Category Archives: Clinical Trials

FDA gives go-ahead for CRISPR-based sickle cell disease trial

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Development of a stem cell therapy for sickle cell disease from Vertex and development partner CRISPR therapeutics can go ahead, after the FDA lifted a hold on a review.

The companies had applied to begin an early stage trial of CTX001, a gene therapy derived from a patient’s own stem cells, for beta-thalassemia and sickle cell disease.

Although it’s a long way from the market, the drug could be one of the first to use the revolutionary CRISPR/Cas9 gene editing technology to correct a genetic defect causing a disease.

After an application in April for a phase 1/2 trial in the UNS for adults with sickle cell disease, the FDA had further questions that needed to be resolved.

Without revealing further details, the companies said the trial had been put on hold until they could provide the information the FDA required.

The FDA has now lifted the clinical hold and allowed development to go ahead, although the companies gave no further information about the information required by the regulator.

CRISPR and Vertex have obtained approval for clinical trial applications for several countries outside the US for beta-thalassemia and SCD.

They said they are on track to begin a phase 1/2 study in SCD by the end of 2018 and are enrolling patients transfusion dependent beta-thalassemia in a phase 1/2 trial in Europe.

CTX001 uses the CRISPR gene editing technique to make a patient’s haematopoietic stem cells produce high levels of foetal haemoglobin (HbF) in red blood cells.

HbF is a form of the oxygen carrying molecule haemoglobin naturally present at birth, which is replaced by the adult form of haemoglobin.

The elevation of HbF by CTX001 could alleviate transfusion requirements for beta-thalassemia patients and painful and debilitating sickle crises for sickle cell patients.

CRISPR and Vertex began a strategic research collaboration in 2015 to discover and develop gene editing treatments using the CRISPR/Cas9 technology to correct defects in genes known to cause or contribute to certain diseases.

Vertex has exclusive rights to license up to six new CRISPR/Cas9-based treatments that emerge from the collaboration, and CTX001 represents the first treatment to emerge from the joint research program.

For CTX001, CRISPR and Vertex will equally share all research and development costs and profits worldwide.

Novartis yesterday unveiled data showing its crizanlizumab reduced occurrence of the painful and potentially fatal vaso-occlusive crises that occur when blood cells become stacked in patients with SCD, blocking arteries and cutting the oxygen supply to vital organs.

SOURCE: www.pharmaphorum.com/news/fda

Study using DFMO shows positive results for children with high risk neuroblastoma

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A paper published September 27 in Scientific Reports shows the positive results of a phase II clinical trial using the oral medication DFMO to prevent relapse in children with High Risk Neuroblastoma (HRNB).

Neuroblastoma is a form of cancer that develops from immature nerve cells found in several areas of the body. It occurs most often in infants and young children, usually under the age of five. The disease remains a challenge in pediatric oncology and current treatments include therapies that have significant long-term side effects for patients.

HRNB accounts for 15 percent of all childhood cancer deaths, in part, due to the fact that nearly half of all patients who reach remission will relapse.

“These results are promising and have changed the outlook for our patients with high risk neuroblastoma,” said Giselle Sholler, MD, director of pediatric oncology research at Spectrum Health Helen DeVos Children’s Hospital and principal investigator of the study.

“By using DFMO for two years after finishing conventional therapy, we’ve seen an overall two-year survival rate for these children of 97 percent. This is a large increase in survival,” Sholler added. “Previously it was believed that children with refractory and relapsed neuroblastoma were considered incurable. This study shows more than 50 percent of patients remaining in remission up to four years.”

Beat Childhood Cancer’s trial studied the use of difluoromethylornithine (DFMO) as a single agent for enrolled patients at 20 children’s hospitals from June 2012 to February 2016. The children received two years of oral DFMO twice daily and were evaluated for outcomes of event free survival (EFS*) and overall survival (OS). The study used targeted oral therapy of an ODC inhibitor (DFMO), as a maintenance therapy to prevent relapse in HRNB patients after standard therapy. DFMO works by targeting specific cancer stem cell pathways and “turning off” the cells, thereby preventing the cancer from growing back.

There were two arms in this study, the first designed for patients who had completed standard therapy, and the second for children who were able to achieve remission after having previously relapsed. Both of these patient populations are at very high risk of relapsing after completing treatment and therefore can be very good candidates for using a maintenance therapy with the goal of preventing relapse.

With a median follow up of 3.5 years, the first arm of the study had 100 eligible patients. The results show that two-year EFS was 84 percent and two-year OS was 97 percent.

With a median follow up of 3.7 years, the study enrolled 39 previously relapsed patients and the results reported in the journal showed that two year EFS was 54 percent and two-year OS was 84 percent for these children who had previously relapsed.

“While these EFS and OS figures at two years are remarkable, the really exciting part of these results is that EFS and OS are stable out to four years,” said Patrick Lacey of Beat NB Cancer Foundation, one of the childhood cancer parent-led foundations that funded this clinical trial. “Not only did this oral drug lead to a prolonged and stable remission for the children in this study, but the drug was extremely safe and well tolerated in this patient population.”

“While many children have been able to attain remission with the current, albeit harsh, upfront therapies, these remissions are not historically durable,” Dr. Sholler added. “The current five-year survival curves have not changed significantly in the past two decades despite recent increases in two-year survival as a result of intensified therapies and new multimodal therapies.”

Principal Investigator at MUSC, Jaqueline Kraveka, MD, states survival for children with high-risk neuroblastoma remains a challenge. “These results are groundbreaking and very exciting for oncologists and their patient families. I am thrilled to have our confirmatory study open at so many sites across the USA and Canada, enabling children to receive this treatment close to home.”

SOURCE: www.news-medical.net/news/20181001

Bacterial therapy shows early promise in patients with advanced solid tumours

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Researchers have presented results of a Phase I clinical trial using bacterial Clostridium novyi-NT spores to target advanced solid tumours.

A Phase I clinical trial that investigated the use of bacterial Clostridium novyi-NT spores as an injectable monotherapy showed toxicities that were manageable and early clinical efficacy in patients with treatment-refractory solid tumour malignancies.

“Even after a single injection of this bacterial therapy, we see biological and, in some patients, clinically meaningful activity,” said Dr Filip Janku, Associate Professor at the Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Centre, Houston.

“This strategy is feasible, has manageable adverse effects, and could be clinically meaningful in patients with few therapeutic options.”

Previous therapies have tested the use of bacteria, but have often caused infection. In this study, the use of C. novyi-NT spores in the open-label, first-in-human study, the researchers explained how a hypoxic environemnt is necessary for the bacterium. It requires a feature of cancerous lesions to survive and proliferate, and thus does not affect healthy cells.

“By exploiting the inherent differences between healthy and cancerous tissue, C. novyi-NT represents a very precise anticancer therapeutic that can specifically attack a patient’s cancer,” Prof Janku said.

Between 2013 and 2017, 24 patients were enrolled with treatment-refractory solid tumors, with 15 patients having sarcoma, seven patients having diverse carcinoma and two with melanoma.

Tumours were injected with a single dose of C. novyi-NT, from 10,000 to 3 million spores. Patients administered with 3 million spores experienced dose-limiting toxicities of grade 4 sepsis, and as such the highest tolerated dose was determined to be 1 million spores.

Tumour shrinkage of greater than 10 percent was identified in 23 percent of the patients, and 21 had stable disease, measured by RECIST. Prof Janku mentioned that RECIST may not accurately capture results of the trial.

“Despite the absence of clinical signs of germination in some patients, we saw improved tumor-specific immune responses through the increased secretion of T-cell cytokines and increased presence of tumor infiltrating lymphocytes in injected tumors,” said Prof Janku.

“From these preliminary results, it appears that C. novyi-NT is able to activate the immune response besides causing tumor destruction.”

C. novyi-NT elicits an immune response, and as such Prof Janku believes this therapy will be synergistic with checkpoint inhibition.

“We were extremely encouraged by the results of this trial, especially in patients with advanced sarcomas, where immunotherapy hasn’t proven very efficacious,” Prof Janku concluded. “This bacteriolytic strategy has the potential to be clinically meaningful, especially in combination with checkpoint inhibitors, for patients with advanced solid tumors.”

The data was presented at the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival.

SOURCE: www.europeanpharmaceuticalreview.com/news/79682

Cancer immunotherapy pioneers awarded Nobel medicine prize

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Cancer immunotherapy pioneers James Allison and Tasuku Honjo have been awarded this year’s Nobel Prize in Physiology or Medicine.

The Karolinska Institutet’s Nobel Assembly awarded the prize for their discovery of cancer therapy “by inhibition of negative immune regulation.”

The work by Allison and Honjo paved the way for drugs such as Bristol-Myers Squibb’s Yervoy (ipilimumab), which work by turning off the safety mechanisms in the immune system that prevents it from attacking the patient’s own body.

This allows the immune system to launch an attack against cancer – a mechanism that is fast becoming the basis for standard therapy in diseases such as melanoma and lung cancer.

Allison, currently professor and chair of Immunology and executive director, immunotherapy platform at the M. D. Anderson Cancer Center, studied a known protein, cytotoxic T-lymphocyte associated protein-4 (CTLA-4), that functions as a brake on the immune system.

He realised the potential of releasing the brake and thereby unleashing our immune cells to attack tumours. He then developed this concept into a brand new approach for treating patients.

Inhibition of CTLA-4 is the mechanism exploited by Bristol-Myers Squibb’s Yervoy (ipilimumab), the first checkpoint inhibitor approved by the FDA in 2011, to treat melanoma.

Honjo, now deputy director-general at the Kyoto University Institute for Advanced Study (KUIAS), discovered the programmed cell death protein (PD-1)  protein on immune cells.

After careful exploration of its function, he eventually revealed that it also operates as a brake, but with a different mechanism of action.

In inhibition of PD-1, or its ligand, PD-L1, it forms the basis for all the other checkpoint inhibitors approved so far, including Merck’s blockbuster Keytruda (pembrolizumab).

In its statement the Nobel assembly noted that although PD-1 had proved to be more effective overall, combining the two forms of therapy could be even more effective, as demonstrated in patients with melanoma.

(c) Nobel Media

James Allison

The committee concluded in its statement: “Allison and Honjo have inspired efforts to combine different strategies to release the brakes on the immune system with the aim of eliminating tumour cells even more efficiently.

(c) Nobel Media

Tasuku Honjo

“A large number of checkpoint therapy trials are currently underway against most types of cancer, and new checkpoint proteins are being tested as targets. For more than 100 years scientists attempted to engage the immune system in the fight against cancer. Until the seminal discoveries by the two laureates, progress into clinical development was modest. Checkpoint therapy has now revolutionised cancer treatment and has fundamentally changed the way we view how cancer can be managed.”

In a statement, Shigefumi More, director general and distinguished professor at KUIAS, said: “It is wonderful that the efficacy of cancer immunotherapy by PD-1 blockade has now been demonstrated worldwide, and that this therapy is actually saving the lives of many people. I would like to express my respect for his important work for human beings, and wish Distinguished Professor Honjo continued success in the future.”

SOURCE: www.pharmaphorum.com/news

Teva wins FDA OK for crucial migraine drug

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Vital to Teva’s turnaround, Ajovy will challenge Novartis/Amgen’s Aimovig.

Teva has secured US approval for migraine drug Ajovy, a key part of new chief execeutive Kåre Schultz’s turnaround plan for the company.

The FDA approved the CGRP inhibitor for the prevention of migraine in adults with either monthly or quarterly dosing, based on two phase 3 studies showing that it could reduce the number of migraine days over a 12 -week period compared to placebo.

Ajovy (fremanezumab) is the second CGRP inhibitor to be approved for marketing after Novartis and Amgen’s Aimovig (erenumab), which got the green light in May and is dosed monthly, and ahead of late-stage rivals from Eli Lilly (galcanezumab) and Alder Biopharma (eptinezumab).

Teva would have been earlier to market but the FDA review for its products was delayed by three months while it sorted out some manufacturing issues. With Lilly due to hear from the FDA any day now, potentially setting up a three-way marketing battle, the Israeli drugmaker will be hoping the three-monthly dosing option will be popular with doctors and patients – particularly as there seems to be little to separate the antibodies when it comes to efficacy.

In a statement, Teva said that it had set a list price of $575 for the monthly dose and $1,725 for the quarterly dose, giving an annual cost of $6,900 before rebates and discounts – exactly the same level as Novartis and Amgen positioned Aimovig, and in line with stablished therapies like Allergan’s Botox.

It is estimated that with discounts the annual cost of the drugs could be around the $5,000 mark. However, the US-based Institute for Clinical and Economic Review (ICER) said recently that – even at that lower price – the new drugs should only be used with prior authorisation and after other preventive options such as Botox and anti-epilepsy drugs like topiramate because their long-tern safety is still unclear.

It is estimated that more than 36 million people in the US suffer from migraines, with around 40% of these would be suitable for preventive treatment, and that has led some analysts to predict buoyant sales of the CGRP inhibitors.

GlobalData said recently that it expects the market for migraine drugs to grow at more than 10% a year to reach almost $9bn by 2026, with the prevention category driven by the injectable CGRP inhibitors.

”Market share is going to come down to…variables such as frequency of administration, position to market, and market access strategy,” according to GlobalData analyst Rahael Maladwala.

“Each drug has its own set of advantages; Aimovig will be the first to market, Eli Lilly’s has significant experience in marketing drugs, and an extensive sales force, while both of the other drugs have a quarterly dosing regimen compared to monthly.”

On balance, GlobalData is putting Aimovig out in front in 2026 given its first-mover advantage generating nearly $1.4bn in sales in the seven major pharma markets (US, France, Germany, Italy, Spain, UK, and Japan).  Teva filed Ajovy in Europe earlier this year, but here it will also lag behind Aimovig as Novartis and Amgen picked up EMA approval for their drug in July.

Analysts at Jefferies have suggested Ajovy could become a $500m product in 2022, which will go some way towards counteracting the decline in sales of Teva’s blockbuster multiple sclerosis therapy Copaxone (glatiramer acetate), its rapidly ageing cash-cow product.

Since Schultz took the helm last year, Teva has been shedding staff and restructuring the business to cut costs, selling off its women’s health business for almost $2.5bn in order to pay down a very high level of debt stemming from its $39bn acquisition of Allergan’s generics business Actavis in 2015.

Ajovy is one of 23 New Drug Application (NDA) approvals Teva is targeting between fiscal 2019 and fiscal 2023 to help replace Copaxone and drive top-line growth, along with other new products such as movement disorder therapy Austedo (deutetrabenazine).

SOURCE: www.pmlive.com/pharma_news

New C.diff drug to be tested on patients for first time

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A new drug aimed at treating potentially deadly Clostridium difficile (C. diff) infections is set to be tested on patients for the first time.

Glasgow-based life sciences firm MGB Biopharma (MGB) said it was preparing to launch a Phase II clinical trial of its anti-bacterial agent MGB-BP-3.

The trial is expected to involve 30 patients based in North America.

All have been diagnosed with C.diff-associated disease (CDAD).

C.diff infections can cause diarrhoea and fever.

They have been a major problem in hospitals around the world, with thousands of deaths in the US alone linked to the bug each year.

The bacteria are able to take over the gut when a course of antibiotics kills off the bugs that normally live there.

MGB’s announcement came after it raised £1.3m from investors for trials of the new drug, which was invented at the University of Strathclyde.

The funding round was led by Edinburgh-based Archangels, with co-funding from a range of sources, including the Scottish Investment Bank, Barwell and Melrose-based Tri Capital.

The cash supplements a £2.7m grant awarded earlier this year by Innovate UK.

MGB said its trial would “evaluate safety and tolerability, efficacy and in particular look for improvement in global (or sustained) cure rates”.

Chief executive Dr Miroslav Ravic said: “We are already witnessing renewed interest in our new anti-bacterial agent and its trial in key medical centres in North America where CDAD is particularly prevalent.

“This offers opportunities both to progress the study rapidly and to attract increased attention to the results for this important trial.”

The company said it was aiming to start the trials in areas of the US and Canada with a high incidence of CDAD early next year.

SOURCE: www.bbc.co.uk/news/

Celgene’s Otezla produces “meaningful benefits” beyond beyond traditional metrics in plaque psoriasis

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Celgene made its voice heard amongst the chorus of new psoriasis data emerging from the European Academy of Dermatology and Venereology (EADV) Congress in Paris, revealing that Otezla (apremilast) achieved “meaningful improvements” in outcomes of patients with moderate to severe plaque psoriasis that may not be captured by common metrics that focus only on skin clearance, such as the Psoriasis Area Severity Index (PASI).

“Only considering skin clearance may not fully capture the effect a treatment may have on an individual’s disease burden and its impact on daily life,” explained Dr Denis Jullien, Department of Dermatology and Venereology at Edouard Herriot Hospital, and an author of the study. “For example, itching, which is not accounted for by PASI, is cited by over a third of patients as their overriding quality-of-life issue. These new analyses of Otezla studies can help inform both prescribers and patients when evaluating treatment decisions.”

The new findings included a post hoc sub-analysis of the phase 3 ESTEEM 1 trial, examining moderate to severe plaque psoriasis patients who did not achieve a PASI score of 75 after either 32 or 52 weeks of treatment with Otezla during the trial. In this group, over half achieved a 50% reduction in PASI score over the same periods – findings that Celgene argues “may more reliably indicate clinically meaningful benefit” when taken together with disease-specific quality-of-life measures.

For example, the data showed that itching was reduced from baseline by around 30% during weeks 4 to 52 for those who started treatment of Otezla, and during weeks 20 to 52 in patients who were switched form placebo at week 16. Additionally, patients reported an increase of at least five points in the Dermatology Life Quality Index (DLQI) over the same period.

“The ESTEEM and UNVEIL clinical trials continue to provide important learnings about Otezla for the treatment of psoriasis as well as quality of life for people who live with this chronic condition,” said Volker Koscielny, Vice President of Global Medical Affairs, Inflammation & Immunology at Celgene. “These sub-analyses of UNVEIL and ESTEEM suggest that appropriate patients with moderate to severe plaque psoriasis who experience manifestations beyond skin may benefit from treatment with Otezla.”

SOURCE: www.pharmafile.com/news/518748

Can sugar pills actually relieve chronic pain?

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A sugar pill could benefit patients suffering from chronic pain with specific brain anatomy and psychological traits.

Doctors could begin to prescribe sugar pills for some patients suffering from chronic pain, based on their brain anatomy and psychology. The pills are said to reduce their pain as effectively as new powerful pain relief drugs.

Scientists from Northwestern University have shown that they are able to reliably identify patients with chronic pain, that will respond to a sugar placebo pill based on their brain anatomy and psychological characteristics.

The scientists also suggests that it’s not necessary to hide this from the patient.

“Their brain is already tuned to respond,” said senior study author Professor of Physiology at  Northwestern University Feinberg School of Medicine, Dr Vania Apkarian.

“They have the appropriate psychology and biology that puts them in a cognitive state that as soon as you say, ‘this may make your pain better,’ their pain gets better.”

“You can tell them, ‘I’m giving you a drug that has no physiological effect but your brain will respond to it,’” he said. “You don’t need to hide it. There is a biology behind the placebo response.”

For the study, 60 patients with chronic back pain were randomised into two groups. The first group did not know whether they received the drug or the placebo, and the second group included people who came to the clinic, but received neither the drug nor the placebo.

The scientists did not study the people receiving the real drug, instead focusing on those receiving the sugar pill. The second group was used a control.

Individuals who had a decrease in their level of pain had similar brain anatomy. The right side of their emotional brain was larger than the left, and they had a larger cortical sensory area than people who were not responsive to the placebo. Psychologically, these individuals were also emotionally self-aware, sensitive to painful situations and mindful of their environment.

The researchers mention three main potential benefits: prescribing non-active drugs rather than active drugs, eliminating the placebo effect from drug trials, and reducing healthcare costs.

“It’s much better to give someone a non-active drug rather than an active drug and get the same result,” Prof Apkarian said. “Most pharmacological treatments have long-term adverse effects or addictive properties. Placebo becomes as good an option for treatment as any drug we have on the market.”

“Clinicians who are treating chronic pain patients should seriously consider that some will get as good a response to a sugar pill as any other drug,” he concluded. “They should use it and see the outcome. This opens up a whole new field.”

The study was published in Nature Communications.

SOURCE: www.europeanpharmaceuticalreview.com/news/79045

Gilead, Galapagos JAK inhibitor clears phase II test

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A mid-stage trial of Gilead and Galapagos’ JAK1 inhibitor filgotinib has set up a phase III programme for the drug in ankylosing spondylitis as it chases down two already-marketed dugs from Pfizer and Eli Lilly – and a late-stage rival from AbbVie.

In the TORTUGA trial, filgotinib met its clinical objective of reducing disease activity scores compared to placebo in patients with AS, a severe form of arthritis affecting the spine, with more patients achieving the target 20% improvement with the drug (76%) than in the control group (40%).

The drug is also in development for rheumatoid arthritis (RA), ulcerative colitis and Crohn’s disease with phase III trials already underway in those indications and results due in the coming weeks.

The drug was generally well-tolerated in TORTUGA but one case of deep vein thrombosis gave investors some cause for concern, putting some pressure on Gilead and Galapagos’ share price yesterday before share staged a partial recovery.

DVT is a recognised side effect with Eli Lilly’s JAK1 inhibitor Olumiant(baricitinib), which finally made it to market for rheumatoid arthritis in Europe last year but was rejected in the US at its first filing attempt over the safety issue. Gilead said that in the phase II AS trial the patient had an inherited condition that raised the risk of blood clots and the DVT was not thought to be drug-related.

First-to-market JAK inhibitor Xeljanz (tofacitinib) from Pfizer has already achieved $1bn-plus sales in RA, and with Olumiant somewhat hamstring by the safety issue on its label analysts are viewing the tussle between filgotinib and AbbVie’s upadacitinib as the next big battleground in the JAK inhibitor market.

AbbVie is a little ahead in the race to market, with phase III data in hand showing that upadacitinib is more effective than AbbVie’s $18bn-a-year injectable TNF blocker Humira (adalimumab) in RA when it comes to clinical responses gauged by doctors and patients. Like filgotinib, upadacitinib is also being tested in a string of other indications, including psoriatic arthritis, Crohn’s disease, ulcerative colitis and atopic dermatitis.

The rivalry is particularly strong as AbbVie was formerly Gilead’s partner for filgotinib, before ducking out of the collaboration and throwing its weight behind its in-house candidate.

SOURCE: http://www.pmlive.com/pharma_news

Jazz’ Vyxeos wins EU nod for certain acute myeloid leukaemias

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Dublin, Ireland-based Jazz Pharmaceuticals will be celebrating news of European approval of its leukaemia drug Vyxeos.

The European Commission is allowing use of the drug to treat adults with newly diagnosed, therapy-related acute myeloid leukaemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC).

Vyxeos is an advanced liposomal formulation that delivers a synergistic molar ratio of daunorubicin and cytarabine, and is “the first chemotherapy to demonstrate an overall survival advantage versus the standard of care in a Phase III study of older adult patients” with these conditions, said Daniel Swisher, Jazz’ president and chief operating officer.

The application included clinical data from five studies, including the pivotal Phase III study, data from which was published in the Journal of Clinical Oncology in July.

The study hits its primary target showing a superior improvement in overall survival compared to an alternative chemotherapy regimen, with 9.6 months versus 5.9 months, respectively.

“AML is a rare cancer in Europe and patients with therapy-related AML or AML with myelodysplasia-related changes have a particularly poor prognosis compared to people with other forms of leukaemia,” said Professor Charles Craddock CBE, academic director, Centre for Clinical Haematology at University Hospitals Birmingham NHS Foundation Trust.

“Vyxeos is a new and clinically meaningful treatment option that provides a welcome advance for patients and health care professionals across the European Union.”

SOURCE: www.pharmatimes.com/news