Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

	Data integrity has become a more serious compliance problem at pharmaceutical manufacturing plants throughout the world. Over the past three years, as the FDA has increased inspections of offshore facilities, the agency has penalized a number of API manufacturers in India and China for cGMP violations, many of them involving data integrity. In some of the FDA inspection reports, quality control staffers said that they were ordered by superiors to back date lab data, or to delete information and perform tests until samples passed.  Some of the companies whose plants were penalized were also put on an import ban list, preventing them from shipping products to the United States. 
	As more of these plant issues became public, rumors spread in India in February 2016 that the US was banning all imports of API from India and China (1). In fact, the ban only affects supplies that are covered by US government contract.  

	The panic might be understandable, given the growing number of regulatory citations directed at offshore API facilities. Because India and China supply 80% of the APIs used in US pharmaceutical production, mostly commodity-type products, the US government has been questioning FDA’s ability to monitor quality in Chinese and Indian plants, according to a February 2016 report in the Regulatory Affairs Professionals Society (RAPS) journal, Regulatory Focus. API manufacturing company executives believe that data integrity issues and perceptions that offshore suppliers are not sufficiently trained in current good manufacuring practices (cGMPs) are driving a move back to outsourcing more APIs manufactured in the U.S. and Europe. 

	According to the RAPS report (2), 41 manufacturing sites in China are now on import alert, five are on alert in Hong Kong, and 42 sites in India (some of which have only been cited for problems with specific products, not all of their manufacturing output). In December 2015, RAPS reported, US representatives wrote to the US Government Accountability Office asking that it look into whether FDA could handle the load of inspections now required in India and China. RAPS also pointed out logistical issues that FDA has faced in getting visas that would allow more of its new inspectors to work in China. The agency closed two Chinese offices in 2014 to consolidate activities in Beijing, according to RAPS.  In India, FDA plans to increase the number of inspectors from nine to 19, RAPS reports. Below are just a few of the offshore API manufacturing facilities involved and the penalties they received:

		A Dr. Reddy’s facility in India received a warning letter for documentation problems

		Zhejiang Hisung’s plant in China was cited for data manipulation 

		Ipca Labs’ three API plants in India were cited for data integrity problems.

Misleading Reporting:  Indian Pharma Company APIs are NOT Banned in the U.S.

US FDA Inspections in China: An Analysis of Form 483s from 2015

,” Regulatory Affairs Focus, Regulatory Affairs Professionals (RAPS) Society, www.raps.org.


	When referring to this article, please cite it as A. Shanley, “Concerns Mount Over Data Integrity and Compliance Issues Abroad," 

	On March 02, 2016 in our Volume 40, issue 3 we had published a story titled “Concerns Mount Over Data Integrity and Compliance Issues Abroad” authored by Agnes Shanley.  In the said story we have erroneously reported that "Indian-based Biocon Ltd. was placed on an import ban list"

	The averments in the said article that Biocon was placed on an import ban list are wrong and incorrect and have been published due to a proof reading error committed by the author of the said article. We hereby specifically state and clarify that we have no knowledge that product of Biocon Ltd. has been placed on an import ban list.  We sincerely regret the mistake made in the said article.

Articles

Data integrity has become a more serious compliance problem at pharmaceutical manufacturing plants throughout the world.

Concerns Mount Over Data Integrity and Compliance Issues Abroad

As pharmaceutical manufacturers continue to outsource more manufacturing and quality functions to contract partners, the question of who owns final product quality has become more complex. In the end, the company marketing the product is responsible, but achieving that quality is increasingly becoming a joint responsibility involving contract partners.

	In 2015, FDA released draft guidance (1) that attempts to guide both sponsor companies and their partners in understanding the most important product quality metrics.  The goal behind the guidance is to help the agency schedule plant inspections based on risk, so that companies with the most rigorous quality-assurance (QA) metrics would be inspected less frequently than those with weaker quality systems. Another goal is to help FDA inspectors better understand, and take steps to help address, potential product shortages.

	The guidance would assess certain measurements as a baseline and consider data from both sponsor and contract labs and manufacturing organizations including the number of out-of-specification (OOS) results, the number of lot-release and stability tests, and whether annual product reviews are published on a timely basis.  

	FDA’s draft would also assess corporate commitment to quality by requiring that senior quality executives review and sign off on documentation, evaluating the effectiveness of the company’s corrective actions and preventive actions (CAPA) programs, and checking on how well it is using process capability analysis to look at critical product quality attributes.  

	Industry’s reaction to the draft guidance was strong and immediate, with some companies and trade groups voicing criticism and calling for revisions (2). For contract laboratories and sponsors alike, the draft guidance reaffirms basic benchmarks and offers new reasons to assess programs and interactions, and establish best practices.  

 interviewed quality assurance consultant Susan Schniepp, chair of the Parenteral Drug Association’s (PDA) regulatory affairs and quality advisory board, as well as Eurofins Lancaster Laboratories’ quality assurance specialists Art Pezzica, senior director of quality assurance, and Brittany Cloud, senior quality assurance specialist, for their views on best practices, as well as industry reaction to the draft guidance.  

 In its draft guidance on quality metrics, FDA seems to be focusing on the basics, such as OOS.  Without having sponsors micromanage their partners, what do you feel should be reported for optimal results and to justify a sponsor’s comfort with a contract laboratory?

 For contract laboratories, FDA is only looking for unconfirmed out-of-spec results, but there are other metrics that laboratories monitor that can provide a certain comfort level for sponsors. These might include operator errors, unconfirmed deviations, and misreported data. Data quality is very important. It’s our laboratory’s product.

 Quantitative data, such as invalidated OOS rates and CAPAs, are very important, but so is qualitative information. For instance, does your contract partner have any Six Sigma or Lean projects underway? These can speak volumes as to how far the company is willing to go to achieve continued excellence or success.  

	If a contract partner is making positive changes, how is it handling change control? Is it investing in improving infrastructure or adding new employees?  These questions provide insights into the overall quality culture of the firm, and go beyond the compliance statistics to give a picture of what is going on.

 CAPA has been a compliance challenge for many companies. Complexity would seem to increase with the number of functions being outsourced and the number of contract partners involved. How should concerns about CAPA influence reporting metrics?

 The key is having a dynamic and transparent relationship in which both partner and sponsor can speak openly. This involves not only reporting on open or completed CAPA items, but also looking at effectiveness trends to see whether any special programs and initiatives that the lab has established are actually working.

	It is also important to hold regular quality meetings with the client to review CAPA. These meetings allow the contract partner to develop best practices to address client issues, but also to learn from clients. In some cases, we’ve been able to implement some of our clients’ best internal and external audit practices to improve our overall quality assurance.

	Communication should be dynamic, and should go beyond merely reporting metrics.  Ideally, it becomes a fluent discussion that improves not just the way you operate your lab, but the overall relationship as well as the quality of the product that eventually reaches the consumer.

 With CAPAs, clients should share more information on their investigations with contract partners.  As a contract lab, you are typically just one part of a CAPA investigation. You run your tests and report results to the client, but you often don’t learn what the final results were. That information could be very helpful in improving your understanding of the client’s process and what can affect it. It would be helpful to have that information loop back, to help you improve your systems.

 Data integrity has been a crucial issue for manufacturers and their contract partners, and many contract partners are falling short of FDA’s expectations. How should contract labs and sponsors work together to ensure that requirements are being met?

 It’s crucial to have a strong validation program in place, and to focus on ethics and training. We know that we have good systems, but, due to the recent cases of insufficient data integrity affecting the industry, we recently formed a team to reassess our electronic systems. This team has implemented a risk-assessment program that is reviewing all our electronic data systems to identify any potential risks that might affect data integrity. Once the analysis is complete, we plan to focus on the top 20 potential risk areas and assess each electronic system for any potential risk to data integrity.

	We also have an ethics program in place and emphasize the importance of training. We make sure that our employees are fully aware that, while human error may occur, any attempt at falsification would be grounds for immediate dismissal.  It is essential for any contract lab to ensure that its employees divulge errors and strive to maintain the highest quality data results.

 Do you find that you have to work with clients to help them better understand data integrity requirements from global regulatory agencies, and the need to assess risks?

 I routinely host audits and have found the level of expertise varies among sponsors. Some clients are experts in this area and can share best practices with us. Others may know very little about regulators’ expectations for data integrity, while other clients are in between. Our job is to work with companies of all types to ensure that they understand requirements and can be comfortable with their data.

	When we work on product risk assessments with clients, we always share our standard operating procedures (SOPs) when that is requested, so that clients will know that we are following our procedures and policies.

	In some cases, we will even visit client sites to discuss our processes and how we incorporate quality into our data integrity systems. We have to take a holistic approach to meet the needs of all our clients, since they come from so many different areas of the business

 Do you see a lack of understanding of what documentation processes should be?

 Some clients may not understand differences between various regulatory agencies’ expectations. They may, for example, only want to follow FDA or European Medicines Agency (EMA) or, in the UK, the Medicines and Health Regulatory Agency (MHRA) guidance. In these cases, we must impress upon them the need to be ready on all fronts, and be ready to defend that position and our practices.

	Whenever a discrepancy comes up with a client, we need to triage it first and ask two crucial questions:  

		Could performing this function this way cause us to violate a regulatory requirement?  

		Would we be violating any of our own SOPs?

	If we can confidently say that we’re not failing on either front, then we are meeting the goals of that intended practice and procedure, and there is no need to change it.

 Clients should have a clear understanding of contract lab realities. A process that may work at a client’s manufacturing facility that is producing 10 or 20 products may be difficult to manage at a facility where thousands of different products are being tested using different analytical methods and test procedures.

	We always try to accommodate client requests, but we must also ask some hard questions:  Can we implement that process here and do it correctly all the time?  Does the change in process increase, even slightly, the potential of creating more errors? If so, we discuss our concerns with our customers.

	If the procedure or process will add value, but also add costs, is it a cost that all clients are willing to absorb, or will it be a single client-specific request? In the end, it is really a balancing act. We always need to assess the potential impact on our operations and whether it will add value. Managing client-specific requests will always make a project more difficult and add costs to our operation.

 How can both sides balance the need for maximum transparency with realistic expectations?

 We meet twice a year with some of our larger customers, and always include both of our quality departments, to discuss any issues that come up. For some clients, we’ll follow their OOS procedures instead of our own, but their request has to be reasonable, and involve something that we can be successful doing. Whenever differences of opinion come up, we discuss and resolve them.

 As a contractor, you’re often in a tough spot. This is especially evident with early reporting. You want to tell clients when numbers start trending in a certain way, to warn them, like Paul Revere, that something may start to go wrong.  

	However, in reality, when you do that, clients can overreact and take over, to a point where they can get in the way of root cause investigations and other lab work. Over time, if this keeps happening, a contract laboratory might not want to tell its clients about anything too early, before they have something concrete to report. But then, clients may be angry that they weren’t given advanced warning. It is definitely a difficult balancing act.

	You’re between the proverbial rock and a hard place.  I used to address this by calling clients and managing their expectations and fears with a ‘Don’t panic yet.’

 Transparency is so important to any contract lab-sponsor relationship. If a contractor is transparent and builds quality into its relationships with clients up front, clients tend to trust them. Having quality assurance involved, on both sides of the team, is very important, and this involvement is needed as early as possible.

	I do a lot of onboarding, and we tend to find that, when the quality assurance department is involved early and clients can put a face to a name, trust will be built and will make any challenges easier to manage if and when they come up. In this type of relationship, you can call or email each other at any time, even for things that may seem relatively trivial. Proactive communication can help avoid problems, and also clarify boundaries and prevent micromanagement.

 For any investigation that we do, we notify our clients within 24 hours. At that point, we are open to discussion, and we ask them to share additional inside knowledge about the product. We find that most clients are comfortable with this approach. At times, some have made unreasonable requests, but we’ve been able to rely on our knowledge of FDA and other regulatory agency requirements to enable open communication.

 Can you give any examples of unreasonable scope requests?

 Sometimes, we get test results that may not be what was expected, but still within specifications. The company may want us to invalidate the result, even though results were within specifications, and all method requirements were met.  In the end, we may agree that the result might be considered out of trend, but the data do not support invalidating the result.

 Some companies may try to set unreasonable expectations through quality agreements. For example, a company might require monthly metrics reporting of many different metrics, or dedicated QA personnel just for their investigations, as well as daily status reports on any investigations and CAPAs. Excessive levels of reporting and custom requests would have a negative impact on our operations without adding value for our clients.

 Are more pharmaceutical companies building IT connections to facilitate data reporting?

 With some larger companies, we record data and results directly into portions of their laboratory information management systems (LIMS).  A few companies may have special data acquisitions systems that they want us to use, so we’ll bring them onsite and work with them. We’ve even had clients recommend certain systems for instruments and equipment that we’ve brought online.  

	As a contract partner, flexibility in adapting to client needs is important to sustaining the relationship. We’re open to working with different data and IT systems.

 We offer our clients secure access to their data through our online portal, LabAccess.com, which provides a window into our LIMs, and scans and links raw data so that clients can see how all the data support the final COA report.  They receive a full data package, including any investigations related to the group of samples that was submitted for testing. Each client can only see its specific data. The software also allows us to control who receives the data, for instance, in cases where we may be working on multiple projects with different divisions of the same company, those data could be restricted to specific individuals from the different divisions.

	Some clients review all of the raw data. We use this system to provide companies the assurance that we’re showing them everything that we did. This is important for data integrity and compliance.

 Are you becoming more involved in customer operational excellence programs?  Do you have one in place at your company?

 Throughout the years, we’ve had a process improvement program, where anyone in the company can suggest lean or process improvement projects, which are taken on not just by management but by quality, data review, lab, document control, and other departments. Anyone can be involved in this program throughout the lifespan of a project.

	In one of our most effective recent projects, we renovated a raw material wet chemistry lab to reduce human error significantly. We like to share this information with our clients, because we feel that it enhances our relationship and improves the quality of the final products overall. Numbers alone don’t measure quality.

 Do you find that more of your pharma and biopharma customers have continuous improvement programs in place?

 A few of the larger companies do, but most do not, apart from executive-level programs. By definition, such programs don’t go into the trenches and ask the people working in the labs to suggest improvements.  

 You can’t manage what you don’t measure. Our QA department leaders meet with all department directors and managers to review all quality metrics.

	We ask them to come prepared to explain trends, whether positive or negative. This allows us to assess issues as well as solutions so that we can improve our processes.

	Currently, we do this quarterly for 18 different departments, analyzing a series of metrics such as OOS, report reprints, client complaints, and various other quality indicators. We find that the results are worth the investment in time and effort that this approach requires.  

	We have also just implemented a new quality program that we call ‘Integrated QA.’ We’ve hired and transferred QA people who will be physically located in technical departments so that they can observe operations and eliminate potential problems or errors.

	In the traditional approach, QA staff is in the office.  They perform audits and problems or issues are generally brought to them. We want to reverse this, so that QA goes to problems to help identify and prevent them. We also want to give our analysts guidance on how to document issues that might occur. In two years, when somebody looks at these data, they need to tell the entire story of how they were generated and any decisions that were made based on them. They need to be able to stand on their own.

Request for Quality Metrics Guidance For Industry

Draft Guidance (CDER, July 2015), accessed Jan. 19, 2015.
	2. R. Hernandez, “

Overwhelming Response from Industry on FDA’s Guidance on Quality Metrics

,” December 7, 2015, BioPharmInternational.com, online, accessed Jan. 19, 2015.

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	When referring to this article, please cite it as A. Shanley, “Quality Metrics and Best Practices for Working with Contract Labs," 

Pharmaceutical Technology Partnerships in Outsourcing Supplement

Transparent communications, both qualitative and quantitative data, and a clear understanding of each other’s needs are keys to collaborating on better product quality.

Quality Metrics and Best Practices for Working with Contract Labs

As virtual pharmaceutical companies become more prevalent, so has the outsourcing of laboratory and analytical services. In the heyday of the blockbuster drug, pharmaceutical companies had extensive inhouse laboratories to handle analytical testing for quality and R&D. Today, as more facilities are shut down and staffing cut, many companies are saving the investment in equipment and staffing by outsourcing their analytical testing needs.

 interviewed Keith Moore, vice-president of analytical services at Metrics Contract Services, to get an idea of business and technology trends.

Different approaches for different problems

 What types of analytical operations make the most sense for a pharmaceutical or biopharmaceutical company to outsource?

 It depends on the company and its business model. For virtual pharma companies--whose numbers are on the rise--it makes sense to outsource almost all operations that support a given product’s development to potential commercialization. Traditional pharma companies have more internal capabilities, so they tend to outsource for specific cost, speed, or quality considerations.

	Whether or not to outsource also depends on whether work is related to cGMPs or is non-cGMP; cGMP projects tend to be outsourced because of the effort and overhead associated with compliance requirements.

	Stability management and testing, which usually involves the use of high performance and ultra high-pressure liquid chromatography (HPLC/UHPLC) assays, related substances, dissolution, and moisture testing, are commonly outsourced. Method development is also being outsourced, and working with contract partners is also helping some pharmaceutical companies to improve the way they handle existing testing processes.

	In addition, highly specialized analytical operations that require costly equipment are also increasingly being outsourced. Examples include solid-state chemistry, specialized techniques that can include tools such as mass spectrometry, X-ray powder diffraction (XRPD), nuclear magnetic resonance (NMR), and near-infrared spectroscopy (NIR). These techniques demand experienced users who can interpret data accurately. In addition, some of the equipment is expensive to use and maintain.

 Are most analytical services companies working under subcontract to contract development and manufacturing organizations (CDMOs) and contract manufacturing organizations (CMOs), or by contract with pharma companies?

 Metrics Contract Services, a division of Mayne Pharma, is a CDMO. While we do perform testing for other CDMOs, most of our contract work is for pharma and biopharm companies directly. It’s been our experience that pharma companies that consistently outsource want a one-stop solution for this scope of work.

 Are there situations in which each approach makes more sense?  

 There are situations in which subcontracting makes sense, such as when a client requires services that can’t be found under one roof.  

	An example would be specialized testing involving the use of NMR spectroscopy. Such techniques require knowledgeable staff and expensive equipment.

Dissolution testing becomes more important

 Please comment on analytical methods available today. Which are becoming most important? Are any ‘workhorse’ methods being used in place of more expensive practices?

  The majority of analytical methods available are the traditional HPLC assay and related substance procedures, dissolution testing by either HPLC or UV, and Karl Fischer testing procedures. Use of these traditional methods is expected by most global regulatory agencies, and the level of scrutiny on these procedures increases with each phase of drug development.

	Demand for charged aerosal detection (CAD) appears to be growing over other detection modes for which UV cannot be utilized, because CAD offers an easier, more affordable solution. There are other techniques for qualitative and quantitative measurements of polymorphs that can be used in-situ instead of XRPD.  In certain instances, differential scanning calorimeter (DSC), Fourier transform infrared spectroscopy (FTIR), and Raman spectroscopy can be used to evaluate polymorphism, and these techniques can also be used for control purposes. XRPD is still a powerful tool, but there are other options and opportunities to determine polymorphic changes.

 Please comment on data retrieval and analysis practices today. How are they different from standard practices five years ago?

 Data retrieval has advanced, thanks to improved automated systems that allow for a much faster throughput. Many companies offer solutions that streamline the movement of data by linking to other independent systems and automating the process of data dissemination.  

 FDA recently published quality metrics for contract services companies. What do you think of the draft guidance? Are there issues that need to be clarified?

 The FDA’s draft is well written and offers proper justification of the new quality metrics. FDA is adopting a more risk-based approach to inspections in place of its prior process of having inspections every two years regardless of a company’s status.

	Reporting windows and requests should be further clarified, however. Currently, companies provide a lot of information in annual reports; I believe metrics could be included in those submissions, which occur annually from product approval. This would suggest that the CDMOs reporting would submit their quality metrics directly to the sponsor, who would then include the required metrics in the submission-- product-specific instead of site-specific.  

	I also believe that communication of metrics without review of commentary could prove challenging. The draft suggests that commentary might not be reviewed, and instead that the focus will be on certain acceptance limits for assigned metrics, which could lead to incorrect conclusions.

	Organizations should have an opportunity to explain or justify when certain quality metrics are not representative, instead of FDA considering values alone to determine whether an organization, or product, should be placed on a high-risk list. Generally, these are common metrics that most organizations collect already to monitor quality performance.

	Overall, the draft guidance is a good step in the right direction. Additional revisions and updates are currently in process, as FDA evaluates comments from the industry.  

 How do you handle communication with clients? Are your IT systems connected to theirs in any cases?

 Communication mostly takes place in weekly or bi-weekly teleconferences; we rely upon web-based conference tools and have videoconference capabilities. We use share sites to update documents for certain clients as well. Our IT systems are not currently directly connected to any clients’ proprietary networks.

 Please comment on trends in analytical instruments, data analysis, and data retrieval. Are technologies becoming better and easier to use? Any criticisms?

 I have not seen a significant breakthrough in analytical instrumentation technology in quite some time that has generated a revolutionary change for routine analysis. While UHPLC offers many advantages, the dominance of HPLC continues. Many companies are reluctant to spend time and money to convert methods from HPLC to UHPLC-as well as taking the time needed to update their regulatory submissions. Use of CAD is growing significantly and much faster than use of evaporating light scattering detector. Other than use of flow-through cell apparatus for dissolution testing (USP Apparatus IV), I am still waiting for another breakthrough in dissolution technology that provides a much better means of predicting in-vivo performance. Traditional apparatus are still being used in in the hope of making that correlation between in-vivo and in-vitro using simulated fluids.  

	Regarding data analysis and data retrieval, technology has greatly improved, thanks to the flexibility of ‘talking’ with different systems, whether electronic notebooks or sophisticated laboratory information management system. Additional improvements in these systems promise to make the laboratory operation functions faster and more compliant. 

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	When referring to this article, please cite it as A. Shanley, “Lab Services: To Outsource or Not to Outsource," 

Lab Services: To Outsource or Not to Outsource

The history of the pharmaceutical industry is filled with examples of brilliant product ideas that ultimately failed. In the case of Pfizer’s revolutionary product, Exubera inhaled insulin, an innovative drug and delivery concept resulted in a drug-delivery form that failed to gain acceptance. Stories like this are not uncommon. The right approach to thinking about drug-delivery options, however, can help ensure success, especially when working with contract partners.

 asked 3M Drug Delivery Services team members Richard Beesley, global business development manager; Louise Righton, global marketing operations manager; and Ross Errington, sales manager, to share some best practices.

 What trends are becoming most important in drug delivery today? Which forms do you expect to be dominant in 5 to 10 years?

 As payers around the world continue to focus on cost reduction alongside improvements in health outcomes, stakeholders need to be open to the possibilities afforded by new digital technologies. On the surface, these options are more expensive, but connected devices allow the payer and the clinician to track usage and, in some cases, disease state, allowing real-time condition management. New technologies to drive patient compliance and adherence will be the future of drug delivery.

 What are the biggest mistakes that pharma companies make when deciding on a drug-delivery platform? What do they typically fail to consider?

 Pharmaceutical manufacturers generally always prefer to start with a tablet, but that doesn’t mean it’s the most efficacious or convenient way to deliver a drug. It’s really important to think about how a drug is going to be administered, by the patient themselves or by a caregiver. Pharma companies need to look at all aspects of drug delivery and consider whether there might be better options.

	It can be easy to get caught up in thinking about ‘how quickly?’ a commercialization can occur, but that approach may overlook key opportunities for differentiation. Take an injectable, for instance. If you broaden the search, you might decide on microneedle technology, because it can have a far easier supply chain, no cold storage, no needles to dispose of, no glass, patients can administer themselves, and, ultimately, to the end user and payer it could be cheaper and more convenient. Now, if the decision on delivery is made too quickly without considering the bigger picture, it’s either too late or too costly to make a change.

 Please outline the ‘ideal’ best practices for deciding on a drug-delivery platform for a new drug. When should the choice be made and based on what criteria? How does this process differ when one is repurposing an off-patent drug for a new indication and new delivery system?

 The short answer is as early as possible so you can assess all options. Use your decision tree to take it all the way to the end user. Who is the end user? You don’t necessarily want to have elderly patients having to remember whether or not they took their pills. In this case, a visual identifier might be needed. Does the therapeutic area have common side effects to be aware of? If you’re developing an anti-nausea medication, patients probably don’t want to swallow one more thing. A transdermal patch might be better. There are a lot of considerations to be weighed.

	Of course, certain drugs for specific therapeutic areas have already established best practices. If you’re dealing with chronic obstructive pulmonary disease (COPD), the obvious delivery choice is an inhaler; so the decision becomes what features do you want to add to the inhaler (i.e., dose counter, breath-actuation, and so on).

	An experienced company with a culture of learning and continuous improvement will leverage past experiences in understanding what can work, early in the process.

 How should patient and healthcare professional preference be factored in? How about issues of pricing and payer acceptance?

 Recent research conducted by 3M highlights three themes that ultimately drive success:

 A growing consumer mindset is being applied to the healthcare world. Devices that are difficult to use or that don’t satisfy the needs of the patient as a consumer will struggle. In addition, recognizing--and addressing--the complex reasons for non-adherence and non-compliance will appeal to payers and clinicians alike.

 Devices are becoming smaller and smarter. Many new developments build on existing devices such as smart phones, helping to make them more cost effective and holistic. New integrated products enable us to move from ‘disease treatment’ to ‘condition management’.

 With continued austerity measures and generic competition, it is likely that the focus on cost will continue.

	This leads to the following product development lessons:

		Keep it simple--new devices need to be robust to accidental, or willful, misuse.

		Make it intuitive--minimize training to reduce costs.

		Ensure it provides improved health outcomes, including quality-of-life measures.

		Find a way to provide added-value services that better match the patient and the condition.

		Ensure all of the real-world health economic benefits can be proven to a payer.

	The primary challenges facing the industry are to develop a product that allows patients to adhere to their medication regimes and to comply with their use, optimizing delivery of the drug, resulting in improved patient outcomes and minimizing utilization of healthcare resources.

	Furthermore, we need to be able to measure positive patient outcomes in a real-world environment and demonstrate that they are real to the payer and healthcare professional. Finally, the industry needs products that are differentiated in today’s competitive landscape, and that also enable protection against generic competition.

 How should pharma sponsors work more successfully with contract partners to ensure that they are not leaving anything out of the decision process?  What internal groups need to be involved?

 Pharmaceutical companies will maximize the contribution of their contract partners if they recognize and leverage their areas of expertise and experience. A contract manufacturer should be able to take a product from start to finish, no matter at what stage they get involved. By far the most important part of this process is the sharing of information. Share as much information as you possibly can. Often, during the bidding process, pharmaceutical sponsors don’t give CMOs all the information they need. A ‘more is less’ mentality can be helpful. More information up front tends to mean fewer surprises down the line, later in development. 

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	When referring to this article, please cite it as A. Shanley, “Keeping It Simple: Collaborating for Success in Drug Delivery," 

Pharmaceutical Technology Partnerships in Outsourcing Supplement 

For successful partnerships, it’s important to take a long-term view, focus on simple designs, and address potential payer concerns up front.

Keeping It Simple: Collaborating for Success in Drug Delivery

In the long road to drug development, Phase III is the ultimate reality check, where a new drug’s safety and efficacy, and the impact of a therapeutic dose, are measured in human beings. It is the point where manufacturing and operations become more involved in the process, where the drug is actually produced for use in clinical evaluation, and where manufacturers can, to a very limited extent, begin marketing the new drug.

	Phase III clinical trials are designed to confirm results of Phase II trials, the goal of which is to demonstrate that a drug will have the desired effect. Half of late Phase III trials, however, fail to show sufficient efficacy or safety (e.g., for oncology drugs, the failure can be as high as 60%).  

	One of the reasons for this alarming failure rate is the tendency for manufacturers to rush to Phase III once an exciting signal shows up at Phase II, said Alberto Grignolo, corporate vice-president of the contract research organization (CRO), Parexel International Corp. at an October 2015 webcast on this topic (1). Subsequently, expectations may be crushed, he said, paraphrasing Thomas Huxley, as the “great tragedy of science” plays out, and a “beautiful hypothesis” is slain by “ugly facts.”

	For the pharmaceutical industry, this tragedy has also become extremely wasteful, not only for companies, which, according to the Pharmaceutical Research and Manufacturers of America (PhRMA), spent an average of $42,000 per patient in Phase III trials ($59,520 for oncology drugs), but for patients, tens of thousands of whom may waste time taking part in studies that they hope will result in new cures for their ailments (2).  

	In 2013, PhRMA estimates that biopharmaceutical manufacturers spent $10 billion to run 1680 clinical trials involving 644,684 patients (2). At the webcast, Parexel’s Grignolo cited FDA analysis of drug applications submitted from 2000 to 2012 that was published in 2014 in the

 Journal of the American Medical Association

. FDA’s research showed that, of 313 new molecular entity (NME) submissions received in 2013, only 151 were approved, and nearly half failed because they couldn’t show efficacy. More than 40% failed, the study found, because they had safety and efficacy problems (3).

	Often, Phase III failure can be traced to flaws in the clinical study design or errors in determining the optimal dose. In the October 2015 webcast (1), Grignolo and Parexel’s Chief Science Officer, Sy Pretorius, examined the issues. A number of companies have developed best practices and rules of thumb to help ensure success, Pretorius noted, citing AstraZeneca’s “5R” approach, which involves ensuring that Phase III work is designed to confirm “Right Target, Right Tissue, Right Safety, Right Patients, and Right Commercial Potential.” A sixth R is “Right Culture,” he adds, in which teams are willing to admit failure early on and to evaluate test data in an open way (4).

	Another model that Parexel suggests for the industry is Pfizer’s Three Pillar framework (5), which focuses on ensuring that test protocols and methods confirm exposure at target site, binding to target site, and expressions of pharmacology. Computer simulations, such as those used by Roche (6), can also be useful in evaluating a proposed protocol, while adapting live simulations (and role playing with mock physicians and patients), as Eli Lilly has done with its Jam Sessions (7), may yield results, Pretorius says, and ensure that a patient-focused approach is taken.

	Pretorius and Grignolo noted that sponsors should comnicate proactively with regulators to get an understanding of their expectations. In addition, they note, sponsors should work closely with clinical research partners to ensure that their initial Phase III protocol drafts or synopses have been carefully reviewed from different points of view.

	At Parexel, Pretorius notes, a multidisciplinary team examines the protocol, breaking it down by segment, and experts evaluate each segment based on regulatory issues, scientific methods, operations, and commercial goals. After evaluation, the CRO can then pose alternative scenarios and compare them to the original protocol based on cost and time required.


	Both Grignolo and Pretorius shared their thoughts with 

, on why Phase III studies fail so often, and what can be done about it.

 Why do so many drugs fail at Phase III? What steps can be taken to help reduce failures at this point?

 While there can be various drivers that lead to the failure of drugs during Phase III, the following represent what we find to be the top five, based on presentations given at a 2014 summit organized by the European Center for Pharmaceutical Medicine (ECPM):

-Animal models that do not translate or are not entirely related to human disease, poor understanding of target disease biology, or drugs that are simply ineffective.

-Changes in patient definitions (inclusion criteria and exclusion criteria) from Phase II to Phase III, insensitive outcomes measures or Phase II surrogate endpoints that are not confirmed by Phase III endpoints. Inappropriate study design can undermine the ability to show efficacy or the sample size may be too small.

-The dose may be inappropriate for Phase III. This can happen when investigators or sponsors become overenthusiastic about Phase II results and rush to Phase III without fully exploring dose finding. Inadequate therapeutic indices may also lead to suboptimal dosing.

-False positive signals from Phase II and overly optimistic assumptions about variability and treatment differences may result in such problems as missing data, attrition bias, rater bias, errors in measurement methods, or inappropriate statistical methods.

-Data integrity issues or good clinical practice (GCP) violations may come into play if the protocol hasn’t been adequately designed. In addition, unexpected variations in recruitment or dropouts can affect results, as can protocol variations, missing data, or unintentional unblinding of subjects.

	All of these problems can result in efficacy failures, safety failures, as well as commercial/financial failures. For instance, the drug may not meet the primary efficacy endpoint, may result in unexpected adverse or serious adverse events, or may fail to demonstrate value compared to existing therapy and standard of care.

	Although there is no simple solution for preventing Phase III failures, several approaches are currently being developed to reduce the risk. These include:

Applying more rigor to the overall development process

-Applying more rigor and discipline to the development process holds potential for weeding out likely failures earlier in the process, thereby reducing Phase III failure rates (e.g., avoiding shortcuts such as truncated Phase I or Phase II studies in the interest of a rush to Phase III and the market, or not listening diligently and thoughtfully to the inputs of regulators prior to launching Phase III).

-Many Phase III trials fail because of a fundamental lack of understanding of the mechanisms of action of NMEs. Rushing to get to Phase III without adequate understanding of critical components is risky and more often leads to unpleasant surprises in Phase III. Not only does this proposed approach in Phase II make intuitive sense, but it also holds potential for reducing late-stage failures.

-Strategies for success would include more disciplined protocol review and optimization, as well as use of modeling and simulation, adaptive trial designs, and biomarkers.

-To mitigate study execution risks, pharma companies and CROs should leverage data from a variety of sources and conduct ongoing surveillance of the quality of data being collected, while tying this to a properly planned risk-based monitoring protocol.

Ensure completeness and clarity of submissions for regulatory agencies

-Pharma companies should seek advice from regulators during the drug development process. FDA offers sponsors and applicants the opportunity to schedule formal meetings at critical points in the development and regulatory process to discuss the plan and identify areas of concern that may need adjustment.

	Regulatory agencies see a vast number of development programs that succeed and fail; their experience can bring significant benefit to sponsors who listen and learn from it.

 How should pharma companies and CROs collaborate to avoid Phase III failure? What role should each play in developing a strategy?

 Although Phase III failures cannot be eliminated, some strategies can provide sponsors a way of minimizing the risk of failure in their drug development plans. This risk assessment and mitigation should start early in the drug-development process.

	Ultimately, pharmaceutical companies and CROs should collaborate to ensure they can anticipate potential threats and opportunities, have a defined governance structure in place, define success metrics, and communicate openly and frequently.

	CROs, not unlike regulatory agencies, are aware of and active participants in numerous development programs across hundreds of diverse sponsors; this experience can be brought to bear on subsequent sponsors and can help them avoid expensive and time-eroding failures.

 What special considerations should be given, up front, to pricing and payer expectations?  

 The use of prescription drugs, as a percentage of total healthcare spending, has increased dramatically over time, driven in large part by the enormous cost of innovation in the biopharmaceutical space.  Payers, now more than ever, dictate whether an adequate return will be generated on this investment.

	However, payers are under huge pressure to control their own costs, which drives a focus on demonstrating clear value to patients and the healthcare system. While this creates obvious challenges to a pharmaceutical company looking to commercialize a newly approved product, it also represents an opportunity to create a ‘win-win’ by identifying key value drivers early on in the development process, generating relevant clinical evidence and demonstrating this value to stakeholders in a compelling manner that supports the needs of patients, payers, physicians, and pharmaceutical companies.

	In this new world, obtaining regulatory approval is no longer sufficient for drug developers to have a successful and profitable drug in the market. Today, companies must be able to demonstrate to payers and other stakeholders that their drug is worthy of being reimbursed at an attractive level and prescribed in the right situations.

	To prepare for commercial needs, it is important to keep a focus on market access, payer and provider considerations throughout development, and specifically during Phase II and Phase III studies.

	In particular, pharmaceutical manufcturers should keep the following goals in mind:

		Differentiated value proposition for the new drug vs. existing standard of care

		Personalized health care strategy, including diagnostics and biomarkers that enable the delivery of “precision medicine” to patients in a cost-effective manner.

, webcast, October 2015.
	2. Battelle Labs (for PhRMA), 

, accessed Jan. 26, 2016.
	3. Sacks et al, 

Journal of the American Medical Association

, 311: 378-384 (2014).
	4. D. Cook, et al, 

, 13 419-431 (May 2014).
	5. P. Morgan et al, 

The Benefits of Using Clinical Trial Simulations

, a Roche Clinical Pharmacology video.
	7. “

Eli Lilly Unveils Innovative Study Design Platform

:
	When referring to this article, please cite it as A. Shanley, “Preventing Phase III Failures," 

Only half of new drugs make it past Phase III. Adopting best practices and collaborating more closely with contract research organizations can help ensure success.

Preventing Phase III Failures

As more pharmaceutical manufacturing, quality, and development functions are outsourced, it has become difficult to get specifics on who is outsourcing to whom and why. Within the past few years, research firms have sprung up to specialize in this niche, and to shed light on trends. That’s Nice published results of its research in January 2016 (1), while Industry Standard Research (ISR) released findings early in 2016 (2,3) and in the last quarter of 2015. ISR uses a “Consumer’s Reports” type style to rank contract development and manufacturing organizations (CDMOs) and contract manufacturing organizations (CMOs) in various specialties, based on reported user experience. 

	Some of the two firms’ research is available only to subscribers, but they shared other data with 

Here is a sampling of trends that they found.


	In its 2016 small-molecule outsourcing survey, ISR found that, out of 199 respondents, most are outsourcing nearly all of their manufacturing to CMOs, according to market research director Kate Hammeke.

Despite the move to more strategic partnerships, research shows that tactical outsourcing is still alive and well.