CRO IQVIA Faulted by FDA for Data Inaccuracy, Quality Issues in Opioid Sales Database

The FDA took vendor IQVIA to task for a discrepancy in data regarding sales of opioid drug products that the agency said could undermine forecasts used in the fight against addiction.

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IQVIA collects data to measure the volume of drugs sold by manufacturers and wholesalers to pharmacies and hospitals. While conducting an analysis to estimate the amount of opioids sold in the U.S., the agency found a discrepancy in the IQVIA data that showed a more than 20 percent drop in the reported amount, expressed in kilograms, of fentanyl sold for a minimum of the past five years compared to what IQVIA’s database had previously reported.

Based on a subsequent investigation and discussions with IQVIA, the FDA determined that IQVIA overestimated past data because of an error in its methods, which the agency believes resulted from the vendor utilizing the wrong weight-based conversion factors to determine the amount of fentanyl in a given unit (such as a single fentanyl patch) for a subset of prescription fentanyl products.

“While data on sales volume expressed in kilograms are used only narrowly by the FDA… we are sharing this information publicly because these data have been used in forecasts that have the potential to impact ongoing work to fight the opioid epidemic,” the agency said.

The agency also looked at IQVIA’s data for similar mistakes related to other controlled substances and found more data quality issues related to controlled substances with similar weight-based conversion factors—including oxymorphone and hydrocodone—raising serious concerns about the data vendor’s data and quality control.

FDA Commissioner Scott Gottlieb requested that IQVIA hire a third party auditor to review its data quality and quality control procedures for the controlled substance data the agency used. He also requested that the third party conduct an independent audit of the data quality and quality control of all IQVIA products used by the agency.

The agency will be “working with federal partners on these issues and briefing members of Congress on IQVIA’s data quality issues and their potential public health implications,” the agency said. “We will provide updates to the public and our public health partners as appropriate.”

IQVIA said it has already addressed the data issues and informed clients about the error.

The company’s “internal processes had already identified the measurement conversion issue prior to the FDA’s notification,” IQVIA said. “We notified our clients about this measurement conversion issue in April of this year. Ongoing steps have been undertaken to correct this measurement conversion issue.”

Clinical Trial Agreements: Do You Understand All the Important Terms in the Contract?

Do you understand everything you need to about the clinical trial agreement contracts you sign?

Likely not, as most contain hidden landmines and not everything in them is as simple as you might think, according to Eric Babineaux, legal counsel for Clintrax Global, who spoke during a WCG webinar last week on the meaning of certain words and concepts often seen in clinical trial agreements.

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Even establishing the date of a contract is not as straightforward as one might assume, said Babineaux. Most contracts start on the date that both parties sign, but often one of the parties will want to back date the contract, and the other party agrees to go along. For instance, signing parties will make the effective date a date from a few months ago to reflect a protocol amendment in the study, usually for budget reasons. But Babineaux warns against it.

“I would argue that this is inappropriate. Avoid back dating agreements,” he said. “Instead what we should be doing is truthfully reflecting that the agreement is being made with the signing of the agreement, then moving forward with drafting language within the body of that amendment to show that the parties are agreeing that any changes to the budget are going to need to be retroactive back to whatever date that protocol amendment might have occurred.”

When in doubt, Babineaux said, it’s better to truthfully represent the date, with both parties agreeing to respect the fact that there may be some rights that go back beyond whenever the contract was actually signed.

Another complicated area, said Babineaux, is indemnification — the clause in which one party agrees to protect the other against potential harms or losses that the other party may incur. This is a big one because if triggered, “it could have a pretty high degree of liability,” Babineaux said.

He advised that those penning contracts be very clear on who exactly is indemnified. He used the example of a Sponsor signing a clinical trial agreement with an institution that has affiliated hospitals. To avoid extending wide indemnification to a whole healthcare system, for example, Sponsors should be specific in the contract about exactly which facilities they will indemnify, naming only those that will touch your study, he said.

And Sponsors and CROs, watch out for the word “gross” when writing the clause stating which types of actions — specifically negligence — will be indemnified and which will be excluded from that protection. Explained Babineaux, gross negligence in the context of a clinical trial is conduct that smacks of intentional wrong doing or implied malice or evil intention or represents an extreme departure from standards of ordinary care. Sometimes one party will negotiate to have the standard for indemnification in a contract raised to gross negligence only, meaning: the Sponsor protects the site from a claim from a third party except when the site has been grossly negligent.

But when that is done, Babineaux explained, the Sponsor or CRO is no longer excluding non-gross negligent acts from the behaviors they will protect, and thus will need to protect an investigator who engages in negligence should a third party file a claim, when that might not be appropriate.

“Gross negligence standard is not applied as consistently across jurisdictions as the negligence standard,” he said. “It’s a much higher standard than plain negligence which results in conduct that only amounts to negligence but not reaching gross negligence being indemnified.”

That one word changes everything.

As a Sponsor, “you want to be careful if you ever see that language being added,” said Babineaux. “You want to make sure exactly how that will affect your duty to indemnify because you want to avoid increasing your risk liability just through overlooking the addition of a single word.”

Babineaux also pointed out that clinical trial agreements are often signed between CROs and sites, not Sponsors and sites, and this pushes into a new legal area called third-party beneficiary law. Explained Babineaux, the CRO signs an agreement on behalf of the Sponsor, under power of attorney or a letter of authority, and the Sponsor is now a third-party beneficiary to the contract. Under this type of agreement, the Sponsor is able to sue to enforce obligations under the contract even though they are not party to the agreement — but because they are not a party to the agreement, the site can’t sue them.

“The site can’t enforce any obligations against the Sponsor” under this type of agreement, said Babineaux. This can leave a site dangerously vulnerable when it comes to indemnity.

To remedy that, he suggests sites draw up a letter of indemnification to have the Sponsor sign so they can enter into a direct relationship over the matter. “That way, you do have the mechanism to enforce your rights that the Sponsor may owe,” he said.

Clinical trial agreements may seem complex, but if you understand key terms and the ramifications they can have, you’ll be well on your way to protecting yourself during the course of a trial, and clearing the space to focus on the trial without worrying about legal exposure.

Novartis paid $1.2 million to Donald Trump’s personal lawyer

Novartis’ general counsel Felix Ehrat is to step down following revelations that the company paid $1.2 million to Donald Trump’s personal lawyer in return for insights into the president’s health policy ideas.

Ehrat said that he is stepping down to take “personal responsibility” for the matter, and pointed out that the agreement had been co-signed by former CEO Joe Jimenez.

The move comes after Novartis was dragged into the scandal surrounding the actions of Trump’s personal lawyer, Michael Cohen, and whether the president attempted to cover up an alleged affair with the former porn star Stormy Daniels in 2006.Novartis-HQ-840x470

Daniels’ attorney, Michael Avenatti, told NBC last week that Novartis was among several firms that paid large sums of money to a company controlled by Cohen.

Novartis confirmed this by saying it had entered into a one-year agreement with Cohen’s firm Essential Consultants in February 2017, shortly after Trump took office.

In the end Novartis only met Cohen once, before deciding that the arrangements would not provide any useful information, but the Swiss firm continued to make monthly payments of $100,000 over the course of a one-year period.

Novartis has said that Ehrat will retire as general counsel in the aftermath of the scandal, and will be replaced by Shannon Thyme Klinger, currently chief ethics, risk, and compliance officer, effective June 1.

Ehrat said: “Although the contract was legally in order, it was an error. As a co-signatory with our former CEO I take personal responsibility to bring the public debate on this matter to an end.”

Jimenez breaks silence

In an interview with Bloomberg, Jimenez, who retired in February, has given his side of the story, outlining how the deal with Cohen quickly turned sour.

Jimenez said Cohen told his team he had left Trump’s organisation and had stopped working for the president before pitching for business with Novartis.

He told Bloomberg: “Michael Cohen was somebody who was introduced to us, and he was unknown to us, but he was said to be somebody who could help.”

“After my team met with him individually, it was clear that he oversold his abilities.”

Jimenez said the contract with Cohen was negotiated with Novartis’ legal team after an introduction from an unidentified “third party”, and that he had not met the lawyer in person.

Jimenez said he wanted to terminate the deal but decided that doing so would have been costlier than letting the agreement expire because of “almost certain litigation”.

“That was a mistake,” said Jimenez who admitted the firm should have “parted ways” with Cohen as soon as it became apparent he could not help.

Jimenez said Cohen had not offered lobbying services, but had advised at one point that Novartis should build a manufacturing site in the US.

Novartis had not acted on the advice and Cohen had never provided any access to anyone in the administration, said Jimenez.

Bloomberg separately reported that Novartis’ new CEO Vas Narasimhan held a conference call with 5,000 managers to pass on the urgent message that the company needs to regain public trust and rethink the way it does business with consulting firms, lobbyists, and other groups.

Novartis is completing a review to determine next steps after an internal investigation conducted by outside advisers, which found it didn’t do anything illegal.

Novartis completes $8.7bn acquisition of AveXis

Novartis has completed its $8.7bn acquisition of US-based clinical stage gene therapy company AveXis via the consummation of a merger of its indirect wholly-owned subsidiary, Novartis AM Merger with and into AveXis.

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In the merger, each share of AveXis common stock outstanding immediately prior to the effective time of the merger (other than shares owned by Novartis, Merger Sub, AveXis or any subsidiary of Novartis or AveXis or by any AveXis stockholders who properly perfected their appraisal rights under the DGCL) has been converted into the right to receive USD 218.00 per share, net to the seller in cash, without interest and subject to any tax withholding.

As a result of the merger, AveXis became an indirect wholly-owned subsidiary of Novartis and AveXis’ shares have ceased to be traded on the NASDAQ Global Select Market.

Novartis CEO Vas Narasimhan said: “We are delighted to add AveXis’ leading gene therapy technology to our company and to welcome our AveXis colleagues to Novartis. Together, we now have the potential to bring to children the first one-time gene-based treatment for the devastating disease, spinal muscular atrophy.

“The deal also supports our strategy to deliver transformative innovation in areas of high unmet medical need, and advances our growing pipeline of gene therapies with the potential to transform the care of diseases, from SMA and cancer to blindness.” 

Novartis Pharmaceuticals CEO Paul Hudson said: “Novartis and Avexis bring truly complementary capabilities behind a shared purpose – transforming the care of patients with life-threatening neurological genetic diseases.

“AveXis has built a team with exceptional depth of expertise and experience, a clinically proven gene delivery platform, manufacturing and R&D capabilities, while Novartis has been for 70 years a leader in Neuroscience, building on a global footprint and its extensive experience in bringing transformational medicines to the clinic stage.”

China removes import duties on 28 medicines; India to get boost

China on Thursday said it has removed import duties on as many as 28 medicines, including all cancer drugs, from May 1, a move which would help India to export these pharmaceuticals to the neighbouring country.

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“China has exempted import tariffs (duties) for 28 drugs, including all cancer drugs, from May 1st. Good news for India’s pharmaceutical industry and medicine export to China. I believe this will help reduce trade imbalance between China and India in the future,” Chinese Ambassador to India Luo Zhaohui said in a tweet.

The development assumes significance as India has time and again asked for greater market access for its goods and services, including IT, pharmaceuticals and agriculture, in the Chinese market to reduce the widening trade deficit.

In the meeting of India China Joint Group on Economic Relations, Trade, Science and Technology here, the issue of trade imbalance was discussed in detail. China on its part promised to address the trade gap issue.

Trade deficit with China stood at $36.73 billion during April-October 2017-18. It was $51 billion in 2016-17. He also said that China would further improve business environment by halving time required to open a business. “China’s door to the outside world will open wider. Indian businesses are welcome,” he added. India too has sought investments from China. The neighbouring country has agreed to set up industry park in India to increase investments and bridge trade deficit.

Wearable Medical Devices Global Market to Reach $19.5B by 2021

The global market for wearable medical devices is expected to nearly $19.5 billion in 2021 at a compound annual growth rate (CAGR) of 28.8% for 2016-2021, according to a new report from Report Linker. The report reveals that the U.S. market for wearable medical devices is expected to grow from $2.5 billion in 2016 to nearly $8.7 billion in 2021 at a CAGR of 27.9% from 2016 through 2021. 

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The rising elderly population, dysfunctional lifestyles, and the rising concern of patients toward their health and fitness is boosting the growth and development of new technologies within the medical device and diagnostics market. The market study provides analysis of the wearable medical device technologies and their applications in dealing with today’s current challenges. It also includes information about emerging wearable technologies, market players, issues and trends, and other information affecting the medical device and diagnostics industry. 

Defining Wearable Medical Devices

Wearable medical devices are electronic mechanisms that act as biosensors that are attached to the human body to detect and monitor changes in various areas of the body and capture physiological data. 

These devices are designed to be non-invasive in nature, autonomous in functioning, and are primarily used in medical and fitness related applications. They also provide local processing, feedbacks and reports, communication capabilities, and easy time sensing abilities. Wearable glucose monitoring and drug delivery devices, activity monitors, smart clothing, smart equipment, wearable vital sign monitors, and smart watches are a few examples of wearable medical devices. 

Chronic disease and pain management require consistent day-to-day actions, rather than visits to the doctor to shape outcomes. There is a growing need for wearable devices which can remind, warn, encourage, and perhaps most importantly, supply the patient with innovative strategies to comply with treatment regimens (and in some cases, provide that treatment). 

Evolution of Wearable Medical Devices

Traditional markets for wearable devices have been focused primarily on non-consumer niche applications, including those in the healthcare, defense/security, enterprise, and industrial markets. 

However, recent advances in materials science, electronics, photonics, and software have enabled the emergence of a potentially vast range of new lightweight, wearable computing products. These technology advances are not only growing in traditional non-consumer markets but are also enabling the emergence of a number of new consumer applications.

These services/solutions offered can be categorized into four segments:

– disease management

– monitoring & feedback

– rehabilitation

– health & fitness processes

Electronic wearable medical devices serve multiple functions in the diagnosis and monitoring of various disease conditions, such as chronic diseases of the heart, diabetes (monitoring blood sugar, glucose etc.), and various other illnesses. 

Key Market Drivers

Wearable or body-borne sensors enable hands-free mobile real-time data monitoring, logical calculation, and network communication. The growth of the wearable device market is mainly driven by factors such as the growing elderly population, rising prevalence of chronic diseases, technological advancements in the medical devices. 

The U.S. dominates the global wearable medical device technology market followed by EuropeAsia, and ROW (rest of the world). The large market share of the U.S. and Europe can be attributed to a greater accessibility of advanced technologies and the presence of a large number of leading market players. 

Novartis app could revolutionise ophthalmic clinical trials

Patients will be able to participate in clinical ophthalmology trials from home thanks to a groundbreaking digital app developed by Novartis.

The FocalView app, which will enable patients with mobility issues to take part in clinical trials, means researchers can study and collect data about eye diseases regardless of a person’s location.

Patients will be able to record their own measurements, which will hopefully mean new treatments are developed and subsequently brought to market more rapidly.

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Traditional ophthalmic trials face challenges due to the practical issues faced by patients, making data capture inflexible and intermittent. The unpredictability caused by the latter has historically meant that researchers are unable to capture real-world information relating to the diseases.

Once users have consented to contribute to the research, the app will prompt patients to complete assessments on their visual function and ask them to detail any changes over time. In the first instance, FocalView will be tested in a prospective, non-interventional study.

Its effectiveness in assessing visual function – including visual acuity and contrast sensitivity – will be assessed.

Dr Mark Bullimore, medical advisor for the creation of FocalView and dean of the Southern California College of Optometry, Marshall B. Ketchum University, said: “Because patients with eye diseases are often not as mobile, FocalView has the potential to offer tremendous benefit for the ophthalmic community and for researchers looking to develop better treatments for these patients.”

“Collating validated patient-reported outcomes in clinical trial research is no longer a nice-to-have. This kind of data is fast becoming a critical element of research and development, because it offers a better reflection of real-world patient experiences, fosters better patient compliance and provides researchers with richer and more accurate data points.”

Ease of use, level of uptake and the capacity to obtain documentation for future clinical trial research, such as informed consent, will be monitored. The results of the app will also be compared to traditional visual testing that takes place in conventional clinical settings.

FocalView is available from the US App Store with additional markets to be added in future. The findings made via FocalView will be freely accessible via the Apple ResearchKit platform.

Last month, Novartis announced plans to begin up to 10 clinical trials over the next three years with Science 37, which develops decentralised clinical trial technology so certain aspects of the trial can be carried out in a patient’s home or by their GP.

Shire considers Takeda’s revised £46bn takeover offer

Shire’s board said that it is willing to recommend Takeda Pharmaceutical’s revised acquisition offer of £46bn to its shareholders.

As per the revised proposal, Takeda offers to pay nearly £49 per each share of Shire in the form of £21.75 in cash and £27.26 in new Takeda shares.

Prior to this, Takeda had offered to pay £46.50 per each share of Shire, in what was a third offer, made on 13 April.

Upon completion of the transaction, Shire shareholders will own almost 50% of the enlarged company that combines the Irish and Japanese pharma firms.

Shire, in a statement, said: “Shire shareholders would also be entitled to any dividends announced, declared, made or paid by Shire in the ordinary course prior to completion of the possible transaction.”

The new Takeda shares will be listed in both Japan and the US through an ADR program.

Shire’s board said that its recommendation of the revised proposal will be subject to satisfactory resolution of the other terms of Takeda’s offer. These include completion of reciprocal due diligence by Shire on the Japanese company.

The company noted that its board has agreed to extend the deadline of concluding ongoing talks with Takeda till 8 May 2018. The deadline could be further extended though if needed, said the Irish firm.

Takeda has been looking to acquire Shire since late March when it first offered to pay £44 per each share. Since then, the Japanese firm made two more offers, which were rejected by Shire until the newly revised proposal made on 24 April.

Shire had turned down the previous offers made by Takeda, citing that they had undervalued the company, its growth prospects and pipeline.

Takeda has been pursuing Shire with the hope that its acquisition would help it accelerate its transformation into a value-based player in research and development driven biopharmaceuticals.

The company also expects to get a balanced geographic footprint, enhanced financial strength and a modality-diverse pipeline through the merger with Shire.

Earlier this month, Shire entered into a deal to offload its oncology business to France-based Servier for $2.4bn.

Glenmark closes Indian trial site over fraud

As regulatory authorities in India move to tighten up oversight of the country’s fast-growing clinical research sector, local company Glenmark Pharmaceuticals has announced the closure of a clinical trial site in Jamnagar, Gujarat state, citing fraudulent activities.

Glenmark started using Guru Gobind Hospital in Jamnagar at the end of last year as one of the sites for a Phase IIb clinical trial of Oglemilast (GRC 3886), its lead compound for asthma/chronic obstructive pulmonary disorder. The multi-centre trial is being conducted for Glenmark by US-based contract research organisation (CRO) Omnicare Clinical Research.

The accusation of fraud is against Dr A. Bhattacharya, who at the time was the clinical investigator for the trial at Guru Gobind Hospital. He was subsequently transferred to Baroda Medical Medical College. Glenmark said Bhattacharya had now been suspended from that position while police investigated the full extent of potential fraud committed by the doctor in studies for other CROs and pharmaceutical companies.

According to Glenmark, signs of irregularities emerged during monitoring of the Guru Gobind site immediately after it joined the trial. Fraud was confirmed in a for-cause audit by the company and Omnicare, which brought the issue to the attention of the hospital’s ethics committee.

“Omnicare along with Glenmark acted swiftly and closed the site in line with normal regulatory requirements, to ensure the appropriate care/safety of the patients was protected,” Glenmark reported, adding: “It is important to confirm that no patients have been put at risk, and no further patients have been or will be recruited in the clinical study at Jamnagar.”

The company also formally notified the Drugs Controller General of India about the situation in early April and updated the regulatory authority on its actions and findings at the site in June.

Glenmark said it would not be considering any of the data generated from Guru Gobind Hospital, while the Phase II trial of Oglemilast “continues to progress as per plan at other sites across the country”.

Pfizer biosimilar of Roche’s cancer drug fails to get FDA approval

The US Food and Drug Administration (FDA) has declined to approve Pfizer’s proposed biosimilar of Roche’s breast cancer drug Herceptin (trastuzumab) and asked for more technical information.

Pfizer said that the additional requested information asked in the Complete Response Letter (CRL) sent by the US regulator is not related to safety or clinical data submitted in the drug’s application.

The company said it is working with the FDA to address the contents of the letter and remains committed to bringing this important medicine to patients in the US.

“Pfizer believes that biosimilars are critically important to the future of cancer care, with the potential to increase patient access to life-changing therapies that will help address the evolving needs of healthcare systems, patients, physicians and payers,” the company said.

Pfizer’s trastuzumab biosimilar, PF-05280014, is an investigational monoclonal antibody, which had succeeded in the Reflections B3271002 breast cancer trial in late 2016 by meeting the primary endpoint of objective response rate.

PF-05280014 was assessed against trastuzumab in combination with paclitaxel, in first line patients with HER2-positive metastatic breast cancer.

Pfizer then said that a separate trial, known as Reflections B3271004, also met its primary endpoint of steady-state Ctrough concentrations in early breast cancer patients, who were treated with the company’s biosimilar and Herceptin.

Apart from the CRL for the trastuzumab biosimilar, Pfizer made two separate announcements with one of them being the FDA breakthrough therapy designation for Trumenba (meningococcal group B vaccine) and an approval in the European Union for Mylotarg (gemtuzumab ozogamicin).

Trumenba secured the FDA designation for providing active immunization in children in the age group of 1-9 years to protect them against invasive disease caused by Neisseria meningitidis group B (MenB)

On the other hand, Pfizer secured the approval for Mylotarg in combination with chemotherapy from the European Commission for the treatment of previously untreated, de novo, cd33-positive acute myeloid leukemia.

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