Life Science Compliance Update

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30 posts from February 2013

February 28, 2013

Strict Conflict of interest Policies at Academic Medical Centers Lead to Prescribing Older Generic Drugs

Teacher with a Ruler
We have dedicated a large portion of this blog to covering “conflicts of interest” or COIs, and the various claims being made about the potential influence COIs may have on physicians, researchers, and CME providers.  COIs raise concerns because often, the latter group of individuals have relationships with industry—whether consulting, research, advisory, or other—that cause some to believe that those same individuals cannot remain impartial when writing prescriptions or teaching colleagues or even students. 

Consequently, a recent study, published in the British Medical Journal (BMJ) found that doctors who attended medical schools that limited gifts to students from pharmaceutical companies -- sponsored lunches, for example -- may be less open to drug marketing.   

The objective of the study was to “examine the effect of attending a medical school with an active policy on restricting gifts from representatives of pharmaceutical and device industries on subsequent prescribing behavior.” 

Interestingly, the study was funded by the National Institute of Mental Health (NIMH), the National Institute on Aging, the American Federation on Aging, and NIH.   Which we all know means the study is completely unbiased. 

Specifically, the authors looked at the probability that a physician would prescribe a newly marketed medication over existing alternatives of three psychotropic classes: lisdexamfetamine among stimulants, paliperidone among antipsychotics, and desvenlafaxine among antidepressants.  “None of these medications represented radical breakthroughs in their respective classes,” according to the authors. 

For two of the three medications examined, attending a medical school with an active gift restriction policy was associated with reduced prescribing of the newly marketed drug.  Physicians who attended a medical school with an active conflict of interest policy were less likely to prescribe lisdexamfetamine over older stimulants and paliperidone over older antipsychotics.  A significant effect was not observed for desvenlafaxine (1.54, 0.79 to 3.03; P=0.20).  Among cohorts of students who had a longer exposure to the policy or were exposed to more stringent policies, prescribing rates were further reduced. 

Thus, the authors concluded that “Exposure to a gift restriction policy during medical school was associated with reduced prescribing of two out of three newly introduced psychotropic medications.”   

One of the major weaknesses of this study is that the authors used students who have recently graduated from medical school within the last five years.  Thus, their prescribing habits are likely to change significantly over time as they gain more experience, training and knowledge about the diseases they treat and drugs they use.  It may seem obvious that these individuals are hesitant to prescribe these drugs because they have been brainwashed during medical school to think any brand-name medication is evil and if there is marketing on such drug to outright ignore that information—despite the harm this may have to patients about important safety updates. 

In fact, the authors acknowledged that “In instances where the newly introduced medication is a noticeable improvement over alternatives,” such an effect (e.g., not prescribing it) “could slow the diffusion of medical advances.”  However, in instances instances “where the newly introduced medication offers no additional benefit to patients, such an effect may limit the unnecessary use of newer, more expensive brand name medications, potentially slowing the escalation of healthcare costs.” 

Moreover, what is also problematic about this study is that it does not attempt to reconcile patient outcomes with these prescribing patterns.  In other words, we don’t know whether the patients not receiving these prescriptions are doing better, worse or the same.  For all we know, these recent graduates are prescribing drugs that might be harming patients or causing poorer outcomes, leading to higher costs in the future and lower quality of life. 

Additionally, another major weakness of this study--as was pointed out to us by our colleagues--is that the authors attempt to group pharmacetuical and medical device manufacturers and their relationships with AMCs and physicians into the same category.  While AMC policies may lump together pharma and device interactions, that does not mean they are equivalent to one another, something the authors failed to analyze or assess.  Nothing in the article justifies even the slightest mention of the medical device industry and the device industry is vastly different from pharma. 

Often, interactions with medical device manufacturers are required, and indeed necessary in some cases to achieve the proper standard of care to perform a procedure.  Moreover, and most often, the inventor of a particular device or technique must give hands-on training to physicians--either at the manufacturer's office or on-site, to ensure that physicians can implant or use the device in compliance with its FDA clearance.  In fact, many FDA clearance letters for medical devices--particularly for high-risk, Class III devices--mandate that the manufacturer provide specific training and show proof of such training through annual medical device reporting.  The study's failure to acknowledge this is problematic and shows their misunderstanding of the device industry and the importance of their interactions, training and education with physicians.

Another similar study, published in the February Issue of Medical Care, found that “Psychiatrists exposed to conflict-of-interest (COI) policies while completing their residency program are less likely to prescribe brand-name antidepressants after completion of their residency. 

Andrew J. Epstein, Ph.D., of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and colleagues used 2009 prescribing data from IMS Health to compare the prescribing behavior of 1,652 psychiatrists from 162 residency programs. The authors sought to determine whether exposure to COI policies during residency affected antidepressant prescribing behavior after training completion. 

About half of the residents graduated in 2001, before COI training guidelines were implemented, and the remaining half graduated in 2008, after COI adoption.  The researchers found that prescription rates for heavily promoted, brand-name, or reformulated antidepressant medications were lower for those graduating in 2008, after COI adoption, but were lowest for those programs with the most restrictive COI policies. 

“In psychiatry, we found that physicians who were exposed to maximally restrictive COI policies during residency training had lower rates of prescribing heavily marketed antidepressants,” the authors write.  “Although physician-industry interactions may serve an important informational function, our results offer one piece of evidence that these COI policies have helped inoculate physicians against the persuasive aspects of pharmaceutical promotion.” 

BMJ Study  

As background for their study, the authors noted that the American Medical Student Association (AMSA) established a PharmFree Campaign to advocate for evidence based, rather than marketing based, prescribing in 2002.  In 2007, AMSA released the first “PharmFree scorecard”, which graded US medical schools on the presence or absence of a policy regulating interactions between students and faculty and representatives of the pharmaceutical and medical device industries.  Since the first PharmFree scorecard was adopted, the number of US medical schools with conflict of interest policies has grown exponentially and most now have policies restricting gifts. 

Studies conducted before the PharmaFree Campaign found that most medical students were exposed to marketing efforts during their medical education.  On average, students either received a gift or attended an industry sponsored event weekly.  “Exposure to marketing efforts by the pharmaceutical industry during medical school has been associated with favorable attitudes towards the pharmaceutical industry.”  

Furthermore, marketing efforts have been shown to reduce the time to new drug adoption and increase the probability that a physician will adopt a new drug.   

Research has found that educational interventions strongly influence students’ attitudes toward pharmaceutical marketing and are associated with increased support for policies banning interactions between representatives of pharmaceutical companies and students.  Similarly, students attending a medical school with restrictive marketing policies tend to have less favorable attitudes about promotional items than their peers who were not exposed to a conflict of interest policy and are less likely to trust the advice they receive from representatives of pharmaceutical companies.  

Although research has found that educational interventions and conflict of interest policies are associated with increased skepticism about pharmaceutical marketing, the effect of medical school gift restriction polices on subsequent prescribing remains unknown.  Accordingly, the authors studied the impact of attending a medical school with a gift restriction policy on the adoption of new drugs.   

Overview and Methodology  

To see whether attending a medical school with a gift restriction policy affected prescribing of new drugs, they used a difference-in-differences design to compare prescribing patterns of physicians who attended a school with a gift restriction policy when the policy was in place with those of physicians who attended the same school before the policy was in place, as well as with the prescriptions written by two matched control groups. 

The authors used prescribing data from IMS health on the three drug classes July 2008 and March 2009.  Using internet searches, as well as information contained in the Institute of Medicine (IOM) as a profession’s conflict of interest database and AMSA’s PharmFree scorecard, one investigator either determined the initial implementation date of the gift restriction policy for medical schools that had a policy or verified that the school did not have a policy in place by the end of the study period.  They also looked for revision dates if policies were changed or updated and verified these as well. 

The authors identified 14 medical schools with a policy that explicitly prohibited or restricted gifts as of 2004.  A restrictive cut-off date of policy implementation by 2004 was necessary to allow for the average time required to complete postgraduate residency training after graduation from medical school for physicians to be eligible to independently prescribe medications by July 2008, the beginning of our prescribing observation period.  Many of the schools that had a policy in place by 2004 had adopted policies as a result of state laws or military restrictions governing gifts.  The policies varied in strength from almost complete bans on gifts to much weaker and ambiguous restrictions.   

Next the authors identified two cohorts of physicians to permit comparisons among those who attended the same medical school before and after implementation of a gift policy.  The first cohort included physicians that graduated two years before the policy was implemented and therefore were not exposed or affected since the policy was enacted after they had graduated.  The second cohort graduated in 2003 or 2004, after implementation of the policy.   

To account for changes in prescribing over time, the authors created a matched control sample composed of physicians who graduated from 20 different medical schools that adopted a policy restricting gifts in 2008.  These physicians were never exposed to the policy since they graduated before implementation.  

To determine the effect of gift restriction policies during medical training on prescribing as physicians, the author examined physicians’ propensity to prescribe newly introduced and marketed psychotropic medications over older medications in the same class.  During the study period, antipsychotics, antidepressants, and stimulants were among the top selling classes of medications, with US sales ranks of 1, 5, and 15, respectively.  Stimulants, antidepressants, and antipsychotics were also among the most promoted classes of medications.  

Given the importance of these three classes of medications to the pharmaceutical industry, the authors identified a newly marketed medication in each class for our study: lisdexamfetamine (Vyvanse; Shire, Wayne, PA) among stimulants, paliperidone (Invega; Janssen Pharmaceuticals, Titusville, NJ) among antipsychotics, and desvenlafaxine (Pristiq; Pfizer, New York, NY) among antidepressants. Lisdexamfetamine was introduced in March of 2007, paliperidone in December of 2006, and desvenlafaxine in February of 2008.  

Although the drugs examined in the study vary in their level of innovation, none represented radical breakthroughs in their class and all relied on mechanisms of action already available on the market.  These medications were the only oral medications within the three classes of data that we had access to that were approved within our study period. 


In total, 27.8% of prescribers wrote at least one prescription for lisdexamfetamine, 8.7% at least one prescription for paliperidone, and 6.9% at least one prescription for desvenlafaxine.  There were compositional differences between schools that adopted gift restriction policies before 2004 and later adopters, as well as between cohorts, in specialty composition and methods of payment. 

Stimulant Prescribing:  Physicians who were exposed to a gift restriction policy during medical school were significantly less likely than non-exposed physicians to prescribe lisdexamfetamine over older stimulants.  Of prescriptions written by physicians who attended a medical school with an active gift restriction policy, 5.9% were for lisdexamfetamine, in contrast with 7.4% among physicians not exposed to a policy who graduated from the same school before the policy was implemented.   

Among matched controls attending a school that implemented a policy in 2008, 8.3% and 9.1% of prescriptions were for lisdexamfetamine among earlier and later graduates, respectively.  Using a difference-in-differences approach showed that attending a medical school with an active conflict of interest policy significantly reduced the odds that a physician would prescribe lisdexamfetamine, the newly introduced stimulant, over older stimulants.   

In addition, for physicians who attended a medical school in which they would have been exposed to a policy for longer than the group exposed to the policy, the odds of prescribing lisdexamfetamine was further reduced.  Attending a school with a strong active policy also reduced the odds of prescribing lisdexamfetamine. 

Antipsychotic prescribing—paliperidone:  Physicians who were exposed to a gift restriction policy during medical school were significantly less likely than non-exposed physicians to prescribe paliperidone over older antipsychotics.  Of prescriptions written by physicians who attended a medical school with an active gift restriction policy, 0.5% were for paliperidone, in contrast with 1.7% among physicians who were not exposed to the policy and graduated from the same school. 

Among matched controls attending a school that implemented a policy in 2008, 1.2% and 1.4% of prescriptions were for paliperidone among the earlier and later cohorts, respectively.  Using a difference-in-differences approach, attending a medical school with an active conflict of interest policy was associated with a significantly decreased odds of prescribing paliperidone, the newly introduced antipsychotic.   

Antidepressant prescribing—desvenlafaxine:  Exposure to a gift restriction policy during medical school was not associated with differential prescribing of desvenlafaxine.  In all three models using a difference-in-differences approach, attending a medical school with an active gift restriction policy was not associated with significantly decreased odds of prescribing desvenlafaxine, the newly introduced antidepressant.   

In the main model, the odds ratio for students exposed to an active conflict of interest policy was 1.54.  Results were also insignificant in models examining students who were exposed to the policy for a longer duration or were exposed to a stricter policy.  


Implementation of a policy to restrict the receipt of gifts from the pharmaceutical industry at US medical schools was associated with significantly reduced prescribing of two out of three newly marketed psychotropic medications among students once they reached clinical practice. The odds of prescribing a newly marketed stimulant and a newly introduced antipsychotic medication were reduced among physicians who graduated from a medical school that had an active gift restriction policy.  The propensity to prescribe these two newly introduced medications was further reduced if the students were exposed to the policy for a longer duration or if the policy was relatively stringent.  

While these findings may suggest the ability to reduce prescribing of newly marketed pharmaceuticals, it remains yet to be seen whether such findings will result in only lower costs, or also better patient outcomes.  There is a significant chance, particularly given the complex nature of many of these drugs and the diseases they treat, that failing to prescribe new drugs may only further harm patients. 

February 27, 2013

FDA Strategic Plan to Address Drug Shortages, Solicitation for Comment

Drug Shortages Out of Stock
Earlier this month, the Food and Drug Administration (FDA) released a notice for public comment in the Federal Register regarding ideas stakeholders and the public may have for combating drug shortages.  As noted on FDA’s own blog, the agency believes that despite the progress made over the last year, even more can be done and is therefore turning to the American public for advice. 

Comments due by Thursday, March 14, 2013.  The Docket Number is FDA-2013-N-0124. 


As we previously wrote this summer, the President signed into law the Food and Drug Administration Safety and Innovation Act (FDASIA) (Pub. L. 112-144) on July 9, 2012.  Section 1003 of FDASIA adds section 506D to the Federal Food, Drug, and Cosmetic Act (the FDCA) to require the formation of a task force to develop and implement a strategic plan for enhancing the Agency's response to preventing and mitigating drug shortages.  Section 506D of the FDCA (21 U.S.C. 356) requires that the drug shortages strategic plan include the following: 

  • Plans for enhanced interagency and intra-agency coordination, communication, and decisionmaking;
  • Plans for ensuring that drug shortages are considered when the Secretary initiates a regulatory action that could precipitate a drug shortage or exacerbate an existing drug shortage;
  • Plans for effective communication with outside stakeholders, including who the Secretary should alert about potential or actual drug shortages, how the communication should occur, and what types of information should be shared;
  • Plans for considering the impact of drug shortages on research and clinical trials; and
  • An examination of whether to establish a “qualified manufacturing partner program” as described in section 506D(a)(1)(C) of the FD&C Act. 

Per the directive in section 506D, FDA has formed an internal Drug Shortages Task Force (Task Force) to develop and implement the drug shortages strategic plan.  The Task Force is seeking comments from the public on issues related to the development of this strategic plan.  Importantly, although FDASIA refers only to a drug shortages strategic plan, FDA anticipates that the strategic plan will consider prevention and mitigation of both drug and biological product shortages.  Accordingly, FDA expressed its interest in receiving comments on the following questions from all parties, including those with an interest in biological products: 

  1. In an effort to address the major underlying causes of drug and biological product shortages, FDA is seeking new ideas to encourage high-quality manufacturing and to facilitate expansion of manufacturing capacity. 
  2. To assist in the evaluation of product manufacturing quality, FDA is exploring the broader use of manufacturing quality metrics.  With that in mind, FDA would like input on the following issues:  What metrics do manufacturers currently use to monitor production quality?  To what extent do purchasers and prescribers use information about manufacturing quality when deciding how to purchase or utilize products? What kinds of manufacturing quality metrics might be valuable for purchasers and prescribers when determining which manufacturers to purchase from or which manufacturers' products to prescribe? What kinds of manufacturing quality metrics might be valuable for manufacturers when choosing a contract manufacturer? How frequently would such metrics need to be updated to be meaningful. 
  3. The use of a qualified manufacturing partner program similar to one used under the Biomedical Advanced Research and Development Authority (BARDA) has been suggested as a potentially useful approach to expanding manufacturing capacity and preventing shortages. FDA recognizes that there are important potential differences between the BARDA program and the use of a parallel program to address shortages. For example, the BARDA program covers a relatively stable and limited number of products, but drugs at risk of shortage are many, may change rapidly over time, and are difficult to predict in advance. In addition, FDA does not have funding to pay manufacturers to participate in a drug shortages qualified manufacturing partner program or to guarantee purchase of the end product. With these differences in mind, is it possible to design a qualified manufacturing partner program that would have a positive impact on shortages? 
  4. Are there incentives that FDA can provide to encourage manufacturers to establish and maintain high-quality manufacturing practices, to develop redundancy in manufacturing operations, to expand capacity, and/or to create other conditions to prevent or mitigate shortages? 
  5. In FDA’s work to prevent shortages of drugs and biological products, FDA regularly engages with other U.S. Government Agencies.  Are there incentives these Agencies can provide, separately or in partnership with FDA, to prevent shortages? 
  6. When notified of a potential or actual drug or biological product shortage, FDA may take certain actions to mitigate the impact of the shortage, including expediting review of regulatory submissions, expediting inspections, exercising enforcement discretion, identifying alternative manufacturing sources, extending expiration dates based on stability data, and working with the manufacturer to resolve the underlying cause of the shortage. Are there changes to these existing tools that FDA can make to improve their utility in managing shortages? Are there other actions that FDA can take under its existing authority to address impending shortages? 
  7. To manage communications to help alleviate potential or actual shortages, FDA uses a variety of tools, including posting information on our public shortages Web sites and sending targeted notifications to specialty groups. Are there other communication tools that FDA should use or additional information the Agency should share to help health care professionals, manufacturers, distributors, patients, and others manage shortages more effectively? Are there changes to FDA’s public shortage Web sites that would help enhance their utility for patients, prescribers, and others in managing shortages? 
  8. What impact do drug and biological product shortages have on research and clinical trials? What actions can FDA take to mitigate any negative impact of shortages on research and clinical trials? 
  9. What other actions or activities should FDA consider including in the strategic plan to help prevent or mitigate shortages? 

Other Drug Shortage News 

In addition, FDA recently announced the approval of the first generic version of the cancer drug Doxil (doxorubicin hydrochloride liposome injection).  Doxil is currently on FDA’s drug shortage list.  The generic is made by Sun Pharma Global FZE (Sun).  Doxorubicin hydrochloride liposome injection is administered intravenously by a health care professional. Sun’s generic will be available in 20 milligram and 50 milligram vials. 

In February 2012, to address the shortage of doxorubicin hydrochloride liposome injection, FDA announced it would exercise enforcement discretion for temporary controlled importation of Lipodox (doxorubicin hydrochloride liposome injection), an alternative to Doxil produced by Sun and its authorized distributor, Caraco Pharmaceutical Laboratories Ltd. that is not approved in the United States.  Enforcement discretion was also used to release one lot of Janssen’s Doxil made under an unapproved manufacturing process. 

In addition, a federal judge also recently approved a consent decree with Ben Venue Laboratories, FDA announced.  The company, a subsidiary of Boehringer Ingelheim, suspended its manufacturing capabilities in 2011 after receiving a string of warning letters from FDA over the maintenance of its current good manufacturing practices (CGMPs). 

According to RAPS, “the quality control problems had led to widespread shortages of various critical medications, including Doxil (doxorubicin), a cancer drug.”  As of October 2012, that enforcement discretion continues even as Ben Venue's manufacturing capabilities have started to come back online.  That same month, Ben Venue announced that both “FDA and the European Medicines Agency (EMA) were reviewing a new shared manufacturing method that would see initial supplies of Doxil manufactured at Ben Venue, while a second facility would ensure the quality and sterility of the drug.”   

“Under the terms of the consent decree, Ben Venue is permitted to continue to manufacture and distribute more than one hundred important drugs that are essential for patient care,” the company said in a statement.  “Ben Venue is also permitted to continue drug-development activities, and may file abbreviated new drug applications (ANDAs), and, as remediation progresses to the FDA’s satisfaction, receive ANDA approvals and manufacture other products.” 

However, the consent decree restrains Ben Venue from manufacturing and distributing drugs from its Bedford, Ohio, facility until FDA determines that its operations are compliant with the FDCA. 

In a statement, FDA's Acting Associate Commissioner for Regulatory Affairs Melinda Plaiser explained that the consent decree was enacted in response to serious, systemic concerns.  “The company’s failure to promptly address these problems put patients at risk of receiving poor-quality drugs and compromises the availability of medically necessary products,” said Plaisier.  “This company continued to violate the law, and FDA took action to help ensure that medicines that consumers rely on are safe, effective, and of high quality.” 

Ben Venue acknowledged those concerns in its own statement, noting that it has already spent more than $300 million to upgrade its facilities to address some of the systemic quality deficiencies that had plagued it in recent years.  The company also noted that since its October 2012 announcement of the return of limited manufacturing capabilities, it has resumed production on additional manufacturing lines.  That consent decree was subject to the approval of a federal court, which FDA announced it received on 31 January 2013.  

FDA's statement on the matter also indicates that Ben Venue's CEO, vice president of operations and vice president of quality operations were all named defendants under the decree, providing it with significant leverage if the company violates its terms.

The agency will also likely be glad to have the facility's capacity back up and running. Ben Venue is a manufacturer of numerous sterile injectable drugs, and in the wake of its shut down and subsequent drug shortages, FDA came under fire from Congress for two reasons: the shortages and pharmaceutical compounding. 

In the first instance, FDA was slammed by legislators for not working harder to keep the manufacturing facility open, with a congressional report alleging that FDA did not have a “sufficient focus in ensuring access to and a continued supply of needed medicines over the last several years.” 

“Although manufacturers are reluctant to speak publicly about problems with their governing agency, the Committee found that the new political regime at FDA is largely to blame for the sudden spike of shortages that began in 2010,” quoted RAPS.  FDA, meanwhile, hit back at that report, saying that responsibilities for the shortages “live largely outside of FDA's purview.” 

“It is the manufacturer’s responsibility to ensure that its products are safe, effective and of high quality,” wrote Jeanne Ireland, then-assistant commissioner for legislation at FDA.  “When products manufacture under problematic manufacturing conditions pose a safety threat to patients—such as glass shards or metal shavings in vials of injectable drug products or fungal contamination of the product—manufacturers generally must stop production to resolve the problem before resuming manufacturing and distribution.”

February 26, 2013

DOJ to Target Pharma and Device Current Good Manufacturing Practices (cGMP) Violations

Current Good Management Practices
Over the last several years, we have written extensively about the ongoing government prosecution of pharmaceutical and medical device manufacturers involved in off-label promotion, misbranding, and other illegal marketing and promotional activities.  Much of the focus and resources of the federal government, including the US Department of Justice (DOJ), the Department of Health and Human Services (HHS), and the Office of the Inspector General (OIG) for HHS have been devoted to investigating and prosecuting such large-scale cases, including the largest in history—a $3 billion fine against GlaxoSmithKline

While the ongoing prosecution of these cases into the future likely will remain stable despite the U.S. Second Circuit’s decision in United States v. Caronia, DOJ recently announced in late January of this year, that compliance with current good manufacturing practices (cGMPs) will be one of the agency's “top areas of focus” in the coming year, “opening up new areas of uncertainty for those involved in compliance and regulatory activities for the pharmaceutical industry,” writes RAPS.

cGMP regulations are designed to assure that drugs meet safety, identity, and strength requirements and that they meet the quality and purity characteristics which they are represented to possess.  

In remarks made at the Pharmaceutical Compliance Congress (PCC) on 29 January 2012, Maame Ewusi-Mensah Frimpong, Deputy Assistant Attorney General (DAAG) for DOJ's Consumer Protection Branch (CPB), noted her division has long worked closely with the Food and Drug Administration (FDA) to promote the safety of pharmaceutical products.   

As Frimpong explained, the role of CPB is to protect “consumers, and our highest priority is to protect consumers where they are most vulnerable—where the harm to consumers is widespread and substantial or where consumers are at greatest risk of harm.”  CPB does so “through the prosecution and litigation of both civil and criminal matters in the areas of food, drugs, consumer goods, services, and financial fraud.” 

CPB is largely responsible for all of the cases involving off-label promotion, and works closely with other federal healthcare law enforcement officials such as OIG and the FBI.  

CPB led the charge in the GSK settlements, as well as the settlements with Abbott Laboratories and Merck, however, all three of those settlements focused on one thing: misbranding.  “In the area of misbranding, when companies make promotional claims that are not truthful and balanced, or when they do not disclose all relevant safety information to FDA and doctors, they place patients at great risk of harm because neither doctors nor patients can make informed choices about their drugs,” Frimpong said.  

She later summarized that each of these case involved “a company making misrepresentations regarding safety and placing patients at an unacceptably high risk of harm in the service of the bottom line.”  Accordingly, Frimpong explained that companies “will likely continue to see this as a theme of our Food, Drug, and Cosmetic Act prosecutions, and you should know that we will be taking an especially hard look whenever there are misrepresentations of safety.” 

Similarly, Frimpong noted that “when companies fail to follow current good manufacturing practices, they often place patients at great risk of harm that neither they nor their doctors have any way of mitigating or even recognizing.”  Further, she expounded that CPB will take “an especially hard look whenever patients are placed at an unacceptably high risk of harm by those violations of current good manufacturing practices.”   She acknowledged that “compliance is not easy given that safety is not a simple black and white issue” and noted that compliance “is a continuous process of assessing and eliminating or minimizing risks.” 

Nevertheless, she maintained that the cGMP regulations and guidance are “intended to guide you and your organizations in calibrating those risks.  Because it helps the industry to strike the appropriate balance between ensuring adequate safeguards for drug safety and optimizing efficiency in light of the dictates of science and the marketplace, companies disregard this regime at their peril and that of millions of Americans.”  Although companies may face enormous pressures to produce drugs more “quickly, cheaply, and efficiently,” Frimpong’s message was that companies “cannot sacrifice drug safety in service of these pressures.”   

She also recognized that many companies “have implemented strong compliance programs to detect and provide early warnings before misconduct develops into a criminal violation, and our enforcement priorities and approach are intended to recognize that in a meaningful way.” 

“This focus on cGMPs would mark a dramatic change in practice for the agency, remarked Scott Liebman, a principal at Porzio Bromberg & Newman and vice president of Porzio Life Sciences, in an interview with Regulatory Focus.”  “This is out of their normal zone of activity … and the direct focus on CGMPs is a shock.”  Liebman explained that Frimpong’s remarks raised a huge number of unanswered questions among those in attendance, including  

  • whether the agency has the capacity to take on additional areas of focus while maintaining current levels of attention on misbranding issues,
  • which areas will represent the 'low-hanging fruit' for initial agency actions, and
  • where the majority of the agency's focus might eventually come to rest. 

RAPS cited to a “number of high-profile pharmaceutical compliance issues came to light in 2012, including a rash of drug shortages caused by CGMP issues in a number of facilities, including ones overseen by Genzyme and Ben Venue Laboratories, as well as pharmaceutical compounding problems seen at facilities large (Hospira) and small (New England Compounding Center). Many of those drugs were sterile injectable drug products, though Frimpong's remarks did not specify if those types of drugs would be of particular interest.” 

Advice for Industry 

Despite the uncertainty, Frimpong offered several factors and considerations companies and attorneys should consider with respect to cGMPs in order to understand what DOJ is looking for and to avoid U.S. Attorney’s knocking on their door.  Accordingly, Frimpong suggested that companies ask themselves five questions: 

1. Do we have the right people in place with the right training and expertise? 

She noted that companies “need people with the right training and expertise to recognize problems that can arise when manufacturing pharmaceuticals.  People are not fungible, especially when it comes to the complex and highly technical issues that arise in a pharmaceutical production line.”  For instance, in CPB’s recent civil resolution with Genzyme to resolve a number of GMP violations at their Massachusetts facility, “one issue was failure to use equipment constructed so that the surfaces contacting drugs or drug components were not reactive, additive, or absorptive.”  Clearly, “you need the right people to recognize such a risk and ensure that the right equipment is used.” 

2. Do our people have the right incentives to see problems, to report problems, and to fix problems?  

For this factor, Frimpong explained that CPB sometimes sees in cases that individuals in companies cut corners in order to meet production goals or to cut costs.  Companies “want to make sure that there are strong incentives that go the other way, incentives for people to see problems, report problems, and fix problems.  Internal communication—and systems to encourage that communication—are key.”  One thing that is notable in many of CPB’s “recent GMP resolutions, for instance, the civil consent decree against Ranbaxy, is that the investigation followed numerous early red flags within the company and warning letters from the FDA that were never adequately addressed.”  She explained that companies “want to ensure that the system of formal and informal incentives within your company compel and encourage prompt and fulsome responses to issues that arise.” 

3. Are regulatory and compliance people engaged and satisfied such that they are less likely to leave the company, leaving a vacuum of oversight? 

CPB’s “investigations have revealed that often the departure of key employees can be a crucial turning point for an organization.  It can be a red flag of existing problems or of problems to come, particularly if departures leave a vacuum in key positions or leave remaining employees overwhelmed and unable to meet the dictates of safety.”  For example, in the Cidra case in which SB Pharmco, a GSK subsidiary, was prosecuted for GMP violations at its plant in Cidra, Puerto Rico, “the departure of certain key employees with responsibility for drug safety led to many of the conduct supporting the criminal charges.”  Frimpong noted that “having a reputation as being fair and honest can enhance employee morale and aid in recruiting and retaining the best and brightest employees, and this can be critical in maintaining a seamless and airtight culture of compliance.” 

4. Are our people and policies working in harmony?  Put another way, do our policies acknowledge how real people work and what they are capable of?  

“Quality assurance processes that rely on unrealistic expectations are doomed to fail. Using the Cidra example again, some of the safety problems resulted from relying on a policy of 100% visual inspection of certain tablets when visual inspection could not actually reveal problems given the speed of the production line.” 

5. Do we personally have visibility into what our people are actually doing? 

“Avoiding knowledge of problems in your organization will not shield you from liability,” Frimpong explained—this is particularly true for executives of companies who may be prosecuted under the Park doctrine and also because FDA’s recent consent decree with Ben Venue listed corporate officers in the documents.  She noted that “many companies are increasingly doing independent audits or bringing experts in to examine their compliance in a rigorous way” and that “this is one way to make sure that your systems are not masking any problems that exist, and we encourage you to consider this approach.” 


The key takeaway, Frimpong said, is to focus on the human element of the equation. “People are not fungible, especially when it comes to the complex and highly technical issues that arise in a pharmaceutical production line,” she added. 

Interestingly, Frimpong emphasized that the “GMP regime as we see it presents a great opportunity for partnership and cooperation between government and industry, especially when we are dealing with critical drugs.  Not only does the statute explicitly look to companies to determine the appropriate balance in the first instance, thereby making you partners with government, but also strong enforcement protects those companies that do follow the rules.”  

She noted that “Weak enforcement that encourages deviations from GMP and noncompliance in this area affects the entire industry, as it erodes the confidence of the American public in our drug system.”  She concluded by noting that “In a day and age where consumers are increasingly looking outside the regulated drug delivery system for their medication, such as to illegal online pharmacies, it is important that we maintain the rigorous standards we have in the regulated system.” 

Liebman told RAPs that companies would do best breaking “down regulatory and compliance silos to make sure people are more broadly educated about both CGMP and Prescription Drug Marketing Act (PMDA) requirements to be able to handle DOJ’s increased scope of interest, particularly in light of Frimpong's advice to break down barriers between segments.” 

Consequently, it is unclear what the effect of this speech will have on companies.  Largely, companies have been “willing to settle with DOJ over misbranding complaints, paying huge sums of money and agreeing to marketing-based corporate integrity agreements (CIAs) that are meant to improve internal compliance to prevent future deficiencies.”  However, these fines are mainly associated with marketing and promotional expenses, “while CGMP legal actions might distribute them differently,” RAPS notes. 

For example, RAPS pointed to the case of Johnson & Johnson manufacturing subsidiary Ben Venue Laboratories, where CGMP deficiencies caused its Bedford, Ohio plant to be shut down while the company spent nearly $300 million to upgrade the facility in addition to the cost of recalled products.  It eventually signed a consent agreement with FDA to resume limited operations, but is still not up to its full manufacturing capacity, even years after its initial shutdown.  

Liebman said this scenario illustrates that “the consequences are going to be different” for companies found to have severely violated CGMP regulations relative to those have severely violated branding or advertising regulations. “They could be more painful,” he added.


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