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Save the Date - FDA Social Media Guidance Panel

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Social media has exploded over the last decade, yet the biotech and pharmaceutical sectors have been reluctant to harness the full power of platforms like Linked In, Facebook and Twitter. But now we have draft guidances from the FDA providing some clarity on how to communicate over social media channels and engage with patients, physicians and caregivers in a fair and balanced way.

LaVoieHealthScience and Burns & Levinson are getting lawyers and communications and marketing professionals together to discuss these new guidelines and how we should move forward with fewer than 140 characters (too late), likes and status updates.

Save the date below and stay tuned for more details:

Date:    Tuesday, September 9, 2014
Time:    8:30 -11:00 am ET
Where:  Burns & Levinson LLP
            125 Summer Street
            Boston MA 02110

LHS Helps DARA BioSciences Launch Patient Smartphone App, Gain Targeted Media Coverage

Opportunity: DARA BioSciences launched a smartphone app to provide cancer patients an educational resource to help patients diagnosed with cancer improve oral care and management of oral mucositis in support of Gelclair®, a bioadherent oral rinse gel.

LHS Solution: In an effort to maximize exposure for this announcement, LHS developed and released “Top 10 Oral Hygiene Tips for Patients with Cancer“ with images in a movie format and worked with the Oral Cancer Foundation to gain a quote in the press release supporting the Oral Mucositis Care app. 

Results: LHS was successful in gaining media coverage in targeted publications and news outlets, including Oral Cancer Foundation news page, Dental Product Review, and Oncology Business Review with interviews pending at two additional outlets. Dental Product Review, a new site with more than 500,000 unique visitors in its first few months online, embedded the Top 10 Oral Hygiene Tips for Patients with Cancer video.

Our multimedia release more than 3,000 views and the “Top 10 Oral Hygiene Tips for Patients with Cancer” video has been viewed more than 300 times, not counting Business Wire plays.

Traffic to was up 300 percent the week of the announcement.

To download the app, visit the iTunes Store or Google Play and search for “Oral Mucositis Care.”

Synchroneuron Nets $20M to Combat Drug-Induced Movement Disorder


describe the image                Xconomy resized 600

Ben Fidler July 2, 2014

With a few tweaks, Synchroneuron believes it’s been able to turn an old, flawed drug for alcoholism into a new one for a completely different disorder. Now the Waltham, MA-based startup has just banked a big round of cash to go prove it in clinical trials.

Synchroneuron is announcing today that it’s raised a $20 million Series B round of equity financing, all from its sole backer, Hong Kong investment firm Morningside Technology Ventures. The cash will help Synchroneuron get to a key point in its development. SNC-102—the souped-up formulation of the alcoholism drug acamprosate calcium the company is developing to treat a debilitating movement disorder called tardive dyskinesia (TD)—is currently in a Phase 2 study.

By the time that study produces results in the first quarter of 2015, Synchroneuron will have a good read on whether or not it has a potential drug—and where it stands compared to San Diego-based Neurocrine Biosciences (NASDAQ: NBIX), which is developing a rival treatment for the diseaseand is further along in development.

“We think [there’s] going to be good news, but the question is how good,” says scientific founder Barry Fogel, of the mid-stage trial. “We’d be quite surprised if we see no benefit, and we’d be shocked if we saw adverse effects because the safety record for this drug is so impressive.”

The winner gets the first crack at an FDA-approved drug for TD, a debilitating disorder characterized by involuntary, repetitive movements—primarily of the lips, tongue, or jaw— tied to the chronic use of certain antipsychotic drugs that block dopamine. For most people, the disorder is irreversible. Around 300,000 people in the U.S. are affected with severe forms of TD, and they’re typically treated either with preventative measures—like lowering the doses of their antipsychotics—or with other drugs like calcium channel blockers or benzodiazepines that at times have worked to help certain patients.

“Nothing has emerged, though, as a standard of pharmacologic practice,” Fogel says. “[TD] is a disabling, stigmatizing thing.”

Synchroneuron is based on the work of Fogel, a neuropsychiatrist and professor of neurology at Harvard Medical School who began searching for a treatment for TD in the 1990s. Fogel determined that modulating the brain chemical glutamate could relieve the symptoms of TD, so he began using approved drugs that affect glutamate to treat his patients. That led him to acamprosate, a decades-old drug that works by essentially balancing out the glutamate and GABA neurotransmitters in the brain, as a potential treatment. Fogel found that certain patients responded particularly well to acamprosate, but the problem was the drug couldn’t be given chronically because its pharmacokinetic properties were poor—it doesn’t absorb into the blood particularly well. So while acamprosate has been approved for some 25 years to reduce the withdrawal symptoms alcoholics get when they stop drinking, it isn’t widely prescribed for alcoholism because it’s not very effective, according to Fogel; patients have to take a very high dose for it to work well (Fogel says upwards of nine pills per day), and if they take those doses, the drug often irritates the stomach and produces side effects like nausea, vomiting, and diarrhea.

The concept behind Synchroneuron is to essentially fix those flaws by making a version of acamprosate with better pharmacokinetic properties—as in, it can produce a bigger effect at a smaller dose, while limiting the GI side effects. Fogel co-founded the company in February 2012 with the help of drug development consulting firm Accellient Partners, and then raised $6 million in VC backing from Morningside to carry out that plan. Synchroneuron has since done the formulation work to create SNC-102 and test it in an early-stage clinical trial of healthy volunteers.

Chief executive William Kerns says that the company has seen positive signs so far: it’s been able to significantly reduce the daily dose of acamprosate through the formulation work, and is testing a regimen of one or two pills per day.

Ultimately, the company’s big plan is not just to target TD, but potentially other related diseases like Tourette’s syndrome and post-traumatic stress disorder. Synchroneuron will use some of the cash, for instance, to begin an exploratory study in Tourette’s patients later this year, according to Fogel.

All of these disorders “may have an underlying problem with the regulation of glutamate transmission,” he says.

The reality, however, is that Synchroneuron has much to prove in the clinic before it can succeed—like whether its drug, which would be taken chronically either once or twice a day, can really prove much more effective and tolerable than the approved acamprosate formulation. It’s also got some catching up to do, as its competitor Neurocrine has already finished a Phase 2 trial for its own candidate, a new chemical entity called NBI-98854.

For its part, Synchroneuron is pointing to the fact that SNC-102 is based on a well-studied, approved drug. That means safety wouldn’t be a primary study endpoint— the company could theoretically run shorter, smaller Phase 3 studies testing solely for efficacy, rather than waiting longer to guard for safety signals, according to Kerns. That also means Synchroneuron might have an opportunity to catch up to Neurocrine if things break right, since the San Diego company is testing a new chemical compound for TD.

The big test is now underway. Synchroneuron is enrolling 90 patients in a Phase 2 study in 12 sites across the U.S, which should give the company the chance to prove, in a placebo-controlled study, if SNC-102 can reduce the number of abnormal tics patients experience. By that point, it’ll have a better read on whether its formulation work is producing a meaningful clinical effect.

“The challenge is to determine whether our delivery system—our formulation—is delivering enough drug in a once-a-day or twice-a-day form,” Kerns says. “I think that’s an area of risk, and we’ll know soon.”

LaVoieHealthScience Wins Three Awards for Work with Mass. Department of Public Health and Chelsea Therapeutics

LHS Wins Bronze Bell Ringer for DPH ‘Together We’re Ready’ Emergency Preparedness Campaign
Communications Program for Chelsea FDA Approval Process Nets LACP’s Impact Award and Bell Ringer Honors

Boston, MA, June 11, 2014 – LaVoieHealthScience, Inc., (LHS) provider of strategic communications programs that integrate public and investor relations, marketing and communications to engage target stakeholders to create behavioral change, won multiple awards from the 2013 LACP Impact Awards and the 2013 Bell Ringer Awards. LaVoieHealthScience this week received the Bronze Bell Ringer Award and a merit award in the Product/Service Launch: Healthcare Campaign category for their work with Chelsea Therapeutics. LHS also received a best program award for its communications plan for Chelsea Therapeutics in the 2013 League of American Communications Professionals (LACP) Impact Awards.

The Publicity Club of New England recognized LHS’ Massachusetts Department of Public Health, “Together We’re Ready” campaign with a Bronze Bell Ringer in the Community and Consumer Affairs Category. The campaign increased awareness of emergency preparedness efforts for individuals, families and communities, promoted easy to understand messaging, branding collateral, videos, social media content and a media buy all illustrating the importance of emergency preparedness. LHS developed this campaign in partnership with Carroll Communications and NewTV. Since being implemented last year, the campaign has earned Platinum at the 2013 MarCom Awards, Top 25 Communications Campaigns, Platinum, and Best on a Limited Budget at the Magellan Awards.

Judges for the Impact Awards recognized LaVoieHealthScience’s Chelsea Therapeutics NORTHERA Plan as the Best Sales Communications Program in this year’s competition. The plan, developed to support Chelsea’s application for new drug approval to the FDA for NORTHERA™, consisted of comprehensive messaging and strategic external communications to media, patients and stakeholders.

“We are honored to have worked with both organizations on these campaigns and are pleased to be recognized in both award competitions,” said Donna L. LaVoie president and chief executive officer of LaVoieHealthScience. “I am proud of the team for developing and executing on these complex communications plans and getting results for our clients.”

The Publicity Club of New England prestigious Bell Ringer Awards recognize excellence in communications and public relations work in every field and industry, across all forms of media. The awards honor the communications and PR professionals who leverage unique and creative strategy, tactics, and tools to achieve meaningful results for their clients, companies, organizations, and institutions. 

The League of American Communications Professionals (LACP) was established in 2001 in order to create a forum within the public relations industry that facilitates discussion of best-in-class practices within the profession while also recognizing those who demonstrate exemplary communications capabilities.  This year the Impact Awards debuted nearly 100 entries, from some of the most recognized organizations throughout the world, creating exceptional competition.

About LaVoieHealthScience

LaVoieHealthScience partners with leading life sciences brands to build value for their companies, attract capital, and reach key stakeholders through integrated communications and marketing. The firm provides strategy consulting and integrated communications programs designed to properly position, create visibility and drive value. The agency has received 25 awards over the past four years in recognition of the work it has done for its many clients.

LaVoieHealthScience is ranked by O'Dwyer's PR Report as one of the leading independent healthcare PR firms in the U.S. and has been honored for the past four years by the LACP for best agency awards, including the 2011 "Best Small Agency."


Media contact:
David Connolly
Vice President, LaVoieHealthScience

LaVoieHealthScience's Client Ocugen Featured in BioWorld Today

ocugen     bioworld logo


New LaVoieHealthScience client, Ocugen, which recently licensed two development assets in ophthalmology from the University of Colorado and gained orphan status from the FDA for one of them, is featured in BioWorld Today.  See the press release.

LaVoieHealthScience's Aurora Krause Wins NIRI Individual Leadership Award

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NIRI Announces 2013-2014 Individual Leadership Award Winners

LAS VEGAS – The National Investor Relations Institute (NIRI) today announced its  annual Individual Leadership Award winners. 

NIRI Chairman John Chevalier, Director of Global Investor Relations, The Procter & Gamble Company, said, “These individuals represent the best ideals of NIRI membership. NIRI relies on the tireless efforts of these volunteers, and many more like them, to drive its success. I applaud their spirit of volunteerism, and thank them for their devotion to NIRI’s mission.”

The 2013-2014 NIRI Individual Leadership Award winners and associated NIRI chapters are:

Aurora Krause, Boston; David Dixon, Capital Area; Matthew Schlarb, Central Ohio; Roy Granato, Charlotte; Christine Hanneman, Chicago; Kenneth Lovik, Cincinnati Tri State; Shannon Gaycheck, Cleveland/Northern Ohio; Liz Kline, Dallas*Ft. Worth; Kim Pinyopusarerk, Houston; Debbie Hagen, Kansas City; Scott Cunningham, Los Angeles; Theresa Molloy, New York; Cynthia Skoglund, Orange County; John Demming, Philadelphia; Kathleen Marvin, Rocky Mountain; Pete De Spain, San Diego; Brenda Ropoulos, Silicon Valley; Howard Goldman, South Florida; John Hastings, St. Louis; Justin Vieira, Triangle; and Bernadette McCormick, Virtual.

Theresa Molloy, Director, Governance and Shareholder Services, Prudential Financial, received the NIRI National Volunteer of the Year Award. This award, introduced in 2009, honors a NIRI member who best exemplifies the NIRI mission of “advancing the practice of investor relations and professional competency and stature NIRI members” at the national level. An active volunteer at both the national and chapter levels, Ms. Molloy has:  spoken at NIRI national programs and webinars; contributed to IR Update magazine; appeared as a guest on NIRI video programs; served as a member of the IR Certification Subject Matter Expert Committee; participated as a member of the NIRI Annual Conference Committee; and served as a Vice President of Programs for the New York chapter.  

The awards were presented at the NIRI Volunteer Appreciation Dinner in Las Vegas, site of the 2014 NIRI Annual Conference (, the world’s largest and most comprehensive investor relations education and networking event.

About the National Investor Relations Institute (NIRI)

Founded in 1969, NIRI ( is the professional association of corporate officers and investor relations consultants responsible for communication among corporate management, shareholders, securities analysts and other financial community constituents.  NIRI is the largest professional investor relations association in the world with more than 3,300 members representing over 1,600 publicly held companies and $9 trillion in stock market capitalization.


Local Biotech's Heart Failure Treatment Shows Promise; Juventas to Launch Phase 3 Study Next Year

juventas logoThe Plain Dealer

Plain Dealer Doctor
Dr. Marc Penn studies a slide of mouse heart tissue in this 2012 photo taken in Rootstown. Penn and his team at Juventas have been working on JVS-100, a method of treating damaged heart muscle that recruits the body's innate healing abilities, for the past decade. The company was a Cleveland Clinic spinoff formed in 2007 when Penn still worked for the hospital system; he is now Director of Cardiovascular Research at Summa Health System in Akron. (Thomas Ondrey/ The Plain Dealer)



By Brie Zeltner, The Plain Dealer
May 28, 2014 at 8:00 AM, updated May 28, 2014 at 8:18 AM

CLEVELAND, Ohio— A potential new treatment for heart failure developed by Cleveland Clinic spinoff Juventas Therapeutics has shown new promise in a Phase 2 trial, according to data recently released by the company.

The treatment, a gene therapy called JVS-100 that recruits the body's own stem cells to repair damaged areas of the heart, was safe and improved cardiac function in patients with advanced heart failure who had heart attacks more than a decade ago.

In the trial, called STOP-HF, 93 participants received either a single treatment of a low dose of JVS-100, a high dose of JVS-100, or placebo. They were then followed and evaluated at two points -- four months and one year later -- to test their heart function.

"We're very excited by the results," said Dr. Marc Penn, a former Cleveland Clinic doctor and founder and Chief Medical Officer for Juventas, who is now Director of Cardiovascular Research at Summa Health System in Akron. "This is a high risk population probably approaching most cancer mortalities."

About 6 million Americans suffer from heart failure, which happens when the heart can no longer keep up with its workload. About half of people diagnosed with heart failure die within five years, according to the Centers for Disease Control and Prevention.

Penn estimates that about 1.5 million people with heart failure do not benefit from current treatments, and still suffer daily symptoms, which include shortness of breath, fatigue and swelling from fluid buildup in the limbs. As the heart muscle weakens over time, the heart grows larger to compensate and becomes less efficient, pumping less blood (a measure referred to as ejection fraction) per heartbeat.

In the STOP-HF trial, JVS-100 reduced the size of the heart by about 8 percent and improved ejection fraction by about 2 percent overall, and higher doses of the treatment worked better. Participants in the trial had symptomatic heart failure, were about 65 years old on average, and had suffered a heart attack an average of 11 years prior to enrolling in the trial. JVS-100 was delivered via catheter to 15 spots in the heart muscle that showed signs of damage from a previous heart attack.

In a subgroup of high-risk patients within the trial who had more advanced heart failure, there was a decrease in a key heart function measure called end systolic volume, which indicates the size of the heart after it finishes its squeeze. Smaller values correlate with better heart function.

"This level of reduction correlates with a greater than 80 percent chance of us having a meaningful mortality benefit over two years -- at least a 20 percent reduction in mortality," Penn said.

STOP-HF was not designed to measure the impact of the drug on the risk of dying from heart failure over time, so these interim Phase 2 results can only give a suggestion of how the therapy may affect a patient's survival. A definitive test of the drug, in a Phase 3 trial, is set to launch next summer and should enroll several hundred heart failure patients.

Participants in the STOP-HF trial are still being followed and the company will report final results by the end of this year.

Juventas, which was spun out of the Cleveland Clinic in July 2007, has since attracted $32 million in private investment and grants. The company is also testing JVS-100 for people with critical limb ischemia, a severe blockage of blood flow in the legs that causes pain, blood clots and amputations.

The company believes the treatment works by stimulating the patient's stem cells to heal and regenerate tissue that has been damaged, reduce the amount of scarring, and block any ongoing cell damage caused by the chronic disease.

"This repair mechanism isn't just about the heart, it's really about any organ in the body and having a specific drug that activates this repair pathway that allows us now to attack disease in a new and fundamentally novel way," Penn said.

"It's very exciting to be working on this for so many years and to see this pathway become so important."

Boston's Zakim Bridge Lighting for Neuropathy Awareness

Last night was a beautiful evening to watch the purple and gold lighting of the Zakim Bridge, a beacon of hope for millions living with Neuropathy. LaVoieHealthScience was thrilled to advocate for the lighting along with Leslie Levine, (coordinator for the Association’s Weston-MA neuropathy support group). 

Zakim Bridge Lighting for Neuropathy Awareness

Several staff members got together for dinner last night at Pier 6 in Charlestown to watch the lighting of the bridge.  The weather was perfect, and the view of the bridge was amazing!


Even though it is the leading cause of disability in the U.S. and one of the most common chronic neurological diseases, neuropathy is often misunderstood, mis- and under-diagnosed, and inadequately treated.  However, early diagnosis and treatment is critical to preventing and slowing the progression of neuropathy.Since 1995, The Neuropathy Association has been working to change the public’s perception of neuropathy and help patients, health care providers, and the public at large understand the true scope of this debilitating disease. And since 2005, The Neuropathy Association has annually designated the third week of May as National Neuropathy Awareness Week on the federal government’s calendar of National Health Observances.

Thanks to the MassDOT team for this lighting opportunity.

FDA's Fast-Track Agenda

Catalyst Pharmaceutical Partners

FDASIA adds another expedited approval path while seeking continuous improvement to manufacturing operations


MAY 05, 2014

With the Food and Drug Administration’s Safety and Innovation Act (FDASIA), the Agency’s added a fourth expedited approval pathway – “Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review, Expediting Availability of New Drugs for Patients with Serious Conditions,” which expedites development and review for drugs intended to treat serious conditions, and provides significant improvement over existing therapies. As of April 2014, FDA received 165 requests for breakthrough status and has granted 42 such designations.

Most Breakthroughs are cancer drugs, although the latest designation (March 20) was earned by Pfizer for a meningococcal vaccine.

Breakthrough was in part a reaction to criticisms that FDA’s approval times were inordinately long, even though this notion was debunked in a June 14, 2012, New England Journal of Medicine article that compared FDA approval times with those of overseas regulators.

The experience of Catalyst Pharmaceutical Partners (Coral Gables, Fla.) is representative. Catalyst’s Firdapse therapy, for treating Lambert Eaton Myasthenic Syndrome (LEMS), received Breakthrough status in 2013. LEMS is a debilitating neuromuscular disease for which no safe treatment exists. Lack of competition, the seriousness of the disorder and encouraging efficacy signals played decidedly in favor of Firdapse.

While highly desirable, Breakthrough status challenges sponsors to keep product development on track, says Steve Miller, Ph.D., chief scientific officer at Catalyst. “Since the Agency is committing critical resources to expedited reviews, it expects companies to follow through with equal dedication, positioning these programs on the front burner.”

Nothing in FDA guidances or in FDASIA requires the Agency to investigate whether sponsors are capable of attaining development milestones expeditiously. One could imagine some level of due diligence based on a sponsor’s resources and previous compliance issues, but that is only conjecture.

Expedited review helps patients and the sponsor, which enjoys a longer exclusivity period for products. It also improves FDA’s image for facilitating timely approval of critical medicines. One thing it does not do is substantially help sponsors for follow-on indications. “There are no regulatory shortcuts,” Miller emphasizes. “Basic safety studies are of course indication-neutral. Other than that, submissions for second or third indications proceed normally.”

Orphan Drug status is another work-around that continues to be profitable. Sponsors receive a decent return on investment in the short term, says Susan Bain, DRSc, professor of practice, clinical, regulatory and quality at the Keck Graduate Institute of Applied Life Sciences (Claremont, Calif.). “Afterward, they can initiate clinical trials for a second indication and hope for off-label business as well. The idea is to get the drug out faster, with less data, and a lower clinical burden, all while benefiting from the drug’s market presence.”

Closely paralleling FDASIA’s supply chain directives are the EMA’s 2013 Falsified Medicines Act, which tightens requirements and control over drug product ingredients, including excipients, and similar laws in other jurisdictions, particularly in emerging markets. (Editor’s note: For a full account of FDASIA’s supply chain initiatives and additional commentary, see “Taming The Supply Chain Monster.” 

Given the global nature of pharmaceutical industry sourcing, for both materials and services, FDASIA was long overdue. Luba Skibo, executive director at NSF International, an independent global standards-writing, training and education firm predicts rapid and significant growth of auditing activities and inspection readiness, including a rise in paper audits and site visits. “Five years ago, supply chain security was a vision, a plan, an initiative. Today it is a reality,” Skibo says. “It will still be here five years from now, hopefully with clear directions for implementation.”

FDASIA grants FDA the unprecedented authority to regulate foreign suppliers of raw ingredients and active pharmaceutical ingredients that make their way to U.S. markets, whether the eventual manufacturer domiciles stateside or overseas. While no geographic region of the supply chain is invulnerable, FDA will likely direct most of its oversight to countries with less-than-stellar reputations for following accepted business practices.

If the Agency believed, however, that its headaches would begin and end with supply chain regulation, last year’s scandal involving a GlaxoSmithKline (GSK) business unit in China dispelled that notion. The scandal, which involved bribery to promote off-label prescriptions, has deeper relevance in light of the company’s record-setting $3 billion fine in 2012 for engaging in similar behavior in the United States. And just this past April, GSK was found to be employing similar tactics in Iraq.

While FDA has no direct authority over foreign bribery cases, these incidents could alert the Agency to potential domestic wrongdoing. Eventually, FDA will discover that it cannot ignore malfeasance simply because it occurs beyond its territorial jurisdiction.

On the surface, GSK’s overseas troubles suggest that developing countries are beginning to take corruption seriously. Or, conversely, these incidents unveil even deeper malfeasance.

“There is tremendous, intense new global scrutiny of marketing and promotional content, clinical data integrity, manufacturing conduct and quality assurances, which had been traditionally taken up only by the U.S, and, to a lesser degree, the U.K.,” says David Resnicoff, an attorney at Miller & Chevalier (Washington, D.C.).

So far, so good. GSK’s transgressions suggested a pattern of disregard for well-established promotional practices that quite naturally spilled across borders. But Resnicoff suggests that officials in emerging markets and companies eager to establish themselves in those markets (GSK’s China operates generated 4% of the firm’s income before the scandal) are playing a game of double-bluff.

Luba Skibo, executive director at NSF International, identifies two trends that will affect FDA-manufacturer relations for years to come. The first is implementation of the new ICH tripartite model for an effective Pharmaceutical Quality Management System (QMS), as enunciated in ICH Q8, Q9 and Q10 guidances. Based on ISO concepts, ICH Q10 outlines a unifying approach to an effective pharmaceutical quality and incorporates GMPs, ICH Q8 (pharmaceutical development), and ICH Q9 (quality risk management). The ambitious ICH Q10 is a model for a pharmaceutical quality system that spans a product’s lifecycle. 

“These ideas are moving from QMS design, components identification and structure around component to the ‘how-to stage,’” Skibo says. “Over the next few years, industry will be learning how to use and apply knowledge management and quality risk management to different components of QMS. Dropping no-value-added practices and metrics will be an exciting and challenging journey toward continuous improvement.”

She adds that the industry must learn how to implement knowledge and risk enablers to harmonized, lifecycle-long QMSs, and to implement them in a way that fosters innovation, effectiveness and competitiveness while assuring patient benefits.

According to Skibo most companies have identified critical QMS components and infrastructure, and are entering what will inevitably be a trial-and-error exercise for implementing it. This will occur first at best-in-class organizations. As the buzz dies down, lessons learned at the top are expected to trickle down into the industry as a whole.

The other regulation to watch is the 2012 FDA Safety and Innovation Act (FDASIA), particularly its supply chain initiatives. “Attention to the excipients and API supply chain control expected from industry is illustrated by the FDASIA provision that ‘failure to manage the supply chain is GMP failure, and product considered adulterated,’” Skibo says. “Further reinforced by the Drug Quality and Security Act of 2013, supply chain security will be the focus of FDA and industry attention for the next 10 years.

“Certain emerging markets have woken up to the great sums of money they can make by forcing global companies active within their jurisdictions into paying large settlements over alleged malfeasance. GSK’s conflict with Chinese regulatory authorities was a signal event, likely to be replicated in Russia and Brazil. Executives are wondering when, if ever, it will end.”

FDASIA established regulation as an international endeavor. Robert Young, North American life sciences serialization and track and trace lead at Accenture, suggests that oversight has already expanded beyond supply chain issues. “Pharmaceutical industry regulators face unprecedented pressures in the form of increasingly stringent, globally driven health authority requirements and complex product obligations for initial filings, lifecycle management and ongoing compliance.”

These pressures have intensified the challenge to companies of maintaining authorization for a full portfolio of products 12,000 miles away from headquarters, while continuing to innovate and seek greater efficiencies at home. “Meeting these challenges strains capacity and diverts precious resources from the ultimate goal of bringing new, differentiated products to patients,” Young adds.

Regulatory agencies, moreover, must now confront product expansions into new demographics and geographies, while monitoring the flow of goods and services from these overseas markets into the United States (e.g., FDASIA’s supply chain provisions).

Young believes that current practices for managing pharmacovigilance are “unlikely to be sustainable.” Regulators’ workloads are expanding rapidly, at 10–20% a year, a result of higher regulatory expectations, tougher inspection regimes, business growth and more proactive physician/patient reporting.

Companies need to determine how the growing flow of granular data can provide value, while regulators have to make sense of it all. The solution, says Young, will be new ways to process and interpret “big data,” much of which will originate overseas. Moreover notions of patient privacy differ dramatically between the U.S./U.K. and developing markets, which will by necessity involve inter-agency cooperation, similar to that encouraged by FDASIA.

“These data concepts are new territory,” Young says. “Companies recognize that they are not data analysis experts and may not want to staff internally to support this. Hosted services will therefore evolve in this area, but even they require skills that integrate back to companies’ supply chain data to create a full end-to-end picture.”

In keeping with the climate of continuous improvement in manufacturing operations, sponsors often file submissions to implement post-approval production changes. FDA categorizes CMC changes as major, moderate and minor. Major changes carry “substantial potential to have an adverse effect on the identity, strength, quality, purity or potency of a drug product.” Major changes require submitting a supplement, called a Prior Approval Supplement (PAS), and FDA approval before distributing products produced as a result of the change.

As expected, moderate changes carry “a moderate potential to have an adverse effect” on the product. One type of moderate change requires submission 30 days before distribution and is called a “Changes Being Effected in 30 Days” submission, by which FDA has 30 days to decide. If the Agency decides information is missing (the most common reason for denial), the subsequent corrections are identified as Changes Being Effected (CBE). Minor changes, which are expected to have little impact on the product, are handled through the Annual Report submission.

The official book on manufacturing changes is embodied in CFR 314.70(a)(1)(i), which states that “the applicant must notify FDA about each change in each condition established in an approved application…” and 314.70(a)(2): “The holder of an approved application … must assess the effects of the change before distributing a drug product made with a manufacturing change.”

The most common reasons for CMC change submissions are facility (34%), control (34%) and actual manufacturing alterations (16%). Thus, fewer than one-sixth of applications involve what a chemist or chemical engineer would call chemical process changes. Historically, the fraction of these falling into the PAS (riskiest) category has been less than 5%. Perhaps reflecting sponsors’ reliance on risk-based strategies, PAS filings rose to about 10% between 2010 and 2012. Still, significant chemical process changes represent only 1% of all post-approval submissions under the larger umbrella of “CMC changes.”

From filing data alone, it is clear that companies rarely consider significant CMC changes — even when economically justified. But submission data tells only part of the story. Companies appear to be taking more liberties with assessments of CMC change riskiness.

Geoffrey Wu, Ph.D., from FDA’s Office of Generic Drugs, has spoken and written on post-approval CMC changes. In a 2014 study, Wu noted that the total number of supplements for generic drugs, CBE 30 submissions, and CBEs, remained approximately equal between 2005 and 2012. These figures are approximately 3600 for total submissions, 2700 for CBE 30s, and 575 for CBEs. At the same time, PAS submissions rose six-fold, from fewer than 100 in 2005 to approximately 600 in 2012. The rise in PAS applications most likely reflect industry’s embrace of risk management, albeit more in facility, control and packaging than in chemical processing.

At the same time, FDA has subjected medium-risk submissions to greater scrutiny. FDA upgraded 55 CBE/CBE 30 applications, 1.6%, to PAS in 2005. By 2012, 150 such applications, 4%, were upgraded into the higher risk category.

Determining causal factors for the 150% increase in upgrades is not easy, but the consequences are obvious for an industry that lives and dies by market exposure. According to guidances, getting bumped into a higher risk category delays the point at which companies may distribute post-change drug products — a fact that Wu acknowledges.

He disagrees, however, that risk upgrades are a natural result of any new thinking regarding risk-based compliance. “Risk is solely decided by the nature of the proposed change,” he explains. “Any reasonable applicant should conduct risk assessment on proposed changes prior to regulatory submission and implementation. FDA’s risk-based approach is to further assure product quality and safety.”

The most common reasons for upgrading a risk category are lack of scientific or product information, failure to cite appropriate guidances, insufficient investigation of out-of-specification product, lack of supporting information for CMC changes, and paradoxically, too much unnecessary information.

How to explain, then, given the resources devoted to regulatory compliance, the rise in misunderstanding risk levels for relatively straightforward CMC changes? Wu has no explanation. “Industry folks may give you further insights to this question,” he says.

Companies purposely underestimate risk in regulatory filings because they can, says Susan Bain. “They’re looking to shortcut testing time and the amount of data they need to supply to justify the CMC change.” She says the practice is “huge” at top companies. “It’s a matter of resource allocation,” she says. Companies obviously benefit from expending less time, money and product than they normally would to achieve a risky CMC change.

Some companies (particularly startups) are so time-crunched that they may institute changes based solely on a letter-to-file — basically putting a letter into a file that states they observed no risk to products from process changes. Then they play catch-up when regulators ask about the letter. Bain believes that companies consciously weigh the cost of rejection against that of completing studies. “It sometimes comes down to how long it takes to validate a new process before getting caught,” she says. Some tactics resemble grade school strategies. “They will submit a CB30 without the validation data, hoping to have completed the studies before regulators reach that part of the submission. When confronted, they say, ‘Oh yeah, here it is.’”

The submissions that FDA cites are often those that fail to complete validation before time is up due to unsuccessful studies. For these firms the clock starts all over again, often with product sales put on hold, and inventories recalled. “It’s horrible publicity and very expensive, particularly for temperature-sensitive products or those with short shelf-lives,” Bain says.

Incomplete data is a problem that goes beyond post-approval CMC changes, according to Bain. “Forty percent of NDAs are sent back because of incomplete data.” Again, the problem lies mostly with sponsors who believe they will be able to play catch up between submission and FDA action. “The market is so competitive, and with generics knocking at the door, companies are taking more risks to streamline the approval process in any way they can.” She stresses that this activity is limited to regulatory submission risk, not patient safety. “Sponsors are not cutting corners with quality.”

Bain recalls one firm, seeking approval for a new filling line lacked critical validation data. “They didn’t get the work done in time and had to start over. In the long run that didn’t save them any time.” Such companies, she adds, often develop bad reputations with regulators who feel they are wasting Agency time.

Regardless of how the uptick in original and re-designated PAS submissions originates, the risk-based approach to development and regulatory review are here to stay. “Most companies understand and accept this reality,” says Luba Skibo.

FDA has already adopted risk assessment for inspections, as sponsors implement similar practices for auditing suppliers and service providers. How risk plays into post-approval CMC changes is a complex question.

In its landmark 2004 cGMP revision guidance, FDA enunciated its cooperative, risk-based vision to exploit advances in quality management and to allocate limited regulatory resources more effectively. CMC regulatory review, according to the guidance, “should be based on an understanding of product risk and how best to manage this risk.” CDER’s follow up guidance, CMC Post-approval Manufacturing Changes to Be Documented in Annual Reports, extended the risk-based approach to CMC review, and recognized that many post-approval CMC supplements posed low risk.

This extensive list included relaxation of blend uniformity testing, changes in coatings and mixing times for immediate-release drugs, and alterations in filtration parameters excluding pore size. Subsequent guidances outlined how, and to what extent, companies needed to document low-risk changes through the Annual Report. Without going into details, it was obvious that FDA’s goal was to streamline submissions while simultaneously sparing the Agency’s need to review vast volumes of irrelevant data. “While not directly linked to cGMPs for the 21st Century, this certainly seems like an application of risk management,” Skibo says.

LaVoieHealthScience Advocates for May 20 Purple and Gold Lighting on Boston's Zakim Bridge for Neuropathy Awareness Week

SAVE THE DATE! May 20: Purple and Gold Lights on Boston’s Zakim Bridge Shine for Millions Living with Neuropathy

By Natacha T. Pires, MBBS, Director Medical and Public Affairs  

May 1st, 2014

On May 20, 2014, Boston-MA’s landmark Zakim Bridge will light up purple and gold for millions living with neuropathy. 

Zakim Bridge

Plan on visiting Boston, MA soon? Be sure to share your pictures of this special lighting of the Zakim Bridge scheduled for May 20th with our community. Send pictures to, and we'll be sure to share them ... thank you!

The Leonard P. Zakim Bunker Hill Bridge -- part of The Big Dig Project in Boston -- is one of the widest cable-stayed bridges in the world and serves as the northern entrance to and exit from Boston, Massachusetts. And, on May 20th, this Boston landmark will light up purple and gold to raise the public profile of neuropathy, thanks to the efforts of our local advocates – LaVoieHealthScience and Leslie Levine (coordinator for the Association’s Weston-MA neuropathy support group). 

The special lighting comes on the heels of National Neuropathy Awareness Week (May 12-16) -- an annual health observance sponsored by The Neuropathy Association. Additionally, Governor Deval Patrick recently proclaimed May 12-16 as Neuropathy Awareness Week in Massachusetts, at the urging of Ms. Levine. The Neuropathy Association applauds the Massachusetts Department of Transportation (MassDOT) for joining millions of people across the US – and millions more around the world – in recognizing the Week, and bringing much-needed attention to this debilitating neurological disease.

Even though it is the leading cause of disability in the U.S. and one of the most common chronic neurological diseases, neuropathy is often misunderstood, mis- and under-diagnosed, and inadequately treated.  However, early diagnosis and treatment is critical to preventing and slowing the progression of neuropathy.Since 1995, The Neuropathy Association has been working to change the public’s perception of neuropathy and help patients, health care providers, and the public at large understand the true scope of this debilitating disease. And since 2005, The Neuropathy Association has annually designated the third week of May as National Neuropathy Awareness Week on the federal government’s calendar of National Health Observances.

We recognize that neuropathy is a 24/7/365 battle for more than 20,000,000 people in the U.S. … until we find better treatments and cures for neuropathy, every week is National Neuropathy Awareness Week, every day is Neuropathy Awareness Day. So our mission is 24/7/365; but during National Neuropathy Awareness Week, we rally ourselves and our community -- patients, caregivers, and professionals -- to help us take neuropathy awareness to the next level. Awareness and understanding of this disease -- and its impact -- are the drivers for allocating more funding for neuropathy research, developing more programs for the neuropathy community, and, ultimately, finding more therapies and cures.

A special thanks to the MassDOT team for this lighting opportunity -- it is a beacon of hope for millions living with neuropathy!

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