The International Quality & Productivity Center, organizers of the 14th annual Cold Chain GDP & Temperature Management Logistics Global Forum, expect over 850 attendees and 120 sponsors and exhibitors at 

, to be held at the Hynes Convention Center in Boston, Sept. 26-30. Year by year, the program has expanded to incorporate more of the activity in temperature-controlled life sciences logistics; this year, timely topics on cloud technology, the Internet of Things, and cryogenics have dedicated sessions, among over 30 others, plus the usual International Focus Day at the end.

The preliminary schedule includes the following:

Sept 26: Pre-conference master classes on temperature-assured packaging, GDP training and clinical trial logistics

Sept. 27: Pre-conference workshops and site tours

Two topics seem to have a greater prominence in this year’s schedule: cryogenics, which are important for live-tissue trials in cell culturing and regenerative medicine; and controlled room-temperature (CRT) technologies and services—which has been building since the adoption of GDP standards that recommend documented temperature control even for non-refrigerated products. But the traditional heart of the Forum—2-8°C storage and shipping—remains well-covered with topics ranging from active and passive shippers, phase-change materials, to logistics planning and qualification studies.

A keynote presentation is provided by John Rossman, author of 

 on IoT; the book will be available for purchase, with signed copies from Rossman.

Articles

Largest industry gathering for temperature-controlled logistics and distribution

Cold Chain Global Forum is coming up

 Fig. 1. The diagram shows the CAPA process, from start to finish.[/caption]

In pharmaceutical and biopharmaceutical manufacturing, it is generally assumed that somewhere along the process of manufacturing a product, something is likely to go wrong that could affect quality. When that happens, the quality issue must be resolved in a timely, effective and compliant manner.

If the problem is minor and there’s a solution that can be performed immediately and sufficiently, then the quality event can be closed with an effective containment or correction. If the issue is significant, it will be escalated into a corrective action and preventative action (CAPA).

CAPA is inherently tied to the concept of product quality in manufacturing. Companies regulated by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and other regulatory entities, as well as companies that adhere to ISO quality standards, ICH quality guidelines, and similar international standards, typically maintain a CAPA process as part of their quality management system (QMS).

So why can’t clinical research professionals adopt CAPA in clinical trials? In fact, they have been using CAPA more than most people realize. But, unlike in manufacturing, there’s less emphasis in formalizing CAPA procedures and embedding them in a clinical trial’s quality process, or in integrating them with the QMS.

Indeed the term “clinical quality management system” or CQMS was coined by MasterControl only five years ago. There is much to be learned from the manufacturing sector when it comes to leveraging CAPA, not only for compliance purposes but to help accelerate time

Essential CAPA principles come from regulations and quality standards. For clinical research, the FDA’s Good Clinical Practice (GCP) regulations and the International Conference on Harmonization (ICH) E6 GCP Consolidated Guidance, which FDA has adopted, require a CAPA plan and implementation when quality issues arise. The CAPA should include investigation of how widespread the problems are, correction of the problems, and corresponding efforts to prevent their reoccurrence. [1]

The European Medicines Agency (EMA) Good Practice Guide on Risk Minimisation and Prevention of Medication Errors has similar requirements for clinical trials. It says “when medication errors result in adverse outcomes, corrective actions should be taken.” [2]

No clinical research is free of quality issues. They are unavoidable, perhaps inevitable, during the life of a clinical trial. What is important is that they are addressed promptly and properly so they will not occur again, and that the scope of the impact of the issue is clearly understood and mitigated.

Given the regulatory requirements and the inevitability of quality problems, most pharma companies have a procedure or a plan for correcting quality issues even if they don’t have a formal CAPA process. At the minimum, most of them have quality-control and quality-assurance processes embedded into their clinical management plans. For some, a separate risk management process is also in place. These three areas work separately but closely together, providing checks and balances in quality management.

If you work in clinical research, you can use CAPA strategies that have been tried and tested in manufacturing and adopt them for your specific needs. The CAPA framework for investigating a quality issue is applicable in clinical as much as in other areas.

Let us take a look at five CAPA best practices that can strengthen clinical research compliance and also help accomplish a fundamental goal across the board in the pharmaceutical industry—accelerating time to market.

1. Establish a CQMS and make CAPA a part of it.

If you are in the process of creating a clinical quality management system (CQMS), integrate a CAPA process from the get-go for a smoother clinical trial. Take advantage of the latest technology and adopt an electronic CQMS for managing CAPA and also your trial master file (TMF). For those using paper-based or hybrid processes, switch to an electronic CQMS to streamline clinical quality data-management through the life of the trial.

 Fig. 2. This is how a robust CQMS integrates a closed-loop CAPA process.[/caption]

Develop a “closed loop” CAPA process as part of your CQMS. This means every quality event must go through various “loops” or stages for an effective resolution, beginning with a determination of the cause of the problem, implementing an appropriate corrective action, making sure the corrective action is working, and closing the loop by eliminating the cause of the problem to prevent it from reoccurring. Choose a CQMS that will guide your users seamlessly from one loop to the next using robust forms and workflow.

A medical device company successfully revamped its CAPA process when it switched to a fully integrated system. The company used to devote every Friday to reviewing and approving CAPAs and other noncompliance issues at a face-to-face meeting. The process was error-prone and wasted a lot of time. The CAPA and training processes were not connected. On top of it all, 10 employees managed documents full time. The company has since switched to a holistic electronic quality system, vastly improving CAPA, training and document management. No more Friday CAPA-marathon meetings. [3]

2. Integrate training control with CAPA to boost compliance.

Clinical trial sites must follow the study protocol and corresponding SOPs to exact specification. One way to make sure that this happens is by training investigators and support staff on the protocol and SOPs, and to conduct ongoing training with regard to protocol amendments.

In the event of a deviation from procedures, it should be documented properly and corrected through the CAPA process. However, corrective actions cannot exist in a vacuum. If a CAPA resulted in a substantial change in a protocol, SOP or some other important document, it will require a retraining of all affected employees. In a paper-based or hybrid process that uses disparate systems, CAPA is not connected to training. Employees could still be performing their jobs based on outdated SOPs, manuals and other documents.

The quality of clinical research results can be significantly affected by inadequate staff training and retraining. An effective training management system will serve as a “gate” that opens when staffers are properly trained and tested, and closes for control (and alerts stakeholders) when training tasks are incomplete or unfulfilled.

3. Integrate CAPA with risk management for a holistic approach to quality.

If your company has a risk management process but not a CAPA process or vice versa, you are not optimizing each process. Use them to complement each other.

Risk management is the task of identifying, measuring and prioritizing the impact of the uncertainty of various variables throughout a clinical trial. For example, a protocol that contains complex tests and procedures has a higher risk of noncompliance than one that contains basic testing only. As part of risk management, you might establish a stricter screening process for selecting study sites. You can integrate such screening protocol in CAPA as a preventative action.

If your risk management and CAPA processes are connected, you will be able to respond in a timely manner. For example, if a site reports a serious deviation from the complex testing during the course of risk assessment, that site will be able to launch a corrective action seamlessly. The staff managing those two processes will be able to communicate and act in unison to resolve the issue.

4. Identify which deviations warrant a CAPA and match the corrective action to the severity of the problem.

Not every quality issue requires a corrective action and not every corrective action calls for a preventive action. The decision on what type of action is needed should be based on a number of factors, such as risk, impact, severity and frequency of the event. The depth of a CAPA investigation and implementation should match the risk. The ICH GCP guidelines acknowledge that not all clinical trial deviations affect the scientific value of clinical trial results. The guidelines outline the types of protocol deviations that should be reported as “serious breaches” and require appropriately serious CAPAs. [4]

A good clinical quality plan should not rely solely on a CAPA process. It should have quality procedures in place from the get-go, before any quality problems occur. The procedures should identify necessary actions prior to, during and after a CAPA is executed. It should also include criteria for evaluating when a CAPA is (or is not) necessary.

An electronic CQMS will equip you with tools for better assessment of quality issues. Choose a system with robust tools, such as CAPA matrix, analytics and reporting tools; best-practice forms for collecting and tracking data for risk assessment; and checklists for monitoring visits.

5. Make your CAPA process transparent to increase your audit and inspection readiness.

All essential documents are subject to audits and inspections. Regulatory agencies evaluate the conduct of a clinical trial and the data it generates by reviewing all essential documents. During an audit or inspection, those documents will be scrutinized.

In a manual process, paper documents are hard to track and can be easily misplaced. There’s nothing worse than failing to produce an important document during an audit. When you automate your CQMS, you will have a single centralized repository for all CAPA documents and other important records. Auditors will need to look at only one place for anything they need. An electronic CQMS makes it easier to search, track and retrieve documents.

For some companies, this best practice can be a hard-earned lesson. A regulated company with presence in six countries adopted an electronic QMS with an integrated CAPA process as a corrective action in itself after an audit. The company used to manage about a hundred CAPAs annually with an ineffective homegrown process that resulted in audit findings. In a complete reversal of fortune, auditors now commend the company’s CAPA process and holistic quality system. [5]

Pharma and biopharma companies like yours face the challenge of sustaining growth and innovation in the face of fierce competition in the global market. Noncompliance in clinical research can be extremely costly.

High-risk deviations can result in high numbers of patient dropouts, disqualification of sites, clinical hold, and may even result in the FDA’s “refuse to file” action. Identifying deviations and taking corrective actions in early stages of a clinical trial can reduce cost, reduce risk to patients and increase time to market.

In establishing or implementing a CQMS, take advantage of what the latest technology has to offer to facilitate compliance with GCP requirements throughout a clinical trial.

FDA GCP/Clinical Trial Guidance Documents, from FDA website 

http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/GuidancesInformationSheetsandNotices/ucm219433.htm

MA’s Good Practice Guide on Risk Minimisation and Prevention of Medication Errors, from the EMA website, 

http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2015/11/WC500196981.pdf

A Case Study from the Perspective of Executives: MasterControl Helps MicroMed Leverage Resources, published by MasterControl, 2013.

E6 GCP Consolidated Guidance, from the ICH website: 

http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/good-clinical-practice.html

In 2009, Chart Industries successfully overhauled its quality system and improved its CAPA process by switching from a paper-based QMS to MasterControl All Access, which integrates CAPA, training, audit, change control and other modules.

http://www.mastercontrol.comPatricia Santos-Serrao, RAC, is the product management director of 

clinical and regulatory solutions for life sciences 

. She has two decades of experience in regulatory affairs and clinical areas in the pharmaceutical industry, including working for Schering-Plough and Boehringer Ingelheim. She earned her Regulatory Affairs Certification from the Regulatory Affairs Professional Society and the Regulatory Affairs Certification Board.

5 CAPA best practices for clinical research

Product launch is a critical moment in a brand’s ultimate success. Product launches for pharmaceuticals are complex and differ in many ways from other industries, with multiple key players such as research and development, formulation specialists, analysts, regulatory affairs, device engineers, commercial/brand teams, and many others intimately involved. This process takes on additional complexity with combination products—generally, drug-device combinations such as prefilled syringes, inhalation devices and the like.

To stand out from the crowd and to increase brand loyalty and adherence, an increasing number of pharmaceutical companies are offering more robust patient support programs that include educational and training tools in an effort to assist the growing number of patients required to self-administer injections. As part of the commercial launch strategy, patient training, education and support programs must be in place and ready to launch when the drug is launched.

The introduction of reusable drug-delivery device trainers has fostered an evolution of patient training platforms. Prior to these training technologies, the available training options outside a healthcare provider's office included Instructions for Use (IFU) and saline-filled prefilled syringes or autoinjectors, where users practice administration by injecting into an analog such as an orange. This process did not prove to be cost-effective and limited the amount of exposures for users to learn correct injection technique. In addition, it did not allow for vital learning experiences that help facilitate proper self-administration of an injection device, such as being familiar with a drug delivery device’s functionality, operational sequence and understanding of the IFU.

According to a study conducted by the University of Texas Medical Branch at Galveston (UTMB), 84% of patients failed to demonstrate correct use of an autoinjector and 92% failed to demonstrate correct use of an inhaler. [1] Another study found 45% of patients avoid injections due to anxiety. [2] Data suggests rates for consistent, daily use are also low. Additionally, a study conducted by Noble and researchers from Auburn University surveyed more than 700 patients who self-inject and found that more than half admitted they did not completely read the IFU prior to beginning treatment. [3] These findings suggest a lack of patient training could result in low adherence, errors, discontinuation of drug use and a decrease in brand loyalty.

To address the market need for patient training and education, reusable drug-delivery training devices and educational platforms have been developed. These drug-delivery device trainers are device-comparable solutions, which accurately replicate an actual drug delivery device’s form, functionality, operational sequence, haptic feedback, plunger speed and more. They come in a variety of platforms, ranging from mechanical trainers to smart, error-correcting technologies providing audio feedback. Drug-delivery training devices provide brand patient programs with highly realistic, but cost-effective, reusable patient training solutions compared to saline-filled syringes with real needles that may result in injury or limited learning. Their value over another training option—using the actual, medication-filled device—is obvious, especially when wastage of valuable biotech products is considered.

As the biologic and biosimilar market grows, and self-administration becomes more commonplace, more premarket and on-market brands are investing in reusable drug-delivery training devices. With biologics accounting for one-third of new medicine approvals over the last decade [4] and the emergence of biosimilars, brand teams are searching for competitive differentiators. Better training devices can be part of that differentiation.

Launch Readiness: An In-depth Overview of Training Devices and Patient Support Implementation

Since combination product development for pharmaceutical companies is an expensive, intensive and lengthy process, it’s important for brands to be able to launch once FDA clearance is granted. Brand teams need not only to roll out the drug to market, but also have the flexibility, depending on FDA review time, to have in place practitioner and patient training and educational materials. Noble’s HCP and patient training materials (Fig. 1.) include autoinjectors, prefilled syringe and respiratory drug-delivery device trainers, angle assist tools, training IFUs, smart packaging and standard packaging, printing, travel assets, and more, all based on a pharmaceutical company’s preference and patients’ feedback.

To ensure training devices and educational assets are launch-ready, a proven process has been developed to help provide continual support and guidance to clients from preproduction through postproduction. This process ensures client requirements remain on schedule via status meetings and global or country-specific strategic planning for risk mitigation, design, development and distribution.

The following is an overview of our development process for launch readiness:

 gathering requirements with the brand and/or device teams, leading to a Product Requirements Definition. A scope-of-work Project Control Plan is determined by agreeing on resource commitments and development phases.

Product requirements gathering includes device analysis, existing literature review and a user needs assessment. A Requirements Summary Matrix is then developed.

• The Research and Concept Development stage

 includes product development research, functional value assessments, and initial design and engineering activities to develop concept architectures. A Product Development Research Report is produced based upon research in this phase, and includes user and usage profiles, and recommended concept designs. As part of best practices, the training device is engineered to emulate the real device as closely as possible to ensure patients receive a realistic representation of the functionality of the actual drug delivery device. This engineering process is more complex than with a real device because the trainer involves internal components that replicate a consistent operational sequence of a real device while also being resettable, so the patient can use the device repeatedly for training purposes.

Several steps are taken during the design and manufacturing process to ensure training devices function as closely as possible to the actual drug delivery device, such as matching external dimensions; developing internal mechanisms to accurately represent functionality and administration; and sequencing attributes, such as plunger drop speed, breakout and glide forces, sound replication, and actuation forces.

After client review and concept revisions have been completed

, a Final Requirements Definition document is created, which details product specifications and engineering activities, and provides final concept renderings for approvals. Various forms of prototyping and bench testing, as well as initial design transfer activities, occur during this phase. With launch readiness being essential for a brand, 3-D printing technologies have proven to be valuable assets allowing for rapid prototyping. Multiple iterations of drug delivery device trainer prototypes can be produced, improved upon and optimized for high-volume manufacturing.

The Design Transfer and Prototyping phase

 is when major functions are analyzed for performance, various functional prototypes are produced and product tests take place to optimize the design for high-volume production. Manufacturing cost estimates are developed and submitted for client approval.

Following the Design Transfer and Prototyping phase

, production planning and tooling occurs. Some of the key activities occurring during this phase include component design review, procurement and production planning, and capacity planning. A Quality Control Plan is developed and put into effect, and assembly instructions and validation activities are determined. A detailed production schedule is developed based upon client launch requirements and pre-production samples are produced for final approval.

, based upon the Quality Control Plan. During this phase, client products are produced, inspected and tested. 100% verification testing takes place to ensure final quality. Besides manufacturing and quality assurance testing, other key activities include confirmation of distribution center addresses, receiving requirements, carton marks, administration of all freight documentation and final delivery to distribution centers.

 after patient training, education and support products are delivered and introduced into the market. The client services team continues working with clients on any additional support needs, including reorders, additional product development and education materials.

 Fig. 2. By the time a product is launched, a strategy for addressing patient training should be well-established.[/caption]

As the launch process for the pharmaceutical industry evolves, there has been a shift to beginning launch strategy planning sooner (Fig. 2.). Device and commercial teams are collaborating earlier in the process, and leveraging human factor findings for refining product development and building patient-centric training and education programs to better prepare for launching in a competitive marketplace.

The use of training devices is highly beneficial for patients during the onboarding process because it allows them to more easily understand and retain training information before anxiety can build around at-home treatment. Through multisensory learning, multiple pathways are established in separate areas of the brain, resulting in a highly effective training experience and improved safety for patients. Other findings from the previously referenced Noble study found 90% of patients who used a training device rated the value of the device at a seven or higher, with 10 receiving the most selections. Additionally, 74% reported that in hindsight they would have preferred being recommended a training device when treatment was initiated. [3]

Brands that implement device trainers during the onboarding process will see higher levels of patient compliance and adherence as a result of lowered patient anxiety and an increased understanding of how to use drug delivery devices. By providing patients a better understanding of the device, with the ability to practice administration techniques as often as needed, trainers help promote positive onboarding experiences and empower patients to lead healthier lives. In the patient-centric era, companies providing reusable, device-comparable training products will be well positioned for competitive differentiation through improved patient satisfaction, adherence and outcomes.

Bonds, R., Asawa, A., & Ghazi, A. (2014, November 18). Misuse of medical devices: a persistent problem in self-management of asthma and allergic disease. Retrieved from 

www.annallergy.org/article/S1081-1206(14)00752-2/fulltext

Zambanini, A., Newson, R. B., Maisey, M., & Feher, M. D. (December 1999). Injection related anxiety in insulin-treated diabetes. Retrieved from 

http://www.ncbi.nlm.nih.gov/pubmed/10624790

Noble. (2015, November). The link between device training and patient compliance. Poster session presented at PDA - Universe of Prefilled Syringes 2015, Vienna, Austria

Pharmaceutical Research and Manufacturers of America. (2013). 2013 Overview medicines in development: Biologics. Retrieved from 

http://phrma.org/sites/default/files/pdf/biologicsoverview2013.pdf

Paul Sullivan is the associate director of business development at Noble (Orlando, FL; 

), a product development company with a focus in designing and manufacturing drug delivery training and patient onboarding solutions. Prior to Noble, Paul worked at Informed Medical Communications, as a director of business development and client service and before that, as a pharmaceutical sales representative with Procter & Gamble Pharmaceuticals. He holds a Kinesiology degree with honours from the University of Western Ontario.

The growing market for self-administered injectables calls for better patient-training resources

Integrating patient training into product launches

 Fig 1. The interplay between frameworks to evaluate drug-therapy value,

 and then to justify its cost. Source: Precision[/caption]

Over the last 20 years, new health care innovations have had a dramatic effect on patient longevity and quality of life. A near cure for the hepatitis C virus has been developed. Disease modifying therapies have dramatically changed the prognosis for patients with multiple sclerosis. Patients with cancer can expect to live longer, healthier lives in the future due to a variety of innovations, including recently approved immuno-oncology agents.

At the same time, the cost of many of these innovations has been high. The cost per treatment for some hepatitis C products was near $100,000 per year at one point, and novel oncology treatments can be even more expensive. Not surprisingly, the cost of drugs has become one of the top issues in the 2016 election.

In response to rising health care prices, there have been two dramatic changes in the way new treatments are evaluated and reimbursed. First, value frameworks are increasingly being used to assess treatment value. Second, provider and health plan reimbursement are being increasingly tied to measures of value. In this article, I briefly discuss each of these developments in turn and provide some recommendations on how innovators can generate evidence in this increasingly value-based world.

In response to rising drug costs, there have been no less than six value frameworks developed. These include frameworks developed by the American College of Cardiology and the American Heart Association (ACC/AHA), the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), the Institute for Clinical and Economic Review (ICER), Memorial Sloan Kettering Cancer Center (MSKCC), and the National Comprehensive Cancer Network (NCCN).

All value frameworks rely on four broad steps to compare treatment value to cost. [1] These steps include:

(i) Selecting health outcomes of interest (e.g., efficacy or safety)

(ii) Identifying a relevant evidence base to identify the impact of treatment on each outcome of interest

(iii) Aggregating the outcomes into a single measure of health benefit; and

(iv) Calculating the cost of care and comparing it to health benefit.

Nevertheless, the audience and exact methodology do differ across value frameworks. For instance, ICER says its framework can be used by insurers to “guide their assessment of the value of medical services, including drugs, medical devices, and procedures” [2] whereas ASCO states that its value framework should be used to facilitate the patient-physician decision-making process. The value calculation also varies across frameworks. For instance, ASCO uses a transparent, formulaic points system tied largely to efficacy and safety measures, by assigning an efficacy score that is proportional to the hazard ratio measured in the treatment’s clinical trial. NCCN, on the other hand, relies on expert opinion to rate treatments on a 1 to 5 scale in its efficacy domain.

In addition to differences in methodology, the output of the value frameworks are used in different ways. ASCO and NCCN calculate a value measure to help patients and physicians compare the value of different treatments, while ICER and MSKCC use their value framework to recommend explicit prices that firms should be charging for their products.

Not only are new treatments being measured in terms of value, the reimbursement received by providers and payers is increasingly being tied to value. Hospitals that treat Medicare patients are already subject to a number of value-based reimbursement programs, including the Hospital Value-Based Purchasing Program (HVBP), the Hospital Readmissions Reduction Program (HRRP), and the Hospital-Acquired Conditions (HAC) Reduction Program. Hospitals are not the only providers subject to value-based reimbursement. Medicare began the Home Health Value-Based Purchasing Model (HHVBP) in January 2016, is in the process of implementing the Merit-Based Incentive Payment System (MIPS) for physicians, and will implement a value-based purchasing program for skilled nursing facilities by fiscal year 2019. [3] In fact, within two years, CMS aims to have 90% of Medicare fee-for-service payments be tied to value in some form. [4]

In addition to provider value-based purchasing programs for Medicare beneficiaries, providers also receive value-based payments for patients enrolled in commercial and Medicaid health plans. UnitedHealthcare, for instance, paid out more than $148 million in quality of care bonuses in 2015. [5]

Further, health plans themselves are also subject measures of value. The CMS Star rating system ties Medicare Advantage plan premium support and other incentives to the quality of care their patients receive.

In light of the increasing importance of value measurement and value-based reimbursement, innovators should adopt a forward-thinking evidence generation strategy. This strategy should both demonstrate the value of their products under value frameworks, and also demonstrate the treatment’s value to providers and health plans whose own reimbursement is tied to quality of care. I describe a three-step approach for demonstrating treatment value below (Fig. 1.).

Value measurement should begin at the stage of clinical trial development. Clinical trials often use biologic endpoints (e.g., HbA1c levels for type 2 diabetes treatments) or some validated measure of functional status (e.g., the Health Assessment Questionnaire (HAQ) for rheumatoid arthritis treatments). In some cases—such as A1c levels—these metrics will already be included as quality measures in existing value-based purchasing programs. In other examples—such as the HAQ score for RA—that is not the case. Including secondary endpoints such as avoided hospitalizations, or reduced readmissions can help demonstrate the value of your product to potential customers. These endpoints should be tailored to the specific disease area of interest; there is no one-size-fits-all approach.

Once a drug is approved by FDA, innovators should already have a plan in place to quantify the full value of their treatment. When a drug is approved, the cost of treatment is well known, but treatment benefits are uncertain. Consider the case of a new disease modifying therapy for multiple sclerosis. Payers will know the cost and the results of the clinical trial, but at launch other components of value—such as its effect on caregiver burden and worker productivity—are typically not known. And, although treatment efficacy is well measured in clinical trials, treatment effectiveness is not. Even where two treatments have identical efficacy, effectiveness in the real world may differ if patient adherence is much higher to one treatment than another. In general, a treatment’s estimated value will change over time as more evidence comes to light; it is incumbent on innovators to help fund the research to estimate that value in a scientifically rigorous manner.

Finally, when a treatment is in the process of being evaluated by a value framework, innovators should ensure that the organization conducting the evaluation uses the highest quality evidence available. Ideally, value frameworks should release full methodological details to better enable manufacturers to identify and test all assumptions made; some of these seemingly minute details can have large effects on the value a framework assigns to a treatment. In the case of ICER’s review of multiple myeloma, for instance, changing a single parameter regarding dose intensity altered the estimated incremental cost effectiveness ratio from $255,000 in its draft report to $428,000 in its revised report. Because the estimated value of a product may hinge on a few critical parameters, manufacturers should be prepared to critique these value frameworks when appropriate. Oftentimes, creating one’s own cost-effectiveness model for the US market is useful for providing these critiques and identifying the model assumptions that have the largest influence on estimated treatment value.

Value frameworks and value-based reimbursement are likely to remain, but will evolve over time. The merits of these two value initiatives, however, depend on the quality of evidence available in the public sphere. Innovators dedicated to providing value to patients, providers, health plans and broader society should actively participate in efforts to generate evidence to better measure treatment value. These evidence generation initiatives will not only be good for manufacturers’ bottom line, but more importantly, they will be used to ensure that patients receive the highest value care available.

http://jama.jamanetwork.com/article.aspx?articleid=2521978

https://icer-review.org/methodology/icers-methods/icer-value-assessment-framework/

https://www.cms.gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/Value-Based-Programs/Other-VBPs/SNF-VBP.html

https://www.cms.gov/Newsroom/MediaReleaseDatabase/Fact-sheets/2015-Fact-sheets-items/2015-01-26-3.html

https://www.uhc.com/news-room/2016-news-release-archive/quality-of-care-bonus-payments

Jason Shafrin, PhD is a senior research economist at Precision Health Economics and the Director of Research at the Innovation and Value Initiative. He is an expert in value-based purchasing, Medicare reimbursement systems, advanced econometric analyses using claims data, and the evolving field of value networks. His doctorate in economics is from the University of California – San Diego.

A host of evaluation methodologies are defining ‘value’ in drug prices

Value frameworks are here: What to do about them?

Despite their moniker, rare diseases are anything but rare when taken in the aggregate. By definition, a rare disease, often genetic in nature, is chronic, life-threatening and impacts fewer than 200,000 people in the US, or five per 10,000 in the European Union. Today, more than 7,000 rare diseases have been identified, and collectively, they impact 30 million Americans (about 1 in 10 in the US population). Half of those affected worldwide are children.

More than 500 orphan drugs have been approved for the treatment of rare diseases since the passage of the Orphan Drug Act (ODA) in 1983, and the pace is quickening. Over the past decade, more than 230 new orphan drugs have received FDA approval. In 2015, FDA approved 21 novel drugs with a rare-disease designation, out of 45 new drugs overall.

Also in 2015, FDA’s Office of Orphan Products Development (OOPD) received a record number of requests (440) seeking orphan drug designation, and granted 355 of them—a 22% increase over 2014. Per the ODA, this designation provides for multiple incentives, including R&D tax credits, waiver of the Prescription Drug User Fee Act (PDUFA) filing fee ($2.3 million per filing in FY 2016), seven years of marketing exclusivity, and more. The ODA provisions were designed to spur innovation by helping drug sponsors recover development costs and to provide a pathway to profitability for products that are usually limited to a small patient population.

The evidence seems clear that ODA incentives have helped drive venture funding in rare diseases. 

A 2015 report by the Biotechnology Innovation Organization

, which studied trends in $38-billion in venture capital funding to 1,200 drug companies, compared the 2004–2008 (pre-Great Recession) and 2009–2013 periods. Funding for new drugs in major disease states (diabetes, psychiatry, cardiovascular and others) had dropped by large double-digit factors (as much as 81% in diabetes); for rare diseases, new highs have been seen for every year since 2012. Venture cap isn’t the only source of drug-discovery funding, of course, and other factors come into play with research-funding decisions; but the doors for new rare-disease drug development are more open now than ever.

“The ODA has been an unqualified success, and not just in terms of addressing unmet patient need,” says Tim Coté, MD, MPH, CEO of consultancy Coté Orphan, LLC, and former director of FDA’s Office of Orphan Products Development. “Many of the groundbreaking discoveries in rare diseases have helped the entire biotech industry to flourish.”

According to PhRMA, 566 therapies are currently in development for patients with rare diseases. These include:

151 for rare cancers and 82 for rare blood cancers (40% of all orphan drugs in development target oncology indications)

148 for genetic disorders, including cystic fibrosis and spinal muscular atrophy

38 for neurological disorders, including amyotrophic lateral sclerosis (ALS)

31 for infectious diseases, including rare bacterial infections and hepatitis

25 for autoimmune diseases, including systemic sclerosis and juvenile arthritis.

“It’s hard to say what would have happened without the ODA, but it’s safe to say the program’s provisions have definitely been successful in terms of spurring drug development in these areas of unmet medical need,” says Ed Pezalla, MD, MPH, VP and national medical director for pharmacy policy and strategy for Aetna. “We really don’t know which incentives have had the biggest impact—each one addresses a different issue that may be experienced by, or important to, companies of different sizes or resources or expertise.”

While some critics complain that the seven years of market exclusivity is partly to blame, allowing the sky-high prices of orphan drugs to go unchallenged, Coté feels that this incentive has been particularly critical in ODA’s success, because it gives drug developers a fighting chance to recoup their development costs over a relatively short time frame. “The high drug prices that come with market exclusivity are time-limited, yet the knowledge that comes from the discovery is eternal, so eventually competition will arise, once the exclusivity period has expired, and this will help to bring drug prices down over time.”

Coté notes that, to the surprise of some, the tax credits provided by the ODA have not been an important incentive, largely because many of the companies pursuing orphan drugs have been smaller companies that have no real revenue (and thus no major tax liabilities) yet.

While many applaud the success of the ODA, some say it is unfair (or even unethical) when developers of orphan drugs are able to first take advantage of the financial subsidies and market exclusivity provisions to bring an orphan drug to market for a targeted rare disease indication, but then use that approval as a springboard to seek additional, broader-market indications for the same drug. Others see this strategy as a win-win for all.

“Why should we penalize subsequent drug-development successes when sponsors are able to show that a new therapy’s reach can be extended to help other patients in other indications?” says John Doyle, DrPH, MPH, SVP, Advisory Services, for Quintiles. “The ODA was put in place to help focus drug developers’ attention on the 7,000 rare diseases and we’re only just beginning to scratch the surface.”

“I think there’s this ‘pharma karma’ thing at work here,” adds Coté. “If you’ve been fortunate to unlock some key breakthrough for an underlying biomedical condition, you should try to discover how many other patients may benefit from the discovery, and you should be allowed to benefit financially when you take risks to pursue those other commercial opportunities.”

“There have been some cases where follow-ons were delayed or denied when the more stringent efficacy requirements for larger study populations were applied,” adds Mary Dorholt, PharmD, senior director and clinical practice leader, specialty, for Express Scripts.

Part of the criticism is that orphan drugs typically enter the market at very high retail prices—sometimes on the order of $100,000 to $400,000 per year—and these prices end up getting locked in for the later indications, too, even if the later indication has potential blockbuster market opportunities.

Rituxin (rituximab) from Genentech is considered by many to be the poster child for this phenomenon. “Originally granted its ODA designation and approval to treat non-Hodgkin’s lymphoma, it has had a steady drumbeat of approvals for use in other diseases since then, so yes, the sponsor has benefitted but so have the patients,” says Doyle of Quintiles.

The practice of “indication-based pricing”—pricing a drug with multiple indications differently to match, for instance, the disease state and potential market size—is not currently used in the US, but many argue that such an approach could help to blunt some of the frustration about premium-priced orphan drugs being able to benefit from larger patient populations in later-approved indications. “Indication-based pricing is happening now in the EU and there’s a lot of speculation as to whether we can do something about it in the US, but it’s not that simple; it remains an open question and it’s something the industry as a whole is studying right now,” says Pezalla of Aetna.

A more practical approach to help stakeholders to either justify or challenge the high price of today’s orphan drugs is for drug sponsors to develop real-world evidence (RWE) after the drug has entered the marketplace. “Therapies for rare diseases are often approved more quickly, based on less clinical trial data, and there needs to be an acknowledgement that benefit/risk profile must be validated over time with real-world evidence,” says Doyle. “FDA has issued some recent guidance on this, and there is discussion in PDUFA VI, but the orphan drug regulations need to connect the dots between orphan drugs and real-world evidence.”

And stronger RWE can help drug makers make the case to justify the high prices of their orphan drugs. “While the products may be more costly per dose, they may also be more effective for the individual patient,” says Matt Sarnes, SVP of the Commercial Consulting practice at Xcenda.

Historically, there has been relatively little pushback from insurers on these high-cost therapies. The traditional thinking has been that the total number of impacted patients on any given plan is so small that the cost to address their severe unmet need and the lack of alternative treatment options helps to justify the prevailing “treat at any cost” mentality. Similarly, industry observers point out that many rare disease patient populations have, by necessity, formed vocal advocacy groups which can bring significant swift unwanted publicity to insurers who might otherwise restrict or deny coverage.

Nonetheless, the times are changing. “In terms of the per-member, per-month dynamics, the increased volume of orphan drugs in use today, especially across oncology, means that payers are managing access for orphan drugs in ways they did not before, and, in some cases, excluding certain therapies from their formulary altogether,” says Sarnes. For example, patients with certain cancers will face access issues for Gleevec (imatinib mesylate; Novartis), which is approved for the treatment of several diseases, in 2017, as some payers and healthcare companies have removed it from their formulary lists.

Nonetheless “insurers are responding to high-cost orphan products by increasing Prior Authorization (PA) requirements to disease states and drugs that did not historically require PA, and by imposing quantity and days-supply limits,” says Dorholt of Express Scripts. Accredo Specialty Pharmacy (a division of Express Scripts) works with plans, physicians and patients to ensure that orphan medications remain accessible and affordable in the face of increasing restrictions. This can be done not only by helping to expedite PA requirements, but “by providing clinical insight and expertise to plans to help guide and refine authorization requirements,” says Dorholt.

When managed-care companies use utilization-management tools and controls for orphan drugs, “the goal is not to be punitive, but rather to steer patients toward more cost-effective drugs if available, to make sure that the patient has been properly diagnosed and the disease has the particular form or stage of the disease needed to justify treatment with that medication, and to work with the patient and physician to maximize adherence to the prescribed medication and so on,” says Pezalla of Aetna.

However, Pezalla is quick to point out that when it comes to payers imposing restrictions on coverage and reimbursement of costly orphan drugs, “it very much depends on the drug—we continue to look at each one individually. Many orphan drugs are the only disease-modifying treatment available for those patients, so we are committed to making sure patients have access to the drugs they need.”

“Payers are also looking more closely at how the drugs may contribute to the plan’s ability to meet certain quality metrics,” adds Sarnes of Xcenda. “Consideration of quality metrics, strong clinical trial and real-world data, and pharmacoeconomic evidence is increasingly important for payers when making coverage decisions in orphan indications.”

In some drug categories (for instance the newest class of PCSK9 cholesterol-lowering agents within the cardiovascular market), a base of knowledge is growing around the use of so-called “value-based contracting”—whereby the negotiated price of an agent is tied directly to patient outcomes over time, with the manufacturer eating more of the cost (through ongoing discounts and rebates to payers) if patient outcome objectives are not met. Doyle of Quintiles says that this innovative model may, eventually, serve as a useful paradigm to help manage the cost of orphan drugs. “However, my feeling is that, over the short term, with limited bandwidth and expertise, payers will first begin piloting such pay-for-performance programs in more prevalent, chronic high-cost conditions (such as rheumatoid arthritis, diabetes and cardiovascular diseases), and only later expend the effort on doing it with orphan drugs.”

Meanwhile, with the orphan drug sector now firmly in its third decade, some rare disease indications have begun to see the arrival of next-in-class therapies. Technically, this should, eventually, open the door for more widespread use of more price negotiation and payer-contracting strategies. However, this trend has not really taken hold yet. “For many ultra-rare diseases, there are still often only one or two options available, which doesn’t allow for much formulary negotiation,” says Dorholt of Express Scripts. “And in some cases, even when there are increasing options, many of the second-in-class drugs are extended-release formulations or bring some other clinical benefits (such as better side effects profile), so this usually means they come to market at a relatively high price point. And in many orphan drug scenarios, we see in-class innovation with the new approvals being targeted for specific or previously untreated subsets of the condition.”

Nonetheless, Dorholt adds, “For some orphan conditions, where we do see the number of therapy options expanding, we are beginning to see more plans explore step therapy. We may begin to see more strategies like this in immune disorders and other categories.”

“We are seeing more cost sharing in orphan drugs and it seems to correlate with the cost of these expensive agents, and not just in traditional private-pay insurers but in some of the health exchanges, too (with 30–40% co-insurance required for some orphan drugs),” says Doyle of Quintiles. However, since affordability has a direct impact on adherence, he adds: “This short-term control mechanism is something we need to address, because it is not a long-term, sustainable solution.”

Meanwhile, Pezalla of Aetna says “while there are no specific examples yet, we are also looking forward to eventually seeing generic small-molecule and biosimilars competitors come to market in some orphan categories. This will certainly create competition and help to bring down some orphan drug prices.”

In recent years, the use of modeling and simulation (often referred to as biosimulation) has gained traction within the realm of drug development, and has a particularly valuable role to play in the development of orphan drugs. In a 

2015 survey conducted by the International Consortium for Innovation and Quality in Pharmaceutical Development

 (IQ Consortium), more than 95% of the leading pharma companies participating used modeling and simulation in key therapeutic areas.

“One key technology—Physiologically based pharmacokinetic (PBPK) modeling—is increasingly used to facilitate decisions about specific clinical studies, to identify better inclusion/exclusion criteria, to inform study design and to guide appropriate labeling language,” says Edmundo Muniz, MD, PhD, CEO of Certara, a provider of biosimulation technology and consulting services.

Such efforts are now increasingly being used to shorten the developmental timelines (thereby reducing costs) and improve the probability of commercial success (by informing ‘go/no-go’ decisions); help regulators to review such findings; and enabling users to design safer, more-targeted and efficient clinical trials (and in some cases, helping to eliminate the need for some trials). Modeling and simulation has begun to earn its place at the table as an essential enabling technology that is not only accepted but encouraged by regulators worldwide.

Nowhere are these capabilities more important than within the realm of orphan drug development, which faces particularly intense clinical, regulatory and commercial challenges. With such small patient populations, it is often hard to identify and recruit patients for clinical trials, and rare disease patients often have complex phenotypes that react very differently to proposed treatment protocols.

PBPK modeling lets drug companies test assumptions using virtual populations, based on in vitro data, to predict the absorption, distribution, metabolism and excretion of a drug. Substituting certain actual clinical studies with informative virtual trials allows sponsors and regulators to answer many “what-if” questions that are designed to test the limits of safety and efficacy.

“Within the realm of orphan drugs, we often don’t have the ability to scale our knowledge from small clinical trials to real numbers,” says Muniz. “Modeling and simulation—to create and study the impact of candidate therapies in so-called ‘in silico’ patients—thrives when you cannot find enough patients, or when they are too frail to participate, or when it may be unethical to test developmental drugs on them in a clinical trial setting.

“Clinical trial designs are often underpowered or overpowered due to lack of adequate information or understanding,” adds Rick Sax, MD, SVP of Advisory Services for Quintiles. “At the extreme, a Phase III trial with a marginal outcome could mean that the drug is actually working, but the design chosen was insufficient to enable registration. A failure of this type is painful for companies of any size, and could be especially perilous for smaller companies with more at stake on a single molecule.”

According to Certara research, among FDA’s 2015 drug approvals alone:

More than 90% of all 2015 drug approvals leveraged one or more modeling and simulation technologies

Of the 21 approved drugs for orphan drugs designated for rare diseases, 19

used one or more modeling and simulation technologies

5 of the 21 drugs leveraged the use of PBPK models used to describe and predict the handling of drugs by the body, based on demography, physiology, biochemistry and genetics, in virtual patient populations.

Modeling and trial simulation can also be particularly effective to leverage information developed for the approval of a drug for one indication and help the sponsor to gain approval for its use in another, different indication. A 

 describes the techniques that were essential in helping to secure a second approval for Soliris (eculizumab), a humanized monoclonal antibody (mAb). Initially approved for the treatment of PNH (paroxysmal nocturnal hemoglobinuria), a rare, progressive and life-threatening disease that causes destruction of red blood cells and excessive blood clotting, eculizumab was later approved for the treatment of another ultra-rare condition—aHUS (atypical hemolytic-uremic syndrome), an ultrarare genetic disease that causes abnormal blood clots to form in small blood vessels throughout the body, and can lead to organ failure and premature death.

“This would not have been achieved using real-life clinical trials alone—the total number of patients (57) who participated would not have been enough without the use of simulation to assess the efficacy of treatment using two biomarkers and to recommend dosing regimens for adult and pediatric aHUS patients,” says Muniz of Certara. “And more importantly, the insight that modeling and simulation was able to provide without having to run dose-escalation studies gave FDA the confidence to receive the drug with open arms.”

Existing incentives continue to draw in new drug developers; payers begin to look at competitive markets to drive down drug costs

Orphan drug commercialization is maturing

The Rare Pediatric Disease Priority Review Voucher (PRV) program has been a lightning rod within the orphan drug sector, and pending Congressional action, the program is set (at presstime) to sunset on October 1. Designed to spur innovation in the pursuit of drugs for “rare pediatric diseases,” the PRV program rewards a drug company that gains regulatory approval for such a drug with a voucher. The voucher entitles its owner to get a priority review of a subsequent drug—thereby shortening the FDA-review cycle from 10 months to 6 months. In FY 2015, FDA’s OOPD granted 21 of 31 requests for the “rare pediatric disease” designation (not all such designated drugs are eligible for the PRV program).

Since the program was created in 2012, six PRVs have been granted. Per the program rules, the drug company awarded the voucher can monetize it in one of two ways—it can either exercise the voucher itself to expedite the review of any future product (orphan or mass market) in its own pipeline, or, it can sell it to another drug developer (thereby generating what could be a huge cash influx for itself), allowing that buyer to speed the review for a new drug filing in its pipeline, orphan or otherwise. To date, sales of these vouchers have fetched purchase prices ranging from $67 million to $350 million, clearly demonstrating their perceived value in the marketplace.

Last March, the Government Accountability Office (GAO) published an assessment of the voucher program to date, and suggested that the jury’s still out on whether or not the program itself could take credit for spurring innovation in drug development for rare pediatric diseases. Within that GAO report, some FDA officials have been very outspoken against the voucher program, even calling for it to end (http://www.gao.gov/assets/680/675544.pdf). In essence, the program takes some of the discretion on how clinical reviews are prioritized at FDA out of its hands.

Not surprisingly, the National Organization of Rare Disorders (NORD) is a supporter of PRV, says Peter Saltonstall, CEO. “It’s been very effective in terms of spurring development, and has by no means been overused. And in fact, the first few vouchers granted have demonstrated every possible scenario that the program designers had envisioned.”

Robin Huff, PhD, global regulatory strategy leader at Quintiles and a member of the company’s Pediatric and Diabetes Centers of Excellence (and who spent seven years at FDA prior to joining Quintiles) agrees with Saltonstall. The first few vouchers that have been granted and sold in the open market “have demonstrated their financial value in terms of providing an economic incentive,” she says. “It’s a really interesting way to use private capital, in amounts that greatly exceed any direct government support possible, to drive biomedical innovation and focus efforts on an area of particularly high unmet need.”

“While we were disappointed that the US Senate would not vote on its Cures legislation (also known as the Senate Innovations for Healthier Americans Initiatives) before it broke for summer recess, we feel confident that the Pediatric Rare Diseases Priority Review Voucher program will be reauthorized in September, as part of the 21st Century Cures Act—it’s just a matter of what the specific language will look like,” says Saltonstall of NORD. “We’ve asked for it to be permanently reauthorized, but if Congress decides to set another sunset date, we support the Senate language that reauthorizes the program through 2022, and allows vouchers to be awarded through 2027 that had been designated before 2022.”

Uncertainty around the pediatric priority review voucher (PRV) program

With apologies to Rodgers and Hammerstein of Broadway musical fame, we can say that “biopharma cold chain is bustin’ out all over” in 2016. The steady stream of openings of dedicated, temperature-controlled warehouses and intermediate storage areas for biopharma products ticked up noticeably in the past year. More and more freight forwarders, air carriers, trucking firms and 3PLs (third-party logistics providers) now have branded life sciences services. Technologies for packaging life sciences products and clinical trial materials (CTMs) are advancing, as are digitally based networks and devices for tracking shipments through supply chains.

According to estimates by the Economist Intelligence Unit, WHO, IMS Health and others, global healthcare spending is ripping along at a 3–4% annual rate currently, and is approaching $10 trillion globally. That’s 2–3 times the rate of population growth. Within that, global pharmaceutical spending is projected to rise by 4–5% through 2020. And within that, according to Pharmaceutical Commerce’s 2016 Biopharma Cold Chain Sourcebook, spending on refrigerated (2–8°C) drugs is growing about 7% annually, or 41% during the 2014–2020 period (Fig. 1).

Looking at the entirety of pharmaceutical logistics, the Sourcebook projects that cold chain currently represents 19% ($12.6 billion) of a $78.8-billion industry, rising to 22% ($16.7 billion) of a $93.8-billion industry by 2020 (Fig. 3).

A second, related driver to this growth is that more and more of the pharma industry is biotechnology-based. While there are refrigerated small-molecule pharmaceuticals, and while not all biotech products require refrigeration, the great majority of biotech products do, and they command the highest value in the healthcare market. Of necessity, biotechnology manufacturers (as well as vaccines, insulin and blood products, and others) need to spend liberally on technologies and services that ensure the quality and efficacy of the products they ship around the world. Spurring this on is the latest R&D on cellular therapies, including stem cells, regenerative medicine and varieties of genetic therapies. On a commercial basis, these are still relatively small markets, but the logistics of managing their distribution will add complexity and cost to healthcare.

A third driver is, to some degree, self-imposed. Through collaboration between leading industry organizations, and national and international government regulators, the restrictions on how pharmaceuticals, medical devices and other healthcare products are transported are becoming significantly tighter. A key factor here is the imposition of Good Distribution Practices (GDPs), which are beginning to address not just refrigerated products, but also so-called controlled room-temperature (CRT) ones. The days of tossing any pharma product into a cardboard box and dropping it off at the local parcel delivery company are fading. While the industry globally has not, as yet, adopted insulation and cooling systems for CRT products across the board, the use of techniques like thermal blanketing and regulated warehouse room temperatures is become widespread.

DHL, one of the world’s largest mover of healthcare products globally, organizes an annual life sciences customer event each spring, and surveys the attendees to get their views on current industry trends. According to Angelos Orfanos, president of the Global Life Sciences Sector at DHL, there was a shift this year in attendee priorities. “For many years, cost and quality traded back and forth as the No. 1 and No. 2 priorities for our attendees,” he says. “This year, the No. 1 priority was vendor capabilities to meet evolving industry needs.” That translates, he says, into a greater emphasis on performance in delivering products safely and on time.

Orfanos goes on to note that mergers and acquisitions activity has been intense in the industry for the past couple years; when these combinations are announced, Wall Street and other investors expect to hear about synergies that result in better cost effectiveness for the invested capital. That, in turn, usually calls for rationalizing supply chain activities like warehousing and distribution. Logistics providers’ capabilities to manage client supply chains as these complex corporate mergers take place is one important performance factor; but another is to raise the level of performance of both the logistics provider like DHL and also its service partners, such as air carriers, trucking companies and warehousing facilities. Orfanos notes that his company has taken a leadership role in the CEIV for Pharma (Center of Excellence for Independent Validators in Pharma) program of the International Air Transport Assn. (IATA). Under this program, IATA validators certify the capabilities of air carriers, freight forwarders, ground handlers and trucking companies to ensure a common level of quality. Just over 20 organizations have been certified so far.

(For its part, IATA notes that it is in a competitive position vis a vis other forms of transportation, such as ocean carriers, for pharma trade; CEIV for Pharma is looked on as “supporting the air transport industry to comply with pharmaceutical manufacturers’ requirements.”)

The Sourcebook, as in the previous editions, is premised primarily on two things: a methodical review of the labels of most common pharmaceutical and biotech products to calculate how much of the overall pharma supply chain is dedicated to cold chain practices; and an analysis of as much data as can be collected on the costs of pharmaceutical logistics in the US and globally. A third element is an evaluation of the pharmaceutical “pipeline”—the pace at which drugs under development will come on the market, and how the market will grow for those and for existing commercial products. The forecast timeframe is five years (2016–2020).

Since the 1980s, when the commercial biotechnology industry introduced its first products, the global market for such products has expanded enormously. As of 2016, it exceeds $250 billion in value, and the special logistics for maintaining the quality of temperature-sensitive products as they are shipped from manufacturers to hospitals, clinics, pharmacies and patients around the world account for more than 15% of all biopharma logistics spending.

Our updated forecast for cold-chain logistics spending in 2016 is that it will be more than $12 billion worldwide, in a $79 billion overall pharma logistics market, of which $9 billion will be transportation and $3 billion will be specialized tertiary packaging and instrumentation, such as insulated boxes, blankets, phase-change materials, active-temperature-control shipping containers, and various temperature sensors and recorders (Fig. 4). By 2020, cold-chain biopharma logistics spending will expand to more than $16 billion.

The bulk of this spending is on refrigerated (2–8°C) products; the amount of frozen products or clinical trial materials is trivial by comparison. There is a trend toward more spending on devices and system for controlled room-temperature (CRT) shipping, but to date, most of this involves more careful monitoring of shipping conditions and not necessarily extensive use of insulation or other environmental controls.

$3 billion annual spending" alignment="left"/>

Vendors and service providers scramble to serve a growing market

Pharmaceutical Commerce - September/October 2016

Cold Chain Global Forum is coming up

5 CAPA best practices for clinical research

Integrating patient training into product launches

Value frameworks are here: What to do about them?

Orphan drug commercialization is maturing

Uncertainty around the pediatric priority review voucher (PRV) program

Advancing the biopharma cold chain

Using near real-time medical claims to target physicians with newly diagnosed patients

A conversation with Gerry Gleeson, Walgreens Specialty Pharmacy

Since 1841: The Story of an Enduring Family Business

Specialty drug market access reality check

Moving From Big Pharma To A Small Company? You May Be In For A Few Surprises

Big data analytics is a work in progress in pharma

MannKind calls on Asembia to assist in relaunch of Afreeza inhalable insulin

Sonoco ThermoSafe offers cold chain training—with an academic contribution

Open-SCS group gains momentum for industry-wide serialization data standard

Where are those missing billions in new-product pharma sales?

Guilty verdict is handed down in 2012 MOMS Pharmacy drug-diversion case

Generics distributor Anda, Inc. has a new owner: Teva Pharma

Pharma company runs afoul of child-resistant packaging rules

UPS steps into clinical trial materials management

A jurisdictional battle breaks out over physician assistant certification