Wednesday, 14 October 2015

Do regulators have a role in pharmaceutical innovation?

The prime drug development regions of the world remain the US, Europe and Japan and to a large extent, these countries have harmonised many of the regulatory requirements. For example, ICH-GCP is now considered as the global standard for clinical trials and has become a legal requirement in many countries. As well as standardising and harmonising regulations, US, European and Japanese regulators have also publicly acknowledged that part of their mission is to support medical innovation.

All three regulatory agencies believe that medical innovation can be stimulated through the discipline of regulatory science and are increasing their collaboration with each other. Regulatory science involves the use of improved regulatory tools, such as new methods, models or technologies, to overcome barriers in translating research into real products so that new medicines can be made available for society. This requires collaboration between different specialist groups within the regulatory agencies and between agencies so that appropriate expertise can be harnessed for different regulatory scenarios. It also involves better communication so that stakeholders understand how a decision was reached and its implications for other drugs in development.

One area in which this regulatory input has been apparent has been the introduction of orphan drug legislation to stimulate drug development for rare diseases. Previously, due to the low potential for financial return on R&D investment there had been little interest from pharmaceutical companies in developing products for this area. This regulatory framework, which has been adopted in the US, Japan, EU and other regions, has transformed R&D for rare diseases, and many patients have benefited. Although the details and benefits of orphan drug legislation vary between regions, there is general consensus that many orphan drugs would not have been developed without appropriate legislation.

Initiatives to improve the regulatory framework and stimulate innovation are continuing, with the major regulatory agencies actively collaborating with industry, government, academia and other stakeholders. In March 2004, alarmed by the decline in the number of innovative medical products being submitted for approval, the FDA created The Critical Path Initiative. The Initiative represented a national US strategy to drive innovation in the scientific processes through which FDA-regulated medical products were developed, evaluated, and manufactured. In 2003, the EMA set up the Innovation Task Force (ITF) and brought together relevant competencies from different parts of the Agency. The Agency also launched a consultation process with industry and other stakeholders concerning bottlenecks and redundant or irrelevant requirements perceived as holding back innovation.

While the regulators’ primary role is to ensure patient safety, it is clear that they want to be seen as playing an active role in promoting innovation. New collaborative initiatives with stakeholders are emerging and there are a number of opportunities for more companies to get involved.

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Thursday, 17 September 2015

How can clinical trials better reflect local priorities?

Clinical trials are valuable as they have the potential to reduce disease burdens by helping developing safe and effective new therapies and vaccines. Although they are conducted in many countries around the world the local benefits are not guaranteed.

For example, although so-called emerging markets are routinely included in global clinical trial programmes, the focus is primarily on the disease of interest to the international sponsor and may not necessarily reflect local priorities. While some non-governmental organisations (NGOs) do conduct clinical studies with local partners that are focused on diseases reflecting urgent local needs, these trials represent a minority of trials in emerging markets.

Imbalances certainly exist between the burden of disease in emerging regions and the types of trials in these locations, indicating that certain diseases are being under-investigated relative to their morbidity and mortality. A recent study of randomized trials published in the PubMed database found little association across disease areas between burden of disease and the quantity of randomized trials. The findings strongly suggested that clinical trials being conducted in low income regions were less suited to local healthcare needs than are those conducted in high income regions.

A continuing problem in aligning clinical trials with public health priorities is that little reliable information exists on how much different countries are spending on health and disease-related R&D. One ambitious idea proposed by WHO is the Global Observatory for Health R&D platform. The project is being planned and developed in a phased approach and its success depends on attracting sufficient funding and support from WHO member countries and organisations involved in international healthcare. 

This ambitious plan does have a number of obstacles standing in its way. For example, the platform will be designed to build on existing sources as much as possible. However, since existing sources in many countries are limited, technical support will be needed for the countries in order to establish a system to monitor national R&D investments and pipelines. This means openly acknowledging the considerable gaps that exist in the capacity of many partners to produce this data. An initial estimate is that the Global Observatory for Health R&D platform will require $11.5 billion to be developed and run for the first 5 years. At present it is unclear who will fund the necessary projects, and this means that any proposed timelines must be viewed with caution.

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Thursday, 13 August 2015

Progress at EMA for more public representation

Since one of the European Medicines Agency’s roles is to ensure that medicines are developed for the benefit of public health, it has been keen to involve patients and other stakeholders in its work wherever possible. Most of the Agency’s scientific evaluation work is carried out by its scientific committees, which have various tasks related to the development, assessment and supervision of medicines. The members of these committees are nominated by the Member States or the European Commission. 

Recently, there has been a new drive to feature more Civil Society involvement in the Agency’s work. The European Commission has launched a selection procedure to appoint representatives of the public to the Management Board of the EMA. The aim is to have two members representing patients’ organisations and one member representing doctors’ organisations. These Members will be appointed for a renewable period of three years. The deadline for expressions of interest to represent civil society at PRAC and CAT to be submitted to European Commission was set for 30 September 2015.

The main impact will on the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) and the Committee for Advanced Therapies (CAT). PRAC’s main role is to assess all aspects of the risk management of medicines for human use and it meets once a month. CAT’s responsibility is assessing the quality, safety and efficacy of advanced-therapy medicinal products (ATMPs) and following scientific developments in the field. The multidisciplinary nature of CAT’s work means it must draw upon experts from different scientific areas. Like PRAC, CAT meets once a month according to a published schedule. 

Since increased transparency is a stated objective for EMA, the further involvement of civil society members should be welcomed. Patient organisation representatives will want to ensure that patients’ needs are considered in discussions, while those representing healthcare-professional organisation will be focused on representing the views of health professionals. Civil society members will be expected to take an active role in discussions as well as the assessment of documents central to the work of the committees. 

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Wednesday, 8 July 2015

3D printing and pharmaceuticals

3D printing is the manufacturing process used to make three dimensional solid objects from a digital file. At present there are various types of 3D printing processes, which use varying printer technologies, speeds, and resolutions, and different sorts of materials. Despite this variation, it appears possible to develop a 3D object in almost any shape imaginable through computer-aided design.

3D printing technology has received a great deal of attention since it can be used for a variety of purposes, ranging from use on Earth to develop new parts for cars and aircraft engines to far above in space. 3D printing technology has also found use in healthcare, particularly in the area of replacement and reconstructive surgery and customised medical devices. This area of work is seeing increasing cooperation between medical researchers and engineers and a number of commercial companies operate in this field. While some observers are cautious about the extent of progress in using 3D printing in healthcare, others are boldly optimistic and predict a huge market for resulting products.

A new application of 3D printing in the world of pharmaceuticals is set to gain attention, based on technology originally developed by MIT. This is thanks to FDA’s approval of a 3D-printed pill called Spritam for epilepsy. The Agency has already held workshops with various stakeholders to discuss the technicalities of using 3D printing in healthcare. According to the manufacturer of the recently-approved product, the 3D printing technology involves using an aqueous fluid to stitch together multiple layers of powder. This approach apparently packages layers more tightly in precise dosages. As a result it is being positioned to help patients who have difficulties with current dosages. The company hopes to apply the technology to other products.

One hope for use of 3D printing as a novel medicine formulation technique is to develop personalised medicines. A future scenario could involve relatively rapid print-on-demand production of medicines to custom doses. There could be particular benefits for paediatric medicine and another advantage would be a reduction in production costs. Although 3D technology is in its infancy for the printing of drugs, the recent US approval will surely not be the last and could lead to major changes in the industry.

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Friday, 5 June 2015

Predicting the impact of the Falsified Medicines Directive (FMD) - Part 2

A forum for expert views

In early 2015, the British Embassy in Switzerland and UK Trade & Investment organised a workshop in Berne, Switzerland to bring together expert stakeholders, medicines authentication experts and other leading professionals to provide a forum to communicate the impact of the EU Falsified Medicines Directive (FMD) (2011/62/EU), particularly with respect to Switzerland. 

The workshop was opened by Her Britannic Majesty’s Ambassador to Switzerland and Liechtenstein, Mr David Moran. He described how bilateral trade between the UK and Switzerland, worth over £27.4 billion a year, continues to prosper. He also highlighted the UK and Switzerland’s excellence in the life sciences sector. 

The first speaker, Dr. Heiner Sandmeier, Deputy Secretary General of Interpharma, cited the intact supply chain Switzerland and the absence of parallel trade as important reasons for the relatively low number of falsified medicines in Switzerland. Following an increase in the number of illegal imports for a number of years, the Swiss authorities had observed a drop of around 42% between 2010 and 2012. 

Dr. Sandmeier stated that the country is taking several efforts to fight falsified medicines and that the research based pharmaceutical industry is supporting the implementation of the FMD in Switzerland. The Swiss Anti-Counterfeiting and Piracy Platform is a non-profit association with 40 members from the public sector, private enterprises and consumer organisations. Its high profile “Stop Piracy” educational and awareness public campaigns emphasise the criminal background behind such falsification operations. In addition, the Revision of Swiss Medicines Law includes new measures relating to these issues (Art. 86/87). The imitation and falsification of medicines is clearly outlined as a criminal offence. In addition, Switzerland signed the Medicrime Convention on 23th October 2011, which is the Council of Europe convention on the counterfeiting of medical products and similar crimes involving threats to public health. Switzerland has considered ratification and a report by the Federal Office of Public Health (FOPH) on a Draft Implementation Act is expected during the second half of 2015.

Dr. Sandmeier went on to describe the European Stakeholder Model (ESM), a partnership of organisations involved in the pharmaceutical supply chain, and their work on a pan-European medicines verification system [1]. In Switzerland, a Working Group of the Refdata Foundation has started a consultation on a joint stakeholder-run verification system on the basis of the ESM. The Foundation membership includes the key stakeholders in the Swiss healthcare system. 

Real life experiences 

In the next presentation, Graham Smith, ‎Commercial Director at Aegate, provided further details on the Directive and its technical implications. Manufacturers will need to invest in order to meet new requirements. He estimated that 47% of the total cost of compliance to the FMD would relate to tamper evidence, 37% to serialisation and 16% to authentication costs [2]. However, there will be longterm benefits to be gained as this will also create a digitised network connecting manufacturers, wholesalers, pharmacy and patients. The FMD would effectively link 10 billion prescription medicine packs across Europe, 500 million people, 150,000 pharmacies and 4,000 manufacturers [2].

In a complementary presentation, David Brindley, from Oxford University discussed other opportunities that might arise as a result of the new end-to-end medicine verification system. In particular, he highlighted the potential benefits for improving patient adherence. Through better understanding of patient behaviour when taking their medicines coupled with harnessing appropriate elements of the system arising from the EU FMD it should be possible to make improvements. For example, the system could represent a vehicle for messaging to both patients and pharmacists. He described a UK pilot program that was being run in conjunction with Aegate based on their medicine verification and authentication system. The aims included an independent evaluation of and efficient integration of the company’s system into existing pharmacy software.

Graham Smith then provided an in-depth, practical look at Aegate’s End to End Service. He highlighted the wealth of experience that had been gained by the company across Europe and also in the US. To date, in Europe, the Aegate system has checked 3 billion medicine packs at 15,000 dispensing points, while maintaining a round trip response time to pharmacies of 250 milliseconds [2]. In order to develop an efficient system suitable for different national markets he stressed the importance of working closely with local stakeholders. This ranges from working with pharmacists to ensure integration with different software platforms to working with manufacturers to help them resolve serialisation data transfer issues.

As well as protecting patients from genuine dangers, he pointed out the need for any system to be able to rule out anomalous and false-positive results. He cited an incident in Belgium, where 79 packs with the same unique identifier had been found by the Aegate system [2]. An investigation quickly revealed that this was due to a manufacturer error and so Aegate were able to ensure pharmacists were reimbursed and the manufacturer avoided an expensive recall. 

Preparing for a new environment

Following the presentations, the attendees discussed their own experiences and expectations regarding medicine verification and authentication. One of the concerns was the delay by some stakeholders in preparing for the FMD. It was considered imperative for all parties to make the necessary investment in order to have appropriate measures in place as soon as possible. Other topics discussed centered on the developments in Switzerland regarding the FMD in relation to the bilateral agreements with the EU. Swiss experts at the meeting confirmed that the details of the FMD were being closely examined at an official level and details on Switzerland’s approach would be forthcoming.

In conclusion, the meeting organised by the British Embassy in Switzerland and  UK Trade & Investment highlighted the importance of a comprehensive strategy to deal with falsified medicines both at European and international level. The attendees were optimistic that ongoing dialogue between different healthcare stakeholders would help minimise this serious threat to public health. 

References 

1. European Stakeholder Model (ESM)
2. Aegate.  

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Thursday, 2 April 2015

Predicting the impact of the Falsified Medicines Directive (FMD) - Part 1

Tackling a major threat to public health and safety

Falsified medicines are fake medicines that are passed off as real, authorised medicines and so pose a global threat to patient safety and public health [1]. They may contain ingredients of low quality or in the wrong doses; be deliberately and fraudulently mislabelled with respect to their identity or source; have false packaging; or contain low levels of the active ingredients or the wrong ingredients altogether [2].

Falsified medicines represent a major area of criminal activity. In September 2014, Europol, the EU’s law enforcement body, together with counterparts from the UK, Austria, Belgium, Cyprus, France, Hungary, Slovakia, and Spain seized several fake million pills with an estimated value well in excess of EUR 10 million. The crackdown led to a several arrests and the freezing of more than EUR 7.5 million in financial assets [3].

The scale of this criminal activity has led to fears that fake medicines may penetrate the legal medicines supply chain. Often, falsified medicines are manufactured abroad and imported to the UK [4]. The Medicine and Healthcare products Regulatory Agency (MHRA) has an ongoing strategy to combat falsified medicines and collaborates with international counterparts and law enforcement agencies. Between 2004 and 2011, the MHRA intercepted 18 falsified medicines in the UK supply chain [4]. Most cases were at pharmacy and wholesale level, but in one case a falsified anti-platelet product was identified at clinical trial level [4]. 

The Falsified Medicines Directive

The serious health threat posed by falsified medicines, led to the EU adopting Directive 2011/62/EU, often referred to as the Falsified Medicines Directive (FMD) [1]. This new legislation became applicable across the EU on 2 January 2013. To avoid making EU legislation over-complicated and technical a system exists for delegating to the European Commission limited powers to make minor changes to laws, provided these do not affect the "core" legislation decided by European Parliament and the Council [5]. Therefore, in parallel to the core legislation for the FMD, the European Commission started work on a Delegated Act to ensure uniformity and standardisation of key safety features required by the legislation [1].

The adoption and subsequent publication of this Delegated Act, sets off a three-year timeline for implementation at EU member state level [6,7]. By 2018, the full requirements are envisaged to be implemented across the region. The FMD represents a major development for pharmaceutical manufacturers, wholesalers and pharmacists and will also have an impact on national healthcare providers and regulators. 

Table 1: Some key features of the EU FMD (2011/62/EU) [1,4,8]


Feature
Details
Packaging
An obligatory authenticity feature on the outer packaging of the medicines. This feature was set to be decided at a later stage via a Delegated Act
Safety features of medicines
Barcodes to be printed on or attached to each pack of medicines subject to prescription and other medicines at risk of being falsified. The barcodes will be checked into a database by the manufacturer and checked out when dispensed by a pharmacy.
Supply chain and good distribution practice
Strengthened record-keeping requirements for wholesale distributors. Will be required to verify that they are dealing with authorised suppliers. Brokers will have obligations similar to those of wholesale distributors.
Active pharmaceutical ingredients
Tougher rules on the controls and inspections of producers of active pharmaceutical ingredients
Internet sales
A common, EU-wide logo to identify legal online pharmacies. This will make it easier to distinguish between legal and illegal online pharmacies in the EU.

References

1. EC (2015). Falsified medicines. European Commission.  
2. EFPIA (2014). Stamping out Falsified Medicines. EFPIA.  
3. International law enforcement action against fake medicines. Europol.   
4. MHRA (2013). Falsified Medicines Directive.  
5. European Parliament (2010). Legislating more efficiently: questions & answers on new delegated acts
6. Aegate.  
7. Jones G. (2015) The Falsified Medicines Directive: time to get it right. The Pharmaceutical Journal. 
8. EMA (2015). Falsified Medicines. European Medicines Agency. 

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Wednesday, 4 February 2015

Report on the TOPRA In Switzerland networking event, Basel Technology Park

The Basel Technology Park was the setting for the recent TOPRA In Switzerland networking meeting, held on 10 September 2014. The main theme of this event was biosimilars, which are presenting regulators and developers with unique challenges due to their complexity and potential role in healthcare. Around 40 delegates from across the industry in Switzerland and from nearby registered to hear the latest thinking on this important subject.

The first presentation 'EVA - the Basel Life Sciences Start-up Agency' and the Basel Spin-off Incubator, given by Dr. Peter Burckhardt, was topical given the location of the event. Since 2011, the Basel Technology Park has been encouraging innovative new companies from various technology sectors. Dr Burkhard explained how Basel as a whole offered various mechanisms to new companies for financing and support, whilst also giving a realistic picture of the obstacles to be overcome.

The next presentation centred on biosimilars, with Dr. Katrin Appenzeller and Dr. Anna Barbara Stalder offering a perspective from the view of Swissmedic. They gave a thorough overview of developments that are shaping the field of biosimilars and the way in which different regulators around the world are approaching this subject. With 8 biosimilars having been approved since 2008 by Swissmedic (and a further 4 biosimilars currently under review), the Agency has gained considerable expertise in this area of regulation, which has led to various guidelines and documentation, including the Administrative ordinance Authorisation of similar biological medicinal products (Biosimilars). They explained how a step-wise approach to gain evidence on similarity between the biosimilar candidate and the reference product was used and that it was the totality of evidence that was the important factor for regulatory decision-making. While Swissmedic was very much in line with the general thinking of other major regulators, such as EMA, the Agency stressed that there were particular situations that would make the Swiss situation unique. Therefore it was critical for manufacturers working in this field to engage early on with Swissmedic with respect to any product-related regulatory matters and not to make automatic assumptions based on experience elsewhere, such as in the EU. Furthermore, the speakers encouraged the delegates to consult the Swissmedic website for more information and to keep abreast of developments.

Finally, Dr. Frank Wierckx from Clinipace offered an industry view of the situation for biosimilars in Switzerland. He outlined the challenges that companies had experienced while the regulatory framework had been in transition and the practical difficulties they might face in meeting new requirements. One of the areas that companies needed to pay particular attention to was for the reference product, as the ideal situation would be for a biosimilar to be compared with the originator product approved in Switzerland. Otherwise proof would be needed that the product used for the comparison of the biosimilar with the originator product was identical to the product approved in Switzerland. The limitations in information available to the manufacturer might impact their ability to meet such requirements. Dr. Wierckx then explained the approach needed for a realistic development strategy, and the necessary features of the quality, non-clinical and clinical data expected. At this point of the presentation, the scope to reduce the burden of nonclinical/clinical studies by providing more extensive and detailed quality data was also discussed. To end the presentation, he briefly reviewed the potential review strategies for the US, EU as well as Switzerland.

The lively discussions during and after the presentations, illustrated the great interest among the delegates concerning biosimilars. The fast moving pace of developments in this field and the ongoing efforts by regulators to introduce appropriate framework suggest that this will be an interesting topic to revisit at a future TOPRA In Switzerland.

To conclude the event, Mr. Christian Harr from the Basel Technology Park gave delegates a unique behind the scenes tour. He explained how the Technology Park offered companies a setting that was particularly suited to the life sciences and showed how some of the recent occupants were benefitting from the expanded facilities and growing support network.

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