Clinical trial material supply is an integral part of the supply strategy of pharmaceutical companies. As the number of clinical trials outside the US and Europe increases, companies, clinical trial material supply chains are becoming increasingly global and complex. DCAT Value Chain Insights (VCI) examines key trends and issues.

Optimizing the clinical trial material supply chain is one key aspect to facilitate drug development and accelerate speed to market. Coordination of active pharmaceutical ingredient and drug product manufacturing is crucial to meet requirements for clinical supplies. That coordination becomes even more critical as the number of clinical trials outside developed markets increases. DCAT Value Chain Insights (VCI) examines best practices and clinical trial material supply.

Assessing the pipeline and R&D productivity
A recent analysis, “Profiles of New Approaches to Improving the Efficiency and Performance of Pharmaceutical Drug Development,” by the Center for the Study of Drug Development at the Tufts University School of Medicine (Tufts CSDD) provides key insight into the drug development process. The study, published in May 2015, is based on a literature review followed by nearly three-dozen interviews with experts and company representatives conducted in 2014. Tufts CSDD also convened a roundtable to stimulate discussion and gather insights into the results from the literature review and interviews (1).

The study revealed several key points. First, biopharmaceutical drug development has been experiencing one of its most productive periods in recent history. During the past decade, the total number of new chemical and biologic entities in the R&D pipeline has been rising 6% each year and now exceeds 10,000 active drug candidates. At the same, time, however, the pharmaceutical industry has faced a challenging operating environment, marked by increasing costs, inefficient and lengthy cycle times, and increased risk, uncertainty and complexity.Total spending worldwide on biopharmaceutical R&D is projected at $140 billion in 2014, representing a 4.9% compound annual growth rate during the past 10 years.

While the number of new drugs entering development and the amount of R&D spending has increased, success rates have declined. Recent Tufts CSDD research indicates that only 11.3% of drugs that enter clinical testing will be approved in the United States, down from a 16.4% success rate ten years ago. Since at least 10 years are required to bring a single molecular entity through R&D and approval, the total average capitalized cost to successfully introduce a marketed drug, including the shared cost of compounds that fail in development, exceeds $2.6 billion.The Tufts CSDD updated this figure in November 2014 based on information provided by 10 pharmaceutical companies on 106 randomly selected drugs that were first tested in human subjects anywhere in the world from 1995 to 2007. The $2.558 billion figure per approved compound is based on estimated: average out-of-pocket cost of $1.395 billion and time costs (expected returns that investors forego while a drug is in development) of $1.163 billion. The estimated average cost of post-approval R&D—studies to test new indications, new formulations, new dosage strengths and regimens, and to monitor safety and long-term side effects in patients required by the US. Food and Drug Administration as a condition of approval—of $312 million boosts the full product lifecycle cost per approved drug to $2.870 billion. All figures are expressed in 2013 dollars.

At the same time, the average clinical phase duration is 6.8 years and has increased 15% during the past decade. Longer clinical-phase durations are in large part a function of the therapeutic classes that dominate research activity, such as oncology and central nervous system drugs, as these drugs target diseases that require more time to demonstrate safety and efficacy.The Tufts CSDD research shows that rising cost and duration of drug development activity are a function of increasing protocol design complexity. The average number of procedures per protocol, average number of eligibility criteria, average number of investigative sites and countries where clinical trials are conducted simultaneously, have all increased dramatically during the past 10 years creating more demanding protocols both scientifically and operationally.

With regard to increased globalization of clinical trials, a report from the European Medicines Agency (EMA) shows the shift in the number of investigative sites involved in pivotal trials submitted in marketing authorization applications to the EMA. In 2005, 89.5% of sites conducting these trials were either in North American or the European Union. By 2011, that figure had dropped to 71.9%, with the rest of the world picking up the balance (2,3). Recent data from clinicaltrials.gov, an information resource of the US National Institutes of Health that list 194,916 studies with locations in all 50 states and in 190 countries (as of July 2015), 46% of registered studies are being conducted entirely outside the US, as compared to 38% taking place in the US exclusively. Of the 194,916 studies listed with clinicaltrials.gov, 44% of clinical studies are in the US (includes studies conducted both in US and if applicable, other global site), 38% in Europe (all of Europe, Western Europe and Central and Eastern Europe), 13% in Asia (excluding Japan), and 10% combined for South America, Middle East, and Africa.

Assessing strengths and weaknesses in clinical trial material supply
Additionally, the Tufts CSDD, in collaboration with seven major pharmaceutical companies and contract research organizations (CROs), conducted a survey for global site staff directly involved in managing clinical supplies. The survey was designed specifically for the role of study coordinators, investigators and sub-investigators, pharmacists, technicians, and Qualified Persons. The survey examined three broad areas: site capabilities in handling clinical supplies, assessments of sponsor and CRO abilities to handle clinical supply responsibilities, and key areas of opportunity and challenge. The study was conducted in 2013 with results reported in 2014 (4).

The study showed that both sponsor and CRO clinical supply practices were fairly positive. Sites indicate that in general they were satisfied with the availability of drug at their sites and rated most sponsor practices favorably. Top improvement areas include complicated interactive voice response system (IVRS) processes, unexpected amount and arrival time of supplies, cumbersome delivery and return packaging, and defective equipment. Clinical supply challenges were noted in several specific therapeutic areas: oncology, infectious disease, respiratory, and hematology often due to cold-chain requirements (4). The study suggested that as more sites deal with temperature-controlled products throughout different geographies and time zones, additional staff training, facilities, or technology may be required (4).

The study also showed that investigative sites are asking for improvements in communication to help them accommodate supply shipments and returns more effectively and efficiently (4). The study suggested that this provides an opportunity for sponsors to conduct site assessments of their supply practices, including evaluating use of technology and interactive response technology (IRT) systems. The study also said that investigator meetings are another way for sponsors and CROs to improve communication channels among clinical supply and clinical operations functions as well as through routine and systematic collection of feedback from investigator sites (4).

Overall, respondents in the study said that they were generally well prepared to handle clinical trial drug supplies. In general, the majority of investigative sites rate sponsor/CRO clinical supply responsibilities positively. Clinical supply availability, responsiveness to inquiries, and the quality of training are among the areas receiving top ratings. Respondents also indicate that sponsors and CROs perform well with respect to receipt and acknowledgement of drugs and supplies and documentation clarity (4).

There were areas noted for improvement. The study showed that more than half of sites (54%) reported that the amount of space available at their center was “very adequate,” but 74% said that they had limited storage space available on site. Sites also indicate that they have limited abilities to handle novel therapies such as gene therapies or personalized immunotherapies. Another issue examined across sites was the frequency with which delays prevented dosing of first patient (4). The study found that the most critical challenge in receiving supplies was having supplies arrive unexpectedly at a site. Nearly four out of 10 sites report significant challenges with receiving supplies at unanticipated. Other notable issues were having unexpected amount of drug, bulky packaging and insufficient communication about receiving drugs or supplies. Other difficulties mentioned were logs that needed to be completed manually rather than in an automated fashion, ensuring proper security for drugs and supplies, and the need for proper instructions in handling drug. Some of the most frequently mentioned labeling challenges reported were difficulty in reading the kit number or label text and not enough room to write on the label (4).

References
1. M.J. Lamberti and K. Getz, Profiles of New Approaches to Improving the Efficiency and Performance of Pharmaceutical Drug Development, Center for the Study of Drug Development at the Tufts University School of Medicine, Boston, Massachusetts, May 2015.

2. C. Morgan, “Expediting Study Startup Across the Globe,” Applied Clinical Trials,July 2015.

3. European Medicines Agency, Clinical Trials Submitted in Marketing-Authorization Applications to the European Medicines Agency: Overview of Patient Recruitment and the Geographical Location of Investigator Sites, Containing Sata from 2005 to 2011, London, 2013.

4. M.J. Lamberti et al., “Clinical Supply Capabilities, Practices, and Perceptions Among Investigative Sites,” Applied Clinical Trials, August 2014.