By David Gilliland
The ability to maintain patients on drug supplies during clinical studies is of critical importance in support of both the study outcome and the patient. While the ability to ship drugs to sites on the surface appears to be simple, failures to meet demand occur, in my view, far too often.
While many companies approach the management of clinical supplies differently, this article aims to point out some of the issues that impact supply strategies, what is occurring in the industry now to address this, and some important considerations when tackling any study in any therapeutic area.
Single shipments to a Phase 1 site to conduct an early phase study are not the consideration here. However, I intend to critically address the difficulties that are experienced across different therapeutic indications, where the dynamics can be very different, but the same issues persist.
What are some of the issues being faced by pharma/biotech companies, and, in particular, the clinical supply operations (CSO) groups?
Let’s start with country selection, which can change as studies develop or even initiate, as this has several impacts. First, what are the regulations that can impact the timeline to get supplies into countries? Generally, this is region-dependent, and for many countries there are no major obstacles other than having the clinical study appropriately registered. However, within South America, in particular, as well as other regions, requirements vary among countries. For example, in Brazil, the timeline to obtain an import permit, ship the drug, have it get through customs, and then ship to the sites can be anywhere from two to three months. When you add the fact that the drug supply needs to be packaged and released by QA prior to shipping, the forecast of what patient supplies are required is needed as much as five to six months prior to the patients being recruited. This is truly significant, as it requires the CSO team to have a virtual crystal ball, as no-one can confirm exact patient numbers six months in advance. You can, of course, send more supplies than anticipated, but if recruitment is slow you will lose very expensive drugs due to expiry; if you send too little, patients will not have an ongoing supply. Brazil is by no means the only country where import licenses can take a significant amount of time. In addition, other regulations exist that must be adhered to, or you may face impact on drug supply.
I have come across situations in which import permits were about to require upgrading to accommodate importation requirements in a particular country, only to discover the clinical team wished to increase the cap on patients, which requires country regulatory approvals. The impact was that until the approvals for the clinical team came through, the import permit could not be renewed, and hence, we had to stall further recruitment to maintain existing patients on the drug supply; otherwise, new recruitment would have exhausted supplies before new stock could be imported.
Labeling requirements must also be considered. In general, the regulations are similar; however, many countries, including the EU, require items such as expiry dating to be on the patient kits. This is not required in the U.S. Particular warning statements will also vary from region to region. Therefore, just having approved labels in place, fully and accurately translated, and regulatory compliant for all countries is a critical milestone in having drug supply available. So, while bulk drug supply may be available in final packaging configurations, if labels are not available, there is no drug supply to allow studies to initiate. No QA professional will release supplies to patients without all label requirements being fulfilled and applied to the patient kits.
The other rather important aspect I should add here is that there are regulatory requirements for the GMP process that must be fulfilled. This is not an insignificant responsibility, and both the quality organization and the clinical supplies operations have a responsibility to comply from an operational and regulatory perspective. An all-too-important item, which should further be borne in mind, is if the bulk drug is being shipped into the U.S. from outside the U.S., which cannot be done until an IND is filed. As a result, there should be adequate consideration of timing and patient kit design requirements so that all materials can be made available in a reasonable time frame. Indeed, patient supplies cannot be shipped into a country without country-specific regulations being met.
This leads nicely into the next critical item facing the clinical supply project manager – what is the recruitment forecast? As mentioned, it may be difficult to predict all the countries that will eventually take part in the clinical study and, indeed, countries can change, but forecasts of which countries will initiate and when, the expected rate of sites initiating in each country each month, and the number of patients expected per site per month are rarely available and very often change remarkably. Let’s be clear: the expectation is not 100 percent accuracy, but it should be within +/- 30 percent. If I have that, then I can say with complete confidence (subject to planned bulk drug availability) that supplies will be continually available, as and when needed, despite study size or longevity.
I do not believe this is asking a lot, since the sites are pretty well established and the investigators are often well known, so their abilities to recruit patients within a particular therapy are fairly predictable. What is being asked for is not the number of patients being recruited at each individual site but a general forecast of recruitment rates across all sites within the region. It would also be the expectation that this is not the first time running studies in a particular therapeutic area at such sites. Even with this data, lack of availability of drug supply still occurs, and there are many reasons for it, some of which are down to the CSO project manager. There are issues at play across the complexity of the clinical study, and I have seen studies where forecasted recruitment rates were off by a factor of two. In other situations, recruitment rates increase dramatically coming up to holiday periods, so it is important that clinical supplies PMs have an understanding of holidays around the globe. They should strategically plan to ensure ongoing drug supply during such times, as shipping routes are overwhelmed, especially during the Christmas and New Year season, with people on vacation and many companies closed at least for a few days.
Therapeutic Area-Specific Challenges
What are the issues in particular therapeutic areas that impact ongoing supply requirements? If we look at large-scale studies, such as cardiovascular disease (CV), the most obvious issue is the scale – since many of these studies treat thousands, often tens of thousands of patients over many years. It is not reasonable, however, to simply manufacture supplies on a large scale, as a low initial recruitment rate will result in bulk drugs sitting in warehouses and eventually expiring. This will eat into budgets very quickly, both with storage costs and additional API demand and manufacturing costs, plus you now are required to remove all expired product from the field and replace it. If there are comparators involved, then add to that the need to purchase and acquire supplies plus any blinding operations and stability requirements. This is where a reasonable forecast comes in, as you plan manufacturing operations based on demand. Over time in these studies, the expiry dates will improve as ongoing stability develops, and this should alleviate the stress, as should the eventuality that recruitment of targeted patient populations is achieved. Once in the maintenance phase, you should be in a situation in which you know where all patients are and their demand for future supplies is easily understood.
Let’s compare this with oncology studies at the other end of the spectrum. Unfortunately, in many of these studies patient survival is the key criteria. If the drug under investigation is good, we do expect those patients receiving the study drug to survive longer, although it might be a short time. So, while with CV studies, we typically have a general understanding of the timeline needed, we can have an oncology study that may be short-lived or might extend for many months, or even years, for some patients. Additionally, many of the drugs involved are biologics, for which the yields are often low; patient recruitment at sites may only be a single patient or just a few; and the recruitment period can be extensive. Add to this the short expiry dating, ongoing improvements in cell lines, and formulation changes, and the picture starts to emerge that one cannot, again, simply have a lot of supply on hand, nor supply with comparative long expiry dating, to cover the low patient numbers at sites. Due to the study requirements and the nature of the patient populations, it is rare to have a maintenance period for such studies, and even if there is one, it is typically too short. While there are many other issues at play in managing clinical study supplies, at least the logistical challenges should be clear from the above discussion.
Part 2 of this series on ensuring adequate drug supply will look at ways to achieve accurate and strategic management of the clinical supply inventory.
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.