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Friday December 19, 2014 (SW51 2014)
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GLOBAL NEWS
GLOBAL REGULATORY AFFAIRS
EUROPEAN UNION
FRANCE
EUROPE
MIDDLE EAST
RUSSIA & RELATED COUNTRIES
NORTH AMERICA
LATIN AMERICA
AUSTRALIA & NEW ZELAND
INDIA, PAKISTAN & ASIA
DISCOVERY - DESIGN – DEVELOPMENT
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Parmi les sujets sélectionnés dans ce numéro :
Pharma sector may lose $65 bn by 2019: Analyst
The Ugly Cost Of Developing New Drugs -- Can We Make It
Prettier?
ICH Steering Committee, Lisbon, Portugal, November 2014
p.3
p.5
p.6
EMA - Dossier requirements for Pre-submission Procedure: ATMP
Certification
p.15
EMA - Classification and analysis of the GCP inspection findings of GCP
inspections conducted at the request of the CHMP
p.19
ANSM - Statines et risque de diabète: le rapport bénéfice/risque reste
toujours positif
p.23
HAS - Enjeux actuels de l’évaluation médico-économique - une
comparaison avec le NICE
p.26
NICE greenlights dabigatran for treatment of blood clots
p.29
Germany Names 16 Firms with Drugs Suspended Over Concerns of
Clinical Trials Conducted by an Indian Firm
p.32
FDA - Update From the Office of Surveillance and Epidemiology - 11
December 2014
p.38
FDA releases draft guidance on clinical pharmacology in pediatric
studies
p.39
The Top 15 Biologics Deficiencies Cited by FDA in 2014
p.40
The Top 15 Pharmaceutical Deficiencies Cited by FDA in 2014
p.43
GPhA supports state legislation that eliminates barriers to auto
substitution of biologics at the pharmacy
p.51
CFDA provides direction to local agencies on injectable drug technology
transfer
p.62
Indian regulator soliciting feedback on regulatory system upgrade
plan
p.63
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© Adrien Tillet
«Beyond words, the world »
Season’s Greetings and Best Wishes
Yves Tillet and Associate Consultants & Experts
Cabinet WHITE-TILLET
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GLOBAL NEWS
 Pharma sector may lose $65 bn by 2019: Analyst
Pharmaceutical companies will suffer an estimated $65 billion drop in sales by 2019 worldwide due to the
patent expiry of several leading drugs, according to research and consulting firm GlobalData.
According to the analyst's report, the drug makers hit hardest will include Otsuka, Eli Lilly, and AstraZeneca
(AZ), with a significant proportion of losses coming in the Central Nervous System (CNS) treatment sector.
Mr Adam Dion, healthcare anakyst, GlobalData, stated that Eli Lilly and AZ have seen profits fall in the CNS
therapeutics market since 2010, with the latter losing the greatest share over the past three years.
Mr Dion commented, "AZ's CNS segment has been bleeding sales as a result of the company losing its
patent on Seroquel (quetiapine fumarate), a treatment for bipolar disorder, which led to the entry of
cheaper generic alternatives from Teva and Sandoz. GlobalData estimates AZ's share to have been around 9
percent in 2010, which has now fallen to only 3 percent in 2013. … (Source: Biospectrum)
 Returns on pharmaceutical R&D improving as pipelines revive
Drugmakers are finally getting more bang for their scientific buck, with the rate of return on
pharmaceutical research and development (R&D) increasing for the first time since 2010.
Overall R&D returns have improved to 5.5 percent this year from 5.1 percent in 2013, reflecting a modest
uptick in productivity in company labs, according to the latest annual survey of the industry by Deloitte
released on Wednesday.
The global pharmaceuticals sector needs to replenish its medicine chest after a wave of patent expiries that
peaked in 2012, and the numbers show that pipelines are getting fuller.
So far this year the U.S. Food and Drug Administration, which acts as gatekeeper to the world's biggest
market, has approved 35 new products, up from 27 in the whole of 2013 and close to the bumper 39
cleared in 2012, the agency's website shows. (here)
There are significant variations between companies, however, with the largest firms having the greatest
development costs for each new medicine and the lowest returns on R&D investment.
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The most successful of the 12 leading drugmakers assessed in the survey had an R&D return of 11.7 percent
in 2014, while the worst-performing saw a negative return of 0.7 percent.
"There are signs that returns from pharmaceutical R&D are turning a corner," Julian Remnant, head of
Deloitte's European R&D advisory practice, said. … (Source: Reuters)
AUDIT & OUTSOURCING in CHINA
The Cabinet WHITE- TILLET is now present in China with Alban Tacquet who took
the general direction of our local representation in order to:
• Conduct audits secured at a reasonable cost according to GMP standards (Drugs
and API) , ISO 9001, ISO 13485 (MD) , GMP Cosmetics;
• Complete outsourcing assignments in the areas of active ingredients of drugs,
medical devices and cosmetics;
• Support for legal and regulatory approaches to the authorities.
Alban Tacquet (41) has made a career in quality management and regulation of
health products in France before running a business in China. Married to a Chinese
wife, Alban lives in Beijing (Pekin) for 7 years.
For more information, please contact Yves TILLET CEO/CSO to:
[email protected]
GLOBAL REGULATORY AFFAIRS
Government and Regulatory Bodies
http://www.pharmweb.net/pwmirror/pwk/pharmwebk.html
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http://www.who.int/en/
 Current projects (WHO)
New texts under review for medicines quality assurance
 The Ugly Cost Of Developing New Drugs -- Can We Make It Prettier?
Since 2000, the historic big pharma have produced an average 12 new drugs (NCEs) per year, with a flat
trend. Their annual spending on drug R&D is currently about $71 billion, an amount that has changed little
since 2010. If we take the authors’ estimate at face value, it explains about 50% of this spending, which
begs the question, “where does the rest of the money go”? Does it support legitimate activities that foster
innovation? Is it waste? Misclassified costs? Marketing support relabeled as research? The authors should
raise the question because the sheer magnitude of this unexplained research spending raises the possibility
that something big has been missed. For the industry as a whole, the picture is the same: the average
output since 2000 is 27 new drug per year, also with a flat trend. The annual R&D spending is $140 billion.
This leaves about $60 billion (43%) of annual unexplained spending.
The average is not very informative, and misses perhaps some key points. Since 2000, 416 new drugs
(NCEs) have been approved by FDA (not including cosmetics and imaging agents). Of these, 161 have been
licensed to companies that produced just one or two drugs, and most of them did not come close to
spending $1.4 billion out-of-pocket to bring their drugs to market. For example, Chelsea Therapeutics
received approval for Northera, a drug for neurogenic orthostatic hypotension, in 2014. The company,
which was founded in 2002, is public and discloses its R&D spending. Since its creation, it adds up to $172
million. Likewise, Vanda received approval for Hetlioz, a sleep disorder drug in 2014, and for Fanapt, a
schizophrenia treatment in 2009. Its cumulative R&D spending since its creation in 2002 is about $276
million. I would submit that the distribution of the costs of developing new drugs is heavily lopsided, with
the highest figures likely to be 10- or 20-times bigger than the lowest ones. In such situations, the
“average” is not very meaningful, as it is hardly representative of the population – unlike in a bell-curve
situation. Rather than just showing the average, the authors would do the industry a great service by
disclosing the entire distribution of their figures. We should not regard high-costs as a fixture of the
industry. The fact that some companies can do the job much cheaper is a call to the high-spenders to
transform themselves in order to deliver affordable drugs. … (Source: Forbes)
 Good Documentation Practices Are Key for Government Drug
Reimbursement Establishing Procedures and Recording Assumptions
Help Companies Address Regulatory-Based Inquiries
Whether seeking payer support for a single blockbuster drug or for multiple products, companies with
adequate documentation about internal procedures and assumptions are better positioned to successfully
navigate the government drug reimbursement process, according to pharmaceutical business intelligence
provider Cutting Edge Information.
The company's newest market access report -- "US Government Reimbursement: Winning Key Formulary
Positions and Managing Pricing Systems" -- discusses how formal standard operating procedures (SOPs) and
documentation practices provide a roadmap for navigating the drug reimbursement process. Companies
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without such policies risk challenges, whereas those with recorded procedures are better positioned to
address issues from potential regulatory-based inquiries.
"From establishing SOPs to recording assumptions, the documentation surrounding the government drug
reimbursement process increases accountability and keeps employees on the same page," said Jacob
Presson, senior research analyst at Cutting Edge Information. "This is critical for companies seeking payer
support, especially when current regulations are unclear."
Under the Medicaid Rebate Program, drug manufacturers can make reasonable assumptions about
calculations when sufficient guidance does not exist or when current regulations are not clear, which may
occur when companies have enacted atypical pricing arrangements or are targeting a specific consumer
class. However, it is critical that these companies demonstrate that their assumptions are reasonable,
thereby necessitating good documentation practices. … (Source: PMPnews)
http://www.ipec-europe.org
http://www.ich.org/
http://www.picscheme.org/
International Network of Agencies for Health Technology Assessment
(INAHTA)
 ICH Steering Committee, Lisbon, Portugal, November 2014
The International Conference on Harmonisation (ICH) Steering Committee (SC) and its Expert Working
Groups (EWGs) met in Lisbon, Portugal, EU on November 8-13, 2014. The meeting was hosted by the
European Commission and included over 300 participants.
The SC agreed on the key issues relating to the reform of ICH in terms of governance, new membership and
funding. ICH remains committed to enhanced communication, transparency and the openness of ICH to all
relevant stakeholders. The SC will now proceed with finalising the Articles of Association and funding model
that will allow the ICH parties to carry out their internal consultations, which will pave the way towards
establishing ICH as a legal entity as an international association under Swiss law. Membership in the
Assembly, which will be the overarching body of the Association, will be established as soon as the legal
entity has been set up.
The SC had also organised a special session to inform interested parties on the state-of-play of the reform
and to seek their views. All participants recognised the essential role of ICH in the development of
internationally harmonised technical requirements for the registration of medicinal products and
welcomed the objectives of the reform. They will be kept informed of ongoing developments.
Safety Update
The SC adopted the Concept Paper on Nonclinical Safety Testing of Development of Paediatric Medicines
(S11). This Guideline is needed to establish standards for the conditions under which nonclinical juvenile
animal testing is considered informative and necessary to support paediatric clinical trials, and to provide
guidance on the design of the studies.
Efficacy Update
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The EWG created to develop an Addendum to E6, Good Clinical Practices (GCP), made good progress
towards a Step 2a document (expected in June 2015) considering innovative approaches to GCP.
A new EWG on E9(R1) met to create an Addendum addressing the appropriate estimand in a clinical trial
and the definition of the sensitivity analysis. The focus is to harmonise what “effect” a clinical trial should
seek to estimate to avoid risk of inconsistent decision making. A newly created EWG met to address
scientific and technical advances in paediatric drug development by developing an Addendum to E11. The
Addendum will address methodological approaches, commonality of content in plans for pediatric drug
development, ethical considerations, and age classification. It will also include high level consideration on
extrapolation, modeling and simulation and paediatric formulations.
The EWG developing the Guideline on Multi-Regional Clinical Trials (MRCTs) (E17) met for the first time and
made progress on developing a Guideline which will promote appropriate conduct of MRCTs, resulting in
further use of data from MRCTs in multiple regions and better regulatory decisions.
The development of the E18 Guideline on Genomic Sampling Methodologies for Future Use began with the
first meeting of the EWG. This Guideline will clarify points to consider in collecting Genomic samples in
clinical trials.
The E2B(R3) IWG has finalised its work on a Question & Answer (Q&A) document and updated the ICSR
Implementation Guide package during the Lisbon meeting. The Q&A document, which includes 27 Q&As,
was signed-off by the SC at Step 4.
Work was also progressed on a revision of the CTD Efficacy Guideline by the recently established M4E(R2)
EWG. The aim of the revision is to include greater specificity on the format and structure of benefit-risk
information with the goal of harmonising the presentation of this information in regulatory submissions.
Quality Update
The Q7 Implementation Working Group (IWG), Good Manufacturing Practice Guide for Active
Pharmaceutical Ingredients, also met to continue its work on developing Q&As to address current issues
raised by the use of the Q7 Guideline. The final set of 55 Q&As was agreed upon and will be sent out to
obtain agreement from the constituencies regarding the final Q&A document prior to adoption and posting
on the ICH website.
A new EWG on Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management
(Q12) met for the first time. The aim of the Guideline is to facilitate post-approval changes in a more
predictable and efficient manner, promote innovation, managing quality and continual improvement
throughout the lifecycle.
The ICH SC approved the Concept Paper and Business Plan for the development of Q&As to Q11 for the
purpose of clarifying the selection of starting materials for the manufacture of drug substances and what
information should be provided in the marketing authorisation application or master files. An IWG will be
formed to carry out this work.
Electronic Standards
The M2 EWG (Electronic Standards for the Transfer of Regulatory Information) and the M8 EWG (The
Electronic Common Technical Document - eCTD) met in Lisbon. MedDRA The ICH M1 Points to Consider
Working Group met at EMA in London on November 10 – 12, 2014 to discuss refinements to the coding of
medication errors considering the EU medication error project as well as off label use and other related
concepts in MedDRA.
The next ICH Steering Committee Meeting and its EWG meetings will be held in Fukuoka, Japan on June 6 –
11, 2015. … (Source: ICH)
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EUROPEAN UNION
 Health security: Building stronger global collaboration
Health ministers and high level representatives from Canada, France, Germany, Italy, Japan, UK, US,
Mexico, the European Commission and the World Health Organization attended the 15th ministerial
meeting of the Global Health Security Initiative (GHSI) hosted by Japan in Tokyo. The aim of the GHSI is to
forge stronger global collaboration on health security by addressing health threats from chemical, biological
and radio/nuclear agents and by developing preparedness and response on pandemic influenza.
During this 15th ministerial meeting the key focus was on the collective preparedness and response to
chemical, biological, radiological and nuclear (CBRN) threats, pandemic influenza and other emerging
infectious diseases. Particular attention was given to the ongoing ebola outbreak in West Africa and the
response and support provided by the GHSI countries, specifically the Ebola Virus Disease (EVD) outbreak in
West Africa.
Martin Seychell, Deputy Director General of DG Health and Food Safety of the European Commission
underlined that the Ebola outbreak shows the need to be ready to face the unexpected and demonstrates
that this health crisis should be viewed in a wider context. "When a crisis of this nature strikes the
infrastructures and the economy of countries so forcefully, we, the Global Health Security Initiative
partners also need to reflect on new dimensions such as the consolidation of health structures and on the
support during the recovery phase in the aftermath of a dramatic event."
Mr Seychell pointed out that the EU's top priority is to help stop the epidemic in the affected countries
through deployment of financial and human resources for health care, laboratories, contact tracing,
community outreach and key infrastructure including sanitation. The EU is also providing assistance to help
to rebuild health systems in the long term.
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He also underlined that more support is needed to fight the outbreak in Africa, in particular by deploying
medical teams and experts. Following a recent audit on exit screening in the affected countries he also
stressed the importance of discussing how the affected countries can be supported to make exit screening
sustainable in the longer term.
Other specific topics within the GHSI’s wide range of activities were mentioned, in particular public health
measures, sample sharing, management of global health threats, the deployment of medical
countermeasures, the support to the recovery phase after an emergency and the building of resilience.
A press release setting out the achievements of the GHSI to date and defining future areas of joint work to
promote collective health security was agreed at the end of the meeting.
More information on the EU work on health security
More information on the GHSI
 The European Union's response to Ebola emergency
West Africa is currently facing the largest and most complex Ebola epidemic on record. Guinea, Liberia and
Sierra Leone are the most affected countries. The disease has already claimed more than 6 000 lives and
has seen over 17 000 cases.
The European Union has been monitoring its spread and taken collective action at home and abroad. It has
mobilised political, financial and scientific resources to help contain, control, treat and ultimately defeat
Ebola. On 24 October 2014 the European Council appointed Christos Stylianides, EU Commissioner for
Humanitarian Aid and Crisis Management, as EU Ebola Coordinator. Between 12 and 16 November, he
travelled to the three most affected countries together with the EU Commissioner for Health Vytenis
Andriukaitis. On 5-7 December EU Commissioner for International Cooperation and Development, Neven
Mimica, followed up with a visit to Guinea Conakry to reaffirm the EU’s medium and long term support to
affected and at-risk countries.
Financial assistance
The EU's total financial contribution to fight the epidemic is over €1.1 billion. This includes funding from the
Member States and the European Commission.
The Commission has given €434 million to fight the disease - covering emergency measures and longerterm support.
Since March 2014, the European Commission has allocated close to EUR 60 million in humanitarian funding
to addresses the most urgent needs. These funds are channelled through humanitarian partner
organisations, such as MSF, the International Federation of the Red Cross and Red Crescent societies, IMC,
Save the Children, IRC, Alima, WFP’s Humanitarian Air Service, UNICEF and WHO. EU aid contributes to
epidemic surveillance, diagnostics, treatment and medical supplies; deployment of doctors and nurses and
training of health workers; raising awareness among the population and promotion of safe burials.
In addition to existing EU and bilateral development partnerships, the Commission is also providing some
€210 million in development and early recovery assistance. The funds are thus being delivered now and
into 2015. The objectives are to reinforce the capacity of governments to deliver vital public services,
notably health care, and maintain macro-economic stability. These funds are also used to strengthen food
security and improve water and sanitation. Mobile laboratories for the detection of the virus and training of
health workers are also funded through the development assistance. Furthermore, the EU supports the
African Union's medical mission in West Africa.
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To reduce the risk of further spread of Ebola, EU funding has also been allocated to countries neighboring
the affected region where we support early detection and awareness building.
Emergency supplies and expertise
The EU is also sending emergency supplies and experts. The EU Civil Protection Mechanism facilitates the
coordinated delivery of material support from the Member States through the Emergency Response
Coordination Centre (ERCC).
EU Member States have provided mobile laboratories, treatment centers, ambulances and field hospitals.
The EU has organized logistical support including multiple airlifting operations and supports the
deployment of navy ships to transport emergency supplies provided by the Member States, such as food
aid, medical kits, clean blankets and chlorine for sanitations. EU humanitarian experts, including specialists
in hazardous diseases, have been deployed to the three most affected countries.
Medical evacuation
International health workers operating directly on the ground are the backbone of the response to the
Ebola epidemic. More health workers are needed. To support their mobilization, a European medical
evacuation system has been established to ensure they would get appropriate treatment and would be
transported to hospitals in Europe in case of an infection. Member States are making capacity available for
this. The medevac system ensures evacuation within 48 hours to an equipped hospital in Europe for
international health workers and other EU nationals diagnosed with the virus. Evacuation requests are
received through the ERCC and assessed by the World Health Organisation (WHO).
Research
There is currently no specific treatment or vaccine available against Ebola. To address the urgent need for
research into new treatments, the EU has been stepping up its efforts to look for new effective vaccines
and medication. Through a partnership with the European pharmaceutical industry under the Innovative
Medicines Initiative, a €280 million call for proposals has been launched to support research projects
involving clinical trials of new vaccines in Ebola-affected countries, the development of fast diagnostic tests
and new approaches to manufacture, store and transport vaccines. The call, to which the Commission has
contributed half of the budget, will use a new fast-track procedure to get successful projects up and
running early next year.
This comes on top of the previously mobilised €24.4 million from Horizon2020 that will fund five projects
ranging from large-scale clinical trials to tests of existing and new Ebola compound treatments.
The EU is also helping to fight infectious diseases in sub-Saharan Africa, including Ebola, within the
European and Developing Countries Clinical Trials Partnership programme (EDCTP2). This partnership will
work with a budget of €2 billion over the next ten years, with nearly € 700 million coming from
Horizon2020 and a €1.5 billion contribution from EU countries.
Preparedness
The risk of Ebola to the general public in the EU is very low. Transmission of the virus requires direct
contact with a symptomatic patient’s body fluids. Furthermore, the EU has very high standards of
healthcare infrastructures and preventive care. Nevertheless, there is a small possibility of individuals
arriving in the EU with potential Ebola virus infection.
Since the outbreak of the Ebola virus disease, the Commission and the Member States have also been
working on preparedness and coordination of risk management in close cooperation with of the European
Centre for Disease Prevention and Control (ECDC) and the WHO.
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The Health Security Committee (HSC), bringing together EU Member States and the Commission, meets
regularly to coordinate Ebola prevention and readiness. It surveys Member States' preparedness and has
established a list of available Ebola assets which could be shared, including high security laboratories,
hospital capacity and medical evacuation equipment. The EU's Early Warning and Response System for
medical emergencies has been activated. HSC is also providing information for travellers in all EU languages
and establishing procedures for airports and health authorities on handling possible Ebola cases.
In addition, the Commission has launched the 'Ebola Communication Platform for Clinicians' - an online
platform enabling the rapid exchange of information on the treatment and prevention of the Ebola disease.
The platform brings together EU hospitals and physicians recognised as reference centres for the treatment
of Ebola patients. This network further boosts the level of preparedness and response against Ebola by
linking together expertise on treatment of Ebola patients between health care specialists.
Exit screening
The WHO has recommended exit screening of travellers leaving the affected countries in order to reduce
the risk of spread of Ebola. Since the disease's incubation period is up to 21 days, it is widely recognised
that such screening can be only partially effective.
The Commission in partnership with the WHO has proposed to carry out an audit of the exit screening
measures in the three most affected countries. Its goal is to assess current exit screening practices and
identify any gaps. The audit report is due at the beginning of December.
Advocacy and diplomatic outreach
From the outset of the crisis, the EU has been supporting and calling for a strong international response
coordinated by the United Nations. The EU is in constant contact with the governments of the region
through its Delegations as well as with regional organizations such as the African Union and ECOWAS.
The appointment by the European Council of an EU Ebola Coordinator, Commissioner Christos Stylianides,
aims to ensure that EU institutions and Member States act in coordination with each other and with
international partners. To this end, an EU Ebola Task Force has been set up, bringing together Member
States, Commission services, the European External Action Service (EEAS) and representatives of the UN,
the Red Cross and NGOs. The Task Force meets daily in the Commission'sERCC, which serves as a platform
for coordination of the European response. … (Source: EC)
 DG Sanco clarifies scope of Joint Procurement Agreement
The Commission’s Health and Consumers Directorate (DG Sanco) has clarified the scope of the Joint
Procurement Agreement that allows EU member states to jointly negotiate the price and supply of vaccines
and antiviral medications. The joint procurement procedure can be launched with the agreement of a
minimum of 4 member states and the Commission. … (Source: EC)
 Europe Edges Toward a New Understanding on HTA
The European Union is moving ahead, in its own slightly crabwise fashion, with its attempts to work out
what healthcare budgets should be used for. The characteristic sideways gait results from the fact that this
isn't strictly speaking an EU issue. The EU treaty preserves health spending decisions as a matter for
national governments, and they have long-defended this approach in custom and practice. But health
services in Europe are, as in so many other parts of the world, at serious risk of imploding under their own
weight in these budget-constrained time. In consequence, any close observer of EU machinations can
perceive one new group breaking fresh ground by looking at how to make national health services more
efficient and sustainable, while another group looks at health technology assessment as it as about to take
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on a new lease of life.
Lengthy courtship
The EU has been flirting with health technology assessment (HTA) for some time now, but for a long while
the relationship was conducted in the EU's usual hands-off "don't look at me while I'm doing this" approach
to pharmaceuticals and money. It took a bold step in 2011, when it adopted the cross-border patients'
rights directive— which was really a Trojan horse designed by the European Commission to penetrate the
camp of national regulators, while masquerading as a simplification of rules for the benefit of citizens.
Artfully concealed inside the longwinded rhetoric about equality of opportunity and individual rights were
a handful of hardcore institutional innovations, and the chief interloper among those meticulously
disguised fifth columnists was the first legal base for HTA. No imposition, of course. That would be
unthinkable. But a carefully crafted provision for a voluntary network of national HTA bodies, conveniently
covering all member states, plus Norway and Iceland, and supported by an EU-funded organization with
the unpronounceable title of EUnetHTA.
After a couple of years probing carefully and discreetly at how individual member states make their
judgments on new drugs or devices or medical procedures, the EU is now getting ready for the next stage.
Not quite an ambush, but definitely a fastidiously prepared convergence of thinking about the idea of
something more systematic. Still voluntary, of course. The EU is the EU. But there are unmistakable
indications of EU aspirations to shift to a higher gear. At the end of October, delicate manipulations of
circumstance persuaded members of the HTA network to adopt —unanimously—a "strategy for EU
cooperation on HTA."
Vision embraced
What this amounts to is an acceptance by national authorities of a strategic vision for HTA—something
unthinkable only a few years ago, but now less rebarbative as a concept because of the hard times that
austerity has forced upon healthcare planners. And to serve the development of that strategic vision, EU
officials have convinced national officials that they should identify priority areas to be addressed through
the network.
It is all still carefully wrapped around with allusions to the treaty's ban on any interference with areas of
national competence or any harmonization of national laws or regulations, and explicit opt-out clauses
making clear that "individual member states are free to decide the level at which they are willing to
participate in cooperation efforts." But it is a real advance towards developing a European approach,
rather than leaving all these decisions to the whims, caprices, and local priorities or vested interests of
member states. If it is to be a single market for medicines, then there must be some common elements in
deciding which products merit reimbursement across that market, the logic runs.
HTA, says the new strategy, is "a useful tool to help decision makers achieve sustainable healthcare
systems, in the best interest of European patients." The goal of this new degree of European cooperation is
"to increase use, quality, and efficiency of HTA production in Europe and to promote HTA in decisionmaking." Cooperation can "promote more consistent approaches to HTA as a health policy tool to support
evidence-based, sustainable, equitable choices in healthcare and health technologies." And it can develop
"shared know-how" among national bodies working together to produce and apply shared methodologies.
12
 EU nod for AZ' constipation drug Moventig
AstraZeneca’s Moventig (naloxegol) has been approved in the European Union for the treatment of opioidinduced constipation.
13
The European Commission is allowing the drug’s use in adult patients who have failed to respond to
conventional treatment with laxatives.
The once-daily pill is a first-in-class, peripherally-acting mu-opioid receptor antagonist offering a new
treatment option to millions of people across Europe who suffer from the condition.
The US Food and Drug Administration issued a green light for Moventig back in September for OIC in adults
with non-cancer pain. … (Source: PharmaTimes)
http://www.edqm.eu/en/edqm-homepage-628.html
 Human antithrombin III concentrate (0878)
Rapid implementation of corrected monograph
This monograph was corrected in order to include verbatim the Assay of heparin method in chapter 2.7.5
which appeared in the Ph. Eur. prior to supplement 8.3.
This correction was made because chapter 2.7.5 was revised in Ph. Eur. supplement 8.3 from the clotting
method to more specific methods and now describes an assay for anti-factor IIa activity and an assay for
anti-factor Xa activity which is carried out to determine the ratio of anti-factor Xa activity to anti-factor IIa
activity.
This ratio is meaningful for the potency determination of heparin as a drug substance but not currently
suitable for the determination of heparin in antithrombin III concentrates. The requirements of the
monograph are therefore considered as unchanged.
The monograph with corrected wording is to be taken into account from 01 January 2015.
Read the Resolution AP-CPH (14) 5
Download the corrected monograph (0878)
 150th session of the European pharmacopoeia commission
The European Pharmacopoeia Commission held its 150th session in Strasbourg on 25-26 November 2014.
Since its establishment following the signature of the Convention on the elaboration of a European
Pharmacopoeia in 1964, the Commission has adopted more than 2600 monographs and general texts
covering substances and products vital for patients throughout the continent and beyond. In addition, it
has adopted numerous revisions to ensure that the European Pharmacopoeia stays abreast of scientific
developments. The Commission is composed of delegations appointed by its member States. It decides on
the work programme of the European Pharmacopoeia and defines criteria for setting priorities and decides
on the general policies applied in the work. When opening the session, Dr Jean Louis Robert, Chair of the
Ph. Eur. Commission, stressed that the Commission could not have accomplished its work successfully
without the support and dedication of the more than 700 members of its currently 72 groups of experts
and working parties.
During the session, the Commission adopted 13 new texts for inclusion in the European Pharmacopoeia.
These included three monographs on homoeopathic stocks and two monographs on traditional Chinese
medicines.
14
The Commission also adopted 28 revised monographs and 6 revised general chapters. Among the revised
monographs, 22 texts included the suppression of reference to calomel electrodes, following the entry into
force of EU Regulation 847/2012 restricting the use of mercury in measuring devices. Revisions of the
general chapters Water: micro-determination (2.5.32), Potentiometric titration (2.2.20) and Relationship
between reaction of solution, approximate pH and colour of certain indicators have significantly improved
these widely used chapters and are the first of a series of revisions aimed at reflecting the latest scientific
developments in European Pharmacopoeia general chapters.
The Commission also endorsed a strategy for the inclusion of tests(s) for pro-coagulant activity in
monographs on immunoglobulins (intravenous and subcutaneous). This will require close collaboration
with regulators within and outside of Europe.
The list of revised monographs and the updated version of the adopted work programme will be published
on the EDQM website to inform users of future changes they need to be aware of. All of these texts will
become effective on 1 January 2016 in the 37 member states and will be published in supplement 8.6 of
the Ph. Eur. The list of all adopted texts will be published on the EDQM website.
The Ph. Eur. Commission also took note of the recommendations for the future made by the participants of
the international conference “EDQM: 50 Years of Leadership in the Quality of Medicines - Paving the way
for the future” on 6 to 8 October 2014. These recommendations will be considered by the Ph. Eur.
Commission when reviewing the work programme of its 72 groups of experts and working parties in March
2015.
The next Commission session will take place on 17-18 March 2015
.
European Medicines Agency
http://www.ema.europa.eu/ema/
Human medicines: Regulatory
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/landing/human_medicines_regulatory.js
p&mid=WC0b01ac058001ff89
 Dossier requirements for Pre-submission Procedure: ATMP
Certification
Submission of application dossiers to the European Medicines Agency and members of the Committee for
Advanced Therapies (CAT)
15
 Adaptive pathways: a future approach to bring new medicines to
patients?
Scientists argue that scientific and political changes will make adaptive pathways the preferred
approach to make new treatments available
“Adaptive pathways should be the preferred approach in the near future to bring new medicines to
patients.” A number of scientists, including members of the European Medicines Agency (EMA) and its
scientific Committees take this position in a co-authored article published in Clinical Pharmacology and
Therapeutics.
The concept of adaptive pathways foresees an early approval of a medicine for a restricted patient
population based on small initial clinical studies. The first approval is followed by progressive
adaptations of the marketing authorisation to expand access to the medicine to broader patient
populations based on data gathered from its use and additional studies.
Under the header 'From adaptive licensing to adaptive pathways: delivering a flexible life-span approach
to bring new drugs to patients ', the authors, who are part of the New Drug Development Paradigm
(NEWDIGS) initiative, analyse the key drivers of adaptive licensing. These include:




The patients’ demand for timely access to medicines, in particular where there are unmet medical
needs. With adaptive licensing, new treatments would be made available to some patients earlier,
on a smaller evidence base, if efficacy has been observed in this patient population.
A better understanding of pathologies which has led to the identification of subgroups of patients
who are likely to better respond to certain medicines than others. For many of these subgroups, a
progressive approach to licensing while learning from real-world experience may become the only
viable access route to new treatments.
The growing financial pressure on healthcare systems and a call for a more targeted use of
medicines to increase their therapeutic value.
The pressure on industry to make the development of medicines, in particular for chronic diseases,
sustainable. Development programs targeting smaller, better defined populations would lower the
threshold for financing a drug’s development and allow for more medicines to be brought forward.
A number of recent developments are fostering the transition from a traditional approach, which
implies large trials and a marketing authorisation for broad groups of patients, to an adaptive approach.
These include the development of innovative clinical trial designs, learning healthcare systems and the
inclusion of patients in decision-making processes to better understand what level of uncertainty they
are willing to accept.
EMA adaptive pathways pilot project
EMA launched a pilot project on adaptive pathways (formerly known as adaptive licensing) in March
2014 to explore this approach with real medicines in development.
As of November 2014, the Agency had received and assessed 29 applications as part of the pilot, nine of
which had been selected for discussion with the applicant.
16
Stage I of the pilot project will close at the end of February 2015. The Agency will then focus on stage II
of the project. This will include in-depth, face-to-face meetings with the applicants for the applications
selected.
After 28 February 2015, EMA will still consider new applications for stage II face-to-face meetings if they
are well-developed. Applicants are invited to contact EMA at [email protected] for
advice on the content and suitability of their request to be considered for stage II of the pilot.
EMA is planning to publish a report on initial experience gained as part of the pilot project by the end of
2014.
EMA recently changed the name of its pilot project from adaptive licensing to adaptive pathways to
better reflect the idea of a life-span approach to bring new medicines to patients with clinical drug
development, licensing, reimbursement, and utilisation in clinical practice, and monitoring viewed as a
continuum. … (Source : EMA)
 Experimental Ebola treatments still at early stage of development
For robust scientific assessment more information on safety and efficacy needed
At this point in time there is not enough evidence for any of the experimental therapies for Ebola Virus
Disease to draw conclusions on their safety or efficacy when used in Ebola patients. This is the finding of an
interim report published by the European Medicines Agency (EMA) that is continuing to review all Ebola
treatments currently under development.
Any new information that becomes available will be added to the review to provide the best possible
overview of data on medicinal treatments for Ebola.
“Treatments for patients infected with the Ebola virus are still in early stages of development,” notes
Marco Cavaleri, Head of Anti-infectives and Vaccines at EMA. “We encourage developersto generate more
information on the use of these medicines in the treatment of Ebola patients. We will review any new
information as soon as it becomes available to support the response to this ongoing public health crisis.”
The EMA review was started by the Agency’s Committee for Medicinal Products for Human Use (CHMP) to
support decision-making by health authorities. This first interim report includes information on seven
experimental medicines intended for the treatment of people infected with the Ebola virus:

BCX4430 (Biocryst);

Brincidofovir (Chimerix);

Favipiravir (Fujifilm Corporation/Toyama);

TKM-100802 (Tekmira);

AVI-7537 (Sarepta);

ZMapp (Leafbio Inc.);

Anti-Ebola F(ab’)2 (Fab’entech).
The amount of information available for the seven treatments is highly variable. For some compounds
there is no data from use in human subjects available. A small number of treatments have been
administered to patients in the current Ebola outbreak as compassionate use. Finally, there are also
17
medicines included in this review that have already been studied in humans, albeit for the treatment of
other viral diseases.
Vaccines to protect people against contracting the disease and treatments that do not directly target the
Ebola virus have not been included in the review.
EMA’s role in the Ebola outbreak
The review of experimental Ebola treatments is part of EMA’s overall contribution to the global response to
the Ebola outbreak in West Africa. The scale and complexity of this outbreak requires an unprecedented
level of cooperation of the international health community. The Agency is working together with regulatory
authorities around the world to support the World Health Organization and to advise on possible pathways
for the development, evaluation and approval of medicines to fight Ebola.
Experimental Ebola treatments still at early stage of development
 Reflection paper on clinical aspects related to tissue engineered
products
This reflection paper is intended to provide specific guidance on clinical testing for tissue engineered
products as defined in Regulation (EC) No 1394/2007. This also applies to cells or tissues combined with a
medical device and considered a combined Advanced Therapy Medicinal Product (ATMP) according to Art.
2(d) of Regulation (EC) No 1394/2007.
This reflection paper should be read in conjunction with the clinical part of Annex I, part IV Directive
2001/83/EC and the Guideline on human cell-based medicinal products (EMEA/CHMP/410869/2006).
According to 2 (5) of Regulation (EC) No 1394/2007, a TEP can also be classified as a Gene Therapy
Medicinal Product (GTMP) as defined in Annex I, Part IV of Directive 2001/83/EC. In this case the principles
as outlined in this reflection paper apply equally to such products.
The Guideline on the risk-based approach according to Annex I, part IV of Dir. 2001/83/EC applied to
ATMPs (EMA/CAT/CPWP/686637/2011) applies on a case-by-case basis and is intended to support the
developer in risk analysis and planning of the development program. It can further be used as one starting
point for planning risk minimization and risk management plans. Reference should also be made to the
guideline on safety and efficacy follow-up and risk management of Advanced Therapy medicinal products
(EMEA/149995/2008).
Existing guidelines on developing medicinal products including specific guidance for the studied indication
or disease should be taken into account where/as far as relevant.
EMA - Reflection paper on clinical aspects related to tissue engineered product - Sep2014.pdf
EMA - Overview of comments on 'Reflection paper on clinical aspects related to tissue engineered products'
- Sep2014.pdf
 Classification and analysis of the GCP inspection findings
EMA - Classification and analysis of the GCP inspection findings.pdf
 EMA updates compilation of EU inspection procedures
The EMA has updated the Compilation of Community Procedures on Inspections and Exchange of
Information, which facilitates co-operation on GMP inspections between the Member States. … (Source:
EMA)
18
 Classification and analysis of the GCP inspection findings of GCP
inspections conducted at the request of the CHMP
The EMA has issued a retrospective analysis of the Good Clinical Practice (GCP) inspections that were
conducted by the agency from January 2000 through December 2012. In that timeframe, a total of 398
GCP inspections of centralized products were conducted at the request of the Committee on Human
Medicinal Products (CHMP). The primary purpose of the report is to provide some examples of analysis and
highlight the potential value in identifying areas of concern. … (Source: EMA)
 CVMP opinion harmonizes Baytril national approvals
The EMA has posted the opinion of the Committee on Veterinary Medicinal Products (CVMP) that
harmonizes the divergent national product information concerning target species, indications, posology,
and withdrawal periods for the veterinary antibacterial drug Baytril. The European Commission converted
the final CVMP opinion into a Decision on September 1, 2014:
Baytril injectable, enrofloxacin – Article 34
Baytril injectable and generics, enrofloxacin – Article 35
 Q/A-LIST FOR THE SUBMISSION OF VARIATIONS ACCORDING TO
COMMISSION REGULATION (EC) 1234/2008
CMDh Q&A Variations Dec2014.pdf
 Summary - Benefit-risk communication to medicines users – Dec 2014
On 17 September 2014, the EMA convened a workshop to look at how we communicate benefit-risk to
medicines users, attended by representatives of patients, consumers and healthcare professionals,
academic researchers, representatives of regulatory authorities, members of EMA scientific committees
including the chairs of the Committee for Medicinal Products for Human Use (CHMP) and
Pharmacovigilance Risk Assessment Committee (PRAC), members of EMA staff and representatives of the
Agency’s Management Board.
The objectives of the workshop were to review the current practice in communicating benefit-risk, to
examine recent initiatives into how research can help inform best practice, to discuss the role of
communications in risk minimisation and to explore how they can aid patients and healthcare professionals
in making decisions throughout the therapeutic journey.
The European Medicines Agency continues to work to incorporate the voices of medicines users in the
regulatory process. As part of this work, it has organised three workshops involving representatives of
patients and healthcare professionals together with members of EMA staff and scientific committees and
other interested stakeholders. The first of these, held in September 2013, looked at how to involve the
patients’ voice in the evaluation of benefit-risk throughout the product lifecycle. This was followed by a
workshop in February 2014 exploring methodologies and standards for the evaluation of benefitrisk and
this third workshop in the series explored communication on this topic. _.___
EMA - Summary - Benefit-risk communication to medicines users - Dec2014.pdf
EMA - Report - Benefit-risk communication to medicines users - 21Oct2014.pdf
19
 Innovative Medicines Initiative WEB-RADR workshop
The Innovative Medicines Initiative (IMI) WEB-RADR project aims to explore the use of mobile technologies
and social media to further improve the collection and analysis of information on the suspected adverse
drug reactions (ADRs). This includes the use of mobile apps to report adverse reactions, the possibility
identifying potential safety issues with medicines from user comments (posts) on social media based on
new visualisation technology and analytical methods as well as the safety information on medicines for
patients, consumers and healthcare professionals. The workshop aims to identify stakeholder needs and
expectations. Registration by invitation only. Places limited. … (Source: EMA)
 Phthalates as excipients - Corrected
EMA - NfG - Phthalates as excipients - Corrected.pdf
 EMA posts monthly committee meetings
The EMA has posted information concerning the December meeting of the Committee for Medicinal
Products for Veterinary Use (CVMP) and the November meeting of the Herbal Medicinal Products
Committtee (HMPC).
Committee for Medicinal Products for Veterinary Use (CVMP) meeting of 9-11 December 2014
HMPC meeting report on Community herbal monographs, guidelines and other activities - November 24,
2014
 EMA publishes 2nd pharmacovigilance program update
(Source: EMA)
 PV update
Appendix V - Adverse-drug-reaction reporting details (updated)
 Human Medicines

CHMP

PDCO

COMP

HMPC

CAT

PRAC
20
 Human Medicines – Regulatory and Referal Procedures
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_00
0150.jsp&mid=WC0b01ac0580024e98
 Human Medicines – Orphan Drugs
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000029.jsp
 Human Medicines – Herbals
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000208.jsp
(Final Community herbal monograph, Opinion of the HMPC on a Community herbal monograph, Final
assessment report, Final list of references supporting the assessment, Overview of comments received on
Community herbal monograph)
 Human Medicines – Advanced Therapies
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000294.jsp
http://www.hma.eu/cmdh.html
WHAT’S NEW: http://www.hma.eu/186.html
 HMA posts joint EMA/CMDh note on variations
The HMA has posted a joint EMA/CMDh note to provide more clarification on how the new Variation
Application Form should be completed by marketing application holders. … (Source: HMA)
 HMA posts agenda for CMDh December meeting
(Source: HMA)
 HMA updates PSUR Work Sharing list
The HMA has updated the Periodic Safety Update Report (PSUR) Work Sharing list of nationally authorized
products that have data lock points (DLP) as of November 2014. Substances with harmonized birth dates
allow marketing application holders to submit PSURs for products containing the same substance at the
same time, thereby allowing work sharing and reducing administrative burden on national agencies.
List of substances under PSUR Work Sharing scheme and other substances contained in Nationally
Authorised Products with DLP synchronised-Excel (November 2014)
.
FRANCE
21
http://ansm.sante.fr/
 Lancement de l'étape IV de la phase pilote du dispositif CESP
(Common European Submission Platform)
L’étape IV de la phase pilote débutera le 12 janvier 2015.
Elle concernera tous types de dossiers d’autorisation de mise sur le marché de médicaments (tous types de
médicaments) : toutes les activités réglementaires structurées au format eCTD ou EU-NeeS.
Une nouvelle version de l’avis aux demandeurs détaille les caractéristiques du CESP ainsi que les modalités
de soumission des dossiers dans le cadre de cette phase pilote. … (Source: ANSM)
 Rupture de stock à venir de la spécialité Marsilid (iproniazide)
L’Agence nationale de sécurité du médicament et des produits de santé (ANSM) a été informée d’une
rupture de stock de l’antidépresseur Marsilid à compter de la fin du mois de décembre 2014, et ce pour
une durée indéterminée.
Afin de pallier cette indisponibilité, la spécialité Nardelzine (phénelzine) est disponible dans les pharmacies
hospitalières par le biais d’une Autorisation Temporaire d'Utilisation (ATU) nominative. … (Source: ANSM)
 Spécialités pour instillations intra-vésicales à base de BCG : reprise
d’un approvisionnement temporaire en quantité limitée
Dans un contexte de tensions d’approvisionnement avec les spécialités pour instillations intra-vésicales à
base de BCG (Immucyst©, BCG-Medac© et OncoTICE©), l’ANSM vous informe qu’un approvisionnement
en quantité limitée avec la spécialité ONCOTICE a repris depuis le 15 décembre.
Le retour à un approvisionnement normal en BCG intra-vésical n’est toutefois pas envisagé avant la fin du
1er trimestre 2015.
Dans ce contexte, l’ANSM rappelle la nécessité de suivre les recommandations temporaires de prise en
charge des tumeurs de la vessie édictées en collaboration avec l’AFU.
Pour rappel, les principales recommandations dans une situation de contingentement (BCG
temporairement en quantité limitée) sont de:

réserver de façon prioritaire ce traitement pour les patients ayant une tumeur de la vessie
n’infiltrant pas le muscle (TVNIM) de risque élevé

réaliser uniquement un traitement d’induction limité à 6 instillations hebdomadaires de BCG

ne plus utiliser le schéma 6+3 en induction

ne plus faire de traitement d’entretien (Schéma de Lamm)
(Source: ANSM)
22
 Remise à disposition de la spécialité Vogalène lyoc 7,5 mg, lyophilisat
oral
Les spécialités de la gamme Vogalène (métopimazine), exploitées par le laboratoire Téva sont en rupture de
stock depuis le mois de mai 2014.
L’Agence nationale de sécurité du médicament et des produits de santé (ANSM) a été informée de la
remise à disposition de la spécialité Vogalène lyoc 7,5 mg, lyophilisat oral, indiquée dans le traitement
symptomatique des nausées et vomissements, à compter du 17 décembre 2014. Une information liée à
cette remise à disposition a par ailleurs été adressée par le laboratoire aux professionnels de santé
concernés. … (Source: ANSM)
 Résultats de l’appel à projets de l’ANSM lancé auprès des
associations de patients et des usagers du système de santé en 2014
En 2014, l’Agence nationale de sécurité du médicament et des produits de santé (ANSM) a lancé, pour la
troisième année consécutive, un appel à projets compétitif auprès des associations de patients, afin de
stimuler des initiatives visant à favoriser le bon usage et la sécurité d’emploi des médicaments et autres
produits de santé.
Parmi les 22 projets éligibles, la procédure de sélection a permis d’en retenir 7, notamment pour leur
impact potentiel en termes de santé publique et leurs propositions face à des problématiques spécifiques.
Le montant global des subventions attribuées est de 165 300 euros. … (Source: ANSM)
Décision attributive - Appels à projets 2014 (17/12/2014)
 Statines et risque de diabète: le rapport bénéfice/risque reste
toujours positif
Les statines sont commercialisées en France depuis la fin des années 80. Cinq statines sont actuellement
commercialisées : la pravastatine, la simvastatine, l’atorvastatine, la rosuvastatine, la fluvastatine. Ces
médicaments sont indiqués pour diminuer le taux de cholestérol dans le sang:

soit en prévention primaire (c’est-à-dire pour éviter un accident cardiovasculaire chez un sujet qui
n’en n’a jamais été victime) chez des patients présentant des facteurs de risques cardiovasculaires
(dont le diabète), lorsque les mesures hygiéno-diététiques ne suffisent pas à la diminution du taux
de cholestérol

soit en prévention secondaire chez des patients présentant des antécédents notamment d’infarctus
du myocarde, d’insuffisance coronaire ou d’accident vasculaire cérébral.
En 2012, l’Agence européenne des médicaments (EMA) et l’Agence américaine FDA (Food and Drug
Administration) ont initié une actualisation des résumés des caractéristiques des produits (RCP) et des
notices des médicaments contenant une statine, en raison d’une augmentation du risque de survenue de
diabète sous ce traitement mise en évidence dans plusieurs méta-analyses.[1]
Pour l’EMA, comme pour la FDA, cette augmentation du risque de survenue de diabète de 9 à 15% n’est
pas de nature à remettre en question le rapport bénéfice/risque de cette classe thérapeutique qui reste
positif dans la prévention cardiovasculaire selon les indications définies pour chacune de ces statines.
L’efficacité de ces médicaments a été démontrée aussi bien en prévention primaire que secondaire par de
nombreuses études cliniques de grande ampleur qui ont permis d’établir que leur bénéfice est largement
23
supérieur à leurs risques. Toutes statines confondues, le traitement permet de réduire le risque
d’événement cardio-vasculaire de 15 à 23 % selon le type d’événement et de 10 % les risques de mortalité
toutes causes.
La survenue d’un diabète lors d’un traitement par statines est, par ailleurs, favorisée par la présence de
facteurs de risque pré-existants à la prescription[2] , à savoir :

une glycémie à jeun > 5,6 mmol/L

un index de masse corporelle (IMC) > 30 kg/m2

une augmentation des triglycérides

des antécédents d’hypertension artérielle
En dehors de la survenue d’un diabète, une augmentation modérée de la glycémie et de l’HbA1c [3] peut
aussi être observée.
Cette augmentation du risque de survenue d’un diabète semble être directement liée au mécanisme
d’action des statines qui inhibent une enzyme clé de la physiologie du cholestérol l’hydroxy-méthyl-glutaryl
coenzyme A réductase (HMG-CoA-réductase). En effet, une nouvelle méta-analyse de 20 essais randomisés
a pu analyser la survenue d’un diabète de type 2 chez plus de 120 000 patients au total. Ce risque est
augmenté de 11% contre placebo et de 12% en cas de traitement intensif par statines par rapport à une
dose moyenne[4] . Pour 100 000 patients traités pendant la durée de ces études cela correspond à environ 5
diabètes supplémentaires par rapport aux 50 nouveaux cas attendus.
Cette étude montre pour la première fois que deux polymorphismes du gène de l’HMG-CoA-réductase
(rs17238484-G et rs12916-T) sont associés à une baisse des taux de LDL-cholestérol, un poids plus élevé,
une insulinémie et une glycémie augmentées ainsi qu’une augmentation du risque de diabète. Autrement
dit, de la même façon que ces polymorphismes sont associés à un risque diabétogène augmenté
(indépendamment de la prise de statines), les statines qui sont de puissants inhibiteurs de l’HMG-CoAréductase entraînent par cette action spécifique (responsable de la baisse du cholestérol) une
augmentation de la glycémie. … (Source: ANSM)
 Médicaments contenant de l’ambroxol ou de la bromhexine,
médicaments contenant de l’ibuprofène utilisés à fortes doses, retour
d’information sur le PRAC de décembre 2014
En avril 2014, a été initié une réévaluation du rapport bénéfice / risque pour les médicaments contenant de
l’ambroxol et de la bromhexine par le Comité d’évaluation des risques en matière de pharmacovigilance
(PRAC) de l’Agence Européenne du médicament (EMA). Cette réévaluation, demandée par la Belgique s’est
faite au vu de l’augmentation du nombre de réactions allergiques (hypersensibilité immédiate)
potentiellement graves, incluant des réactions anaphylactiques, et de réactions cutanées graves avec
l’ambroxol et dans un contexte de rapport bénéfice / risque jugé négatif par la Belgique dans les troubles
de la sécrétion bronchique au sein de la population pédiatrique. Par ailleurs, l’ambroxol étant un
métabolite de la bromhexine, celle-ci a également été incluse dans le périmètre de l’arbitrage européen.
Les médicaments à base d’ambroxol ou de bromhexine sont indiqués dans les troubles de la sécrétion
bronchique ou dans le soulagement des maux de gorge.
En France, les spécialités contenant de l’ambroxol ou de la bromhexine destinées au traitement des
troubles de la sécrétion bronchique sont réservées à l’adulte. Les spécialités contenant de l’ambroxol et
utilisées pour soulager les maux de gorge sont autorisées chez l’enfant à partir de 12 ans.
24
En septembre 2014, le comité européen pédiatrique a été sollicité et des questions complémentaires ont
été établies pour l’ensemble des laboratoires concernées. Au vu des réponses apportées, à l’issue des
discussions lors du PRAC de décembre, ce dernier n’a pas adopté de recommandations et les discussions
finales sont prévues pour le PRAC de janvier 2015.
Discussions sur la réévaluation du risque cardiovasculaire des médicaments contenant de l’ibuprofène
utilisés à fortes doses (traitement prolongé de pathologies chroniques par plus de 2400 mg par jour)
A la demande de l’Agence du médicament du Royaume-Uni (MHRA), le PRAC a débuté une réévaluation du
rapport bénéfice/risque des médicaments contenant de l’ibuprofène et utilisés à fortes doses par voie
orale[1] chez l’adulte.
Le profil de sécurité cardiovasculaire de l’ensemble des Anti-inflammatoires Non Stéroidiens (AINS) est
étudié par les autorités sanitaires européennes depuis 2006. Dans ce contexte, une méta-analyse de plus
de 600 essais cliniques avec des AINS[2] a été publiée en 2013. Elle suggérait que le risque cardiovasculaire
associé à de fortes doses de diclofénac et d’ibuprofène pourrait être similaire à celui décrit pour
les « coxibs », les inhibiteurs de la cyclo-oxygénase 2 (COX-2).
En tenant compte de ces données, le PRAC a mené une première réévaluation du rapport bénéfice / risque
des médicaments contenant du diclofénac. La décision, rendue par la Commission européenne en
septembre 2013, avait mis en place des mesures de minimisation des risques, notamment une modification
des informations des médicaments contenant du diclofénac et une communication auprès des
professionnels de santé. Dans ce contexte, la MHRA a demandé au PRAC de mener une réévaluation
similaire pour les médicaments contenant de l’ibuprofène et utilisés à fortes doses.
L’ibuprofène est l’un des médicaments les plus utilisés pour la prise en charge de la douleur et de de la
fièvre, et son profil de sécurité aux doses usuelles antalgiques est bien établi. Cette réévaluation ne
concerne que les fortes doses d’ibuprofène utilisées chez l’adulte dans un but anti inflammatoire (c’est-àdire à partir de 2400 mg par jour) et pris lors de traitements prolongés pour des pathologies chroniques.
Les doses d’ibuprofène utilisées chez l’adulte en traitement antalgique ponctuel (doses de 200 mg à 1200
mg maximum par jour) ne sont pas concernées par cette réévaluation. Les données actuellement
disponibles n’identifient pas de risque comparable à celui décrit pour les fortes doses.
Cette réévaluation porte également sur l’interaction entre l’ibuprofène et de faibles doses d’acide
acétylsalicylique (indiquée dans la prise en charge des infarctus du myocarde et des accidents vasculaires
cérébraux), afin d’évaluer si l’information à destination des professionnels de santé et des patients est
suffisante et adaptée.
Les premières discussions ont eu lieu au PRAC en décembre 2014. Des questions portant sur les résultats
rapportés avec l’ibuprofène ont été envoyées aux auteurs de la méta-analyse afin d’approfondir
l’évaluation de ces données. Les réponses devraient être discutées au PRAC en mars 2015. … (Source:
ANSM)
25
http://www.has-sante.fr/portail/jcms/j_5/accueil
 Enjeux actuels de
comparaison avec le NICE
l’évaluation
médico-économique
-
une
Les questions d’organisation et de soutenabilité des systèmes de santé ainsi que l’évaluation économique
des traitements ne sont plus des sujets purement nationaux. Plusieurs sujets d’actualité récents ont montré
que les pays européens sont confrontés aux mêmes difficultés et aux mêmes problématiques et ce malgré
des systèmes de santé différents. La HAS fait aujourd’hui le point sur ses derniers travaux et « dialogue »
avec le NICE*, institution britannique homologue, à l’occasion d’un colloque intitulé « Contribuer à la
qualité et l’efficience », tenu à la Cité internationale.
Poursuivre l’exploration de la dimension économique dans nos évaluations, notamment des
médicaments et dispositifs médicaux
Depuis plus d’un an, la HAS met en œuvre l’évaluation de l’efficience des médicaments et dispositifs
médicaux. Sont concernés par ce dispositif les produits de santé qui ont « un impact significatif sur les
dépenses de l’assurance maladie compte tenu de [leur] incidence sur l’organisation des soins, les pratiques
professionnelles ou les conditions de prise en charge des malades et, le cas échéant, de [leur] prix ». Les
avis d’efficience, par les nouvelles données qu’ils apportent au Comité Economique des Produits de Santé
(CEPS), participent à la définition du prix des produits concernés. La négociation du prix des traitements
très innovants mais coûteux présentés au remboursement s’appuie désormais également sur des données
de rapport coût-avantages ou sur des données d’efficience. En pratique, 26 produits de santé (25
médicaments et 1 dispositif médical) ont été éligibles à une évaluation médico-économique par la HAS.
Actuellement, 15 avis d’efficience ont été rendus par la Commission Évaluation Économique et de Santé
Publique (CEESP). Trois avis d’efficience sont aujourd’hui disponibles sur le site de la HAS, les autres le
seront dans les prochaines semaines.
Parallèlement à ces avis d’efficience, la HAS a poursuivi son évaluation de l’efficience des stratégies
diagnostiques et thérapeutiques et a publié au cours du dernier trimestre les évaluations relatives à la prise
en charge de l’apnée du sommeil et de l’insuffisance rénale terminale.
Une comparaison avec le système anglais via les activités du NICE
Dans l’objectif d’améliorer ses méthodes de travail et de répondre à sa mission d’aide à la décision, la HAS
entend constamment s’enrichir des apports des expériences étrangères. Une réflexion comparative des
modes de fonctionnement et de travail entre la HAS et son homologue britannique, le NICE, s’inscrit dans
cette perspective. Elle doit toutefois tenir compte des différences profondes d’organisation entre les deux
systèmes de santé et des différences culturelles entre les deux pays.
Au niveau des avis d’efficience, si des points de concordance existent, des différences notables subsistent.
Par exemple, ces avis ont en France vocation à aider les décideurs (CEPS, ministère) à affiner leurs prises de
décision concernant le prix. Ils ne constituent pas un avis conforme de remboursement ou non comme c’est
le cas outre-manche.
En France, aucune valeur de référence n’est à ce jour spécifiée. Ainsi, il est possible de déterminer le coût
du gain en santé produit par une innovation mais il n’est pas possible de dire si ce coût est acceptable pour
26
la collectivité. Si la HAS n’est pas légitime pour édicter seule cette valeur, elle est en situation de fournir les
éléments qui permettront à terme d’initier un débat démocratique sur ce sujet et a engagé un travail de
recherche et d’analyse documentaire sur ce thème.
Plusieurs autres différences sont à souligner, par exemple :
- la hiérarchisation des recommandations cliniques du NICE par une analyse coût/avantage établit ainsi un
lien mécanique et démontré entre efficience et pertinence des soins ;
- les liens entre le NICE et les universités, la recherche académique ou encore les organismes de
professionnels permettent une synergie plus grande pour produire des synthèses des connaissances
scientifiques ;
- la stratégie de diffusion des productions et de leur appropriation auprès des professionnels très aboutie,
qui permet une meilleure appropriation par les professionnels britanniques, domaine où la HAS poursuit
ses efforts;
- la grande sélectivité dans les évaluations à mener tant dans leur nombre que dans leur thématique
conférant une plus grande force aux positions du NICE ;
- enfin, le rôle des usagers en tant que contributeurs pleins et entiers plus affirmé notamment au travers de
la définition de choix de valeurs mais également avec la mise en place d’un conseil permanent des citoyens
au sein de l’institution.
Des parcours de soins pour garantir l’efficience des prises en charge
La HAS a initié plusieurs travaux destinés à mieux coordonner les parcours de soins des patients et éviter
les ruptures de suivi entre les prestations : structuration des soins primaires et organisation de la sortie
d’hospitalisation par exemple, notamment appliquées au parcours de santé des personnes âgées, travaux
sur le repérage et la prise en charge des personnes âgées fragiles, prévention des événements indésirables
liés aux médicaments, coordination des acteurs dans les territoires.
La pertinence des pratiques professionnelles pour dépenser mieux
La HAS a entrepris de travailler sur la pertinence des actes et des pratiques en analysant la variabilité des
pratiques. En effet, si les bonnes pratiques professionnelles sont définies, comment identifier et réduire ces
variabilités, sources potentielles de problèmes de sécurité des soins et du patient mais également de coûts
supplémentaires ? L’analyse approfondie de plusieurs situations (césarienne programmée, chirurgie
bariatrique, etc.) via les bases de données disponibles (PMSI, SNIIRAM…) devraient permettre de
progresser dans ce domaine. L’expérience du NICE, comme d’autres institutions internationales en charge
de garantir la qualité et l’efficience du système de santé (freins et facteurs clés de succès) et ses méthodes
peut apporter des éléments d’éclairage pour les actions actuelles et futures de la HAS. … (Source: HAS)
COMMISSION DE LA TRANSPARENCE
 Derniers avis
http://www.has-sante.fr/portail/jcms/c_6056/fr/rechercheavancee?expression=exact&expression=exact&text=Saisir+vos+mots+cl%C3%A9s&text=Saisir+vos+mots+cl%C3%A9s&liaison_word=and&searchOn
=fullText&catMode=or&dateMiseEnLigne=indexDateFrom&dateDebut=&dateFin=&typesf=opinions%2Fgenerated.AVISMedicament&search_antido
t=&portlet=c_39085&sort=pdate&replies=50
27
CEPS
http://www.sante.gouv.fr/comite-economique-des-produits-de-sante-ceps.html
L’objet du site est:

de décrire les missions du CEPS,

de décrire son organisation et son fonctionnement,

de retracer son activité,

de fournir les informations de base concernant le prix des médicaments et les tarifs des dispositifs
médicauxainsi que les informations pratiques relatives au dépôt et au traitement des demandes.
EUROPE
http://www.mhra.gov.uk/
 Final reminder to cancel licences by the end of December 2014
Periodic fees and cancellation of licences - holders of authorisations, registrations and licences are required
to notify the MHRA by 31 December 2014 to cancel authorisations, registrations and licences from 31
March 2015. If you have not cancelled them yet please do so as soon as possible.
This will ensure that you are not liable for a periodic fee in connection with a specific licence for the fee
period 1 April 2015 to 31 March 2016.
Regulation 37 (5) (a) of the Medicines (Products for Human Use) (Fees) Regulations 2013 SI 2013
No.532 requires authorisation, registration or licence holders to give three-months notice to the licensing
authority before the beginning of a fee period (ie 1 April) if they wish to cancel a licence. They will then not
be liable for the periodic fee. … (Source: MHRA)
 ARSAC application forms
Application and renewal forms for a certificate from the Administration of Radioactive Substances Advisory
Committee (ARSAC).
ARSAC form: full application (Source: Gov.Uk)
 Big pharma opens up abandoned drugs
68 stalled pharmaceutical compounds are being made available for academic research through the UK
Medical Research Council (MRC). Seven major drug companies, including AstraZeneca (AZ) and Pfizer, have
partnered with the MRC to release molecules that dropped out of their pipelines.
28
The new initiative takes its cue from an existing collaboration between the MRC and AZ, which has allowed
researchers access to 22 of its compounds. AZ, Pfizer, GlaxoSmithKline, Janssen, Lilly, Takeda and UCB have
all contributed to the library of deprioritised pharma molecules. The library includes compounds that were
initially developed for diseases such as cancer and diabetes. However, their development stalled during
testing for various reasons.
‘These compounds are valuable to academic researchers,’ said UK business secretary Vince Cable when he
announced the partnership in July 2014. ‘Repurposing abandoned compounds could lead to the
development of new medicines for many debilitating conditions.’ The MRC hopes to expand the
partnership to include more companies and molecules in the future. … (Source: RSC)
 NHS cost watchdog in favour of Bayer's Xofigo
It is looking likely that patients with prostate cancer will, in certain circumstances, get ‘routine’ access to
treatment with Bayer’s Xofigo (radium 223) on the National Health Service in England and Wales.
The National Institute for Health and Care Excellence has published draft guideline’s endorsing the drug as
an option to treat adults with hormone-relapsed prostate cancer, symptomatic bone metastases and no
known visceral metastases.
But this only extends to patients who have already been treated with docetaxel, and the recommendation
is contingent upon on Bayer providing the drug with a confidential discount agreed in a patient access
scheme.
Xofigo is a radio-pharmaceutical agent designed to directly deliver alpha radiation to bone metastases
without affecting normal bone marrow. Bayer estimates the average cost for a six-month course with the
drug (administered intravenously every four weeks) to be around £24,240.
In March NICE issued draft guidance rejecting the drug’s use after calculating its incremental costeffectiveness ratio to be around £57,000 per QALY gained, and thus outside value-for-money boundaries.
But now its Expert Review Group has concluded that the drug is likely to be a cost-effective option for those
patients pre-treated with docetaxel. … (Source: PharmaTimes)
 Drug Safety Update: December 2014 (Volume 8, Issue 5)
(Source: MHRA)
http://www.nice.org.uk/
 NICE greenlights dabigatran for treatment of blood clots
In latest guidance, NICE recommends the drug as an option for treating and preventing recurrent deep vein
thrombosis (DVT) and pulmonary embolism in adults.
29
Around 1 in every 1000 people in the UK is affected by DVT, a condition that increases in risk with age.
Further risk factors include a previous DVT or pulmonary embolism, obesity and the presence of
comorbidities such as heart disease.
In current practice, people with suspected DVT or a pulmonary embolism are generally treated immediately
with anticoagulant drugs, most commonly with injections of low molecular weight heparin.
When the diagnosis has been confirmed, it is overlapped with an oral anticoagulant, such as warfarin. The
usual length of treatment is for 3 months or more, though this can be life-long in certain patients to
prevent further episodes.
However, some patients find warfarin inconvenient due to the need for careful monitoring, and regular
blood tests which require frequent clinic visits to ensure the blood’s clotting properties remain within
acceptable limits.
Following guidance published today, patients can now be offered dabigatran etexilate to prevent recurring
DVT and pulmonary embolism in adults.
Professor Carole Longson, NICE Health Technology Evaluation Centre Director, said: “For many people,
using warfarin can be difficult because of the need for frequent tests to see if the blood is clotting properly,
and having to adjust the dose of the drug if it is not.
“The Appraisal Committee felt that dabigatran represents a potential benefit for many people who have
had a DVT or a pulmonary embolism, particularly those who have risk factors for recurrence of a blood clot
and who therefore need longer term treatment.
“We are pleased, therefore, to be able to recommend dabigatran as a cost-effective option for treating DVT
and pulmonary embolism and preventing further episodes in adults.” … (Source: NICE)
 NICE U-turn backs biologics for ulcerative colitis
The National Institute for Health and Care Excellence has reversed a previous guidance and recommended
use on the NHS of three big-selling biologics - Merck & Co’s Remicade and Simponi and AbbVie’s Humira for treating moderately to severely active ulcerative colitis.
The cost watchdog has issued its final appraisal document to allow use of Remicade (infliximab), Simponi
(golimumab) and Humira (adalimumab) within their marketing authorisations, as options for UC.
Specifically, they can be prescribed for adults whose disease has responded inadequately to conventional
therapy including corticosteroids and mercaptopurine or azathioprine, or who cannot tolerate these drugs.
Simponi is recommended only if Merck provides the 100mg dose at the same cost as the 50mg dose, as
agreed in the patient access scheme. Also the NICE FAD has backed Remicade as an option for severely
active UC in children and young people aged six-17.
This is the first time children have been granted access to these therapies in the UK. Previously, access was
limited to children with acute severe UC as an alternative to ciclosporin and in Scotland only.
Previously NICE restricted the use of biologics only for those hospitalised with severe UC, and issued
guidance rejected them in September. However, after working with stakeholders, the agency has now
changed that and Merck notes that the decision offers “a much-needed alternative to colectomy”. …
(Source: PharmaTimes)
30
 Fluorouracil chemotherapy: the My5-FU assay for guiding dose
adjustment
NICE has assessed the My5-FU assay to help the NHS decide whether to use this product.
The My5-FU assay is used to measure levels of 5-fluorouracil (5-FU) in blood samples of patients having 5FU chemotherapy. These measurements may guide changes to the dose of 5-FU so it is enough to treat the
cancer, but is not toxic to the patient.
NICE has recommended the My5-FU assay only for use in research for guiding changes to the 5-FU dose
given during chemotherapy. The technique shows promise, and NICE recommends that more evidence on
its use in NHS clinical practice is needed. … (Source: NICE)
 Psoriatic arthritis (active) - ustekinumab (Rapid Rev TA313) [ID819]

Psoriatic arthritis (active) - ustekinumab (Rapid Rev TA313): appraisal consultation document

Psoriatic arthritis (active) - ustekinumab (Rapid Rev TA313): committee papers
 Latest Consultation
Virtual Touch Quantification to diagnose and monitor liver fibrosis: 17 December 2014 - 19
consultation
January 2015
Diagnosing prostate cancer - PROGENSA PCA3 assay and Prostate Health 17 December 2014 - 12
Index: consultation
January 2015
Bipolar disorder, psychosis and schizophrenia in children and young people:
topic engagement exercise
15 December 2014 - 08
January 2015
Prostate cancer (hormone relapsed, bone metastases) - radium-223 15 December 2014 - 09
dichloride [ID576]: appraisal consultation 2
January 2015
http://www.hpra.ie/
 Update on national oral anticoagulant monitoring experience
published
The HPRA has posted a summary update of recent experience with old and new oral anticoagulants. The
older oral anticoagulants, such as warfarin, are vitamin K antagonists. The newer oral anticoagulants,
apixaban (Eliquis), dabigatran (Pradaxa) and rivaroxaban (Xarelto), collectively known as ‘NOACs’, exert
their effects through inhibition of factor Xa or of thrombin, and are subject to additional monitoring, both
at the national and EU level. … (Source: HPRA)
31
 HPRA publishes reminder of importance of liver function monitoring
with Agomelatine (Valdoxan)
Agomelatine is a melatonergic agonist (MT1 and MT2 receptors) and 5-HT2C antagonist indicated in the
treatment of major depressive episodes in adults, authorized for use in the EU since 2009. Since
agomelatine has a different mode of action and a different safety profile to existing antidepressants, it was
concluded that, as long as their liver function is tested regularly, agomelatine could be a valuable treatment
for some patients. In the post marketing setting, hepatic adverse reactions have continued to be reported
and although a recent EU level review concluded that the benefit risk balance for the drug remains positive,
the HPRA has issued a reminder of the importance of liver monitoring during treatment. … (Source: HPRA)
http://www.fagg-afmps.be/fr/
http://www.bfarm.de/DE/Home/home_node.html
 Germany Names 16 Firms with Drugs Suspended Over Concerns of
Clinical Trials Conducted by an Indian Firm
Germany has named 16 generic drugmakers, including Stada and Dr. Reddy's, that produce drugs affected
by its suspension of marketing approval over concerns about clinical trials conducted by an Indian
company.
Regulators in France, Germany, Belgium and Luxembourg last week suspended marketing approval for 25
drugs over the quality of trial data from India's GVK Biosciences.
Germany's Federal Institute for Drugs and Medical Devices (BfArM) on Tuesday published a list of 80
affected products, including multiple entries for different dosages of the same active ingredients, and the
drugmakers that marketed them.
The companies affected also include U.S. drugmaker Mylan as well as German subsidiaries of India's
Torrent Pharmaceuticals and Lupin.
The drugs include generic versions of blood thinner Plavix, also called clopidogrel, or generic version of
heartburn treatment Nexium, or esomeprazol.
BfArM said there is no shortage of freely available treatments that have the same active ingredients as the
suspended drugs.
French and German regulators have said they were investigating the drug approvals based on clinical trials,
which were meant to show that these generic drugs were equivalent to the original branded versions,
conducted by GVK Bio between 2008 and 2014.
The regulators said that anomalies were found in the way electrocardiograms (ECG) were monitored by
GVK Biosciences during the bioequivalence studies. GVK has disputed the findings.
Germany's BfArM reiterated on Tuesday that there have been no signs that the health of patients was put
at risk.
(Reporting by Ludwig Burger; Editing by David Goodman)
32
 Valproate and related substances: risks to the unborn child in the
event of exposure during pregnancy
The marketing authorization holders of drugs containing valproate and related substances has informed
BfArM that valproate may be used in female adolescents and women of childbearing age for the treatment
of manic episodes in bipolar disorder and for the treatment of epilepsy only if other drugs are not effective
or not tolerated.
As part of the risk mitigation measures adopted at the European level by the CMDh, training materials and
a form for confirmation of the risk disclosure are being provided to physicians and patients.
Form for confirmation of the risk disclosure - treatment of patients with valproate
Guide for medical professionals
 Procoralan (ivabradine): new contraindication and recommendations
to minimize risk of cardiovascular events and severe bradycardia
Servier Germany GmbH has informed BfArM that the concomitant use of ivabradine with verapamil or
diltiazem is now contraindicated. In the symptomatic treatment of patients with chronic stable angina
pectoris, treatment with ivabradine should only be started when the resting heart rate of the patient is
greater than or equal to 70 beats per minute. … (Source: BfArM)
 IQWiG begins evaluation of simoctocog alfa (Nuwig)
IQWiG has launched an assessment of simoctocog alfa (Nuwig), a recombinant blood coagulation factor VIII
manufactured by Octapharma AB. … (Source: IQWIG)
 Autumn Symposium 2014: papers and posters online now
On the occasion of its 10th anniversary, IQWiG’s symposium took a look into the future. Discussion
centered around the direction that evidence-based care should take, and what IQWiG can contribute to the
challenges ahead. The presentations from the symposium are now available online. … (Source: IQWIG)
http://www.agenziafarmaco.gov.it/en
 AIFA hosts national Fakeshare conference
What drugs can be purchased online? Through which entities? With what guarantees? How do you
distinguish an illegal online pharmacy from a legitimate one? These were the themes covered during the
national Fakeshare conference held last week in Rome, entitled "Drugs online: the protection of patients."
The conference provided an overview of the communication and awareness activities and initiatives in
connection with the risks of buying medicines from unauthorized channels.
"Fakeshare" is a European cooperation and intelligence project, which aims to share information on illegal
pharmacies through a dedicated web platform. Together with AIFA, lead manager of Fakeshare, other
participants include the regulatory authorities of Portugal and Spain, the Sapienza University of Romea, the
University of Trento and the Ministry of Economic Development. Partners include the Carabinieri for the
33
Protection of Health-NAS, the UK’s Pharmaceutical Security Institute, the European Federation of
Pharmaceutical Industries and Associations (EFPIA), the regulatory agency of Chile and experts in the IT
industry such as the US agency LegitScript. It also supports activities of the Alliance for Safe Online
Pharmacies (ASOP). Launched in 2013, the project is co-financed by the European Commission under the
program "Prevention of and Fight against Crime". … (Source: AIFA)
http://www.aemps.gob.es/en/home.htm
 Latin American drug regulatory authorities to strengthen cooperation
Heads of State and government officials from Ibero-American countries, meeting in Veracruz, Mexico,
during the XXIV Iberoamerican Summit issued a statement with a decision to strengthen cooperation
between the Latin American drug regulatory health authorities and recognizing their work over the years as
key to securing the the efficacy, safety and quality of medicines. Numerous projects and initiatives have
been developed within the group since its inception in February 1997 in Madrid in areas such as increased
safety in the use of drugs, efforts to combat counterfeit and fraudulent medicines, increases in protection
of the rights of research subjects and strengthening of evaluating bioequivalence studies. … (Source:
AEMPS)
 Coordination Group for Therapeutic Positioning meeting summary
posted
The AEMPS’ Coordination Group for Therapeutic Positioning agreed at its meeting on December 2 to begin
consideration of drugs that received a positive opinion at the November meeting of the European
Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP). Drugs to be considered
include:
• Cerdelga (eliglustat): Genzyme Europe BV for the treatment of type 1 Gaucher disease.
• Cosentyx (secukinumab): Novartis Europharm Ltd. for the treatment of psoriasis.
• Exviera (dasabuvir): AbbVie Ltd for the treatment of chronic hepatitis C.
• Ofev (nintedanib): Boehringer Ingelheim International GmbH for the treatment of idiopathic pulmonary
fibrosis.
• Otezla (apremilast): Celgene Europe Ltd. for the treatment of psoriasis.
• Viekirax (ombitasvir / paritaprevir / ritonavir): AbbVie Ltd for the treatment of chronic hepatitis C.
• Zontivity (vorapaxar): Merck Sharp & Dohme Ltd. for the reduction of atherothrombotic events.
 Committee for Medicines for Human Use posts summary of
December meeting
The AEMPS Committee for Medicines for Human Use (CMH) has posted a summary of its meeting on
December 10th, listing new brand and generic drug approvals.
34
 AEMPS updates information on its Pharmacovigilance and PostAuthorization Study Committees
AEMPS has updated the information on its website relating to its Technical Committee of the Spanish
Pharmacovigilance System for Medicinal Products for Human Use and its Committee for the Coordination
of Post-Authorization Studies,
 AEMPS posts recommendations on safe use of mycophenolate
immunosuppressants
Both mycophenolate mofetil and mycophenolate sodium as prodrugs are absorbed rapidly after they are
administered, and completely transformed into their active drug form, mycophenolic acid, endowed with
potent cytostatic effects on T and B lymphocytes. In combination with cyclosporine and corticosteroids,
mycophenolate sodium is indicated for the prophylaxis of acute rejection in adult patients undergoing
allogeneic renal transplantation and mycophenolate mofetil for prophylaxis of acute transplant rejection
and the same heart and liver.
When administered in combination with other immunosuppressants, these drugs can cause
hypogammaglobulinemia and bronchiectasis. AEMPS is cautioning:
• There must be a determination of serum immunoglobulins in all patients treated with mycophenolate
(mofetil and sodium) who develop recurrent infections.
• In cases of clinically relevant sustained hypogammaglobulinemia, the most appropriate clinical action
should be considered.
• Monitoring is recommended as early as possible in patients who develop persistent pulmonary symptoms
such as cough and dyspnea. … (Source: AEMPS)
http://www.legemiddelverket.no/English/Sider/default.aspx
http://www.lakemedelsverket.se/english/
 MPA report favors development of progressive approval
The Swedish government in 2013 commissioned the MPA to study various international initiatives and
processes for the progressive approval and pricing of new drugs. The assignment also included
consideration of a common national position, proposal of measures that contribute to developing the
process, and assessment of whether the process is consistent with the European regulatory system.
The report issued by the MPA on December 8th states that there is consensus on the need to move
ahead with further measures to develop progressive approval and finding ways of contributing from a
national perspective. The Swedish health care system and individual-based registry provide the foundation
for a good infrastructure for monitoring and Sweden can strongly contribute to the further development of
progressive approval, says Brother Jonzon at the MPA. It is important that collaboration between
government, healthcare and pharmaceutical manufacturers develop further and start early in drug
development. Progressive approval builds on earlier regulatory initiatives to stimulate drug development in
the desired direction. Concepts such as Adaptive Licensing, Staggered Approval, and the Medicines
35
Adaptive Pathways to Patients are used interchangeably internationally to describe the concept of tiered
approval. … (Source: Lakemedelsverket)
http://www.eum.hu/about-us/the-ministry/ministry-of-health
http://www.swissmedic.ch/index.html?lang=fr
 Manipulation d’études cliniques par la société GVK Bioscience – La
Suisse peu concernée
Une inspection menée par l’autorité française « Agence nationale de sécurité du médicament » (ANSM) en
juillet 2014 auprès de la société GVK Biosciences, sise à Hyderabad (Inde), a mis au jour des infractions aux
règles des « Bonnes Pratiques Cliniques ».
Les manipulations de données effectuées par l’entreprise GVK Biosciences dans le cadre de la réalisation
d’études de bioéquivalence constituent une infraction majeure aux règles régissant la conduite des études
cliniques. Les études de bioéquivalence sont effectuées principalement pour des médicaments contenant
des principes actifs connus (appelés « génériques ») et visent à démontrer la comparabilité thérapeutique
entre ces médicaments et les préparations originales.
Swissmedic prend ces accusations très au sérieux. L’analyse des données est toujours en cours et devrait
être achevée d’ici la fin du mois de janvier 2015. Au vu cependant des documents d’autorisation examinés à
ce jour et parce que le nombre de génériques commercialisés est nettement supérieur en Europe qu’en
Suisse, Swissmedic estime qu’un nombre bien moindre de préparations sont concernées qu’en France ou
en Allemagne, par exemple.
Swissmedic a ouvert une procédure de réexamen pour les quelques produits déjà identifiés. S’il se
confirmait que des médicaments ont obtenu une autorisation de mise sur le marché en Suisse sur la base
de données expérimentales manipulées, cela signifierait que les conditions d’autorisation ne sont plus
remplies. Swissmedic prononcerait dès lors la suspension ou le retrait de l’autorisation de mise sur le
marché de ces préparations, qui seraient donc retirées du marché.
Important: Les manipulations de données constatées par l’ANSM sont sans conséquence sur la sécurité
d’utilisation des médicaments concernés. Swissmedic n’a en effet reçu aucun signalement d’éventuels
dangers pour la santé des patients. De plus, si les préparations concernées s’avéraient peu ou pas efficaces,
Swissmedic aurait reçu des annonces en nombre, ce qui n’a jusqu’à présent pas été le cas.
Ces derniers jours, certaines autorités sanitaires européennes ont publié des communiqués d’information
annonçant la suspension (c.-à-d. le retrait temporaire) des autorisations de mise sur le marché de
médicaments qui avaient été délivrées sur la base d’études réalisées par la société GVK Biosciences.
D’autres, à l’instar de Swissmedic, ont préféré ne pas prendre encore une telle mesure.
L’Agence européenne du médicament (EMA) recense actuellement tous les produits concernés en Europe.
Par ailleurs, une évaluation scientifique de toutes les données disponibles est en cours, qui vise à
déterminer les conséquences pour les produits concernés. L’EMA devrait publier fin janvier 2015 une
recommandation sur les mesures à prendre. Swissmedic suit avec attention les développements de ce
dossier dans l’UE et la recommandation de l’EMA sera prise en considération dans la décision qui sera
rendue en Suisse. … (Source: SwissMedic)
36
 Nouvelle étape dans la lutte contre les drogues de synthèse
Dans le cadre de sa lutte contre les nouvelles drogues de synthèse, la Suisse interdit vingt-neuf
substances ainsi que deux groupes de substances supplémentaires. Leur introduction dans l’Ordonnance
sur les tableaux des stupéfiants a en effet eu lieu le 1er décembre 2014.
Ces nouvelles substances sont assimilées aux stupéfiants, ce qui signifie que leur fabrication, leur
commerce et leur usage sont illégaux et passibles des sanctions pénales prévues dans la loi sur les
stupéfiants. Cette classification permet en outre aux services de police et des douanes de saisir
immédiatement les marchandises concernées. Avant que de nouvelles drogues de synthèse ne soient
soumises à la loi sur les stupéfiants, elles sont souvent vendues en toute légalité sur Internet comme sels
de bain, engrais pour plantes ou produits chimiques destinés à la recherche.
La loi sur les stupéfiants prévoit que les drogues de synthèse, appelées en anglais New Psychoactive
Substances (NPS), soient soumises à contrôle en raison de leur dangerosité. Les nouvelles drogues qui
circulent sont par conséquent régulièrement introduites dans les listes de substances de l'ordonnance, ce
qui permet de lutter efficacement contre leur propagation sur le marché noir. Eu égard à ce nouvel ajout,
plus de 150 drogues de synthèse sont aujourd'hui interdites.
S'agissant enfin des entreprises et des laboratoires qui utilisent les substances concernées au quotidien, la
loi prévoit la possibilité de demander une autorisation spéciale, qui est accordée au cas par cas et après
examen détaillé par le DFI.
Ordonnance sur les tableaux des stupéfiants – Modification du 3 novembre 2014 (PDF)
 Questions et réponses pour la mise en œuvre des nouvelles
dispositions de l’ordonnance sur les exigences relatives aux
médicaments (OEMéd; RS 812.212.22) du 1er Janvier 2013, concernant
l’emballage et l’étiquetage
(Source: SwissMedic)
Ministry of Health of Ukraine
http://www.kmu.gov.ua/control/en/publish/article?art_id=88456
MIDDLE EAST & AFRICA
 TITCK updates certified testing centers
The TITCK has updated the list of testing centers that have been inspected and certified to conduct
bioavailability and bioequivalence testing, and Phase I clinical testing. … (Source: TITCK)
37
 The first conference for medicines regulatory authorities
in Sudan and neighbouring countries
Sudan hosted the first conference of medicines regulatory authorities in neighbouring countries from 6 to 8
December 2014, with the participation of representatives of medicines regulatory authorities from Central
Africa Republic, Chad, Congo, Egypt, Eritrea, Ethiopia, Jordan, Kenya, Saudi Arabia, South Sudan, Tanzania,
and Uganda. The World Health Organization (WHO), the European Medicines Agency (EMA) and the African
Union (AU) took part of the event given their role in the regulation and control of medicines. The
conference aimed at improving the coordination and cooperation between the neighbouring countries and
consequently to promote the unification of medicines legislation between them. … (Source: EMA)
RUSSIA & RELATED COUNTRIES
Ministry of Healthcare of the Russian Federation
http://government.ru/eng/power/23/
 Roszdravnadzor urges evaluation of affordability of essential drugs
Roszdravnadzor is advising regional leaders on the need for stricter control over the affordability of
medicines included in the list of vital and essential drugs (VED), which is approved annually by the federal
government. Under existing law, regional state control over use of the VED listed price is the responsibility
of regional federal authorities. A recent assessment by Roszdravnadzor, however, showed that this issue
does not receive appropriate attention in some of regions. Roszdravnadzor is recommending that regional
leaders instruct federal executive authorities to evaluate the affordability of VED, with particular attention
to wholesale and government pricing, as well as the adequacy of the range of drugs in regional pharmacy
organizations. … (Source: Roszdravnadzor)
 Roszdravnadzor approves 35 new drugs
Roszdravnadzor approved 35 new medicinal products during the period from November 7 to November 25,
2014. … (Source: Roszdravnadzor)
NORTH AMERICA
http://www.fda.gov/
 Update From the Office of Surveillance and Epidemiology - 11
December 2014
FDA - Update From the Office of Surveillance and Epidemiology - 11 December 2014.pdf
38
 Patient Counseling Information Section of Labeling for Human
Prescription Drug and Biological Products — Content and Format
FDA - Patient Counseling Information - Biologicals Dec 2104.pdf
 FDA issues draft track and trace reporting guidance
The FDA has issued draft guidance on the annual reporting requirements for prescription drug wholesale
distributors and third-party logistics providers (3PLs) as required under the Drug Supply Chain Security Act
of 2013 (DSCSA). Under the DSCSA, wholesale distributors and 3PLs are required to report certain facility
and state licensure information to FDA on an annual basis. 3PLs were required to begin reporting this
information as of November 27, 2014, and wholesale distributors must begin to report on January 1, 2015.
Wholesale distributors must also report to FDA any significant disciplinary actions taken by the State or
Federal Government, such as revocation or suspension of a license. … (Source: FDA)
 FDA releases draft guidance on clinical pharmacology in pediatric
studies
The FDA has released draft guidance with advice for sponsors of pediatric clinical studies on the clinical
pharmacology information that would support findings of effectiveness and safety and facilitate the
identification of appropriate doses in pediatric populations. The guidance also describes the use of
quantitative approaches (i.e., pharmacometrics) to employ disease and exposure-response knowledge from
relevant prior clinical studies.
Comments on the draft guidance are due February 9, 2015. … (Source: FDA)
 FDA issues draft guidance on patient counseling information
Draft guidance released last week by the FDA is intended to establish consistency in the format and content
of the drug labeling information necessary for a health care provider to counsel a patient (or caregiver
when applicable) on the safe and effective use of the drug. The guidance provides recommendations on
how to select the information to include in the PATIENT COUNSELING INFORMATION section of the
labeling, and establishes enhanced consistency for the content and format of the section. … (Source: FDA)
 CDER posts bioequivalence guidance for Budesonide
The CDER has posted recommendations concerning the bioequivalence testing that should be conducted
for the active ingredient Budesonide. … (Source: FDA)
 CDER New Drug Review - 2014 update
CDER New Drug Review - 2014 update.pdf
December 11, 2014 Approval Letter - Fluzone Intradermal Quadrivalent
December 10, 2014 Approval Letter -GARDASIL 9
December 9, 2014 Approval Letter - TRUMENBA
December 8, 2014 Approval Letter - MMR II
FDA approves Gardasil 9 for prevention of certain cancers caused by five additional types of HPV
39
FDA expands approved use of Cyramza to treat aggressive non-small cell lung cancer
 CDER posts update on OSE
The CDER has posted the update presentation on the Office of Surveillance and Epidemiology (OSE) made
by the OSE Director, Gerald Dal Pan, at the FDA/CMS Summit on December 11, 2014. … (Source: FDA)
 The Top 15 Biologics Deficiencies Cited by FDA in 2014
The US Food and Drug Administration (FDA) has released data on the observations it makes during
inspections of biologics manufacturing facilities, indicating the most common issues faced by biologics
companies.
Total 483s Issued Declines for First Time in Six Years
In its most recent report, FY 2014 Inspectional Observation Summaries, FDA said it issued 146 Form 483s—
forms indicating areas of noncompliance at a facility—to biologics companies in fiscal year 2014.
The number of 473s issued (146) is the lowest since FDA began keeping track of its 483 inspection data in
2006, and is the fifth consecutive year FDA has issued fewer 483s to biologics companies than the year
prior.
The Top 15 Biologics Deficiencies in FDA's 483 Reports
FDA's inspections also noted common deficiencies by biologics manufacturers.
Regulatory
Citation
Short Description
21
CFR Maintained and followed
606.100(b)
Long Description
Frequency
Written standard operating procedures 77
including all steps to be followed in the
40
[collection]
[processing]
[compatibility
testing] [storage] [distribution] of blood and
blood components for [homologous
transfusion]
[autologous
transfusion]
[further manufacturing purposes] are not
always [maintained] [followed] [maintained
on the premises].
21
CFR Concurrent documentation
606.160(a)(1)
Records are not concurrently maintained 23
with the performance of each significant
step in the [collection] [processing]
[compatibility
testing]
[storage]
[distribution] of each unit of blood and
blood components so that all steps can be
clearly traced.
21
CFR Thorough investigations
606.100(c)
Failure to [perform a thorough investigation] 21
[make a record of the conclusions and
follow-up] of [an unexplained discrepancy]
[a failure of a lot or unit to meet any of its
specifications].
21 CFR 606.171
Biological product deviation Failure to submit a biological product 20
report
deviation report [within 45 days from the
date you acquired information suggesting
that a reportable event occurred].
21
CFR Required records
606.160(b)
21
CFR Person performing,
606.160(a)(1)
results, interpretation
21
606.60(a)
Failure to maintain [donor] [processing] 16
[storage and distribution] [compatibility
testing] [quality control] [general] records.
test Records fail to [identify the person 16
performing the work] [include dates of the
various entries] [show test results] [include
interpretation of the results] [show the
expiration date assigned to specific
products] [be as detailed as necessary] so as
to provide a complete history of the work
performed.
CFR Equipment
observed, Equipment used in the [collection] 11
standardized, calibrated
[processing] [compatibility testing] [storage
and distribution] of blood and blood
components is not [observed] [standardized]
[calibrated] on a regularly scheduled basis as
41
prescribed in the SOP Manual.
21
606.65(e)
CFR Following
manufacturer's Failure to use supplies and reagents in a 10
instructions
manner consistent with instructions
provided by the manufacturer.
21
CFR Written SOPs available for Failure to make available written procedures 8
606.100(b)
use by personnel
for use by personnel in the areas where the
procedures are performed.
21
CFR Record
606.100(c)
release
review
prior
21
CFR Legibility and indelibility
606.160(a)(1)
21
606.20(b)
to All records pertinent to a lot or unit were 8
not reviewed before the release or
distribution of a lot or unit of final product.
Records are [illegible] [not indelible].
8
CFR Qualifications of responsible The personnel responsible for the 7
personnel
[collection]
[processing]
[compatibility
testing] [storage] [distribution] of blood or
blood components are not adequate in
[number] [educational background] [training
and experience, including professional
training as necessary] to assure competent
performance of their assigned functions, and
to ensure that the final product has the
safety, purity, potency, identity and
effectiveness it purports or is represented to
possess.
21
CFR Provide
space
606.40(a)(1)
examination
21
606.60(b)
CFR Equipment
frequency
21
606.60(a)
CFR Maintain
equipment
for Failure to provide adequate space for 7
[private] [accurate] examinations of
individuals to determine their suitability as
blood donors.
calibration Equipment
used
in
the 6
[collection][processing][compatibility
testing][storage and distribution] of blood
and blood components is not observed,
standardized and calibrated with at least the
frequency required.
and
clean Failure to [maintain] [locate] equipment 5
used in the [collection] [processing]
[compatibility
testing]
[storage]
42
[distribution] of blood and blood products
[in a clean and orderly manner] [so as to
facilitate cleaning and maintenance].
(Source : Raps)
 The Top 15 Pharmaceutical Deficiencies Cited by FDA in 2014
The US Food and Drug Administration (FDA) has released data on the observations it makes during
inspections of pharmaceutical facilities, indicating the most common issues faced by pharmaceutical
companies.
Total 483s Issued Declines for First Time in Six Years
In its most recent report, FY 2014 Inspectional Observation Summaries, FDA said it issued 645 Form 483s—
forms indicating areas of noncompliance at a facility—to pharmaceutical companies in fiscal year 2014.
The number of 473s issued (645) marked the second consecutive year FDA has issued fewer pharmaceutical
483s than the year prior, and the 2014 total (645) is 19% less than its 2012 high water mark (787
inspections).
The Top 15 Pharmaceutical Deficiencies in FDA's 483 Reports
FDA's inspections also noted common deficiencies by pharmaceutical manufacturers.
Regulatory
Citation
Short Description
Long Description
Frequency
21 CFR 211.22(d) Procedures not in writing,
fully followed
The responsibilities and procedures applicable to the
quality control unit are not [in writing] [fully followed].
21 CFR
211.160(b)
Laboratory controls do not include the establishment of 109
scientifically sound and appropriate [specifications]
[standards] [sampling plans] [test procedures]
designed to assure that [components] [drug product
Scientifically sound
laboratory controls
43
145
containers] [closures] [in-process materials] [labeling]
[drug products] conform to appropriate standards of
identity, strength, quality and purity.
21 CFR 211.192
Investigations of
discrepancies, failures
There is a failure to thoroughly review [any
unexplained discrepancy] [the failure of a batch or any
of its components to meet any of its specifications]
whether or not the batch has been already distributed.
94
21 CFR
211.100(a)
Absence of Written
Procedures
There are no written procedures for production and
process controls designed to assure that the drug
products have the identity, strength, quality, and purity
they purport or are represented to possess.
87
21 CFR 211.67(b) Written procedures not
established/followed
Written procedures are not [established] [followed] for
the cleaning and maintenance of equipment, including
utensils, used in the manufacture, processing, packing
or holding of a drug product.
72
21 CFR
211.113(b)
Procedures for sterile drug
products
Procedures designed to prevent microbiological
contamination of drug products purporting to be sterile
are not [established] [written] [followed].
72
21 CFR
211.165(a)
Testing and release for
distribution
Testing and release of drug product for distribution do
not include appropriate laboratory determination of
satisfactory conformance to the [final specifications]
[identity and strength of each active ingredient] prior to
release.
64
21 CFR 211.67(a) Cleaning / Sanitizing /
Maintenance
Equipment and utensils are not [cleaned] [maintained]
[sanitized] at appropriate intervals to prevent
[malfunctions] [contamination] that would alter the
safety, identity, strength, quality or purity of the drug
product.
63
21 CFR 211.68(a) Calibration/Inspection/Chec
king not done
Routine [calibration] [inspection] [checking] of
[automatic] [mechanical] [electronic] equipment is not
performed according to a written program designed to
assure proper performance.
54
21 CFR
211.166(a)
Lack of written stability
program
There is no written testing program designed to assess 51
the stability characteristics of drug products.
21 CFR
211.110(a)
Control procedures to
monitor and validate
performance
Control procedures are not established which [monitor
the output] [validate the performance] of those
manufacturing processes that may be responsible for
causing variability in the characteristics of in-process
material and the drug product. "
51
21 CFR
211.198(a)
Complaint Handling
Procedure
Procedures describing the handling of written and oral
complaints related to drug products are [not written or
followed] [deficiently written or followed].
47
21 CFR 211.25(a) Training--operations, GMPs, Employees are not given training in [the particular
written procedures
operations they perform as part of their function]
[current good manufacturing practices] [written
procedures required by current good manufacturing
practice regulations].
46
21 CFR
211.100(b)
SOPs not followed /
documented
Written production and process control procedures are
not [followed in the execution of production and
process control functions] [documented at the time of
performance].
43
21 CFR 211.188
Prepared for each batch,
include complete
information
Batch production and control records [are not prepared 43
for each batch of drug product produced] [do not
include complete information relating to the production
and control of each batch].
(Source : RAPS)
44
 FDA - Advisory Committee Calendar
 January 22, 2015: Anti-Infective Drugs Advisory Committee Meeting Announcement
 January 12, 2015: Endocrinologic and Metabolic Drugs Advisory Committee Meeting Announcement
 January 7, 2015: Oncologic Drugs Advisory Committee Meeting Announcement
 CDER posts web updates
The CDER has updated information on the status of drug firm annual registration, FDA data files, the
medication guides page and the National Drug Code Directory.
Drugs@FDA Data Files
Drug Firm Annual Registration Status
Drug Firm Annual Registration Status Download File
Medication Guides Page
National Drug Code Directory
 FDA seeks input on changes to Adverse Event Reporting Forms
The FDA is seeking input on its proposed changes to the adverse event reporting forms 3500, 3500A and
3500B. Changes would make it easier for FDA to scan in forms using optical character recognition
software. Comments are due February 9, 2015. … (Source: GPO)
 Arca's potential Ebola drug gets 'orphan drug status'
Arca Biopharma Inc said the U.S. Food and Drug Administration granted its experimental drug orphan drug
status as a potential treatment for viral hemorrhagic fever after exposure to the Ebola virus.
The Westminster, Colorado-based company, whose stock rose about 11 percent on Wednesday, joins a list
of drugmakers looking for ways to fight the largest Ebola outbreak on record, which has killed at least 6,300
so far.
Securing this designation accords the developer with several incentives, including fee waivers and seven
years of market exclusivity.
Arca's drug, rNAPc2, is a selective inhibitor of tissue factor (TF) - the protein responsible for initiating the
primary coagulation mechanism in humans.
The drug, which was originally being developed as a cardiovascular therapy for thrombosis among other
indications, has shown effectiveness against the Ebola and Marburg virus in animal models. … (Source:
reuters)
 FDA approves Novartis' Signifor drug for rare hormonal disorder
U.S. health regulators have approved Novartis' drug Signifor LAR as a treatment for a rare and lifethreatening hormonal disorder, the Swiss drugmaker said on Tuesday.
The Basel-based firm said the U.S. Food and Drug Administration (FDA) backed its drug Signifor LAR to treat
acromegaly in adults for whom surgery is not an option, after two late-stage studies showed the drug
allowed for greater disease control than existing therapies. … (Source: Reuters)
45
 Genentech receives FDA breakthrough therapy designation for
Lucentis
The U.S. Food and Drug Administration has granted breakthrough therapy designation for Lucentis for
treatment of diabetic retinopathy, according to an announcement from Genentech.
Previously, the FDA accepted the supplemental biologics license application and granted priority review
status for the drug, the announcement said.
Approval of Lucentis (ranibizumab) for treatment of diabetic retinopathy would be the fourth indication
approved for the drug since 2006, the announcement said. … (Source: Healio)
 FDA approves new version of Merck & Co's Gardasil
The US Food and Drug Administration has approved Merck & Co’s new version of Gardasil which protects
against an additional five strains of the human papillomavirus that causes most cases of cervical cancer.
Gardasil 9 has been given the green light for the prevention of certain diseases caused by nine types of
HPV, five more than Gardasil, approved by the FDA back in 2006. The agency added that Gardasil 9 has the
potential to prevent approximately 90% of cervical, vulvar, vaginal and anal cancers.
The FDA noted that Gardasil 9 adds protection against five additional HPV types (31, 33, 45, 52 and 58)
which cause 20% of cervical cancers and are not covered by previously-approved HPV vaccines. It is
approved for use in females ages nine-26 and males (nine-15). … (Source: PharmaTimes)
 Sanofi Pasteur Announces FDA Approval of Fluzone Intradermal
Quadrivalent
Sanofi Pasteur, the vaccines division of Sanofi, today announced that the U.S. Food and Drug
Administration (FDA) has approved the supplemental biologics license application (sBLA) for Fluzone
Intradermal Quadrivalent vaccine. Fluzone Intradermal vaccine, which has been available in trivalent
formulation for three years, is now available in a quadrivalent formulation to help protect against four
strains of influenza virus. Fluzone Intradermal Quadrivalent vaccine is indicated for adults 18 through 64
years of age for active immunization for the prevention of influenza ("the flu") caused by influenza A
subtype viruses and type B viruses contained in the vaccine.
"Influenza B is a common cause of influenza-related morbidity and mortality across all age groups," said
David P. Greenberg, M.D., Vice President, Scientific & Medical Affairs, and Chief Medical Officer, Sanofi
Pasteur US. "Fluzone Intradermal Quadrivalent vaccine will offer another influenza vaccination option for
health care providers and their adult patients with broad coverage against influenza viruses that may be
predominant, coupled with the efficiency of using the intradermal microinjection system."
Traditional three-strain—or trivalent—influenza vaccines contain two strains of influenza A and one strain
of influenza B. Influenza B represents 20 to 25 percent of circulating influenza strains and is associated with
substantial morbidity and mortality.i Two distinct families (lineages) of influenza B (Victoria and Yamagata)
have been co-circulating worldwide for over a decade, making it difficult to predict which will predominate
during a given season.ii,iii In fact, the Centers for Disease Control and Prevention (CDC) has noted that in six
(approximately 50 percent) of the past 13 influenza seasons (2001-2013), the B strain included in the
vaccine did not match the predominant B strain in circulation.ii,iii,iv,v,vi Accurately predicting which
influenza strains will predominate during the upcoming season is critical as the degree of match between
circulating and vaccine strains can significantly impact the effectiveness of seasonal influenza vaccines.vii
46
"An intradermal vaccine provides a similar level of protection to the traditional flu shot," said John Shiver,
Senior Vice President, Research and Development, Sanofi Pasteur. "Fluzone Intradermal Quadrivalent
vaccine offers four-strain protection in a microinjection system that is convenient, efficient and easy to use,
allowing for streamlined administration by health care providers."
Fluzone Intradermal Quadrivalent vaccine was developed to help address frequent B-strain mismatches and
broaden coverage against influenza by incorporating a B strain from each lineage. The vaccine is
administered directly into the skin through a small, 1.5 mm micro-needle, which is 90 percent smaller than
typical needles used for intramuscular injection of influenza vaccines. Because the skin has a high
concentration of immune cells, an intradermal vaccine is able to use the skin's natural defenses.xii In
addition, the microinjection system is ideal for those immunizing since it has a pre-affixed needle and a
needle shield. … (Source: Drugs)
 FDA approves 9-valent HPV vaccine for certain cancers
The FDA today approved a new vaccine for the prevention of certain diseases caused by HPV that has the
potential to prevent approximately 90% of anal, cervical, vaginal and vulvar cancers.
The recombinant HPV 9-valent vaccine (Gardasil 9, Merck) covers nine HPV types, which is five more than
the quadrivalent HPV vaccine (Gardasil).
The vaccine is indicated for females aged 9 to 26 years and males aged 9 to 15 years, and for cancers
caused by HPV types 16, 18, 31, 33, 45, 52 and 58 and for the prevention of genital warts caused by HPV
types 6 or 11.
The additional five types of HPV that Gardasil 9 adds protection against (31, 33, 45, 52 and 58) are the
cause of approximately 20% of cervical cancers and are not covered in previous FDA-approved HPV
vaccines.
“Vaccination is a critical public health measure for lowering the risk of most cervical, genital and anal
cancers caused by HPV,” Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and
Research, said in a press release. “The approval of Gardasil 9 provides broader protection against HPVrelated cancers.”
A randomized controlled international study was conducted using a cohort of approximately 14,000
females (median age, 21 years) who tested negative for vaccine HPV types at the start of the study. Patients
were randomly assigned Gardasil 9 or Gardasil.
Gardasil 9 was found to be 97% effective in preventing cervical, vulvar and vaginal cancers caused by the
additional HPV types.
In addition, Gardasil 9 was equally as effective as Gardasil in the prevention in the four other HPV types (6,
11, 16 and 18).
There is a low incidence of anal cancer caused by the five additional HPV types. As such, the preventive
analysis is based on Gardasil’s demonstrated effectiveness of 78% and additional data on antibodies in
males and females who received Gardasil 9.
For children aged 9 to 15 years, the effectiveness of Gardasil 9 was identified in studies that measured
antibody response to the vaccine. The study group consisted of approximately 1,200 males and 2,800
females. Their response was similar to participants aged 16 to 26 years. Therefore, the vaccine is expected
to have similar effectiveness in the younger age group.
Gardasil 9 is administered as three separate vaccinations, with the initial dose followed by additional
vaccinations 2 to 6 months later.
47
Indications are that patients vaccinated before becoming infected with the HPV strains would benefit the
most from Gardasil 9.
The safety of the agent was evaluated in approximately 13,000 males and females, and the most common
adverse effects were pain at the injection site, swelling, redness and headaches. … (Source: Healio)
 Roche files melanoma combo in USA
Roche’s Genentech unit has filed cobimetinib in combination with already-marketed Zelboraf with
regulators in the USA for the treatment of the deadliest form of skin cancer.
Specifically, cobimetinib, a MEK inhibitor which has been developed with Exelixis, has been submitted to
the US Food and Drug Administration for treatment, in combination with Zelboraf (vemurafenib), for
people with BRAF V600 mutation-positive advanced melanoma. The filing is based on results of the coBRIM
Phase III study, which showed that the combo improved progression-free survival compared to Zelboraf
alone (9.9 versus 6.2 months).
Roche chief medical officer Sandra Horning said “in the past several years we have made significant
progress in treating advanced melanoma, but it remains a serious and difficult to treat cancer that affects
more people each year”. She hopes that the combo “will soon become a new option for people with BRAF
mutation-positive advanced melanoma”. … (Source: PharmaTimes)
 FDA Approves Two Higher Dosage Strengths of Zubsolv
Orexo AB announces today that it has received approval from the U.S. Food and Drug Administration (FDA)
of two higher dosage strengths of Zubsolv (buprenorphine/naloxone CIII sublingual tablet) for maintenance
treatment of opioid dependence. The new dosage strengths are 8.6 mg/2.1 mg and 11.4 mg/2.9 mg
buprenorphine/naloxone CIII sublingual tablets. The 8.6 mg/2.1 mg dosage strength is expected to be
launched early 2015 and the 11.4 mg/2.9 mg strength later in 2015.
The new dosage strengths complement the existing strengths of 5.7 mg/1.4 mg and 1.4 mg/0.36 mg tablets
and enable patients to receive their optimal dose in one tablet. The new strengths are made with the
advanced, proprietary sublingual tablet formulation in Zubsolv providing higher bioavailability, a fast
dissolve time, small tablet size, and menthol flavor.
“Orexo remains fully committed to advancing the treatment of opioid dependence. During the summer, we
received positive data from the largest clinical trials ever conducted in this disease area. Today, we are
proud to announce that the FDA has approved two additional dosage strengths of Zubsolv. These higher
dosage strengths will allow more patients to get the right dosage in only one tablet and thus reduce the
need to combine different dosage strengths. This will improve patient convenience and adherence while
reducing their out-of-pocket cost as only one co-pay will be required,” said Nikolaj Sørensen, CEO and
President of Orexo AB.
The advanced formulation provided by Zubsolv meets the needs expressed by patients, such as improved
taste and fast dissolve time. Meeting patient needs may have the potential to improve patient adherence,
thus reducing relapse rates and improving successful patient outcomes. Zubsolv is the only opioid
dependence treatment option available in the highest level of child resistant, unit dose, F1 packaging,
designed to reduce the chance of unintended pediatric exposure. … (Source: Drugs)
48
 FDA Expands Approved use of Cyramza to Treat Aggressive Non-Small
Cell Lung Cancer
The U.S. Food and Drug Administration today expanded the approved use of Cyramza (ramucirumab) to
treat patients with metastatic non-small cell lung cancer (NSCLC). The most common type of lung cancer,
NSCLC occurs when cancer cells form in the tissues of the lung. The National Cancer Institute estimates that
224,210 Americans will be diagnosed and 159,260 will die from lung cancer in 2014.
Cyramza works by blocking the blood supply that fuels tumor growth. The drug is intended for patients
whose tumor has grown (progressed) during or following treatment with platinum-based chemotherapy,
and it is to be used in combination with docetaxel, another type of chemotherapy.
“Today’s approval is the third indication that Cyramza has received in 2014,” said Richard Pazdur, M.D.,
director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and
Research. “The commitment to study Cyramza in a variety of malignancies provides important treatment
options to patients.”
On April 21, the FDA approved Cyramza as a single agent to treat patients with advanced stomach cancer or
gastroesophageal junction (GEJ) adenocarcinoma, a form of cancer located in the region where the
esophagus joins the stomach. On November 5, the FDA expanded Cyramza’s use to treat patients with
advanced gastric or GEJ adenocarcinoma to include paclitaxel, another chemotherapy drug.
The approval of Cyramza plus docetaxel for metastatic NSCLC is based on a clinical study of 1,253
participants with previously treated and progressive lung cancer. Study participants were randomly
assigned to receive Cyramza plus docetaxel or a placebo plus docetaxel. Treatment was given until disease
progression or development of intolerable side effects.The trial was designed to measure overall survival,
the length of time a participant lived before death. Results showed that half of the participants treated with
Cyramza plus docetaxel survived an average of 10.5 months from the start of treatment, compared to an
average of 9.1 months from the start of treatment for half of the participants who received placebo plus
docetaxel.
The most common side effects associated with Cyramza plus docetaxel observed in the clinical study
included a decrease in infection-fighting white blood cells called neutrophils (neutropenia) fatigue and
inflammation of the lining of the mouth (stomatitis). Cyramza can cause severe bleeding, blood clots,
elevation in blood pressure and may impair wound healing. … (Source: Drugs)
 FDA approves Sanofi's quadrivalent flu vaccine
The FDA today approved an intradermal quadrivalent influenza vaccine containing two influenza A and two
influenza B strains, according to a press release from the manufacturer.
The Fluzone Intradermal Quadrivalent vaccine (Sanofi Pasteur) has been available in trivalent formulation
for the past 3 years. It is indicated for adults aged 18 to 64 years for active immunization and prevention of
influenza caused by influenza A subtype viruses and type B viruses.
“Influenza B is a common cause of influenza-related morbidity and mortality across all age groups,” David P.
Greenberg, MD, vice president of scientific and medical affairs and chief medical officer of Sanofi Pasteur
US, said in the press release. “Fluzone Intradermal Quadrivalent vaccine will offer another influenza
vaccination option for health care providers and their adult patients with broad coverage against influenza
viruses that may be predominant, coupled with the efficiency of using the intradermal microinjection
system.”
49
According to study data, influenza B accounts for 20% to 25% of circulating influenza strains. Tetravalent
vaccines provide coverage against only one B virus, and the co-circulation of two predominant lineages of
influenza B — Victoria and Yamagata — have made it challenging for experts to select which of these to
include in the vaccine. According to the CDC, influenza B strains included in vaccines did not match the
predominant B strain in circulation for approximately half of the influenza seasons during 2001-2013. …
(Source: Healio)
 Celgene ends stellar week with positive Abraxane data
After a highly successful American Society of Hematology meeting in San Francisco earlier this week,
Celgene has been further boosted by positive data for Abraxane at the San Antonio Breast Cancer
Symposium.
Results from a Phase III trial sponsored by the German Breast Group (GBG) demonstrated significant
benefit for patients on Abraxane (nab-paclitaxel) with early high risk breast cancer when compared to
conventional solvent-based paclitaxel. The 1,200-patient study found a statistically significant and clinically
meaningful 9% absolute improvement (from 29% to 38%) in the pCR (pathological complete response) rate,
when neoadjuvant (i.e. preoperative) chemotherapy was started with Abraxane instead of paclitaxel
followed by epirubicin/cyclophosphamide, given all before surgery.
The final dose of Abraxane used was 125mg/m2, about half of the recommended dose used for refractory
breast cancer (260mg/m2). The latter dose was reduced as toxicities had led to more discontinuations for
the Celgene drug (17% vs 6%), although they were fewer incidents of local disease (1.7% vs 5%).
Gunter von Minckwitz, chairman of GBG, a network of over 500 study centres in Germany, said this is the
first time in 18 years of the group running neoadjuvant studies that pCR rates “could be strongly increased
by replacing a key component of the standard neoadjuvant chemotherapy instead of just adding additional
agents to it”. … (Source: PharmaTimes)
 FDA Drug Safety Communication: FDA reporting mental health drug
ziprasidone (Geodon) associated with rare but potentially fatal skin
reactions
The U.S. Food and Drug Administration (FDA) is warning that the antipsychotic drug ziprasidone (marketed
under the brand name, Geodon, and its generics) is associated with a rare but serious skin reaction that can
progress to affect other parts of the body. A new warning has been added to the Geodon drug label to
describe the serious condition known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).
Patients who have a fever with a rash and/or swollen lymph glands should seek urgent medical care. Health
care professionals should immediately stop treatment with ziprasidone if DRESS is suspected.
Ziprasidone is an antipsychotic drug used to treat the serious mental health disorders schizophrenia and
bipolar I disorder. Ziprasidone helps restore certain natural substances in the brain and can decrease
hallucinations, delusions, other psychotic symptoms, and mania. To work properly, ziprasidone should be
taken every day as prescribed. Patients should not stop taking their medicine or change their dose without
first talking to their health care professional.
DRESS may start as a rash that can spread to all parts of the body. It can include fever, swollen lymph
nodes, and inflammation of organs such as the liver, kidney, lungs, heart, or pancreas. DRESS also causes a
higher-than-normal number of a particular type of white blood cell called eosinophils in the blood. DRESS
can lead to death.
50
FDA reviewed information from six patients in whom the signs and symptoms of DRESS appeared between
11 and 30 days after ziprasidone treatment was started. None of these patients died (see Data Summary).
Based on this information, FDA required the manufacturer of Geodon to add a new warning for DRESS to
the Warnings and Precautions section of the drug labels for the capsule, oral suspension, and injection
formulations. … (Source: FDA)
USA
 FDA Issues Guidance Helping Manufacturers Gain Access to REMS
Drugs for Generic Development
The FDA has issued guidance to assist in certain circumstances where brand-name drug companies refuse
to sell to prospective Abbreviated New Drug Application (ANDA) sponsors supplies of reference listed
drugs.
Prospective ANDA sponsors need supplies of reference listed drugs to conduct bioequivalence (BE) and
other testing to support their ANDAs.
The problem of generic companies’ inability to obtain reference listed drug supplies can arise where the
drug product is not available through regular distribution channels because it is subject to distribution
restrictions (imposed either through a Risk Evaluation and Mitigation Strategy (REMS) or voluntarily by the
reference listed drug (RLD) holder).
Because some brand-name drug companies argue that providing adequate supplies of the reference listed
drug to prospective ANDA sponsors would violate their REMS, FDA has developed a process to provide
assurance to the brand-name drug company that the Agency has reviewed the generic company’s
bioequivalence study protocols and determined that they contain safety protections comparable to those
in the REMS.
The guidance is available at: REMS Drugs for Generic Development (Source: CPhI)
 GPhA supports state legislation that eliminates barriers to auto
substitution of biologics at the pharmacy
The Generic Pharmaceutical Association on Tuesday agreed to support compromise automatic substitution
legislation that would allow interchangeable biologics to be automatically substituted at the pharmacy.
The new compromise language includes: "Within a reasonable time following the dispensing of a biological
product, the dispensing pharmacist or the pharmacist's designee shall communicate to the prescriber the
specific product provided to the patient, including the name of the product and the manufacturer."
According to the association, the compromise legislation GPhA supports represents an improvement over
2012 language that originally erected numerous barriers to the automatic substitution of interchangeable
biologics, including pre-dispensation physician notification and written patient consent.
"This step brings millions of Americans closer to the day when they will be able to access safe alternatives
to costly biologic medicines," stated Ralph Neas, GPhA president and CEO. "The compromise legislation was
put forward by several GPhA members and reflects our core principles: Upholding the current pharmacy
practice of automatic substitution; insisting on the science-based FDA determination of interchangeability;
51
and treating all interchangeables and their corresponding brand biologics the same once an
interchangeable is approved."
GPhA expects legislation to advance automatic substitution to be introduced in many states in the
upcoming 2015 legislative session. "[The legislation] must be in place to allow automatic substitution when
the FDA approves the first interchangeable biologics in this country," Neas said. … (Source: DrugStoreNews)
 USA looks at new antibiotics approval pathway
BY KEVIN GROGAN
As superbugs return to the spotlight, US Senators Michael Bennet and Orrin Hatch have introduced a bill to
create a new drug approval pathway “to streamline access and encourage innovation and development” of
antibiotics.
In an effort to address “some of the significant regulatory obstacles facing antibiotic development and
hindering patient and veteran access”, the Promise for Antibiotics and Therapeutics for Health (PATH) Act is
going in front of Congress. It would permit the US Food and Drug Administration to accelerate an
antibacterial’s approval for “an identifiable, limited patient population upon determining that the drug
treats a serious or life-threatening condition and addresses an unmet need”.
In addition, the bill requires a drug’s label to include special designation from the FDA indicating their
intended use in limited, high-risk populations approved under this pathway. The proposed legislation also
calls for “further guidance and potential expansion to other appropriate therapeutic areas”.
Sen Bennet (Democrat, Colorado) said the bill will allow new antibiotics that show promise combating
these bacteria “to reach patients more quickly and save lives. It will also encourage bioscience companies
to invest in innovative research to develop these lifesaving drugs”. Sen Hatch (Republican, Utah) added that
the PATH Act “is needed to spur the innovation of new antibiotics”.
The senators noted that while antibiotic resistance “continues to cost tens of thousands of lives in the USA
each year, less than ten new drugs have made it to market since 2000”. They added that it is also “a
significant concern to our troops, affecting more than a third of returning Iraq and Afghanistan veterans”.
The bill comes as a major review has been published in the UK that ten million people around the world will
die every year by 2050 unless new antibiotics are created to tackle drug-resistant infections. … (Source:
PharmaTimes)
 Judge Rules Drug Maker Can’t Shelve Old Pill
A federal judge has decided to block for now an attempt by the drug company Actavis to halt sales of an
older form of its Alzheimer’s disease drug Namenda in favor of a newer version with a longer patent life.
The decision, issued Thursday, represents a victory for New York’s attorney general, who had filed an
antitrust lawsuit against Actavis in September, accusing the company of forcing patients to switch to the
newer version of the widely used medicine to thwart competition from generic manufacturers.
“Our lawsuit against Actavis sends a clear message: Drug companies cannot illegally prioritize profits over
patients,” the attorney general, Eric T. Schneiderman, said in a statement Thursday.
The decision was made by Judge Robert W. Sweet in Federal District Court in Manhattan but was sealed
because it contained confidential information. Both the attorney general and Actavis, however, confirmed
that the judge had issued a preliminary injunction that would stop Actavis from discontinuing sales of the
older Namenda while the case is being decided.
52
Brent Saunders, chief executive of Actavis, said in a statement that the company was “disappointed by
today’s unprecedented ruling,” but was “prepared to manage our business in a way that provides the least
disruption in our ability to support the marketplace and minimize any financial impact on our company.”
The company said it would immediately appeal the decision. … (Source: NYTimes)
 Gilead sued over 'exorbitant' hepatitis C drug prices
Philadelphia's transportation authority has filed a class action lawsuit accusing Gilead Sciences Inc of
charging "exorbitant" prices for its blockbuster hepatitis C drug Sovaldi.
The lawsuit, filed Tuesday in federal court in Philadelphia by the Southeastern Pennsylvania Transportation
Authority, seeks an unspecified amount of money damages.
Sovaldi, a highly effective treatment for hepatitis C, costs $1,000 per pill in the United States, or $84,000 for
a typical 12-week course. The drug sells for much less in some other countries.
The lawsuit claims that Gilead's pricing is an abuse of its patent monopoly on the drug and violates federal
antitrust laws.
Gilead's "limited rights as a patent holder do not translate into a license to price gouge consumers," the
lawsuit said.
The transportation authority, which said it has paid more than $2.4 million for Sovaldi for its employees, is
seeking to represent a class of everyone in the United States who has paid for Sovaldi or has not been able
to afford needed Sovaldi treatment.
Sovaldi has brought in more than $8.5 billion for Gilead in the first three quarters of 2014, just under half
the company's total sales. … (Source: Reuters)
http://www.pcori.org/
 PCORI and NIH Partner on Request for Applications to Study How to
Improve Blood Pressure Control in High-Risk Individuals
The National Institutes of Health (NIH), as part of a research partnership with the Patient-Centered
Outcomes Research Institute (PCORI), issued a Request for Applications (RFA) to study how to improve
blood pressure control among populations at highest risk for suffering hypertension-related strokes, heart
attacks, and other cardiovascular events.
PCORI has committed up to $25 million to fund up to two patient-centered trials through the Hypertension
Disparities Reduction Program Partnership (HDRPP) with NIH’s National Heart, Lung, and Blood Institute
(NHLBI) and National Institute of Neurological Disorders and Stroke (NINDS).
PCORI’s Addressing Disparities program and NIH agreed to collaborate on this patient-centered research
initiative to fill important evidence gaps on what works best to control high blood pressure, a leading cause
of cardiovascular disease, among high-risk populations. Approximately 67 million U.S. adults have
hypertension, more than half of whom do not have it under control. More than three-quarters of people
who have suffered a stroke have high blood pressure, as do nearly 70 percent of those who have had a
heart attack.
53
Hypertension disproportionately affects certain populations, including racial and ethnic minorities,
individuals with low socioeconomic status, and those who live in rural communities. For example, AfricanAmerican men were 30 percent more likely to die from heart disease than white men in 2007, and rural
residents are more likely to be diagnosed with heart disease than urban dwellers. Moreover, African
Americans’ rate of stroke is more than double that of Caucasians, and this disparity is most pronounced in
middle-aged black men. Previous research studies have rarely targeted these high-risk populations
exclusively nor fully engaged patients and clinicians in the research.
“We’re excited to work with our colleagues at NIH on this initiative to address the burden of high blood
pressure among patients at highest risk for heart failure, heart attacks, and other hypertension-related
events,” said Romana Hasnain-Wynia, MS, PhD, Director of PCORI’s Addressing Disparities program. “By
focusing our efforts on these populations, we expect to generate useful evidence that will fill important
gaps in our knowledge of prevention and treatment and help these patients and their clinicians to gain a
better understanding of how to manage their blood pressure.”
“If we are able to understand how to effectively treat hypertension in high-risk populations, we are certain
to realize reductions in cardiovascular disease among all Americans,” said NHLBI Director Gary Gibbons,
MD. “High blood pressure damages the entire circulatory system. This initiative could help us learn how to
better control high blood pressure and reduce patient’s risk for heart disease, heart failure, and other
serious events, thereby improving the lives of 33 percent of adults in this country living with high blood
pressure.”
“Hypertension is the largest cause of stroke, but it is also mostly controllable with appropriate treatment,”
said NINDS Acting Director Walter Koroshetz, MD. “NINDS research has shown that there are major
disparities in stroke in the U.S., particularly in the southeastern U.S., which has been called the ‘Stroke
Belt.’ By working with PCORI, we are hopeful that these disparities can finally be eradicated through better
blood pressure management.“
The HDRPP funding announcement seeks proposals for comprehensive comparative effectiveness studies
to test a variety of methods and combinations of methods and interventions to improve blood pressure
control, such as self-measured blood pressure monitoring, lifestyle modification, and patient counseling.
Proposals must demonstrate strong patient and stakeholder engagement.
Letters of Intent (LOIs), though not required, may be submitted to NIH by Tuesday, Jan. 13, and applications
are due by Friday, Feb. 13. Interested applicants should consult the full RFA, titled "Testing Multi-Level
Interventions to Improve Blood Pressure Control in Minority Racial/Ethnic, Low Socioeconomic Status,
and/or Rural Populations (UH2/UH3),” for eligibility requirements, application criteria and instructions,
deadline updates, and other details. … (Source: PCORI)
 PCORI Board Approves Providing Up to $50 Million for CER on
Hepatitis C
The Patient-Centered Outcomes Research Institute (PCORI) Board of Governors today approved the
development of a PCORI Funding Announcement (PFA) providing up to $50 million for up to four
comparative clinical effectiveness research (CER) studies on the best ways to diagnose and treat
hepatitis C virus infection.
The Board also approved the issuance of two PFAs totaling up to $150.7 million to support the second
phase of development of PCORnet, PCORI’s initiative to improve the efficiency of health research
nationwide by harnessing the power of data from electronic health records and other sources.
54
With the Board’s approval, PCORI will develop a PFA focused on hepatitis C virus (HCV) research
questions that emerged as the highest priorities during a multi-stakeholder workshop PCORI hosted on
October 17. The four priority topics are:




Finding out which screening methods and testing strategies in which settings lead to the best
detection rates.
Assessing alternative ways to deliver care to high-risk populations.
Exploring the trade-offs between long-term virologic response and adverse effects associated with
different regimens of new oral antiviral medications.
Comparing the benefits and harms of starting treatment immediately after a diagnosis versus active
surveillance, in which treatment starts once a patient shows progression to liver disease or other
manifestations of infection.
Hepatitis C affects more than 3 million people in the United States, the majority of whom are
undiagnosed. About one-third of these individuals will develop chronic liver disease if untreated.
“HCV is a major health threat that can have devastating consequences for infected people and their
families,” said PCORI Executive Director Joe Selby, MD, MPH. “Recently approved medications are
immensely promising and offer vast improvements over previous therapies, but as yet there’s no ‘realworld’ evidence of their long-term effectiveness nor comparative evidence to help inform decisions
about screening, diagnosis, and treatment of HCV.
“In response to the feedback we’ve received from many healthcare stakeholders, and with the approval
of our Board, PCORI will issue a funding announcement in the next few months to support CER that will
build the evidence needed to better inform practice and address questions important to patients,” Selby
said.
PCORI also will issue two funding announcements later this month to support the next stage of
PCORnet’s development, funding up to 13 of the Clinical Data Research Networks (CDRNs) and up to 22
of the Patient-Powered Research Networks (PPRNs) that make up PCORnet. PCORI will provide up to
$8.75 million for each CDRN and up to $1.68 million for each PPRN over the three-year second phase of
PCORnet’s development, which will begin in September 2015 at the end of the 18-month first phase. All
of the 11 current CDRNs and 18 PPRNs are eligible to apply as are new networks that can meet the
baseline requirements within six months of the beginning of Phase II.
In other business, the Board discussed PCORI’s proposed research strategy for the next five years. PCORI
plans to continue to fund research under its broad funding announcements at a reduced level, and shift
funding toward a smaller number of larger studies focused on specific high-priority topics. PCORI will
make extended funding commitments to select topics and in some cases fund clusters of studies around
a particular topic to produce more comprehensive findings that will have greater impact.
The strategy builds on PCORI’s previous investments and leverages the topic prioritization process
facilitated by its six multi-stakeholder advisory panels. The plan also encourages research that will tap
into PCORnet once it is fully operational.
Presentation materials and an archive of the webinar from today’s Board meeting are available on
PCORI’s website. … (Source : PCORI)
55
http://www.ahrq.gov/
http://www.iom.edu/
 Facilitating Patient Understanding of Discharge Instructions
With the implementation of the Patient Protection and Affordable Care Act (ACA), the issue of inadequate
health literacy has become even more important. To explore the aspects of health literacy that impact the
ability of patients to understand and follow discharge instructions and to learn from examples of how
discharge instructions can be written to improve patient understanding of—and hence compliance with—
discharge instructions, the Roundtable on Health Literacy held a 1-day public workshop. The Roundtable on
Health Literacy brings together leaders from academia, industry, government, foundations, and
associations and representatives of patient and consumer interests who work to improve health literacy. To
achieve its mission, the roundtable discusses challenges facing health literacy practice and research and
identifies approaches to promote health literacy through mechanisms and partnerships in both the public
and private sectors.__
IOM - Facilitating Patient Understanding of Discharge Instructions.pdf
SANTE/HEALTH CANADA
http://www.hc-sc.gc.ca/index-fra.php#tabs1_3
 CADTH issues rapid report on Vitamin D toxicity
The CADTH Rapid Response Report found three systematic reviews (including one meta-analysis), 24
randomized controlled trials (RCTs), and six non-randomized studies containing clinical evidence regarding
toxicity associated with different vitamin D dosing regimens. … (Source: CADTH)
 TPD updates Notices of Compliance
The TPD has posted the weekly updates for the Notices of Compliance (NOCs). … (Source: HC-SC)
 TPD posts monograph safety updates
(Source: HC-SC)
 TPD updates list of patented drugs
The TPD has updated its list of patented human and veterinary drugs, including information concerning the
dates when data protection ends and whether the drug has a pediatric extension. … (Source: HC-SC)
56
 TPD updates post-authorization information
The TPD has updated post-authorization activity information for the hodgkins lymphoma drug Acetris and
the wet age-related macular degeneration (AMD) drug Eylea.
Post-Authorization Activity Table for ADCETRIS
Post-Authorization Activity Table for EYLEA
LATIN AMERICA
SSA http://www.salud.gob.mx/
http://portal.anvisa.gov.br/wps/portal/anvisa/home
 Drug API GMP updated
Anvisa has updated the Good Manufacturing Practices (GMP) for Active Pharmaceutical Ingredients (APIs),
repealing the old standards embodied in RDC 249/05. The new standard updates definitions and
requirements in accordance with international guidelines, such as concepts of starting and intermediate
material, and retest date. Provisions on stability were also harmonized with current legislation.
Texts of other resolutions were also incorporated in the new Collegiate Board Resolution (RDC), such as
RDC No. 57/2012 dealing with GMP for APIs obtained by cell cultures / fermentation; and RDC No.14/2013
dealing GMP APIs of plant origin. Both are contained in Chapters XVIII and XIX of the current resolution. …
(Source: ANVISA)
 Anvisa approves two new generics
Anvisa has approved two new generics that do not have any competition in Brazil. The products are
Nitazoxanide and Mebeverine Hydrochloride. Nitazoxanide is used in the treatment of intestinal infections
caused by protozoa, helminths and as well as viral gastroenteritis caused by rotavirus and norovirus.
Mebeverine hydrochloride is indicated for the symptomatic treatment of pain and abdominal cramping,
intestinal discomfort and intestinal disorders related to irritable bowel syndrome. … (Source: ANVISA)
 CMED opens consultation on drug price adjustment factors
The Board of Drug Market Regulation has approved the opening of a public consultation on the
composition of the factors for drug price adjustment. Comments can be submitted until December 23,
2014.
Consultation document
AUSTRALIA – NEW ZELAND
57
http://tga.gov.au/
 Business gateway to eBusiness Services - launching in early 2015
In early 2015, the TGA will be launching the first of a series of upgrades to its existing eBusiness Services.
The first upgrade will allow eBS clients to access a user-friendly gateway to:

access and manage (where appropriate) their contact details and other information held by TGA,
and

view and pay invoices.
All current eBS functions will still be available through the new gateway and you will still be able to submit
applications and provide information to the TGA through eBS.
The new gateway is undergoing extensive user testing with current eBS users to make sure we deliver the
most user-friendly system.
We will communicate with you via email and website updates so you can stay up to date with any actions
that need to be taken before the launch. If you wish to receive emails about any changes to the current eBS
please subscribe to the TGA eBS Notices email list.
Throughout 2015 more improvements will be made to eBS and we will keep you informed about these
upgrades.
This work is being completed as part of our efforts to reduce regulatory burden and in line with our TGA
Business Plan 2014-2015 which outlines one of our major priorities which includes enhancing our business
capability and improving business processes and systems for our clients. … (Source: TGA)
 TGA - presentation on CTs
TGA - Clinical trials - 3 Dec 2014.pdf
 Bosentan receives orphan drug designation for treatment of
pulmonary hypertension
The TGA has added Bosentan for the treatment of primary pulmonary hypertension or pulmonary
hypertension secondary to scleroderma to the designated orphan drugs list. … (Source: TGA)
 Schedule of fees and charges
The TGA has successfully transitioned from Westpac Banking Corporation (Westpac) to the Commonwealth
Bank of Australia (CBA) for all transactional banking services, including all payments for services provided
by the TGA.
The Westpac account will be closed on 23 December 2014 and payments to the TGA through that account
will no longer be accepted after this date.
For your reference, all EFT payments should be made to:
Bank: Commonwealth Bank of Australia
BSB: 062-909
58
Account: 10215498
Payments by credit card should be made through https://www.bpoint.com.au/payments/TGA (link is
external).
Assistance
TGA Accounts Receivable: Ph. +61 2 6221 6900 OR email [email protected] (link sends e-mail) …
(Source: TGA)
 TGA presentation given at the Australasian Ethics Network
Conference workshop, 3 December 2014
(Source: TGA)
 Galantamine: Safety advisory - serious skin reactions
Consumers and health professionals are advised that Janssen-Cilag, in consultation with the TGA, has
updated the Product Information (PI) for galantamine (link is external) (marketed under the brand name
Reminyl, as well as a number of generic brands).
Galantamine is used to treat mild to moderately severe dementia of the Alzheimer type.
The PI update has added a new precaution for serious skin reactions, including Stevens-Johnson syndrome
and acute generalised exanthematous pustulosis. Such reactions have been reported in patients receiving
galantamine.
Stevens-Johnson syndrome and acute generalised exanthematous pustulosis have also been added to the
adverse effects section of the PI as very rare adverse events associated with galantamine treatment. …
(Source: TGA)
 Updates to the prescribing medicines in pregnancy database
The Prescribing Medicines in Pregnancy database has now been updated to include recently registered new
chemical entities as follows:

enzalutamide

peginterferon beta-1a (rch)

perampanel hemisesquihydrate

simeprevir

vedolizumab (rch)
(Source: TGA)
 Reasons for scheduling delegate's final decisions, December 2014
(Chemicals)
(Source: TGA)
 AusPAR: Vedolizumab (rch)
AusPAR: Vedolizumab (rch) (pdf, 962 KB)
59
AusPAR: Vedolizumab (rch) (docx, 966 KB)
Attachment: Product Information: Vedolizumab (rch) (pdf, 203 KB)
Attachment: Product Information: Vedolizumab (rch) (docx, 78 KB)
Attachment: Extract from the Clinical Evaluation Report: Vedolizumab (rch) (pdf, 905 KB)
Attachment: Extract from the Clinical Evaluation Report: Vedolizumab (rch) (docx, 1 MB)
 Submissions and TGA response: Draft OTC medicine monograph:
Mebendazole
(Source: TGA)
 OTC medicine monograph: Mebendazole

Introduction

Active substances

Dosage forms and strengths

Indications

Directions for use

Labels

Quality requirements
 Submissions and TGA response: Draft OTC medicine monograph:
Guaifenesin
(Source: TGA)
 OTC medicine monograph: Guaifenesin

Introduction

Active substances

Dosage forms and strengths

Indications

Directions for use

Labels

Quality requirements
 Submissions and TGA response: Draft OTC medicine monograph:
Ranitidine hydrochloride
(Source: TGA)
60
 OTC medicine monograph: Ranitidine hydrochloride

Introduction

Active substances

Dosage forms and strengths

Indications

Directions for use

Labelling

Quality requirements
 Submissions and TGA response: Draft OTC medicine monograph:
Loperamide hydrochloride
(Source: TGA)
 OTC medicine monograph: Loperamide hydrochloride

Introduction

Active substances

Dosage forms and strengths

Indications

Directions for use

Labelling

Quality requirements
 Meeting dates for 2015 now available
Advisory Committee on Biologicals (ACB)
Advisory Committee on Complementary Medicines (ACCM)
Advisory Committee on the Safety of Medicines (ACSOM)
Advisory Committee on Non-prescription Medicines (ACNM)
INDIA - PAKISTAN & ASIA
61
China SFDA | Hong Kong MDCO & PSDH | India CDSCO | Japan MHLW | Korea KFDA | Malaysia MOH |
Philippines DOH | Singapore HSA | Taiwan TFDA | Thailand FDA | Vietnam MOH
http://www.pmda.go.jp/english/
http://eng.sfda.gov.cn/WS03/CL0755/
 CFDA provides direction to local agencies on injectable drug
technology transfer
The CFDA has notified local food and drug agencies that as of January 1, 2015, applications for the
registration of the transfer of technology for sterile injectable drugs cannot be approved unless the new
company can meet the 2013 revised pharmaceutical production and quality management practices
requirements. … (Source: CFDA)
 CFDA meets with Czech agency director
The CFDA’s deputy director, Wu Zhen, and the director of the Czech National Drug Authority, Brad Huta,
met on December 8 and reached tentative agreement on the establishment of bilateral cooperation in drug
regulatory matters…. (Source: CFDA)
Food and Drug Administration - Department of Health
http://www.taiwan.gov.tw/ct.asp?xItem=25613&ctNode=1970&mp=1001
MFDS
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http://www.mfds.go.kr/eng/index.do;jsessionid=qciHSjRkQKTKw4WNZ1WnOhp4yqR9HwaML5QHjUrGctpVtwPtqyJUamREbNSCgy5c
 MFDS releases 2015 drug control plan
The MFDS has released the 2015 comprehensive plan for inter-agency cooperation to address narcotics
related regulatory concerns. … (Source: MFDS)
 MFDS soliciting input on tissue bank safety management guidance
The MFDS seeks input on tissue bank safety management guidance designed to ensure there is no risk of
cross-contamination in tissue processing rooms and facilities. … (Source: MFDS)
 MFDS seeks input on testosterone marketing authorization changes
The MFDS seeks input on changes to the marketing authorizations for testosterone containing medicines. …
(Source: MFDS)
HSA
http://www.hsa.gov.sg/publish/hsaportal/en/home.html#page=tab1
CDSCO
http://www.cdsco.nic.in/
 Indian regulator soliciting feedback on regulatory system upgrade
plan
India's Central Drugs Standards Control Organisation is soliciting feedback on a Ministry of Health and
Welfare plan to upgrade the country's regulatory system at both national and state levels over the next
three years. The goal of the upgrade is to "facilitate expeditious consideration and faster decision making
and testing of medical products wherever required and serve the objective of the quality, safety and
efficacy of drugs and other medical and cosmetics products."
On both state and national levels, the plan calls for setting up new drug testing laboratories and upgrading
those already running; creation of new lab and regulatory positions, with appropriate training for new
hires; and strengthening enforcement mechanisms. The plan also proposes the establishment of a Training
Academy and implementation of an e-Governance mechanism and networking of CDSCO and State Drugs
Control Departments.
Comments on the proposed plan can be submitted until December 22, 2014. … (Source: CDSCO)
 India extends price caps to 52 more essential drugs
BY ZEBA SIDDIQUI
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An employee of Lupin Limited works at a reception at their headquarters in Mumbai November 22, 2013.
CREDIT: REUTERS/DANISH SIDDIQUI
India has extended price caps to 52 drugs deemed essential by the government, as the country's drug price
regulator enforces measures to improve the affordability of medicines.
The additional drugs, including painkillers and antibiotics, join a list of nearly 400 essential treatments
under price control in India, where a majority of people live on less than $2 a day and health insurance is
scarce.
Indian law allows the National Pharmaceutical Pricing Authority (NPPA) regulator to fix prices of drugs on a
list of essential medicines. In a notice issued in September, the body had fixed the prices of 36 drugs,
including those to treat infections and diabetes.
The latest additions bring the total market size of medicines under price control to about 1.23 billion rupees
($20 million), said market research firm AIOCD Pharmasofttech AWACS Pvt Ltd.
The wide-ranging price cuts have hit both local and foreign drugmakers in India and have been opposed by
many in the industry, who have said drug prices in the country are already among the lowest in the world.
In the latest pricing move, the drugs added also include medicines used to treat cancer and skin disorders, a
notice on the NPPA website said. It cited the price at which the drugs could now be sold but did not say
what that were before.
Price caps on some of these drugs only apply to specific companies , it added.
Companies including Lupin Ltd, Cadila Healthcare Ltd and Merck Ltd, the Indian arm of Germany's Merck
KGaA, are among those selling drugs mentioned in the latest notice, the authority said.
A Lupin spokesman said the company would see no impact from the price caps. Cadila did not
immediately respond to a request for comment and Merck Ltd was not immediately reachable.
NPPA Deputy Director Naresh Arya said the regulator continues to look at other disease areas where the
prices of drugs may need to be fixed.
Indian pharmaceutical industry bodies filed two separate lawsuits against the NPPA in July over its notice to
cap the prices of 108 drugs that were not on India's national list of essential medicines.
The NPPA's powers to cap the prices of non-essential medicines were subsequently revoked by a higher
authority, but the price caps on the 108 drugs remain, while hearings in the cases continue.
 Let India Make Cheap Drugs
Last month, the United States and India announced an important breakthrough concerning India’s “rightto-food” program. The Indian government subsidizes food for its poorest citizens through a system of price
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supports and public stockpiling. The program is critical to India’s future: According to Unicef, one in three of
the world’s malnourished children lives in India.
But as India’s policy has expanded, it has come into conflict with World Trade Organization rules on
agriculture. The conflict heated up last summer when India demanded an explicit assurance at the W.T.O.
that it could maintain its right-to-food program. The United States resisted, and the standoff derailed the
first new global trade agreement at the W.T.O. since the 1990s.
The impasse now seems to be resolved; with American support, India has secured a “peace clause” at the
W.T.O. that protects its food program from legal challenges. As India insisted, the deal applies indefinitely,
until a permanent solution to the conflict is found, which could happen as early as the end of next year.
This is good news for poor people in India, including the children and nursing mothers that the program
particularly helps. It is good news for the poor in other countries that may have programs like India’s. It is
good news for India and the United States, the world’s two largest democracies, which must be able to
cooperate with one another on a range of global issues. And it is good news for the W.T.O., which can move
forward with the delayed agreement on trade facilitation.
This positive development on food, however, is in stark contrast to the United States’ approach to India’s
policies on affordable medicines.
On Nov. 24, while the food deal was being finalized in Geneva, Michael B. Froman, the United States trade
representative, was in India to demand reform of its patent laws. Those laws are friendly to generic
medicines and public health, and the United States wants them restructured to favor American
pharmaceutical corporations, often called Big Pharma.
While he was in New Delhi, Mr. Froman cited the food deal and its impact on the larger trade agreement as
an example of the United States and India “working side by side.” But when it came to intellectual property
disputes that affect medicines, he was pushing for more Indian concessions.
In fact, the United States has been showing no inclination to compromise as it ratchets up the pressure. It
recently initiated a special review of India’s intellectual property laws, signaling possible trade sanctions.
After Prime Minister Narendra Modi’s recent visit to the United States, the two countries announced a new
high-level working group on intellectual property issues, which may foreshadow changes to India’s laws.
India faces a public health crisis no less stark than its food security problem. One potential threat comes
from patents, which can raise the prices of medicines astronomically. For example, according to the World
Health Organization, patented triple-combination therapy medicines for H.I.V./AIDS cost $10,000 per
person per year in industrialized countries, while generics can be purchased across the developing world
from an Indian company, Cipla, for less than $200 a year. It is India’s laws that have enabled the country’s
flourishing generics industry to offer its people and other less-wealthy societies such savings.
India’s existing patent law was introduced in 2005 to conform to W.T.O. requirements under the so-called
Trips agreement. It infuriated Big Pharma by making it more difficult for companies to obtain drug patents
in India than in the United States and elsewhere.
Many experts in the United States agree that our own national patent standards make it too easy for
corporations to get patent protection, which then allows them to expand or maintain their market power in
ways that stifle innovation and keep prices high.
Big Pharma fought the law in India, all the way to its Supreme Court — and lost. Now these companies have
turned instead to the office of the United States trade representative and hope to win their campaign.
Their strategy is to use trade pressure to undermine the pharmaceutical patents policy of India’s
democratically chosen government.
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Just as the United States is now supporting India on its right-to-food program, it should lower the pressure
on India’s patent law, too. For one thing, India’s law almost surely complies with the Trips agreement. This
may be why the United States has never brought an official complaint against India’s law at the W.T.O. …
(Source: NewYorkTimes)
 India's Cadila launches first cheaper copy of world's top-selling drug
Indian drugmaker Cadila Healthcare Ltd said on Tuesday it launched in India the first biosimilar version of
the anti-inflammatory medicine adalimumab, the world's top-selling drug, at a fifth of its U.S. price.
The drug's branded version is sold under the name Humira by U.S. firm AbbVie Inc, and costs $1,000 for a
vial in the United States. Humira had sales of $3.26 billion in the quarter ended September, accounting for
65 percent of AbbVie's total revenue.
A price of $200 a vial would still keep the drug out of reach for most people in India, where more than 70
percent of the population lives on less than $2 a day and health insurance is scarce.
Biosimilars are cheaper copies of biotech drugs - medicines made from proteins and other large molecules.
Cadila expects sales of between 1 billion rupees ($16.16 million) and 2 billion rupees from its biosimilar of
Humira in the Indian market, Deputy Managing Director Sharvil Patel told Reuters.
The company will launch its version under the name Exemptia for treating diseases such as rheumatoid
arthritis, juvenile idiopathic arthritis, psoriatic arthritis, and ankylosing spondylitis.
About 12 million people in India suffer from these disorders, Cadila said in a statement. … (Source: Reuters)
DISCOVERY - DESIGN - DEVELOPMENT
 Ebola vaccine trial suspended over unexpected side effects
Swiss researchers have suspended the testing of one of the leading Ebola vaccine candidates after some
volunteers reported unexpected side effects.
In a statement issued on Thursday, the Hopitaux Universitaires de Geneve said the trial had been
suspended "as a precautionary measure." The study involving 59 people began in November.
Researchers reported four cases of mild joint pain in the hands and feet in people who got the shot 10 to
15 days earlier. Officials will stop giving the vaccine next week to get more data and liaise with others who
are testing the vaccine in the U.S., Canada, Germany and Gabon.
The vaccine was developed by the Canadian government and is licensed to two U.S. companies, NewLink
and Merck. The trial is scheduled to resume in January in Geneva. … (Source: CBSnews)
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 Novartis psoriasis drug tops J&J's Stelara in late-stage study
Novartis said on Friday its experimental psoriasis drug Cosentyx was better at clearing the rough skin
patches associated with the disease than Johnson & Johnson's Stelara.
Results of the late-stage Phase IIIb study involving 679 patients with moderate to severe plaque psoriasis
found those taking Cosentyx achieved clear or almost clear skin after 16 weeks of treatment.
On a secondary measure, patients achieved at least a 75 percent improvement in disease severity at week
four.
Plaque psoriasis is a painful and unsightly skin condition which is known to cause itching and scaling and
affects approximately 125 million people.
The data follows results last year showing Cosentyx, also known as secukinumab, was superior to Amgen's
Embrel in a head-to-head study.
Cosentyx is expected to be the first in a clutch of new treatments for plaque psoriasis which target the
inflammation-causing protein interleukin-17 (IL-17) to gain market approval.
European regulators gave the green light to the drug last month, while an advisory panel to the U.S. Food
and Drug Administration unanimously recommended the use of the drug.
Other drugmakers working on new treatments include Eli Lilly, AstraZeneca and Amgen. … (Source:
Reuters)
 Batu Biologics Files Investigational Drug App With FDA
Batu Biologics Inc., a biotechnology company developing a cancer vaccine that targets a tumor's blood
vessels, announced the filing of an Investigational Drug Application (IND) with the U.S. Food and Drug
Administration (FDA) for its lead immune therapy, ValloVax.
Once the IND is approved, Batu Biologics will proceed with a Phase I/II clinical trial for non-small cell lung
cancer.
ValloVax is a polyvalent cancer vaccine that stimulates an immune response against the tumor-associated
blood vessels, seeking to cut off the blood supply required for sustainable tumor growth. In preclinical
testing, ValloVax was shown to inhibit new blood vessel formation in melanoma and breast and lung cancer
mouse models. Batu Biologics plans to expand clinical trials to additional indications in the future.
The proposed Phase I/II clinical trial will assess safety with signals of efficacy in advanced lung cancer
patients who have failed chemotherapy. Three escalating doses of ValloVax will be administered with five
patients per group. Batu Biologics will be working with the University of Utah to conduct the trials and
plans to initiate dosing of patients in early 2015.
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Within 30 calendar days of the IND filing, the FDA will notify Batu Biologics of any questions it may have or
protocol revisions it may request. … (Source: SDBJ)
 Amgen initiates study to evaluate
laherparepvec, Keytruda for melanoma
combined
talimogene
Amgen announced the beginning of a study to evaluate the safety and efficacy of talimogene laherparepvec
in combination with the investigational use of Merck’s pembrolizumab in patients with regionally or
distantly metastatic melanoma, according to a press release.
Talimogene laherparepvec is an investigational oncolytic immunotherapy and Keytruda (pembrolizumab) is
a U.S. Food and Drug Administration-approved anti-PD-1 therapy. The trial has started enrollment and will
evaluate the combined therapy in 110 patients at 35 clinical trial sites in the United States, Australia and
Europe.
“Talimogene laherparepvec is designed to promote tumor antigen release and presentation to initiate an
anti-tumor response, which may be complementary to Keytruda’s role in releasing PD-1 pathway-mediated
inhibition of anti-tumor responses,” F. Stephen Hodi, MD, steering committee chair for the study, said in
the release.
Data from a phase 3 trial that evaluated the safety and efficacy of intralesional talimogene laherparepvec in
more than 400 patients with stage IIIB, IIIC or IV melanomas that were not surgically resectable compared
with granulocyte-macrophage colony-stimulating factor were included in the regulatory filings, according to
the release.
The new trial will evaluate talimogene laherparepvec in combination with pembrolizumab vs.
pembrolizumab alone and will follow the progression after treatment of pembrolizumab alone, according
to the release. … (Source: Healio)
 Lilly, Incyte Report Successful First Phase III Trial for Baricitinib
Eli Lilly and Incyte said today that their experimental rheumatoid arthritis (RA) drug baricitinib met its
primary endpoint in the Phase III RA-BEACON trial—the first of several pivotal studies assessing the oncedaily, oral, selective JAK1 and JAK2 inhibitor.
Baricitinib yielded RA improvement of at least 20% based on American College of Rheumatology criteria
(ACR20) compared to placebo after 12 weeks of treatment, the companies said.
"These results give us further confidence in the potential for baricitinib to be a meaningful treatment
option for those suffering from this debilitating condition," David Ricks, Lilly svp and president, Lilly BioMedicines, said in a statement.
Added Rich Levy, M.D., Incyte’s chief drug development and medical officer: "We are very pleased by these
results.”
RA-BEACON enrolled 527 patients who had previously failed at least one antitumor necrosis factor (TNF)
therapy, and included a “high” percentage who had also received prior treatment with one or several
nonanti-TNF biologic agents, the companies said. Patients received either one of two doses of once daily
baricitinib or placebo in addition to their background conventional disease-modifying anti-rheumatic drug
therapy (cDMARDs).
Incidence of serious adverse events with baricitinib, including serious infections, was similar to placebo. No
opportunistic infections or gastrointestinal perforations was seen among patients. However, trial results
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also showed a higher incidence of treatment-emergent adverse events with baricitinib compared to
placebo.
The most common adverse events observed with baricitinib were headache, upper respiratory tract
infection, and nasopharyngitis. Discontinuation rates due to adverse events were similar between
treatment groups. According to Lilly and Incyte, a “large” majority of patients completing RA-BEACON
opted to participate in a long-term extension study.
RA-BEACON is part of the companies’ Phase III program for baricitinib. More than 3,000 people with
rheumatoid arthritis have been enrolled in the studies—four in the U.S., one in China. According to Lilly and
Incyte, the clinical trial program includes a wide range of patients including those who are methotrexate
naïve, inadequate responders to methotrexate, inadequate responders to conventional disease-modifying
antirheumatic drugs, or inadequate responders to TNF inhibitors.
"Over the next 12 months we look forward to seeing the data from additional Phase III studies of baricitinib
in rheumatoid arthritis, including patients who have had an inadequate response to conventional DMARDs
and in those with earlier stage disease," Dr. Levy added. … (Source: GEN)
 Bluebird shares leap after gene therapy seen as cure for blood
disorder
Shares of drug developer bluebird bio Inc shot up on Tuesday, after the company presented data that
showed a cure for beta-thalassemia is within reach, prompting several brokerages to raise their price
targets on the stock.
The Cambridge, Massachusetts-based company's stock jumped about 72 percent to $84.00 in early trade.
One of the most common genetic blood disorders, beta-thalassemia, is characterized by a reduction in
hemoglobin, and requires patients to take lifelong transfusions. If left untreated, those affected often die in
their forties.
Data presented at the American Society of Hematology meeting on Monday showed that four betathalassemia patients transplanted with bluebird's LentiGlobin product, including one with the most severe
form of the disease, were essentially cured.
The therapy resulted in sufficient hemoglobin production to reduce or eliminate the need for transfusion
support, bluebird said.
This data represents a "quantum leap" in the management of this disorder by shifting from "life-long
symptom management to once-and-done cures," Roth Capital Partner's Debjit Chattopadhyay said, raising
his price target on the stock to $90 from $50.
LentiGlobin aims to treat beta-thalassemia and sickle cell disease, another blood disorder, by inserting a
gene into the patient's own stem cells and then transplanting those modified cells back through infusion.
LentiGlobin's results read-through favorably to the sickle-cell indication, Piper Jaffray analysts said, raising
their target to $112 from $52.
"With 100,000 sickle patients in the United States and a likely gene therapy price point upwards of
$500,000, this is a $50-100 billion U.S. opportunity alone."
Suntrust Robinson increased its target to $115 from $57, while Wedbush Securities raised theirs to $94
from $51.
Meanwhile, luspatercept, being developed by Acceleron Pharma Inc and Celgene Corp, was found to treat
both the anemia and complications of beta-thalassemia, such as iron overload. … (Source: reuters)
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 First Top-flight Evidence of TKI Benefit in AML
Adding sorafenib (Nexavar, Onyx) to standard chemotherapy improves relapse-free and event-free survival
in younger patients with newly diagnosed acute myeloid leukemia (AML), according to a new study.
Patients who received sorafenib had a 3-year event-free survival rate of 40%, compared with 22% for
placebo (P = .013). In addition, median event-free survival was better with sorafenib than placebo (21 vs 9
months).
Similarly, relapse-free survival was better with sorafenib (58% vs 36%; P = .017). Median relapse-free
survival has not yet been reached in the sorafenib group, but was 23 months in the placebo group.
No improvement was observed in overall survival.
This is the first randomized evidence of a clinical benefit of a tyrosine kinase inhibitor in this type of
leukemia, said lead study author Christoph Röllig, MD, from University Hospital Dresden in Germany.
"These data provide a high level of efficacy for the use of sorafenib in younger patients," he explained.
"Most important, there is now evidence from a randomized trial."
The study results were presented during the plenary session here at the American Society of Hematology
56th Annual Meeting. … (Source: Medscape)
 Growing Brown Fat: Protein Critical To Reprogramming White Fat
Identified, Could Lead To Obesity Treatments
Here’s a quick reminder on fat, if you needed it: We have both brown and white. You probably know the
white fat, because it’s the one that shows on your belly and your thighs. It’s the fat that stores energy as
large droplets, contributing to obesity. Brown fat, however, is special. When we’re born, about five percent
of the fat on our bodies are of the brown kind, small in droplet size and rich in energy-producing
mitochondria, which burn calories. Knowing this, it would make sense to want more brown fat and less
white fat, and new research has found this may be possible by converting the latter to the former.
Using advanced genome sequencing techniques, researchers from the University of Southern Denmark
found that a protein called KLF11, which is found in all fat cells and regulates their expression, could be
manipulated to turn white adipose tissue brown. White adipose tissue is typically classified as either
visceral, meaning it surrounds organs, or subcutaneous, which means it’s under the skin. By turning some
of this white fat brown — or as the researchers call it, turning it “brite” — it wouldn’t only help people who
are obese lose weight but also reduce their risk of obesity-related diseases like heart disease, stroke, type 2
diabetes, and some cancers.
“We stimulated browning in human white adipocytes by [using] a drug used to treat type 2 diabetes, and
compared white and "brite" fat cells,” said Professor Susanne Mandrup, lead author of the study from the
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university’s Department of Biochemistry and Molecular Biology, in a press release. “This showed that ‘brite’
fat cells have distinct gene programs which, when active, make these cells particularly energy-consuming,"
… (Source: Medicaldaily)
 Novel Antibiotic Effective in Fighting Drug-Resistant 'Superbugs'
In the 1920s, the discovery of penicillin revolutionized the treatment of lethal infections. Today the
challenge is how to battle bacteria that have become resistant to the drugs we use to fight them. Now,
some University of Pittsburgh researchers have designed a synthetic compound that might hold promise in
the fight against so-called "superbugs."
The novel, man-made antibiotic works in a completely different way than traditional antibiotics, according
to University of Pittsburgh Center for Vaccine Research co-director Ron Montelaro.
“Antibiotics are drugs that typically poison the bacterial cell by blocking some metabolic process. These
peptides work more by a physical action, by actually punching a hole in the bacterial membrane. So, it is a
physical disruption as opposed to a poisoning of the bacterial cell," said Montelaro.
And finding new ways to kill drug-resistant bacteria that cause diseases like tuberculosis and pneumonia is
becoming a medical necessity.
A study commissioned by the British government reported this month that drug-resistant bacteria could
cause 10 million deaths a year and cost world governments billions of dollars.
The report blamed the rise of "superbugs" mainly on the overuse of antibiotics. Antibiotic use rose 40
percent between 2000 and 2010, according to the British report.
The World Health Organization reports there were some 450,000 cases of multi-drug-resistant TB alone in
2012.
The peptide designed by Montelaro’s team was modeled after the tail end of an HIV protein, which
punches a hole in human immune cells to infect them.
The new synthetic peptides destroy bacteria in much the same way. … (Source: VOA)
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Associate Consultants & Experts
Tel : + 33 1 600 843 85
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