Caroline Hroncich was associate editor for Pharmaceutical Technology, Pharmaceutical Technology Europe, and BioPharm International from 2015 to 2017.

Caroline Hroncich

	Rajesh Singh, senior manager, and Brad Pedrow, manager, S&O Supply Chain Strategy, both at Deloitte Consulting, spoke with 

about the challenges of serialization implementation, and how to improve processes ahead of the Drug Supply Chain Security Act (DSCSA) deadlines. To learn more about this and other topics, attend Singh and Pedrow’s presentation, “

The Role of Track and Trace in a Post-Serialized World

”, at CPhI North America on May 17, 2017 from 10:30 am to 12:00 pm.

What are some typical challenges facing pharma manufacturers as the November 2017 date for serialization approaches?

What we see in the market is multifold. Large pharma [companies] are mostly on track for meeting their obligations, mid-pharma tends to be a mixed bag, and small/virtual pharma seems to be behind. Most of the issues are organizational in nature (e.g., contract manufacturing organization dependency, over-dependence on consulting partner resources, lack of internal expertise, and a general reluctance by some upper management to do this the right way). Quite a few companies underestimated the complex nature of the effort it takes to do this correctly, especially the ones who did not do anything for the ePedigree law in CA. Additionally, we also see some companies, especially those who are late to the game, face some late-stage integration challenges due to lack of expertise and resources.

What kind of advice would you give a company that is unprepared for the DSCSA deadline?

Well, it is spring of 2017 already. If a company is in initial stages for November 2017, it is probably very late, not in terms of technology but finding the right resources. My advice would be not to delay any further and either outsource your serialization requirements to a third party or immediately initiate a program internally.

What kinds of new technologies are making serialization easier for pharma manufacturers? Are there new technologies in development for serialization?

Companies that are late to the game tend to go for easier-to-set-up technologies that are cloud-based. The lead time for such solutions is far less than traditional on-premise (and perhaps more expensive) solutions. There are several vendors who offer this service. There are also talks in the industry on mechanisms to exchange serialization data with trading partners, considering some of the large wholesalers have already issued memos to run pilots with manufacturers. Interesting conversations are currently taking place in this regard.

Aside from the regulatory requirements, what is the value to pharma manufacturers investing in serialization and track and trace?

We see value in serialization as a by-product of this investment and not really the driver. However, had this regulation not been in place, few of these companies would have thought of leveraging the vast amount of data that can be used for efficiencies. We typically see conversations, pilots, and other efforts inside companies to improve inventory visibility, tracking of control substances, rebate and chargeback accuracy, and recall accuracy as main value drivers. Some companies are also investigating the value of block chain, which has an interesting place in this use case. All these trends will take some time to come to fruition. Lastly, we have seen quite a few cases of companies looking to leverage this investment for clinical trial supply management as well.

What will participants learn about serialization and track and trace during your CPhI North America session?

We will share what we are seeing in the market, some tactical aspects on how to get ready, and what the future looks like.

Articles

Pharmaceutical Technology spoke with Brad Pedrow and Rajesh Singh of Deloitte Consulting to discuss serialization implementation, and what to expect as the DSCSA deadline approaches.

Serialization Challenges Facing Pharma Manufacturers

spoke with Jonathan Helfgott, coordinator and adjunct professor for the Johns Hopkins University Graduate Program in Regulatory Science and former associate director, Office of Scientific Investigations, Center for Drug Evaluation and Research (CDER), about challenges pharmaceutical companies face when submitting abbreviated new drug applications (ANDAs). Helfgott will be speaking on this and other related topics during his presentation “

Navigating GDUFA–Reduce Cost and Accelerate Delivery

” at the CPhI North America Conference from May 16–18, 2017 in Philadelphia, PA.

What are some typical challenges facing pharma companies submitting an ANDA? Do you have any suggestions for addressing these challenges?

: Typical challenges facing pharma companies include ensuring that ANDA submissions use the electronic common technical document (eCTD) format and consist of high-quality data.

	As of May 5, 2017, the eCTD format is required for all ANDA applications. All electronic submissions must use the version of eCTD supported by FDA, comply with the required specifications, and be appropriately validated before submissions. Selection of an appropriate eCTD software vendor can be helpful to ensure a successful eCTD submission that complies with FDA’s requirements.

	Janet Woodcock, MD, director of FDA’s Center for Drug Evaluation and Research, has defined the term ‘high quality data’ as the absence of errors that matter-errors that matter are typically errors that can have an impact on the interpretation of study results. Incorrect, missing, or inaccurate data can result in a refuse-to-receive or a complete response letter.

	Pharma companies can address these challenges by hiring people that have experience with and understand the intricacies of the regulatory submission and filing (e.g., eCTD) process to verify proper formatting and application completeness. Perhaps even more importantly, companies should build quality into their processes to avoid these types of challenges all together.

 on prior approval supplements. How does this guidance work to further clarify the ANDA submission process?

: This particular FDA final guidance is focused on clarifying the requirements of prior approval supplements (PASs) and amendments to PASs for ANDAs. The guidance describes how the Generic Drug User Fee Amendments (GDUFA) performance metric goals apply to a PAS subject to the refuse-to-receive standards, a PAS that may or may not require an FDA site inspection, an amendment to a PAS, and other PAS-related matters. The guidance further clarifies sections in the Federal Food Drug and Cosmetic Act that define the following categories of changes to an approved indication-major, moderate, or minor, while noting that the criteria for submitting information as a PAS, as a changes-being-effected (CBE), or in an annual report were not changed by GDUFA.

: How has GDUFA impacted the ANDA review process at FDA? Please comment on efficiency.

 to Congress on GDUFA’s impact on the ANDA review process. Highlights from this report include the GDUFA performance goals, workload, management priorities, review times, inspections, drug safety, and research priorities. As of October 2016, FDA had issued a first action on approximately 93% of the GDUFA backlog applications since program launch, meeting the GDUFA backlog commitment 15 months ahead of the goal. Prior to the passage of GDUFA, domestic facilities were routinely inspected about once every two years while their foreign counterparts were inspected about once every seven to 13 years. This regulatory disparity, combined with limited resources and the associated cost of inspecting foreign facilities, produced an increasing gap in the level of oversight that was needed to ensure the safety of the human generic drug supply. FDA now applies a risk-adjusted inspection focusing on sites that have not been previously inspected, utilizing site inspection outcomes conducted by foreign regulatory bodies, and making inspection classification results publicly available.

 What advice would you give a company conducting a bioequivalence study?

: Companies need to thoroughly understand FDA’s draft guidance on 

Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an Abbreviated New Drug Application

 as well as any product-specific guidances that describe the agency’s current thinking and expectations on how to develop generic drug products therapeutically equivalent to specific reference-listed drugs.

	Companies need to do their homework and make sure that they pick a reputable bioequivalence firm that has a good FDA inspection track record. There could be premiums associated with using higher end bioequivalence services, but I believe the cost of non-compliance will always be greater than not spending the time and effort to do it the right way up front. It’s also important that companies select the right methods, which are validated and well accepted; the reference standards used also need to be pure and clean. Common pitfalls to avoid include poor chain of custody, sloppy documentation, and weak processes.

	A pre-ANDA meeting is a great opportunity for firms to discuss complex and critical issues and for FDA to provide guidance on how to design a bioequivalence study.

 What will participants learn during your CPhI North America session?

: Participants in the CPhI North America session will learn:

		The role of GDUFA and its’ impact on ANDA reviews

		When a bioequivalence study is required to support an ANDA

		How to conduct high-quality bioequivalence studies and prepare for an FDA inspection

		Effective use of technologies to support bioequivalence studies.

Pharmaceutical Technology spoke with CPhI North America presenter Jonathan Helfgott to discuss navigating GDUFA and helpful tips for submitting successful ANDAs.

Former CDER OSI Associate Director for Risk Science to Speak at CPhI North America 2017

	The dispute over who has the rights to key CRISPR-Cas9 patents continues. On April 12, 2017 the University of California, Berkeley, in conjunction with the University of Vienna and Emmanuelle Charpentier, 

 by the United States Patent Trial and Appeal Board (PTAB).

, “terminated the interference” between Berkeley and the Broad Institute. Berkeley said it is appealing the decision in hopes that the PTAB will reinstate the 

-a legal proceeding that aids the court in determining which party first invented a technology.

	“Ultimately, we expect to establish definitively that the team led by Jennifer Doudna and Emmanuelle Charpentier was the first to engineer CRISPR-Cas9 for use in all types of environments, including in non-cellular settings and within plant, animal, and even human cells,” said Edward Penhoet, a special advisor on CRISPR to the UC president and UC Berkeley chancellor, in a 

. Berkeley also said it will continue to pursue patent applications in the US and elsewhere for CRISPR/Cas9 in “non-cellular and cellular settings.”

	The Broad Institute said it was “unlikely” that the court would overturn the PTAB decision. “Given that the facts have not changed, we expect the outcome will once again be the same. We are confident the Federal Circuit will affirm the PTAB decision and recognize the contribution of the Broad, MIT, and Harvard in developing this transformative technology,” they wrote in a 

, the PTAB said that Berkeley and the Broad Institute’s versions of CRISPR-Cas9 are separately patentable. In the 

, the PTAB wrote that Broad’s CRISPR-Cas9 technology is specific to a eukaryotic environment, while Berkley’s is not restricted to any environment. Berkeley claims that the use of CRISPR-Cas9 in a eukaryotic environment can’t be patented separately. Broad, who currently holds 13 of the 28 patents for CRISPR, argues that these are separate inventions.

	CRISPR Therapeutics, Intellia Therapeutics, Caribou Biosciences, and ERS Genomics-all of whom license the technology from Berkeley-released a joint 

 about the appeal. Editas Medicine, a biotech company based in Cambridge, MA, licenses CRISPR-Cas9 from the Broad Institute.

	What does an appeal mean for companies licensing CRISPR-Cas9?

	Although it is still unclear how the results of this case will affect the biotech companies that license CRISPR-Cas9 from Berkeley and Broad Institute, Kevin Noonan, PhD, partner at McDonnell Boehnen Hulbert & Berghoff told 

the decision could impact commercial applications for CRISPR-Cas9. In some cases, he said, third parties may need a license from both Berkeley and Broad.

	“If the court reversed the PTAB and the interference went to a substantive conclusion, one or the other party would have priority and thus have the rights to the technology. Although there may be after-arising variants that become important, in the near term there would be certainty regarding whose patents need to be licensed,” Noonan said

If the PTAB’s decision is upheld, on the other hand, third parties will need a license from both the Broad [Institute] and the University [of California, Berkeley]; if anyone uses the technology and sells products based on it without a license from both patentees there could be liability for infringement.”

	Although it is unlikely, the Broad Institute could file a cross-appeal, Noonan said, but third parties (such as the companies licensing CRISPR-Cas9 from Berkeley or Broad) have no standing to appeal. However, they could file amicus briefs.

	“They could file amicus briefs but those would be in the nature of informing the court about the risks of overturning the PTAB’s decision,” he said. “If the Federal Circuit rules in the University’s favor the case would go back to the PTAB for considerations of priority and other matters the parties raised but the Board ruled were outside the scope of its jurisdiction because there was no interference-in-fact.”

This article has been updated on April 14, 2017 to include comments from Kevin Noonan.

UC Berkeley appealed the February 2017 decision that determined Harvard and MIT’s Broad Institute and Berkeley’s CRISPR-Cas9 technologies were separately patentable.

UC Berkeley Appeals CRISPR Decision

spoke with CPhI North America presenters Ben Locwin, PhD, MBA, MBB, president at Healthcare Science Advisors, and Tom Fox, principal at Advanced Compliance Solutions, to discuss drug pricing, compliance challenges, and corporate social responsibility in the bio/pharmaceutical industry. To hear more about these and other related topics, attend Locwin and Fox’s upcoming presentation “

Legal and Policy Strategies for Drug Companies in Today’s Global Market

” at the inaugural CPhI North America to be held on Wednesday May 17, 2017 from 10:30 am to 12:00 pm.

Recently, there has been a lot of discussion on drug pricing. With a new presidential administration, what kinds of policy changes do you expect to see over the next four years? How might this impact pharma manufacturers?

 Certainly, the antecedent factor in manufacturing and pricing will be if indeed the new White House administration is successful in systematically reducing regulations by FDA on drug discovery, clinical development, and production. Strategic pricing of pharmaceuticals is based in part on the following factors:

		Manifestation of failure probabilities to meet safety and efficacy standards

		Likelihood of amendments to processes and products.

	Potential changes to the rules, therefore, necessarily changes each of these variables, and thus, overall manufacturability and pricing.

	What is incumbent more than ever on manufacturers, because of public perception, is to be able to justify costs based on the inputs. Certainly, drug prices can be arbitrarily set high-It can be done, but should it be done?

 There are quite clearly ramifications to this, and being transparent about processes that lead to pricing makes some of these ethical quandaries a bit easier to defend-if not in front of Congress or FDA, then certainly in the court of public opinion. It's a business risk and so this should be appropriately reflected in a good risk-management process.

FDA issued an increased number of warning letters in 2016. What are some of the most common compliance challenges pharma manufacturers are facing?

 There's a strong misconception behind this statistic: A single elevated data point (2016 having a greater number of warning letters than 2015) doesn't mean that there's been an appreciable change in poor quality coming from the industry, it's only indicative that repeated measurements of a particular data source (e.g., number of annualized warning letters) will necessarily show natural variation. Number of inspections, FDA funding, and many other factors are components of this number; it speaks more to the variation in the underlying processes involved in inspection than it does in the goodness of drug manufacturability.

 Good compliance is taking regulatory pronouncements and putting them as part of a compliance program, taking seriously the nature of the articles within the regulations, and determining best how to operationalize them.

A key indicia of an operationalized compliance program is the extent to which compliance professionals and risk managers incorporate regulatory information directly into corporate risk-management processes and compliance programs. Information provided in FDA warning letters can relate to specific issues and provide insight into how FDA will assess risks. The issues raised in FDA warning letters can be used as the basis for updated and enhanced employee training to drive the message into the fabric of an organization.

A section of your presentation will focus on separating business from ethics and morals. How difficult is this for pharma companies? What kinds of challenges do you see them facing?

 We need to realize that pharma companies are for-profit entities, so even though the overwhelming stance is to be in the 

 (as their taglines variously go), it has to be financially favorable, lest the company not continue to exist. But in any case, when businesses do corporate social responsibility better, corporate financial performance tends to improve as well. This makes thought experiments like 

 even more important for pharma than for other industries: if drugs price out too many patients, they aren't on average providing the benefit they could.

 Rather than focus on separating ethics and values, I think the question should be, how do you incorporate your corporate values into your business ethics? Corporate values should be a driver of business and a market differentiator from your competition. Compliance is the corporate function which puts processes and procedures in place to operationalize your corporate values and business ethics within the risks inherent in an industry regulatory regime. A robust risk management process allows a company to more efficiently manage its risks and at the end of the day, make the company more profitable. It is linear progression, not binary decision between morals and ethics.

 Enough to be dangerous on a number of topics. Our track will discuss the backbone and underpinnings of drug pricing, ethical dilemmas that exist as a result, and how compliance is an irreducible component of doing all the work properly.

 [Our presentation will also discuss how] a robust risk management process allows a company to be more nimble, agile, and able to more quickly respond to market conditions going forward. Through operationalizing compliance, a company can embed the risk-management process closer to the business unit and into the business process.

Pharmaceutical Technology spoke with CPhI North America presenters Ben Locwin, PhD, MBA, MBB, president at Healthcare Science Advisors, and Tom Fox, principal at Advanced Compliance Solutions, to discuss drug pricing, compliance challenges, and corporate social responsibility in the bio/pharmaceutical industry.

Political and Ethical Dilemmas Facing Bio/Pharma Companies in a Global Marketplace

published on April 6, 2017 compares the regulatory review process at FDA with the European Medicines Agency (EMA). The study, which focuses on new therapeutic agents, shows that FDA approved 170 new therapeutic agents between 2011 and 2015, while EMA approved 144.

	The median total review time for therapeutic agents during this period, according to the researchers, was 306 days at FDA and 383 days at EMA. On average, reviews at FDA were 60 days shorter than reviews at EMA for therapeutics approved between 2011 and 2015.

	However, the authors also noted that while review times were shorter at FDA for therapeutics intended to treat cancer and hematologic diseases, this was not the case for other therapeutic areas. They also found the review time was longer at FDA compared with EMA for orphan drugs.

study authors said the statistics are comparable to, and greater than, a 

 of review times of therapeutics approved between 2001 and 2010. “Our analysis provides reassurance that FDA continues to complete regulatory reviews more quickly than the EMA and has the potential to inform discussions regarding the reauthorization of the PDUFA [The Prescription Drug User Fee Act],” they conclude.

	The new presidential administration has become increasingly critical of FDA’s approval process. President Trump has referred to the process as “slow and burdensome” and the administration is putting 

 on FDA to accelerate review of drugs. Although it is still unclear if the administration will recommend any changes to the process, the 

study demonstrates that compared to its counterpart, FDA has been able to review new medicines efficiently.

A new study in NEJM compares the regulatory review processes of FDA and EMA.

Study Compares Regulatory Review at FDA with EMA

 that Meridian Medical Technologies is expanding a voluntarily recall to include 13 lots of Mylan’s EpiPen and EpiPen Junior (epinephrine injection) in the United States due to a potential defective part. Mylan said the defective part may cause activation failure in the autoinjectors. In a 

, Mylan said the recall will also extend to parts of Europe, Asia, and North and South America.

	Earlier in March 2017, the company recalled 81,000 EpiPens in Australia, New Zealand, Europe, and Japan, 

. Mylan said it issued an expanded voluntary recall as a “precautionary measure out of an abundance of caution” after two failures were reported outside of the US.

	Meridian Medical Technologies, a subsidiary of Pfizer, manufactured the recalled part for EpiPen. The recalled lots were distributed between Dec. 17, 2015 and July 1, 2016.

	This is not the first time EpiPen has been in the news recently. Mylan faced 

 from government officials over its decision to increase the price of EpiPen more than 400% since it acquired the drug in 2007. The company also settled with the Department of Justice after it allegedly 

The company announced that Meridian Medical Technologies is extending a recall of EpiPen and EpiPen Junior to the United States.