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.