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Clinical Trial Supply Chain Management: Changing Without Delay

By Adam Runsdorf, WDPrx President

SUPPLY CHAIN OLYMPICS

Compare clinical trial supply chain management to an Olympic sport and ‘balance beam’ would be an appropriate choice.  Successful trials demand a blend of costs and benefits to achieve desired results.

Effective clinical trial supply chains increase efficiency and reduce risk while remaining on budget.  This task is challenging within conventional clinical trial environments.  New technologies for trial management may create more difficulties navigating between ease of use and complex data collection and privacy issues.  With a total of 282,127 clinical trial studies1 being conducted around the world as of August 21, 2018, quality control is another vital factor affecting  patient safety.

Vigorous evaluation should be undertaken before, during and after clinical trial programs to address deficiencies  thereby strengthening positive outcomes.  This collaborative effort involves internal and external stakeholders in order to establish best practices.

Analyzing clinical trial supply chain performance may initially seem as complex as the actual trial. Logistics is becoming an increasingly vital component of trial management.  One practical solution involves breaking down overall clinical trial design into separate areas of examination.

By breaking down supply chain management for clinical trials into representative parts, it is possible to create a continuous improvement loop that will reduce error repetition and incorporate innovation into future programs.

Three primary areas where logistics impacts  the clinical trial supply chain are trial design, location strategy and regulatory compliance.

Collaboration between clinical and logistics teams early in the planning process improves successful outcomes.

TRIAL PLANNING AND  DESIGN STRATEGY

Initial trial design incorporates planning logistics and also clinical and material requirements.  Early-stage involvement from the supply chain team helps coordinate the overall program plan and can anticipate potential hurdles that might otherwise be overlooked. Materials required for the study are determined during trial protocol development.

When the quantity of sites and patients is determined by the clinical team, the scope of logistics requirements becomes clearer.   Trade regulations are confirmed to streamline flow of trial materials.  Data analysis and forecasting provides insights about patient enrollment helping assure trial success. Techniques to maximize patient engagement may involve specific logistics approaches. For example, the use of smartphones or other relevant technologies affects information flow and may also impact patient engagement.

Organizations that stress inclusive collaboration at the outset of clinical trial development help assure greater success compared with siloed operations.  This is primarily because all interested parties – CMOs, laboratories, logistics specialists and CROs – contribute expertise at every stage of trial planning, generating shared responsibility for creating efficiencies that assure a successful outcome.

TIME, TOUCH AND TRAVEL

One of the key components of clinical trial supply chain logistics is to determine the correct balance between successful trial resolution and trial expenditures.  Logistics professionals involved early in trial development work with stakeholders to manage three major cost factors:  time, touch and travel.  Budget is affected when any of these elements is altered.

For example, reducing shipping time increases cost.  A ‘touch’ is defined as any contact that disrupts the direct flow of the medication from manufacturer to patient.  A requirement for in-home supervision of patients for greater program control requires additional budget.  Shortening the distance traveled for medication to reach patients may reduce expenses.

Other considerations affecting time, touch and travel for clinical trial design include stock management control, randomization protocols, results testing procedures and data recording and collection.

Logistics professionals involved early in the planning process streamline program costs while achieving desired clinical results.

MANAGING DELAYS

A common theme in all clinical trials is that delays are inevitable.  Clinical trial planning attempts to reconcile clinical possibilities with economic realities.  Delays in project flow at various stages must be anticipated in advance and incorporated into contingency plans.  Unanticipated delays cause budgetary disruption that may impact outcomes.

ENROLLMENT HURDLES

A common source of delays are derived from patient enrollment and retention problems.  Patient acquisition is a complex game of numbers.  Initial patient pools are drastically reduced due to pre-screening failures and refusals to give consent for the trial.  If the initial pool was large enough to generate the desired patient group, all trials suffer from post-enrollment attrition with patients who leave after acceptance into the program.

DELAYS AT THE DEPOT AND INVESTIGATION SITES

Delays at the depot or clinical site are another major cause of delays in trial implementation.  Clinical trials are complex clinically and organizationally.  Sound medical practice is often at the mercy of shoddy training or record-keeping.  Teaching policies and procedures so they are performed consistently and correctly is a difficult task under ideal circumstances.  A trend toward increasing the number of countries per study and expanding the quantity of investigative trial sites is leading to long investigative site initiation timelines and longer durations for data transmission and updates2.

Multiple sites, countries and languages magnify the problem.  Clearly defined administrative procedures along with properly calibrated equipment reduces false starts and maintains budget integrity.  Proper management of the deposit/site network entails timely distribution of inventory data across the supply chain.

CUSTOMS BROKER BREAKDOWNS

The import brokerage function is an important aspect of the clinical trial supply chain that adds uncertainty and volatility often leading to delays with negative budget implications.

The global nature of clinical trial administration requires knowledge of an intricate and often arcane set of rules and regulations concerning movement of materials across and within geographic borders.  Coupled with this reality is that trial sites may be in locations lacking modern infrastructure.

Complete import/export documentation ahead of time and secure permissions from all authorities prior to trial launch.  Conducting simulations and modeling exercises also help identify problems for pre-emptive resolution.

Despite recognizing these challenges, a recent study3 reveals that 54% of clinical trial sponsors are ‘very concerned or ‘concerned’ about the ability of import brokers to successfully achieve objectives.  This may be a function of the growth in outsourcing all but core clinical services to outside parties.  Courier services are the primary source for import brokerage services, removing this critical process from direct study sponsor control.

LESSONS IN DRUG DEVELOPMENT

Unique challenges are associated with the drug development process for early stage clinical trials.  Problems arise when early stage formulation begins too late after other components of the clinical trial plan have been implemented.  To counter this situation, begin API development for production one year before trial launch4.

In late stage trials, sufficient time must be allocated to refine the active ingredient and modify components and production techniques to enable large-scale manufacturing.  Failure to anticipate the steps necessary to scale up from trial quantities to commercial production could cause a significant financial burden.

SHIP SHIP DELAY!

The clinical trial supply chain addresses similar challenges with additional unique considerations faced by all businesses caused by shipping delays.  Clinical trial clinicians are extremely sensitive to lost or mishandled shipments due to the nature of the package contents.  Each shipment contains samples that are difficult or impossible to replace.  Special circumstances exist for samples that require temperature regulated environments.

Sample viability of cellular structures relies on transport within specific temperature and seismic vibration ranges.  Variation from established guidelines may render samples unacceptable for study results. Verification of temperature maintenance within acceptable range must also be monitored throughout the duration of shipment to assure sample viability.

Selecting a reliable transportation provider is essential for successful trial outcomes.  This function is becoming more significant as the clinical trial supply chain expands into multiple countries with differing abilities to provide the specialized transportation modes required for modern trials.

LOCATION STRATEGY

Budget considerations for many trials require establishing locations in several countries to satisfy patient recruitment goals as efficiently as possible.  Considerations affecting international investigation site selection include regulatory burden, financial issues, study drug accessibility, data quality and monitoring, transportation and training.

According to the National Institutes of Health5, Over half (54%) of registered clinical studies in the world as of August 23, 2018 occur only outside the United States or combine sites within and outside the U.S.  Studies contained within the United States account for 35% of the total study quantity.

The dispersion of sites requires increased vigilance, effort and risk to record data accurately and in a timely manner.  A majority of clinical trial sponsors in a recent pollselected ‘challenging’ to describe logistics issues between depot and clinical sites in four of six world regions: South America, Central America, Asia and Eastern Europe.

The main location-based issues concerning supply chain logistics involve regulatory procedures, drug access and transportation.

REGULATORY FACTORS

Any study with human subjects requires regulatory approvals prior to patient recruitment.  Regulations vary by country and affect authorization to conduct the study as well as movement of samples within and outside national borders.  Trials originating in the United States must submit a list for approval to the U.S. Department of State of all foreign nations with investigational sites.

The optimal time to resolve issues involving international locations is during the initial study planning stage as it may take a considerable length of time for application and approval processes to be completed for multiple country locations.  This process may also need to be conducted in several different languages.

Without precise record-keeping and follow-up at this early phase, more costly delays further into the program can be expected.  Thorough research must be conducted to assure study approvals for import permits, licenses, special packaging and labeling requirements, customs valuation regulations and other trade-specific agreements and protocols.

STUDY DRUG ACCESS

Clinical trial requirements must be realized with close coordination of the logistics team.  For example, a drug used for a trial may not be authorized for use in all countries selected as investigation sites.  The drug or equivalent formulation may need to be locally sourced requiring further training and dispensing protocols.

Although international locations enable trial requirements to be satisfied quickly, these advantages may be lost if regulations for specific countries are overlooked.   For instance, import requirements may affect the randomization sequence for international trial participants.

TRANSPORTATION MANAGEMENT

Geographic diversity adds to the transportation complexity of the clinical trial supply chain.

Multiple transportation partners are required for a successful trial outcome.  The quantity and type of transportation partners may vary within different countries in order to maintain regulatory and safety requirements.   The logistics team evaluates potential transportation partners according to their ability to function efficiently within the requirements for each specific trial.  Transportation logistics solutions may involve a combination of outside couriers, customs brokers and internal capabilities.

With multiple international locations, ‘on-the-ground’ expertise is preferred to navigate local transportation issues that often arise unexpectedly and that may change without notice.  Correct documentation, travel time within and between countries, security protocols, labeling, packaging and monitoring requirements to maintain sample viability in transit are key transportation considerations for clinical trials.

COMPLIANCE STRATEGY

Due to the biological nature of clinical trial shipments, their transport is highly regulated. Rules for shipping diagnostic specimens change regularly affecting documentation requirements that vary internationally and at times may differ within areas of a single nation.  The selection of an experienced transportation provider may save costs by developing optimal routes that shorten transit duration.

PACKAGING

Security of samples must be prioritized in every trial location but this function becomes more complicated when investigation sites are in locations with weak infrastructure or equipment to maintain study requirements. Effective security of clinical trial materials in transit is dependant on the nature of specimens and packaging.  Ambient specimens may require a specific maximum duration for their transport.  Clinical specimens must be handled with more urgency due to the need for a temperature regulated environment which may stipulate a refrigerated (2-8 degrees Celsius) or frozen (-78.5 degrees Celsius) state.

Logistics members of the study planning team will determine the safest, most efficient packaging option for transport based on distance and time and package contents.  For cold chain solutions, phase-change, active and passive shipping systems are among potential options.  Depending on study requirements, shipper validation with documentation may be advised.

Correct packaging helps assure integrity of clinical trial sample contents and minimizes damage in transport between investigation site and hub.

DATA ANALYSIS

Maintaining accurate record-keeping of materials in transit demands constant monitoring.  Temperature excursions can invalidate samples and data.  When studies are conducted in various parts of the world where seasonal temperature shifts may vary widely, the planning team should evaluate the costs and benefits of temperature monitoring on some or all shipments based on time of year, travel time, mode of transport and location.

LABORATORY LOGISTICS

The logistics pipeline for clinical trial management increasingly relies on the location and quantity of laboratories to analyze samples received from investigation sites.  A central hub for analysis of received samples from multiple investigation sites may simplify transit logistics and training requirements.  However, creating an integrated network of strategically located laboratories may reduce processing time, minimize potential for temperature excursions and reduce transportation costs by increasing road travel compared with air travel.

THE NEW NORMAL: DIRECT-TO-PATIENT

The conventional clinical trial supply chain is being disrupted by direct-to-patient distribution and related uses of widely available technology to transmit data to trial sponsors for analysis.  According to a recent report,7 24% of trial sponsors report utilizing direct-to-patient distribution.

Virtual trials affect logistics decisions about patient acquisition and enrollment, patient administration of the sample drug, data transmission, transportation, study duration and other factors.  The potential benefit of virtual trials focuses on reducing bottlenecks that negatively affect traditional trials structure.

For example, patients in virtual trials may be solicited online, enabling a faster method to pinpoint appropriate candidates from a wider population compared with traditional advertising methods where potential patients must show up to be properly screened.  Virtual trial patients administer the treatment themselves.

Program adherence is supported by video-chats with trained personnel at regular intervals.  Many transportation related issues may be minimized as more patients with more diverse backgrounds may be able to be secured in a more limited geographic area.  Proprietary applications downloaded by smartphones may gather and transmit data to a centralized evaluation site for near real-time analysis.

These developments may help to shorten trial duration with commensurate cost reductions.  Further transportation innovations including Uber Health8 may benefit traditional and virtual trial logistics by bringing patients and trial materials closer together.

CLOSING ARGUMENT

The clinical trial supply chain resembles a set of dominos organized in a complicated pattern where the first one to fall triggers subsequent pieces which move at exactly the correct moment in an uninterrupted path to create a desired design.

The logistics process enables the dominos to reach the finish.  Proactive forecasting of potential issues involving planning, supplies, timing and delays, geography and lab logistics help assure smooth progress.  Virtual trials show significant promise by conquering some problem areas in certain types of conventional trials.

The march to create more streamlined clinical trials is increasing the importance of supply chain logistics as an integral component for successful outcomes.

For further information contact Larry Hotz, lhotz@wdprx.com or (5610 998-3885 x304

 

About the Author: Adam Runsdorf is President of WDPrx – Woodfield Pharmaceutical, LLC, a contract manufacturer with extensive clinical trial logistics expertise in Houston, TX specializing in liquids, semi-solids, gels and pastes.

Citations:

  1. “Trends, Charts, and Maps.” Full Text View – ClinicalTrials.gov, U.S. National Library of Medicine, 21 Aug. 2018, clinicaltrials.gov/ct2/resources/trends.
  2. Fassbender, Melissa. “Rapid Increase of Protocol Complexity Contributing to Clinical Trial Delays, Inefficiencies: Tufts Report.” Outsourcing-Pharma.com, William Reed Business Media Ltd., 25 July 2018, www.outsourcing-pharma.com/Article/2018/07/25/Clinical-trials-are-being-delayed-by-the-volume-and-diversity-of-data-collected.
  3. “Assessing the Current and Future State of Clinical Trial Supplies.” Infographic, Thermosafe, 2016, www.thermosafe.com/files/Hidden_Files/CTSSurvey_FinalInfographic.pdf.
  4. Shanley, Agnes. “What to Watch Out for in Clinical Trials Manufacturing.” PharmTech Home, 31 Jan. 2018, www.pharmtech.com/what-watch-out-clinical-trials-manufacturing.
  5. “Trends, Charts, and Maps.” Full Text View – ClinicalTrials.gov, U.S. National Library of Medicine, 21 Aug. 2018, clinicaltrials.gov/ct2/resources/trends.
  6. “Assessing the Current and Future State of Clinical Trial Supplies.” Infographic, Thermosafe, 2016, www.thermosafe.com/files/Hidden_Files/CTSSurvey_FinalInfographic.pdf.
  7. Sookne, Karen. “Survey Reveals Current and Future Trends in Clinical Trial Supplies Market.” Life Sciences Logistics, 14 Mar. 2017, www.logisticsforthelifesciences.com/survey-reveals-current-and-future-trends-clinical-trial-supplies-market.
  8. Ross, Benjamin. “Uber Launches Uber Health, Looks To Improve Patient Experience In Clinical Research.” Clinical Informatics News, 11 Apr. 2018, www.clinicalinformaticsnews.com/2018/04/11/uber-launches-uber-health-looks-to-improve-patient-experience-in-clinical-research.aspx.

References:

Catizone, Dan. “Clinical Trial Shipping: The Essentials.” Applied Clinical Trials Home, 6 Nov. 2017, www.appliedclinicaltrialsonline.com/clinical-trial-shipping-essentials?id=&sk=&date=&%0A%09%09%09&pageID=2.

Minisman, Greg, et al. “Implementing Clinical Trials on an International Platform: Challenges and Perspectives.” Advances in Pediatrics., U.S. National Library of Medicine, 15 Feb. 2012, www.ncbi.nlm.nih.gov/pmc/articles/PMC3254780/.

Arnum, Patricia Van. “Managing the Global Clinical-Trial Material Supply Chain.” PharmTech Home, 23 May 2018, www.pharmtech.com/managing-global-clinical-trial-material-supply-chain?id=&sk=&date=&%0A%09%09%09&pageID=4.

Taylor, Phil. “Novartis Pushes ‘Virtual’ Clinical Trial Concept.” PMLive, PMGroup Worldwide Limited, 9 Mar. 2018, www.pmlive.com/pharma_news/novartis_pushes_virtual_clinical_trial_concept_1226748.