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Archive for the ‘FDA’ Category


37th Annual J.P. Morgan HEALTHCARE CONFERENCE: News at #JPM2019 for Jan. 10, 2019: Deals and Announcements

Reporter: Stephen J. Williams, Ph.D.

From Biospace.com

 

JP Morgan Healthcare Conference Update: Sage, Mersana, Shutdown Woes and Babies

Speaker presenting to audience at a conference

With the J.P. Morgan Healthcare Conference winding down, companies remain busy striking deals and informing investors about pipeline advances. BioSpace snagged some of the interesting news bits to come out of the conference from Wednesday.

SAGE Therapeutics – Following a positive Phase III report that its postpartum depression treatment candidate SAGE-217 hit the mark in its late-stage clinical trial, Sage Therapeutics is eying the potential to have multiple treatment options available for patients. At the start of J.P. Morgan, Sage said that patients treated with SAGE-217 had a statistically significant improvement of 17.8 points in the Hamilton Rating Scale for Depression, compared to 13.6 for placebo. The company plans to seek approval for SAGE-2017, but before that, the FDA is expected to make a decision on Zulresso in March. Zulresso already passed muster from advisory committees in November, and if approved, would be the first drug specifically for postpartum depression. In an interview with the Business Journal, Chief Business Officer Mike Cloonan said the company believes there is room in the market for both medications, particularly since the medications address different patient populations.

 

Mersana Therapeutics – After a breakup with Takeda Pharmaceutical and the shelving of its lead product, Cambridge, Mass.-based Mersana is making a new path. Even though a partial clinical hold was lifted following the death of a patient the company opted to shelve development of XMT-1522. During a presentation at JPM, CEO Anna Protopapas noted that many other companies are developing therapies that target the HER2 protein, which led to the decision, according to the Boston Business Journal. Protopapas said the HER2 space is highly competitive and now the company will focus on its other asset, XMT-1536, an ADC targeting NaPi2b, an antigen highly expressed in the majority of non-squamous NSCLC and epithelial ovarian cancer. XMT-1536 is currently in Phase 1 clinical trials for NaPi2b-expressing cancers, including ovarian cancer, non-small cell lung cancer and other cancers. Data on XMT-1536 is expected in the first half of 2019.

Novavax – During a JPM presentation, Stan Erck, CEO of Novavax, pointed to the company’s RSV vaccine, which is in late-stage development. The vaccine is being developed for the mother, in order to protect an infant. The mother transfers the antibodies to the infant, which will provide the baby with protection from RSV in its first six months. Erck called the program historic. He said the Phase III program is in its fourth year and the company has vaccinated 4,636 women. He said they are tracking the women and the babies. Researchers call the mothers every week through the first six months of the baby’s life to acquire data. Erck said the company anticipates announcing trial data this quarter. If approved, Erck said the market for the vaccine could be a significant revenue driver.

“You have 3.9 million birth cohorts and we expect 80 percent to 90 percent of those mothers to be vaccinated as a pediatric vaccine and in the U.S. the market rate is somewhere between $750 million and a $1 billion and then double that for worldwide market. So it’s a large market and we will be first to market in this,” Erck said, according to a transcript of the presentation.

Denali Therapeutics – Denali forged a collaboration with Germany-based SIRION Biotech to develop gene therapies for central nervous disorders. The two companies plan to develop adeno-associated virus (AAV) vectors to enable therapeutics to cross the blood-brain barrier for clinical applications in neurodegenerative diseases including Parkinson’s, Alzheimer’s disease, ALS and certain other diseases of the CNS.

AstraZeneca – Pharma giant AstraZeneca reported that in 2019 net prices on average across the portfolio will decrease versus 2018. With a backdrop of intense public and government scrutiny over pricing, Market Access head Rick Suarez said the company is increasing its pricing transparency. Additionally, he said the company is looking at new ways to price drugs, such as value-based reimbursement agreements with payers, Pink Sheet reported.

Amarin Corporation – As the company eyes a potential label expansion approval for its cardiovascular disease treatment Vascepa, Amarin Corporation has been proactively hiring hundreds of sales reps. In the fourth quarter, the company hired 265 new sales reps, giving the company a sales team of more than 400, CEO John Thero said. Thero noted that is a label expansion is granted by the FDA, “revenues will increase at least 50 percent over what we did in the prior year, which would give us revenues of approximate $350 million in 2019.”

Government Woes – As the partial government shutdown in the United States continues into its third week, biotech leaders at JPM raised concern as the FDA’s carryover funds are dwindling. With no new funding coming in, reviews of New Drug Applications won’t be able to continue past February, Pink Sheet said. While reviews are currently ongoing, no New Drug Applications are being accepted by the FDA at this time. With the halt of NDA applications, that has also caused some companies to delay plans for an initial public offering. It’s hard to raise potential investor excitement without the regulatory support of a potential drug approval. During a panel discussion, Jonathan Leff, a partner at Deerfield Management, noted that the ongoing government shutdown is a reminder of how “overwhelmingly dependent the whole industry of biotech and drug development is on government,” Pink Sheet said.

Other posts on the JP Morgan 2019 Healthcare Conference on this Open Access Journal include:

#JPM19 Conference: Lilly Announces Agreement To Acquire Loxo Oncology

36th Annual J.P. Morgan HEALTHCARE CONFERENCE January 8 – 11, 2018

37th Annual J.P. Morgan HEALTHCARE CONFERENCE: #JPM2019 for Jan. 8, 2019; Opening Videos, Novartis expands Cell Therapies, January 7 – 10, 2019, Westin St. Francis Hotel | San Francisco, California

37th Annual J.P. Morgan HEALTHCARE CONFERENCE: News at #JPM2019 for Jan. 8, 2019: Deals and Announcements

 

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CALD Gene Therapy Granted “Breakthrough Therapy Designation”

Reporter: Irina Robu, PhD

Bluebird Bio’s Lenti D has been granted as “breakthrough therapy designation” by FDA for the treatment of patients with cerebral adrenoleukodystrophy (CALD), or Lorenzo’s Oil disease due to optimistic data from current ongoing Phase 2/3 study. This therapy contains using patient’s own immature bone marrow cells and modifying them to include a functional copy of ABCD1 gene which permits the expression of functional ALD, the deficient protein in the patient population.

In addition, the data indicated that the safety profile of Lenti-D remains consistent with myeloablative chemotherapy and no graft versus host disease or treatment related mortality were reported. Initial findings from the ongoing Starbeam Study (ALD-102) assessing the investigational gene therapy in boys with CALD aged 17 years or younger who do not have a matched sibling donor were published in the New England Journal of Medicine  in October 2017 and indicated that the drug hit its main effectiveness endpoint. In the study, 88% (n=15) of patients infused with Lenti-D remained alive and free of major functional disabilities at 2 years post-treatment.

According to Mohammed Asmal, Vice President, Clinical Development at bluebird bio “The mechanism by which this would work is very much like how stem cell therapy transplantation is able to correct the disease. The theory was certainly there, it just relied on someone, essentially, being willing to develop the vector and then try it on patients who did not have any other feasible options for transplant, and who had poor predicted outcomes for transplant survival.”

Currently, the only available therapeutic option for patients with CALD is allogeneic hematopoietic stem cell transplant (HSCT). Whereas clinical benefit has been reported if made early during CALD progression, possible complications of allogeneic HSCT can be fatal. According to David Davison, chief medical officer at Bluebird Bio “FDA’s Breakthrough Therapy designation for Lenti-D brings new hope to the patients and families affected by this devastating disease”.

Source

https://patientworthy.com/2018/05/29/gene-therapy-ald-breakthrough-therapy-fda/

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Innovators in Therapeutics: John Maraganore, the CEO of Alnylam, and Sara Nochur, Alnylam’s Senior VP Regulatory Affairs, November 15, 2018, 4:30 PM – 6:30 PM, HMS

Reporter: Aviva Lev-Ari, PhD, RN

 

 

Innovators in Therapeutics, a Student Speaker Series

by Harvard-MIT Center for Regulatory Science

Free

Actions and Detail Panel

Innovators in Therapeutics, a Student Speaker Series

Thu, November 15, 2018, 4:30 PM – 6:30 PM EST

LOCATION

Cannon Room, Building C, Harvard Medical School

240 Longwood Ave

Boston, MA 02115

View Map

 

Free

 

REGISTER

Event Information

DESCRIPTION

Please join us for the Innovators in Therapeutics student speaker series organized by the Harvard-MIT Center for Regulatory Science and the Harvard Program in Therapeutic Science. The first installment of this series will feature John Maraganore, the CEO of Alnylam, and Sara Nochur, Alnylam’s Senior Vice President for Regulatory Affairs. Dr. Maraganore and Dr. Nochur will describe Alnylam’s path through development and FDA approval of the first RNAi therapeutic, ONPATTRO™ (patisiran), for the treatment of polyneuropathy of hereditary transthyretin-mediated amyloidosis. Dr. Maraganore and Dr. Nochur will focus on the regulatory science aspects of gaining approval for this innovative therapeutic.

Prior to the seminar, please join us for a networking session that brings together faculty, students and trainees who are interested in translational research, pharmacology, biotechnology, and regulatory science. Following the speaking program, there will be a small group discussion for students and trainees to engage directly with the expert about the topic at hand. Participation in the small group discussion is limited to students who register and are confirmed prior to the event.

This event is free and open to the Boston research community. Please help us to plan by RSVPing here!

 

AGENDA

4:30 – 5:00pm: Pre-event reception (outside Cannon Room)

5:00 – 5:45pm: Innovators in Therapeutics with Alnylam’s John Maraganore & Sara Nochur (Cannon Room)

5:45 – 6:15pm: [Limited Space] Student and Trainee Q&A with John Maraganore & Sara Nochur (Folin Wu Room)

SOURCE

https://www.eventbrite.com/e/innovators-in-therapeutics-a-student-speaker-series-tickets-50806305026

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Live Conference Coverage @Medcitynews Converge 2018 Philadelphia:Liquid Biopsy and Gene Testing vs Reimbursement Hurdles

9:25- 10:15 Liquid Biopsy and Gene Testing vs. Reimbursement Hurdles

Genetic testing, whether broad-scale or single gene-testing, is being ordered by an increasing number of oncologists, but in many cases, patients are left to pay for these expensive tests themselves. How can this dynamic be shifted? What can be learned from the success stories?

Moderator: Shoshannah Roth, Assistant Director of Health Technology Assessment and Information Services , ECRI Institute @Ecri_Institute
Speakers:
Rob Dumanois, Manager – reimbursement strategy, Thermo Fisher Scientific
Eugean Jiwanmall, Senior Research Analyst for Medical Policy & Technology Evaluation , Independence Blue Cross @IBX
Michael Nall, President and Chief Executive Officer, Biocept

 

Michael: Wide range of liquid biopsy services out there.  There are screening companies however they are young and need lots of data to develop pan diagnostic test.  Most of liquid biopsy is more for predictive analysis… especially therapeutic monitoring.  Sometimes solid biopsies are impossible , limited, or not always reliable due to metastasis or tough to biopsy tissues like lung.

Eugean:  Circulating tumor cells and ctDNA is the only FDA approved liquid biopsies.  However you choose then to evaluate the liquid biopsy, PCR NGS, FISH etc, helps determines what the reimbursement options are available.

Rob:  Adoption of reimbursement for liquid biopsy is moving faster in Europe than the US.  It is possible in US that there may be changes to the payment in one to two years though.

Michael:  China is adopting liquid biopsy rapidly.  Patients are demanding this in China.

Reimbursement

Eugean:  For IBX to make better decisions we need more clinical trials to correlate with treatment outcome.  Most of the major cancer networks, like NCCN, ASCO, CAP, just have recommendations and not approved guidelines at this point.  From his perspective with lung cancer NCCN just makes a suggestion with EGFR mutations however only the companion diagnostic is approved by FDA.

Michael:  Fine needle biopsies are usually needed by the pathologist anyway before they go to liquid biopsy as need to know the underlying mutations in the original tumor, it just is how it is done in most cancer centers.

Eugean:  Whatever the established way of doing things, you have to outperform the clinical results of the old method for adoption of a newer method.

Reimbursement issues have driven a need for more research into clinical validity and utility of predictive and therapeutic markers with regard to liquid biopsies.  However although many academic centers try to partner with Biocept Biocept has a limit of funds and must concentrate only on a few trials.  The different payers use different evidence based methods to evaluate liquid biopsy markers.  ECRI also has a database for LB markers using an evidence based criteria.  IBX does sees consistency among payers as far as decision and policy.

NGS in liquid biopsy

Rob: There is a path to coverage, especially through the FDA.  If you have a FDA cleared NGS test, it will be covered.  These are long and difficult paths to reimbursement for NGS but it is feasible. Medicare line of IBX covers this testing, however on the commercial side they can’t cover this.  @IBX: for colon only kras or nras has clinical utility and only a handful of other cancer related genes for other cancers.  For a companion diagnostic built into that Dx do the other markers in the panel cost too much?

Please follow on Twitter using the following #hash tags and @pharma_BI

#MCConverge

#cancertreatment

#healthIT

#innovation

#precisionmedicine

#healthcaremodels

#personalizedmedicine

#healthcaredata

And at the following handles:

@pharma_BI

@medcitynews

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Skin Regeneration Therapy One of First Tissue Engineering Products Evaluated by FDA

Reporter: Irina Robu, PhD

Under the provisions of 21st Century Cures Act the U.S. Food and Drug Administration approved StrataGraft regenerative skin tissue as the first product designated as a Regenerative Medicine Advanced Therapy (RMAT) produced by Mallinckrodt Pharmaceuticals. StrataGraft is shaped using unmodified NIKS cells grown under standard operating procedures since the continuous NIKS skin cell line has been thoroughly characterized. StrataGraft products are virus-free, non-tumorigenic, and offer batch-to-batch genetic consistency.

Passed in 2016, the 21st Century act allows FDA to grant accelerated review approval to products which meet an RMAT designation. The RMAT designation includes debates of whether priority review and/or accelerated approval would be suitable based on intermediate endpoints that would be reasonably likely to predict long-term clinical benefit.

The designation includes products

  • defined as a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products;
  • intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and
  • preliminary clinical evidence indicates the drug has the potential to address unmet medical needs for such disease or condition.

According to Steven Romano, M.D., Chief Scientific Officer and Executive Vice President, Mallinckrodt “We are very pleased the FDA has determined StrataGraft meets the criteria for RMAT designation, as this offers the possibility of priority review and/or accelerated approval. The company tissue-based therapy is under evaluation in a Phase 3 trial to assess its efficacy and safety in the advancement of autologous skin regeneration of complex skin defects due to thermal burns that contain intact dermal elements.

SOURCE

https://www.rdmag.com/news/2017/07/skin-regeneration-therapy-one-first-be-evaluated-fda

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Real Time Coverage and eProceedings of Presentations on 9/19-9/21 @CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

Curator: Aviva Lev-Ari, PhD, RN

 

LIVE 9/19 8AM – 10AM USING CRISPR/Cas9 FOR FUNCTIONAL SCREENING at CHI’s 2nd Annual Symposium CRISPR: Mechanisms and Applications @CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

https://pharmaceuticalintelligence.com/2016/09/19/live-919-8am-10am-using-crisprcas9-for-functional-screening-at-chis-2nd-annual-symposium-crispr-mechanisms-and-applications-chis-14th-discovery-on-target-919-9222/

 

LIVE 9/19 9:40 – noon CRISPR Engineering Lymphoma Lines & Will Interference from CRISPR Silence RNAi? CHI’s 2nd Annual Symposium CRISPR: Mechanisms and Applications @ CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

https://pharmaceuticalintelligence.com/2016/09/19/live-919-940-noon-crispr-engineering-lymphoma-lines-will-interference-from-crispr-silence-rnai-chis-2nd-annual-symposium-crispr-mechanisms-and-applications-chis-14th/

 

LIVE 9/19 1:40 – 3:20 EMERGING APPLICATIONS OF CRISPR/CAS9 at CHI’s 2nd Annual Symposium CRISPR: Mechanisms and Applications @ CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

https://pharmaceuticalintelligence.com/2016/09/19/live-919-140-320-emerging-applications-of-crisprcas9-at-chis-2nd-annual-symposium-crispr-mechanisms-and-applications-chis-14th-discovery-on-target-919-9222016/

 

LIVE 9/19 4PM – 5:30PM NK CELL-BASED CANCER IMMUNOTHERAPY @CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

https://pharmaceuticalintelligence.com/2016/09/19/live-919-4pm-530pm-nk-cell-based-cancer-immunotherapy-chis-14th-discovery-on-target-919-9222016-westin-boston-waterfront-boston/

 

LIVE 9/20 8AM to noon GENE THERAPIES BREAKTHROUGHS at CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

https://pharmaceuticalintelligence.com/2016/09/20/live-920-8am-to-noon-gene-therapies-breakthroughs-at-chis-14th-discovery-on-target-919-9222016-westin-boston-waterfront-boston/

 

LIVE 9/20 2PM to 5:30PM New Viruses for Therapeutic Gene Delivery at CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

https://pharmaceuticalintelligence.com/2016/09/20/live-920-2pm-to-530pm-new-viruses-for-therapeutic-gene-delivery-at-chis-14th-discovery-on-target-919-9222016-westin-boston-waterfront-boston/

 

LIVE 9/21 8AM to 10:55 AM Expoloring the Versatility of CRISPR/Cas9 at CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

https://pharmaceuticalintelligence.com/2016/09/21/live-921-8am-to-1055-am-expoloring-the-versatility-of-crisprcas9-at-chis-14th-discovery-on-target-919-9222016-westin-boston-waterfront-boston/

 

LIVE 9/21 8AM to 2:40PM Targeting Cardio-Metabolic Diseases: A focus on Liver Fibrosis and NASH Targets at CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

https://pharmaceuticalintelligence.com/2016/09/21/live-921-8am-to-240pm-targeting-cardio-metabolic-diseases-a-focus-on-liver-fibrosis-and-nash-targets-at-chis-14th-discovery-on-target-919-9222016-westin-boston-waterfront-b/

 

LIVE 9/21 12:50 pm Plenary Keynote Program at CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

https://pharmaceuticalintelligence.com/2016/09/21/live-921-1250-pm-plenary-keynote-program-at-chis-14th-discovery-on-target-919-9222016-westin-boston-waterfront-boston/

 

LIVE 9/21 3:20PM to 6:40PM KINASE INHIBITORS FOR CANCER IMMUNOTHERAPY COMBINATIONS & KINASE INHIBITORS FOR AUTOIMMUNE AND INFLAMMATORY DISEASES at CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

https://pharmaceuticalintelligence.com/2016/09/21/live-921-320pm-to-640pm-kinase-inhibitors-for-cancer-immunotherapy-combinations-kinase-inhibitors-for-autoimmune-and-inflammatory-diseases-at-chis-14th-discovery-on-target-919/

 

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Postmarketing Safety or Effectiveness Data Needed: The 2013 paper was funded by the firm Sarepta Therapeutics, sellers of eteplirsen, a surge in its shares seen after the approval. Eteplirsen will cost patients around $300,000 a year.

 

Curator: Aviva Lev-Ari, PhD, RN

 

On September 19, the FDA okayed eteplirsen to treat Duchenne muscular dystrophy (DMD), a rare genetic disorder that results in muscle degeneration and premature death. Several of its top officials disagreed with the drug’s approval, questioning how beneficial it will be for patients, as ForbesMedPage Today and others reported.

http://retractionwatch.com/2016/09/21/amid-controversial-sarepta-approval-decision-fda-head-calls-for-key-study-retraction/

Factors at play for FDA Approval of eteplirsen

  1. the help of the families of young boys with Duchenne muscular dystrophy, emotional scenes from these families who have campaigned for so long
  2. an executive team from Sarepta who wouldn’t give up,

Ed Kaye, Sarepta, CEO – EK: It’s all about resilience. One of the things we’ve had is a group of people of like minds and anytime one of us gets down, somebody else is there to pick you up. One of the things we’ve always done is: Every time we’ve felt sorry for ourselves, we just need to think about those patients and what they go through. Our struggles in comparison very quickly become meaningless. You end up saying to yourself: What am I complaining about? Quit whining; get up and do your job.

and

3. an emerging new philosophy from some within the FDA, eteplirsen, now Exondys 51, was approved in patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping.

http://www.fiercebiotech.com/biotech/sarepta-ceo-ed-kaye-fda-courage-nice-and-resilience?utm_medium=nl&utm_source=internal&mrkid=993697&mkt_tok=eyJpIjoiTXpBeU56aGpNREV3T1RZMiIsInQiOiJIM2poTkVOQ0N6YmxaenVHZDM1RlVvbTFmRkdwZGdxQ0pmYXNVOG5PKzRyenFXTkRMV0dcL3l0bVBPNkJ2NFV3Rnc3bWVFVnUwMCs3YVhWeVhvRkkrUU5FMFJ1RndSQTlHWFRnQmFTbUo3ODg9In0%3D

9/19/2016

FDA grants accelerated approval to first drug for Duchenne muscular dystrophy

The accelerated approval of Exondys 51 is based on the surrogate endpoint of dystrophin increase in skeletal muscle observed in some Exondys 51-treated patients. The FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in some patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. A clinical benefit of Exondys 51, including improved motor function, has not been established. In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease for these children and the lack of available therapy.

The FDA granted Exondys 51 fast track designation, which is a designation to facilitate the development and expedite the review of drugs that are intended to treat serious conditions and that demonstrate the potential to address an unmet medical need. It was also granted priority review and orphan drug designationPriority review status is granted to applications for drugs that, if approved, would be a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan drug designation provides incentives such as clinical trial tax credits, user fee waiver and eligibility for orphan drug exclusivity to assist and encourage the development of drugs for rare diseases.

SOURCE

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm521263.htm

The viability of this drug approval depends  on “to be gathered” Postmarketing safety or effectiveness data, aka follow-up confirmatory trials.

Sarepta CEO Ed Kaye on FDA courage, NICE and resilience

BA: When it comes to flexibility, however, the FDA will likely not be flexible if your drug doesn’t prove the desired efficacy in your longer term postmarketing studies. If at the end of this period your drug doesn’t come through, how easy will it be for you to take this off the market? I don’t think anyone, including the FDA, wants a repeat of what happened in 2011 when Roche saw its breast cancer license for Avastin, which had been approved under an accelerated review, pulled after not being safe or effective enough in the follow-up confirmatory trials. But you face this as a possible scenario.

EK: That’s true, but one of the things we’re trying to do to mitigate that is to obviously, with our ongoing studies, prove the efficacy that the FDA wants to see. And you know, if there is a problem with one study then we’d hope to have other data that are supportive. The other thing we’re doing of course is developing that next-generation chemistry in DMD that could prove more effective, so we could certainly consider using that next-gen chemistry to take our work forward and try and make it better.

We have a lot of shots on goal to make sure we can continue to supply a product for these boys, but there is always a risk. If we can’t show efficacy in the way the FDA wants, then yes they have the option to take it off the market.

http://www.fiercebiotech.com/biotech/sarepta-ceo-ed-kaye-fda-courage-nice-and-resilience?utm_medium=nl&utm_source=internal&mrkid=993697&mkt_tok=eyJpIjoiTXpBeU56aGpNREV3T1RZMiIsInQiOiJIM2poTkVOQ0N6YmxaenVHZDM1RlVvbTFmRkdwZGdxQ0pmYXNVOG5PKzRyenFXTkRMV0dcL3l0bVBPNkJ2NFV3Rnc3bWVFVnUwMCs3YVhWeVhvRkkrUU5FMFJ1RndSQTlHWFRnQmFTbUo3ODg9In0%3D

Need for follow-up confirmatory trials remains outstanding

FDA’s Postmarketing Surveillance Programs

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/ucm090385.htm

FDA’s Regulations and Policies and Procedures for Postmarketing Surveillance Programs

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/ucm090394.htm

 

Positions on Sarepta’s eteplirsen Scientific Approach

Gene Editing for Exon 51: Why CRISPR Snipping might be better than Exon Skipping for DMD

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/01/23/gene-editing-for-exon-51-why-crispr-snipping-might-be-better-than-exon-skipping-for-dmd/

 

QUOTE START

Retraction Watch

Tracking retractions as a window into the scientific process

Amid controversial Sarepta approval decision, FDA head calls for key study retraction

with one comment

FDAThe head of the U.S. Food and Drug Administration (FDA) has called for the retraction of a study about a drug that the agency itself approved earlier this week, despite senior staff opposing the approval.

On September 19, the FDA okayed eteplirsen to treat Duchenne muscular dystrophy (DMD), a rare genetic disorder that results in muscle degeneration and premature death. Several of its top officials disagreed with the drug’s approval, questioning how beneficial it will be for patients, as ForbesMedPage Today and others reported.

In a lengthy report Commissioner Robert Califf sent to senior FDA officials on September 16 — that was made public on September 19 — he called for the retraction of a 2013 study published in Annals of Neurologyfunded by the seller of eteplirsen, which showed beneficial effects of the drug in DMD patients. Califf writes inthe report:

The publication, now known to be misleading, should probably be retracted by its authors.

In a footnote in the report, Califf adds:

In view of the scientific deficiencies identified in this analysis, I believe it would be appropriate to initiate a dialogue that would lead to a formal correction or retraction (as appropriate) of the published report.

The study was not the key factor in the agency’s decision to approve the drug, according to Steve Usdin, Washington editor of the publication BioCentury; still, Usdin told Retraction Watch he is “really surprised” at the call for retraction from top FDA staff, the first he has come across in the last two decades.

The 2013 paper was funded by the firm Sarepta Therapeutics, sellers of eteplirsen, which has seen a surge in its shares after the approval. Eteplirsen will cost patients around $300,000 a year.

DMD affects around 1 in 3,600 boys due to a mutation in the gene that codes for the protein dystrophin, which is important for structural stability of muscles. Eteplirsen is the first drug to treat DMD, and was initially given a green light by Janet Woodcock, director of Center for Drug Evaluation and Research, after a split vote from the FDA’s advisory committee. Despite Califf’s issues with the literature supporting the drug’s use in DMD, he did not overturn Woodcock’s decision, and the agency approved the drug this week.

In 2014, an inspection team visited the Nationwide Children’s Hospital in Columbus, Ohio, where the research was conducted, according to the report. In the report, Ellis Unger, director of the Office of Drug Evaluation I in FDA’s Center for Drug Evaluation, notes:

We found the analytical procedures to be typical of an academic research center, seemingly appropriate for what was simply an exploratory phase 1/2 study, but not suitable for an adequate and well controlled study aimed to serve as the basis for a regulatory action. The procedures and controls that one would expect to see in support of a phase 3 registrational trial were not in evidence.

Specifically, Unger describes concerns about blinding during the experiments, and notes:

The immunohistochemistry images were only faintly stained, and had been read by a single technician using an older liquid crystal display (LCD) computer monitor in a windowed room where lighting was not controlled. (The technician had to suspend reading around mid-day, when brighter light began to fill the room and reading became impossible.)

Unger adds:

Having uncovered numerous technical and operational shortcomings in Columbus, our team worked collaboratively with the applicant to develop improved methods for a reassessment of the stored images…This re-analysis, along with the study published in 2013, provides an instructive example of an investigation with extraordinary results that could not be verified.

Luciana Borio, acting chief scientist at the FDA, is cited in the report saying:

I would be remiss if I did not note that the sponsor has exhibited serious irresponsibility by playing a role in publishing and promoting selective data during the development of this product. Not only was there a misleading published article with respect to the results of Study–which has never been retracted—but Sarepta also issued a press release relying on the misleading article and its findings…As determined by the review team, and as acknowledged by Dr. Woodcock, the article’s scientific findings—with respect to the demonstrated effect of eteplirsen on both surrogate and clinical endpoints—do not withstand proper and objective analyses of the data. Sarepta’s misleading communications led to unrealistic expectations and hope for DMD patients and their families.

Here’s how Sarepta describes the study’s findings in the press release Borio refers to:

Published study results showed that once-weekly treatment with eteplirsen resulted in a statistically significant increase from baseline in novel dystrophin, the protein that is lacking in patients with DMD. In addition, eteplirsen-treated patients evaluable on the 6-minute walk test (6MWT) demonstrated stabilization in walking ability compared to a placebo/delayed-treatment cohort. Eteplirsen was well tolerated in the study with no clinically significant treatment-related adverse events. These data will form the basis of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for eteplirsen planned for the first half of 2014.

However, Usdin noted that the drug’s approval and the study are two independent events, adding that the 2013 study just “got the ball rolling” for eteplirsen, and the FDA conducted many of its own experiments analyses, as detailed in the newly released report.

Jerry Mendell, the corresponding author of the study (which has so far been cited 118 times, according to Thomson Reuters Web of Science) from Ohio State University in Columbus, told us the allegations were “unfounded” and said the data are “valid.” Therefore, he added, he will not be approaching the journal for a retraction, noting that the FDA asked him hundreds of questions about the paper and audited the trials.

Clifford Saper, the editor-in-chief of Annals of Neurology from the Beth Israel Deaconess Medical Center (which is part of Harvard Medical School), said in an email:

It takes more than a call by a politician for retraction of a paper. It takes actual evidence.

He added:

If the FDA commissioner has, or knows of someone who has, evidence for an error in a paper published in Annals of Neurology, I encourage him to send that evidence to me and a copy to the authors of the article, for their reply. At that point we will engage in a scientific review of the evidence and make appropriate responses.

Linda Lowes, sixth author of the present study, is the last author of a 2016 study in Physical Therapy that was retracted months after publication. Its notice reads:

This article has been retracted by the author due to unintentional deviations in the use of the described modified technique to assess plagiocephaly in the study participants, such that the use of the modified technique cannot be defended for the stated purpose in this population at this time.

Califf was a cardiologist at Duke University during the high-profile scandal of researcher Anil Potti at Duke, which led to more than 10 retractions, settled lawsuits, and medical board reprimands. In 2015, he told TheTriangle Business Journal:

I wish I had gotten myself more involved earlier…There were systems that were not adequate, as we stated. … That was a tough one, I think, for the whole institution.

We’ve contacted the FDA for comment, and will update the post with anything else we learn.

END QUOTE

Correction 9/21/16 10:44 p.m. eastern: When originally published, this post incorrectly reported that Califf was part of an inspection team that visited the Nationwide Children’s Hospital in Ohio, and attributed quotes from Ellis Unger to Califf. We have made appropriate corrections, and apologize for the error.

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SOURCE

http://retractionwatch.com/2016/09/21/amid-controversial-sarepta-approval-decision-fda-head-calls-for-key-study-retraction/

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