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After the US Food and Drug Administration (FDA) discovered an abbreviated new drug application (ANDA) relied on data from a disreputable contract researcher, and after repeated attempts over five years to get the company to resubmit new data, the agency on Friday proposed to withdraw the approval for Cipla subsidiary InvaGen Pharmaceuticals’ trandolapril tablets.

“The basis for the proposal is that the holder of the ANDA has repeatedly failed to submit the required data to support a finding of bioequivalence for this ANDA,” FDA said, noting the company can request a hearing.

FDA first approved the InvaGen trandolapril tablets in 2007, but the ANDA was supported by bioanalytical analysis conducted by Houston-based contract research organization Cetero Research. And that analysis was conducted during a five-year window when FDA inspections raised significant concerns about the validity of the site’s reported results. Due to what FDA found to be the “widespread falsification” of data by Cetero, the agency called on any sponsors using the site to redo certain studies.

In 2011, FDA sent a letter to InvaGen explaining that it needed to conduct new bioequivalence studies or re-assay the samples from the original bioequivalence study for this particular ANDA and submit them within six months. But InvaGen did not respond to the letter.

In August 2016, FDA sent another letter to InvaGen requesting that, within 30 calendar days, InvaGen either supplement the ANDA with the requested bioequivalence data or voluntarily seek withdrawal of the ANDA. InvaGen responded a month later and said it needed a nine-month extension to conduct the new studies and submit them.

But in April 2017, FDA sent another letter to InvaGen denying the nine-month extension because InvaGen had already had a significant amount of time to provide the requested data.

InvaGen again did not respond to FDA’s letter, and two months later in the June 2017 Cumulative Supplement to the 37th Edition of the Orange Book, the ANDA for InvaGen Pharmaceuticals’ trandolapril tablets was moved to the discontinued section of the Orange Book.

“In the absence of information showing bioequivalence between the generic drug at issue and the RLD [reference listed drug], there is no basis for concluding that the Agency’s finding of safety and efficacy supporting approval of the RLD can be used as a basis to support approval of the generic drug,” FDA said.

Federal Register

BOSTON & BLUE BELL, Pa.–(BUSINESS WIRE)–Alexion Pharmaceuticals, Inc. (NASDAQ:ALXN) and Achillion Pharmaceuticals, Inc. (NASDAQ:ACHN) today announced that they have entered into a definitive agreement for Alexion to acquire Achillion, a clinical-stage biopharmaceutical company focused on the development of oral small molecule Factor D inhibitors to treat people with complement alternative pathway-mediated rare diseases, such as paroxysmal nocturnal hemoglobinuria (PNH) and C3 glomerulopathy (C3G). Achillion currently has two clinical-stage medicines in development, including danicopan (ACH-4471) in Phase 2 and ACH-5228 in Phase 1.

“Alexion has demonstrated the transformative impact that inhibiting C5 can have on multiple rare and devastating diseases. However, we believe this is just the beginning of what’s possible with complement inhibition,” said Ludwig Hantson, Ph.D., Chief Executive Officer of Alexion. “Targeting a different part of the complement system – the alternative pathway – by inhibiting Factor D production addresses uncontrolled complement activation further upstream in the complement cascade, and importantly, leaves the rest of the complement system intact, which is critical in maintaining the body’s ability to fight infection. We believe this approach has the opportunity to help patients with diseases not currently addressed through C5 inhibition. We look forward to applying our nearly three decades of complement and development expertise to unlock the potential of oral Factor D inhibitors and bring these benefits to patients.”

“We have established great momentum – discovering and advancing several small molecules into clinical development that have the potential to treat immune-related diseases associated with the alternative pathway of the complement system,” said Joe Truitt, President and Chief Executive Officer at Achillion. “Having already demonstrated proof-of-concept and proof-of-mechanism with our lead candidate, danicopan (ACH-4471), in PNH and C3G, respectively, we believe there is significant opportunity for Factor D inhibition in the treatment of other diseases as well. Alexion is an established leader in developing medicines for complement-mediated diseases, and we look forward to working together to accelerate our objective of bringing novel therapies to patients as quickly as possible and ensuring that the broad promise of this approach is fully realized. We thank our employees, investigators and partners for their incredible work and commitment.”

Transaction Details
The initial consideration of approximately $930 million, or $6.30 per share of Achillion common stock, will be funded with cash on hand. As part of the acquisition, Alexion will also be acquiring the cash currently on Achillion’s balance sheet. As of September 30, 2019, this was approximately $230 million; the actual amount will be determined as of the transaction close. The transaction includes the potential for additional consideration in the form of non-tradeable contingent value rights (CVRs), which will be paid to Achillion shareholders if certain clinical and regulatory milestones are achieved within specified periods. These include $1.00 per share for the U.S. FDA approval of danicopan and $1.00 per share for ACH-5228 Phase 3 initiation.

Alexion’s acquisition of Achillion is subject to the approval of Achillion shareholders and satisfaction of customary closing conditions and approval from relevant regulatory agencies, including clearance under the Hart-Scott Rodino Antitrust Improvements Act. Pending these approvals, the transaction is expected to close in the first half of 2020.

The FDA has approved Allergan’s Botox to treat lower-limb spasticity in children, further extending the use of the drug – widely used as a wrinkle treatment – in therapeutic indications.

The US regulator has given the botulinum toxin-based drug a green light for all forms of lower-limb spasticity – increased muscle contraction causing stiffness that can interfere with movement – with one exception: when it is caused by cerebral palsy.

French drugmaker Ipsen has market exclusivity for its rival botulinum toxin drug Dysport (abobotulinumtoxinA) in lower-limb spasticity caused by cerebral palsy under the terms of its 2016 approval, which made it the first drug in the class to be available for lower-limb spasticity in the US.

It’s the reverse situation in upper-limb spasticity associated with cerebral palsy, where Allergan has exclusivity for Botox (onabotulinumtoxinA) after its drug became the first US-approved treatment for this use in June.

It has previously also been licensed by the FDA to treat both upper- and lower-limb spasticity in adults.

The latest approval comes on the back of data from a 12-week, phase 3 study involving more than 300 children aged 2 to 17 years, which showed that treatment with Botox made patients more likely to meet active goals such as improvements in walking, as well as having other benefits on pain, spasm, and the need to wear braces on their legs.

“Lower limb spasticity can impact many aspects of a child’s life and have a drastic influence on their overall development and quality of life,” said Allergan’s head of R&D David Nicholson.

“This milestone will continue to support and advance care for children and their caregivers who may be struggling with lower limb spasticity,” he added.

Allergan has progressively extended the number of approved therapeutic indicationsfor Botox since its launch for blepharospasm and strabismus in 1989, with the latest taking the tally to date to 11.

The extension of Botox’s use is also good news for AbbVie, which is in the process of acquiring Allergan in a $63 billion deal.

The pivotal element of that deal is bolting on Botox’ $3.6 billion annual sales, which are viewed as being almost invulnerable to competition – Dysport made less than a tenth of that last year – while biosimilars are thought to be years from launch.

AbbVie wants to add that to its top-line as it continues a drive to extend its product portfolio and R&D pipeline and reduce its reliance on cash-cow product Humira (adalimumab), which brought in almost $20 billion in sales last year to account for nearly two-thirds of the company’s total turnover for the year.

PHILADELPHIA, Oct. 25, 2019 (GLOBE NEWSWIRE) — Spark Therapeutics (NASDAQ:ONCE), a fully integrated, commercial gene therapy company dedicated to challenging the inevitability of genetic disease, today announced that the Galien Foundation has awarded the prestigious 2019 Prix Galien USA Award for Best Biotechnology Product to LUXTURNA® (voretigene neparvovec-rzyl). The award, announced at the Prix Galien USA Awards Ceremony on Oct. 24, 2019 at the American Museum of Natural History in New York City, recognizes the development of the world’s most innovative medicines that help improve the overall human condition.

“We are honored that LUXTURNA, the first gene therapy for an inherited disease in the U.S., was awarded the prestigious 2019 Prix Galien USA Award for Best Biotechnology Product,” said Katherine A. High, M.D., president and head of research & development at Spark Therapeutics. “We hope the historic approval of LUXTURNA continues to serve as a catalyst for the field of gene therapy, improving our collective capabilities so that we may together, someday, conquer the realm of inherited disease. This recognition would not have been possible without the many contributions of the people who work at Spark Therapeutics, as well as the courage and commitment of patients and their families, and expertise and insights of the investigators, who continue to participate in the clinical development program.”

LUXTURNA is first gene therapy for a genetic disease approved in both the U.S. and EU. On Dec. 19, 2017, the U.S. Food and Drug Administration (FDA) approved LUXTURNA, a one-time gene therapy indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy and viable retinal cells. On Nov. 23, 2018, the European Commission granted marketing authorization for LUXTURNA. Novartis has exclusive rights to pursue development, registration and commercialization rights for LUXTURNA in all countries outside the U.S. Spark Therapeutics previously entered into a separate agreement with Novartis to manufacture and supply LUXTURNA to Novartis.

For more information about LUXTURNA and prescribing information in the U.S. please visit www.LUXTURNA.com.

About Spark Therapeutics
At Spark Therapeutics, a fully integrated, commercial company committed to discovering, developing and delivering gene therapies, we challenge the inevitability of genetic diseases, including blindness, hemophilia, lysosomal storage disorders and neurodegenerative diseases. We currently have four programs in clinical trials. At Spark, we see the path to a world where no life is limited by genetic disease. For more information, visit www.sparktx.com

What does a site need to do to trim its study start-up timeline from several weeks down to just a few days?

Panelists from various site organizations shared their secrets to rapid start-up and other best practices at MAGI’s “Be the Site of Choice” conference in Philadelphia last week.

The timelines panelists reported ranged from 45 days all the way down to 12 days, thanks to various time-saving strategies.

At Anne Arundel Medical Center (AAMC) in Maryland, the start-up timeline is 45 days, said Erika Siegrist, research office manager, who credits their success to the ability to reduce the number of committee meetings involved in protocol review. “We really rely on the department level to do the review of the protocols,” Siegrist said, “and we have completely outsourced all of our institutional IRB review.”

AAMC has one institutional committee that meets monthly to review all protocols, she said.

Coming in at 28 days to start-up, VitaLink Research’s founder and vice president of clinical operations Steve Clemons said the fact that the 13-site network’s leadership is located in one place makes things faster. “You can walk across the hall and say, ‘I need you to sign this now,’” Clemons said.

Triad Clinical Trials credits its size for its rapid turnaround. “We’re small,” said president and general manager Scott Whitt. “My coordinators sit within sight of me all day so we can do 12 to 15 days.”

Whitt said he hires very assertive, Type A personalities — usually former charge nurses — as coordinators and holds them accountable from start to finish for everything. “If they can’t kick me around a little bit, I lose respect for them quickly,” he said.

Christina Brennan, vice president of clinical research at Northwell Health, attributed their rapid start-up success to master trial agreements that keep them from reinventing the trial contract wheel. Using a central IRB for all trials they conduct also saves time and eases coordination. But she cautions against sacrificing enrollment for speed. “At the end of the day, if you don’t enroll, you’re not going to be remembered as the site that was the fastest study start-up.”

To achieve enrollment targets, it’s important to “stay in your lane,” Clemons said. “I think it’s truly knowing your patients, knowing your populations, knowing who you have to deal with” that allows your feasibility judgments to be correct.

Clemons said VitaLink’s first patient, first visit timeline is 4.2 days from completion of study start-up.

Whitt’s key to enrollment success is using a clinical trial management system to track all patient data as well as hiring a full-time recruiter who makes 60 to 70 calls a day. “That’s been a real game-changer for us,” he says, because it usually keeps the staff busy screening patients.

All four panelists reported retention rates in the 90 percent range. Siegrist attributes AAMC’s 95 percent rate to their use of dedicated long-term follow-up coordinators to work with patients for 10 to 20 years. The coordinators build a relationship, and patients really look forward to their calls, Siegrist said.

A comfortable environment is Whitt’s key to 92 percent retention. Located in a 1900s-era farmhouse, patients say it’s just like going to grandma’s house. The site offers comfortable couches and big screen televisions for patients, whose visits sometimes last as long as six hours. And because Triad is located in an area with low employment and health insurance coverage, the clinic serves as some patients’ primary care provider.

“We understand our patients at a very deep level,” Whitt said. “We become an important part of their healthcare.”

Whitt also uses what he calls “patient profiles” of various personality types — the accountant, the lawyer, the gossip, the prophet — and thinks in terms of each type’s needs and attitudes. “We more easily identify break points where we might have a protocol that’s not going to do well for us,” he said. “More than likely, we end up finding things that we can do in the clinic to smooth things over.”

Siegrist touted the team-based model for running a successful trial. “I never want to have one coordinator handling everything for a study,” she said. “I always want to make sure there’s a primary and a secondary or pairing a nurse with a non-RN coordinator.”

“We make sure that we have multiple people trained on the same study,” Brennan said, “so everyone can do the same as the primary.”

Whitt builds team motivation by having all the coordinators review feasibility questionnaires before they go to the sponsors. “It creates a sense of ownership and engagement in the study coordinators very early on,” he said.

Clemons said he focuses on matching staff personalities to the tasks they will perform, “learning the personality traits of the people to mix with the patient population that you’re dealing with.” And VitaLink starts early, he said, trying to get people fresh out of school.

“We like to get them and home grow them over the course of a couple of years,” Clemons said, adding that “typically, at two years, if someone’s still with you then usually they’re a decent coordinator.”

By Leslie Ramsey

In order to promote digital India and ease of doing business, the Central Drugs Standard Control Organisation (CDSCO) has asked for suggestions from the stakeholders to improve Sugam portal for effective online processing of applications.

CDSCO under its e-Governance initiative had rolled out online services for filing of applications through Sugam portal in 2016 for import licensing and registration purpose and offers online licensing services for drugs, cosmetics and biologicals, among others.

A separate medical device online portal has also been started in line with new Medical Device Rules -2017 (MDR-2017) for applications related to medical devices and in-vitro diagnostics (IVDs).

The Union Health Ministry has also recently devised an action plan to regulate all medical devices under Drugs and Cosmetics (D&C) Act to ensure safety, quality and performance of medical devices.

As per the plan, all manufacturers and importers of all non-regulated medical devices will register the details of the devices manufactured and imported by them in the special Sugam portal developed for the purpose and a notification will be issued under the D&C Act in this regard.

As per the CDSCO notice, as the “Medical Device” online system (www.cdscomdonline.gov.in) has already been rolled out, it is desirous to obtain feedback from the stakeholder to improve the system. A detailed feedback form has been circulated.

All stakeholders are requested to provide their valuable feedback as per the form with suggestions about short term, medium term and long term measures to be taken to improve the system.

The feedback should be forwarded to feedback@cdsco.nic.in within two weeks of this notice in scanned pdf format as well as excel document format.

CDSCO envisages uniform implementation of the provisions of Drugs and Cosmetics (D&C) Act,1940 and Rules 1945 to ensure safety and well being of patients by regulating drugs and cosmetics in the country.

Meanwhile, the health ministry’s proposal to the department of expenditure seeking recruitment of manpower to form a vertical in the CDSCO has been approved. “We need human resource to set up laboratories, to test devices. The finance department is agreeable to our demands,” the official said.

As per a report by the department of pharmaceuticals, both imports and exports of medical devices grew at more than 10% between 2011-12 and 2014-15.

The country’s medical devices has grown from $2.02 billion in 2009 to $3.9 billion in 2015, at a compounded annual growth rate (CAGR) of 15.8%.

All imported and locally-made medical devices will have to meet certain standards of quality and efficacy to enter the Indian market. The government has begun framing the rules and a draft notification to this effect is likely to be put out soon, people aware of the matter told ET.

Currently, only 23 categories of medical devices are regulated in India under the Drugs and Cosmetics (D&C) Act. The change to bring all medical devices under regulation will be implemented in a phased manner.

According to the persons cited earlier, certification of devices by the Central Drugs Standard Control Organisation (CDSCO), regulatory authority in this case, will be on voluntary basis up to 18 months from date of notification, and thereafter it will be made mandatory.

Once the rules get notified, all import, manufacture and sale of medical devices will need to be certified by the CDSCO. “The new rules will be incorporated in the existing Act,” said a senior official, requesting not to be named.

“We cannot be lax about standardisation and quality of medical devices. There is a consensus now among all departments and we will soon put up a draft notification. All medical devices will have to be registered with the regulatory authority before they enter the market,” the official said.

The decision is part of a move to increase safety of end users of such devices. Last year, problems due to hip implants manufactured by a subsidiary of Johnson & Johnson (J&J) required some patients to undergo revision surgery.
The rules for regulation are being worked out as per a roadmap that the health ministry has chalked out in consultation with the department of pharmaceuticals, government think tank Niti Aayog, the department of biotechnology, the Indian Council of Medical Research, the Bureau of Indian standards and industry experts and associations. The roadmap mandates every manufacturer and importer of medical devices to report serious adverse events to the drug regulatory authority and the materio-vigilance programme.

The document on roadmap of medical devices, a copy of which is with ET, says that “reports can be analysed to assess the safety and performance of the devices and appropriate regulatory interventions can be taken to ensure patients’ safety”.

The CDSCO will be the nodal authority to investigate quality, safety-related issues and complaints and can suspend the registration based on the outcome of its investigation. At present there is no mechanism for reporting malfunctioning of non-notified medical devices.

Also, the government does not have an exact figure for how many non-notified medical devices are available in the country. There have also been complaints of refurbished imported equipment making their way into the country. “They are being imported and sold in the country. The new rules will take care of all such problems pertaining to medical devices,” said another official.

• FDA approves Eli Lilly’d new migraine drug Reyvow.
• Reyvow was proven to be “significantly” more effective than a placebo in resolving the pain and “most bothersome” migraine symptoms.
• Migraines are three times more common in women than in men and affect more than 10% of people worldwide.The U.S. Food and Drug Administration approved a new drug to treat migraines that’s proven to resolve their pain and other symptoms within two hours, the agency said Friday. 

  The drug, Reyvow, was developed by Eli Lilly and Co.  and was proven to be “significantly” more effective than a placebo in halting the pain and “most bothersome” migraine symptoms, including nausea and light sensitivity.

  Migraines, an intense headache accompanied by a throbbing or pulsing pain, affect one in seven Americans. Those suffering from migraines can also experience nausea, vomiting, and sensitivity to light and sound.

  “Reyvow is a new option for the acute treatment of migraine, a painful condition that affects one in seven Americans,” said Nick Kozauer, M.D., acting deputy director of Neurology Products for the FDA.

  Migraines are three times more common in women than in men and affect more than 10% of people worldwide.

  Reyvow was approved after two randomized, double-blind, placebo-controlled trials with 3,177 adult patients with histories of migraines. After both trials the percentages of patients whose pain or symptoms dissipated were significantly greater than those receiving a placebo.

  The most common side effects patients reported from Reyvow were dizziness, fatigue, a burning or prickling sensation in the skin called paresthesia, and sedation.

  Migraines can be triggered by various factors including stress, hormonal changes, bright or flashing lights, lack of food or sleep, and poor diet.

The O’Neill report on antimicrobial resistance in 2016 generated headlines around the world warning that once-trivial infections may become death sentences without drastic action.

Now, three years on, an update on progress has been published and concludes that there has been a worrying lack of progress on some of the critical recommendations from the original document, including the development of incentives for researching new antibiotics, vaccines and diagnostics.

The review’s main findings – 10 million deaths due to AMR per year by 2050 and an accumulated cost to the global economy of $100 trillion – continue to be widely cited.

It recommended global awareness campaigns, improved hygiene and infection control, a reduction in the use of antibiotics in agriculture, more vaccine use and R&D incentives.

In a foreword to the update, the 2016 report author – ex-Goldman Sachs economist Lord Jim O’Neill – writes that there has been encouraging progress in some areas such as a raised profile for AMR, funding for early-stage antibiotics research and the number of scientists working in this area.

What is missing however, “despite endless words”, is a firm commitment of money from governments or pharmaceutical companies, as well as the introduction of market entry rewards to encourage companies to develop new drugs.

He suspects governments may be waiting for the crisis to escalate to the point that they can justify giving large amounts of money to companies to develop drugs, and that drugmakers – despite assertions to the contrary – “find the antibiotics business increasingly unattractive [and] are simply adhering to their own risk-return calculations.”

The new update, is written by Charles Clift, senior consulting fellow at Chatham House’s Centre on Global Health Security, who writes: “it appears that the threat, in spite of many warnings, is not perceived to be sufficient to merit the exceptional policy action many consider necessary.”

He points to significant advances in reducing antibiotic use in agriculture in high-income countries, but notes this hasn’t been mirrored in less affluent countries, which have also struggled to restrict access to over-the-counter antibiotics – another key recommendation in the 2016 report.

There has been greater investment in awareness raising, but questions remain about its impact and effectiveness in changing behaviour, and poor hygiene controls in low- and mid-income countries continues to undermine messages about infection prevention and control.

On the issue of new drug development, the update welcomes recent announcements by governments that suggest a willingness to reform the way antibiotics are paid for. For example, the UK is planning a new payment system that would see the NHS pay an upfront subscription for access to drugs – whether they are used or not – rather than paying by volume.

In the foreword, O’Neill makes additional recommendations based on developments since the original review was published.

One example is for the World Health organisation and other groups such as the United Nations to tap into social media around the world to spread the message about AMR. He also says governments should allow AMR to be cited as a cause of death on national registers.