Do You Really Understand Clinical Supply — And Its Impact On Your Trials?
By David Gilliland
Clinical supplies (CS) can be a rate-limiting factor to initiation of studies because of factors such as insufficient bulk material, inadequate forecasted demand, accumulation of delays (such as manufacturing delays), or a sudden acceleration in the timeline for the study’s start. Additionally, once a study is underway, there may be a lack of continuity of supplies to maintain patients on the study drug (stockouts), which again may be caused by insufficient forecasted demand. This may be due to an unforeseen high initial rate of recruitment, which puts a strain on limited drug availability, but there also may be low yields from production that limit drug availability, comparator supply may be delayed — a real problem within the industry that deserves to be considered as a separate topic — or drug supply may have an FDA hold or other delay at the point of importation.
Conversely, there can be oversupply, which is typically indicative of a poor forecast and causes problems with budget control and supply control. Oversupply will result in drug supply expiring before it will be used, forcing the CS team to pull drug supply out of the field while at the same time procuring fresh supply for patients. This puts demand on study control, as it is important to ensure that the limited storage space at sites is not overwhelmed. It also means there has been excessive manufacturing, which increases budgets significantly. All of these impact budgets, study quality, and, more seriously, patient risk.
This may sound like a condemnation of the clinical supplies group, but in fact in many cases the issues are caused by lack of understanding of the role of the clinical supplies group. The CS team is the part of the GMP organization that is a clear participant on the clinical project team. As such, it is responsible for the interface between good manufacturing practice (GMP) and good clinical practice (GCP) when it comes to clinical studies at the project level.
Misconceptions About Clinical Supply
As a clinical supplies professional, I have been told the CS group is only responsible for getting drug supplies to sites, which is as relevant as stating that the formulation team is responsible for mixing a recipe or that clinops is responsible for recruiting patients.
What is further revealing is the concept that the CS operation follows a similar path to GCP — it does not. On a basic level, CS has no responsibility to release supplies for use in clinical studies — they can only be released by GMP QA, and in the EU, by the QP. In the GCP environment there is less of an impact from GCP QA. For example, a packaging operation may only take a few days, yet the release process can take a few weeks. What needs to be understood is the regulatory compliance standards dictate this process and everyone needs to be aware of the dynamics involved. Certainly, the relationship between GMP QA and the CS function is a critical one.
So, the questions are obvious — what does the CS team do and how can we improve the current situation? While this short article cannot address everything CS does — and it is a lot — I will attempt to point out the general nature of the responsibilities of CS teams, their needs, and even some suggestions as to how things can be improved.
Working With Significant Constraints
At the outset, let’s start by clarifying that the drug supplies we deal with are in development, and early phase studies often use a basic formulation or even nonformulated APIs. As studies progress the formulation can and will change as the program matures. Why would this be important? One of the biggest impacts to CS is the expiry dating of the product itself, because as a formulation changes, further stability is required. Consequently, the stability testing that is performed by the analytical group ultimately sets the temperature range for storage and distribution and the expiry dating of the product. Add to that the need to blind drugs. In that case, the CS team needs to develop a blinding mechanism, which further necessitates new stability initiatives, and likely new test methods as well. All of this takes time; however, the opportunity to push back timelines to allow adequate expiry dating is often, understandably, not an option.
Consequently, the CS professional must work with limited expiry dating, while ensuring patients receive adequate drug supply and have supplies available at sites where it is unknown when patients will actually be recruited. If we add to that the fact that, in general, 25 percent of initiated sites never recruit a patient, then the drug volumes at sites that are lost due to lack of recruitment and short expiry dates can have significant impact. Some studies, such as those in oncology, may have only one or two or patients per site, where as cardiovascular study sites may have patient populations that are several times larger.
The dynamics of supplying the drugs are very different and have some essential underlying issues, but the problem remains the same — getting adequate quantities of drugs to patients while minimizing cost and waste. There are some tools and processes that can be used to alleviate the stress; however, doing so requires inclusive dialogue, consideration, and understanding right from the start of program/project discussions — and this is where much of the tension resides. Drug supply is not considered until very late in the game. Patient recruitment, regulatory submission, strategy, and many other aspects are critical, and rightly so, but drug supply and availability are often not considered anywhere close to early enough.
The clinical supplies team cannot prepare supplies without bulk drug, clinical directions as to the nature of the study, and supporting data. There can be multiple delays that are not caused by CS — in manufacturing and delivery of bulk drug, in data to support expiry dating and storage conditions, in determination on dosing regimens and dosing requirements, in country selection, in data for interactive response technology (IRT) development, etc. Any one of these or a combination can cause significant delays, resulting in the CS team not being able to initiate any activities. While some delays can be absorbed to an extent, the bottom rung on the ladder is the CS team, which must absorb the often-accumulating delays filtering down from multiple other functions. But somehow they still need to find a way to deliver supplies in time.
What can be done to support the study initiation? In the case of large multi-country studies, we typically initiate with a single panel label as we go through the process of generating booklet labels, which will allow flexibility in the drug supply. We can reduce the number of kits manufactured to allow the study to initiate, but bear in mind this can impact budgets. CS is limited to availability of manufacturing slots at vendors or even in-house. Vendors have multiple clients, and if you are late, they may not be able to squeeze you in a week later when another company that is not late requires its product. Further, you will be charged late fees, as the vendor will otherwise take a financial impact for having rooms, equipment, and people sitting idle on the hope that your late drug may arrive at some point — again resulting in a budget impact and late drugs.
It is not common practice to take all supplies and prepare as many supplies as possible at the study start — especially for large global studies, as it means that as expiry dating is updated, the labeled supplies must be relabeled. Further, the packaged supplies demand more storage space and hence increased costs, along with additional considerations. As a result, logistics plays an important aspect of CS involvement.
At this stage, it is important to note that the GMP processes in CS are not well understood by other GMP functions. While the concept of blinding may be understood, the process required to maintain the blind during the course of a study, the use of IRTs, and the logistical challenges of importation and shipping channels are not as readily understood outside of CS. For example, when a study is blind, we must ensure there is no possibility of the active drug and the placebo being discernible in any way. This comes down to the appearance of the drug, including ensuring the text looks identical on the outside, both in terms of location and expiry dating. The CS professionals will reduce the expiry dating of the longest expiration-dated product to match that of the other comparative drug, causing the limited expiry dating to be even further reduced. Further, the IRT systems used in support of managing drug supply coordination are something that no other part of the GMP organization (with the possible exception of QA) has any involvement with, and even QA has limited interaction with such systems. The importance of full comprehension of IRT systems cannot be overstated, as this feeds into how most CS teams follow the status of the study, the ongoing patient demand, and the overall logistics and resupply strategy for the study.
How Clinical Supply Can Improve Study Efficiency And Efficacy
All of the above demonstrates the importance of communication through program-level decision making and within drug development. Very often, the CS function is not included in program-level discussions, which occur very early in the development life cycle, and they are very often not a key consideration in early project discussions. If other functions are not fully appreciative of the CS team’s needs, communication will break down, and CS will be left somewhat in the cold. If study managers are considering utilizing a pooling strategy across multiple studies in a program, it is unlikely to happen if the CS team is not involved at the program level. A pooling strategy uses inventory of patient supplies across multiple studies, and it can reduce costs by 40 percent or more while reducing manufactured bulk supply and lessening sites’ storage burdens.
Where does CS reporting functionality reside? In some companies, the reporting lines go through commercial, but the blinding process and IRT are absent from commercial, so in such scenarios, management has no real comprehension of the critical needs of the team. Additionally, from a commercial standpoint, the pressure to get drugs out to market is always a much more critical issue than having to deal with the apparent unknowns the CS team needs to deal with. In some companies, reporting is through CMC, and in others, it is through clinical. There is an obvious danger in reporting directly into the clinical teams, as blinded studies may be compromised. As a suggestion, I believe CS should have complete autonomy and report directly to the R&D head. There are numerous reasons for this.
When the CS group has a voice at the table, it has the opportunity to communicate its needs and requirements. Delays from other functions that might impact CS can be addressed more effectively in terms of lessons learned. This provides the ability to address similar issues adequately for the future, rather than simply receiving an obscure report that CS is late again. If CS timelines are compressed, then shortcuts must be taken in order to meet study start dates. This, in turn, tends to impact the quality of the patient kit, which can influence patient compliance and lead to problems dispensing at site.
The CS team also has its own identity — it is not commercial manufacturing, or CMC, or clinical – it is CS and as such has its own processes and SOPs, and can have a voice that communicates strategic resolution to problem areas.
It can act to reduce conflict, and it can reduce study timeline and costs through processes such as pooling, just in time strategies, direct-to-patient shipments, and improved drug supply forecasting, all of which can reduce costs, reduce patient exposure to risk, increase recruitment and improve patient retention.
The following are some examples of how CS can support the clinical trial and the patient.
The booklet label was created to provide the necessary flexibility to allow multiple countries and patients to have access to limited drug supplies. Having booklet labels enables inventory planning that allows sites to be supplied as and when needed. The labeling of supplies is a huge, complex issue in its own right. Labels for the clinical supplies cannot be generated until the stability data is available and approved in writing. Unfortunately, stability testing cannot be accelerated any more than it already is, as it follows the regulatory requirements. The CS group cannot generate the clinical labels until all data is available and all country translations and approvals are in place. This requires multiple functions to work together, but the essential issue is if there are no labels, there are no patient kits available. Very often clinical studies will initiate in one country with a single language, single panel label while translations are underway.
CS teams have also set up processes that allow for other logistical solutions. The use of IRT strategies, study reporting functionality, and having access to forecasted clinical recruitment rates within the IRT system will allow CSs to plan the distribution strategy for the limited drugs they have access too. As mentioned already, other processes, such as the pooling of drugs across multiple protocols at the program level, reduces overages while allowing for patient recruitment, reduces costs, and reduces drug manufacturing. When combined with a just in time strategy, the savings can approach 50 percent of the cost of running the projects independently of each other.
Further solutions from CS teams allow inclusion of patients who previously were not able to partake in studies and improve patient retention. Such enterprises include direct-to-patient shipments, and there are several strategies to accommodate this. New technologies in development will allow label changes to be made remotely under controlled conditions so that supply labels at sites can be amended electronically.
In conclusion, I would urge clinical study teams to be open and actively listen to what their CS teams have to say and how they can contribute. Involve them earlier in planning. I encourage CS professionals to actively promote their activities and what they need to be recognized as part of the team and overall strategy. I would also suggest that clinical conferences include the role and function of CS in their agendas. CS is often not considered as a key component, but I have never seen a clinical study succeed without study drugs.
About The Author:
David Gilliland earned his Ph.D. from the School of Pharmacy at Queens University Belfast, Northern Ireland. He has worked for more than 20 years on both sides of the Atlantic in support of clinical programs, in both pharma and vendor roles. Most recently David worked as the director of clinical supply operations at Daiichi Sankyo, leading the team in support of all phases of clinical studies, including several mega-trials, and covering cardiovascular, oncology, and pain therapeutic areas. He is currently looking for his next leadership opportunity. You can connect with David on LinkedIn.