s vote on proposed legislation for a unitary EU patent system that was due to take place on 4 July has been postponed at the 11^th hour after the European Council concluded that three key articles (6-8) should be deleted from the text:

• Article 6 – Right to prevent the direct use of the invention
• Article 7 – Right to prevent the indirect use of the invention
• Article 8 – Limitation of the effects of the European patent with unitary effect

Rapporteur Bernhard Rapkay requested the delay, saying that the Council had pledged in December 2011 to approve the law as it then stood, provided Parliament did the same. MEP Klaus-Heiner Lehne backed the request, stressing that deleting articles 6-8 would “emasculate” the proposals.

In a press release on 29 June, the Council victoriously announced its conclusion of negotiations on the EU’s future unitary patent system, hailing it as “a historic breakthrough” because the last outstanding issue – ie the seat of the Unified Patent Court’s Central Division of the Court of First Instance – had been resolved. (It will be based in Paris and have two specialised sections, one in London and the other in Munich.)

“The long-awaited decision paves the way for establishing less expensive, simpler and more efficient patent protection for businesses, especially for small and medium-sized enterprises, in the EU,” the press release said. But it kept quiet about the suggested deletion of Articles 6 to 8.

The quest for a common EU patent has spanned over decades and there had been much excitement about Parliament’s upcoming vote. The goal is to have the system up and running for a first unitary patent registration on 1 April 2014. It remains to be seen whether this latest development will impact that timeline.

Hopefully this news won’t overshadow two other important IPR-related votes that are still going ahead this week, and which will have an impact on the pharmaceutical industry:

• 3 July: vote on a new regulation to strengthen customs actions in fighting trade of IPR-infringing goods (to revise Council Regulation (EC) No 1383/2003, which has been in effect since 2004). The new rules would set down procedures enabling customs authorities to stop suspected goods, but deciding what infringes intellectual property rules would continue to be defined by EU and national legislation. A report by MEP Jürgen Creutzmann on the matter expresses concern that the measures could obstruct the legitimate trade in generic drugs between non-EU countries. It also calls for a Commission analysis of the effectiveness of current customs measures aimed at combating trade in falsified medicines.
• 4 July: vote on the controversial Anti-Counterfeiting Trade Agreement (ACTA) intended to address commercial-scale counterfeiting and online piracy by co-ordinating global enforcement of existing intellectual property protection laws. MEP David Martin is recommending that Parliament reject it; he believes the text is too vague on individual criminalisation, the definition of “commercial-scale”, the role of internet service providers and the possible interruption of the transit of generic medicines. He says this could lead to unintended interpretations of the agreement.