The Challenges Of Performing Global Trials

By Ed Miseta, Chief Editor, Clinical Leader

Clinical trials are never an easy endeavor. Issues with patient recruitment, retention, regulatory, supply chain, and a myriad of other reasons present challenges for both pharma and CROs. When performing global trials, many of those issues are compounded as political turmoil could get added to the mix.

To gain an understanding of the challenges that exist when performing global trials, we enlisted the help of three experts to describe issues they have experienced firsthand.

Our panel consisted of:

COLOMBIA AND PANAMA
Be Aware Of Travel Requirements

James Bainbridge has been with Prolong Pharmaceuticals for three years, currently serving as associate director of clinical development. He has worked in the pharmaceutical industry for just under 20 years, working in a clinical capacity for Covance, Ortho McNeil, Ethicon, and Medarex. He also provided legal support to the New Jersey Office of Attorney General and the U.S. District Court in New Jersey before joining Prolong.

How long have you been doing trials in Colombia/Panama?

Prolong Pharmaceuticals is developing products to treat anemias and cancers and has a portfolio of hematology and oncology products in development. The company’s lead product, SANGUINATE, is in clinical testing and is focused on treating the comorbidities of sickle cell disease and other disorders caused by ischemia, hypoxia, and/or hemolysis. It is the company’s research in this area that led it to trial sites in Colombia and Panama.

The first trial for Prolong Pharmaceuticals in this region was in 2012, so we have been performing trials there for just under three years. Personally, I have had experience performing trials in this region for approximately 10 years. We are able to find patients of sickle cell disease not only in Colombia and Panama but also in other Latin American countries. We certainly have those patients in the U.S. as well, but in looking at patient populations, the regulatory environment, and other considerations, we felt these locations would work well.

Are there specific challenges to performing trials there that are due to the current political climate?

The answer to that is no, and I often find people to be a little surprised when I tell them that. Panama has three branches of government, just like in the U.S., and an elected president. I believe Colombia is currently the fastest growing large economy in South America.

While Panama does not have issues with stability, there is certainly less infrastructure than you might find in more developed countries. Ensuring ethics committees are compliant with ICH-GCP standards can also provide a bit more of a challenge due to the number of ICH-GCP certified ethics committees that exist in Panama.

Editor’s Note: Panama was a democracy for most of the 20th century until a coup in 1968 brought the military to power. After the U.S. operation to remove General Noriega from power in 1991, the country became a constitutional representative democracy. The current armed conflict in Colombia started in the 1960s and is a low-intensity war between various groups including the Colombian government, paramilitary groups, crime syndicates, and left-wing guerrillas. However, Colombia has become much more stable of late. President Juan Manuel Santos Calderon, elected in 2010 and reelected in 2014, has made ending the conflict a priority of his presidency.

Getting needed medicines to patients can always be a challenge, but even more so when performing trials in different parts of the world. Were there any supply chain issues you had to deal with?

I find this is not an issue in most major cities, particularly in Colombia. That being said, it may be more of a concern in Panama due to a smaller population. However, using a depot is recommended, when feasible, to avoid import delays. Depots can be used for different reasons, but we had multiple centers so we imported drug in bulk to one location. That way we can provide each site with the minimum supply we believe is required. If a patient comes in, the drug will be available to them. But if no patients enroll or come in, we can minimize the amount of wasted drug. Once you ship a drug to a site, you don’t want it back. By having a depot handle the distribution we can mitigate a lot of that risk.

A thorough audit of the depot, as well as the central laboratory for exporting of samples, should always be conducted. That is just good clinical practice. No one wants to invest a million dollars into a trial only to discover you’re dealing with a central lab that is not GCP compliant or puts your data at risk. The same is true of a depot. If the drug in question is a biologic that must be maintained in a required temperature range; not auditing that facility would once again put your trial, or worse your patient, at risk. As the sponsor running the study you have the obligation to make sure the vendor you use is following the right practices.

In Panama, I think the patients seem to be a bit more apprehensive than they are in Colombia, but that may have more to do with the regulatory infrastructure than anything else. In Colombia they have numerous IRBs and a stronger regulatory authority. I believe they do more trials there as well, which builds more patient trust in them.

Patient recruitment and retention is a hot topic in pharma today. Was this a challenge you faced and how were you able to overcome it?

The primary issue, as is the case with many trials, is overstatement of the patient recruitment potential by the investigators and sites. Questions which were very relevant to the enrollment issues were raised only after 50 percent to 75 percent of the enrollment had been achieved. The protocol discussions should focus on foreseeable recruitment obstacles and their impact on enrollment. When those obstacles and concerns are disregarded on the front end, they may carry a heavy cost on the back end.

In addition to recruitment, logistics also became a concern. Patients are often recruited from areas which require travel-reimbursements and even hotel accommodations for spouses and other family members. These payments are reasonable and are generally expected. However, when there is a possibility that travel payments may come into the picture, it is important to have up-front discussions about the areas from which we will be recruiting those patients. In some countries, a city or town just a few hundred kilometers away could end up being a 6- or 7-hour trip. In many cases, the patients must make that journey by bus.

This travel is also highly contingent upon other factors. An advanced oncology patient may not be able to travel great distances. But you may also have patients whose indication is so rare that they are willing to travel great distances to get the help they need. Also a patient won’t mind traveling several hours for an inpatient study that might take a week, but would be less willing to do so for a study that requires weekly visits over a period of several months.

Were there any specific regulatory issues you had to deal with that made the conduct of trials particularly challenging in this country?

We do not find the regulatory environment to be an issue, but at the same time communication with the Colombian regulatory authority is constant. The interaction seemed to be very paperwork- intensive, although this was mainly due to the difference in language and necessary translations, not the Colombian government or its regulatory authority. I was constantly getting copies of the paperwork that was going to regulatory authorities, as opposed to a quarterly or for-cause update. INVIMA (the Colombian National Institute for Food and Drug Surveillance) will provide confirmation of receipt, and there are translations and translation certificates.

I do not believe the Panamanian Ministry of Health provides approvals for clinical trials, only the import permit. Panama relies on the EC for the approval.

Editor’s Note: While language is generally not an issue, in 2013 INVIMA released a communication stating registration materials pertaining to biocompatibility, risk analysis, sterilization, and clinical studies and test reports could be submitted to reviewers in their language of origin. Summaries of study descriptions, methods, and conclusions must be provided in Spanish.

Any thoughts on what the future of clinical trials might look like in this country? Are there any changes on the horizon that might make the conduct of them easier or more difficult?

I believe the future is evident in the growing number of trials that have shifted away from regulatory-burdensome locations such as Brazil and Argentina, and into Colombia due to the increased stability of the government. Panama has seen an increase in clinical trial activity as well. It is worth noting that many of the physicians have trained and/or practiced in United States or Canada. Panama appears to have some site management organizations that actually operate out of Florida. This makes contractual issues a bit easier.

FRANCE
Patient Recruitment

Linda Strause has a Ph.D. in neurophysiology and biochemistry and has spent over 24 years in education and the pharmaceutical industry working for Quintiles, ACRP (Association of Clinical Research Professionals), Vical, Strategic Clinical Consultants, and her current employer, Strategic Clinical Consultants. Much of her experience is in improving the overall conduct of clinical research programs, with a specialty in oncology and global outsourcing selection and oversight.

What experience do you have performing trials in France?

I recently conducted three melanoma trials in France. There was a fourth trial I conducted there, but that was pre-EU directives, which really changed the paradigm. France is one of the largest R&D member states in the EU. It has a large population, a good medical system in place, and has great thought leaders and scientists. This makes it a popular place to conduct Phase 2 and Phase 3 trials, and what primarily attracted us there.

Are there specific challenges to performing trials there that are due to the current political climate?

The political situation is stable and there were no concerns that we had in regard to the political climate.

Getting needed medicines to patients can always be a challenge, but even more so when performing trials in different parts of the world. Were there any supply chain issues you had to deal with?

There is a QP (qualified person) release that is required to ship investigational products into the EU. Most U.S. companies get QP release out of the U.K. and once you have a qualified person release your product, it can be distributed throughout the EU. However, when shipping to France, there is an additional release that is also required to be completed.

Another way that France is different from the U.S. is in regard to privacy requirements. For example, you cannot use both initials and birthdate, which is how most case report forms are completed. We needed the birthdate because most protocols call for patients to be over the age of 18, and that is how we would determine age. To deal with this issue we actually came up with a code to use throughout the EU.

Patient recruitment and retention is a hot topic in pharma today. Was this a challenge you faced and how were you able to overcome it?

In France, patient recruitment can be a little tricky because they do not allow for direct patient recruitment through billboards, the Internet, or other forms of advertising. All recruitment must be done through doctors and patient organizations. Patient consent forms are also much simpler than they are here in the U.S. There is an information sheet that cannot be longer than two pages. So often what we did was have a complete informed consent and a separate two-page information sheet to comply with that requirement. Everything is written in French so there are a lot of translations that have to be performed as well.

Because our study was for melanoma, we worked primarily through the physicians, because that made the most sense to us. They did the outreach and connected with hospitals as well. I have found you are really at the mercy of the investigator. The investigator drives everything, and I think that is true throughout the EU.

Were there any specific regulatory issues you had to deal with that made the conduct of trials particularly challenging in this country?

Ironically, the healthcare in Europe is different than the healthcare here. For example, you have to publically disclose your clinical trial for 90 days before you can do anything. That can be a challenge because there is certain information you need to disclose, but because it is public you don’t want to disclose any proprietary information that should be kept confidential. I have never heard of anything coming from this requirement, but if someone felt the trial might be unsafe for some reason, they would have the opportunity to make their voice heard.

The EU directive was meant to harmonize across all member states but also allowed each member state to incorporate it into national laws. France was rather slow in implementing the directive. I do not believe that happened until several years after the directive was issued. For that reason not all EU states are created equal, and sponsors will have to do some research into the specific EU nation they wish to conduct trials in.

But at the same time, France does have a true central ethics committee. It is one committee that governs all of the hospitals in the country, which makes working with that committee much easier.

Any thoughts on what the future of clinical trials might look like in this country?

I don’t think so. It is one of the largest countries in which to conduct trials and I don’t see that changing. The investigators and key opinion leaders who run their labs, and the physicians who work for them, are really amazing. They also do a lot of speaking at conferences.

Biologics are big right now, as are bio safety committees. France has a very active one. As we transition into personalized medicine, I believe this will be a key place for pharma to conduct trials for years to come.

EASTERN EUROPE
Complex Supply Distribution

Erin Bettine is a clinical supply chain consultant with over 20 years of experience in pharmaceutical and biotechnology product development. Much of her career was spent as Head of Clinical Supply Management at Wyeth Pharmaceuticals. In 2008, Erin joined the International Partnership for Microbicides (IPM) managing HIV prevention product development projects. More recently, she led the Clinical Supply Chain group at Nuron Biotech.

How many years’ experience do you have performing trials in Eastern Europe (including Belarus, Bulgaria, Croatia, Hungary, Poland, Russia, Serbia, Ukraine)?

I performed trials in this region for two years, from mid-2012 to mid-2014.

Are there specific challenges to performing trials there that are due to the current political climate?

Fortunately, the political climate in Eastern Europe did not have a noticeable impact on the trials that I was involved with. Minor protests and uprisings did not prevent site and CRO staff from performing their duties. Even during the first few months of the Crimean Crisis, patient visits, monitoring visits, and supply shipments continued as scheduled. Our trials completed shortly thereafter. There is no doubt that the potential for political instability carries some risk, and that must be weighed against the potential benefits. In our case, this region was able to recruit patients very quickly. I have heard of other clinical trials in which some Ukrainian sites had to be closed due to the conflict. This risk was mitigated by the involvement of other, less volatile, regions.

Getting needed medicines to patients can always be a challenge, but even more so when performing trials in different parts of the world. Were there any supply chain issues you had to deal with?

Supply distribution is complex in many regions, maybe a little more so in Eastern Europe. It was helpful that our clinical supply production site and central warehouse was in a European Union (EU) country. This made the movement of material to sites in the Eastern EU countries, i.e., Bulgaria, Croatia, Hungary, and Poland, fairly easy. It was more challenging in non-EU countries of Russia, Ukraine, Belarus, and Serbia, with requirements for import licenses and permits. Each of these countries has different requirements and timelines for approving the importation of clinical supplies.

After approval, the time needed to schedule and transport the supplies, as well as the courier cost, can also be significant. It was, therefore, essential that depot warehouses be established in those non-EU countries so that supplies were in country well before supplies needed to be shipped to the study sites. Employing a CRO with local regulatory expertise and a CMO with local logistics expertise was critical to our successful supply distribution.

Patient recruitment and retention is a hot topic in pharma today. Was this a challenge you faced and how were you able to overcome it?

Currently, there is less competition from sponsor companies for investigators and patients in these emerging markets, compared to the more traditional clinical trial locations. This, combined with the large pool of treatment-naive patients, good access to healthcare infrastructure, and highly motivated investigators, made the patient recruitment process quite rapid. In fact, the rate of patient recruitment sometimes threatened to exceed the available drug supply, and investigators had to delay enrolling new patients into the study. This was an unexpected situation, quite opposite of my usual experience in which recruitment lags behind projection. So, the challenges were to accelerate the delivery of drug supplies and to maintain a good relationship with the investigators during the delay.

Patient retention and compliance was also quite good in this region. This may have been due to the indication being studied and limited access to alternative treatments. Even though many patients had to travel a great distance for scheduled visits, very low dropout rates were observed. It was important to have an adequate visit window and to dispense enough extra study medication to continue treatment when visits were delayed due to weather and other travel obstacles.

Were there any specific regulatory issues you had to deal with that made the conduct of trials particularly challenging in this region?

The regulatory requirements for the Eastern European countries that are part of the EU are well-established and easier to navigate, although the timelines for approval of the Clinical Trial Application (CTA) can vary between member states. In some of the other countries, specifically Russia, Ukraine, and Belarus, there have been recent changes in regulatory guidelines and processes. Reorganization of the Ministry of Health in Russia and changes to the ethics approval process in Ukraine initially produced some unexpected delays. But now things have adjusted, and the process is improved compared to the time before the changes were implemented. Overall, there has been an effort to decrease the difficulty of getting trials launched in this part of the world while at the same time ensuring the protection of human subjects and setting standards for investigational site qualification.

Any thoughts on what the future of clinical trials might look like in this region?

I expect the clinical trial activity in Eastern Europe will continue to increase. These countries are interested in the revenue and access to new medicines that clinical trials bring. Recent changes to the regulatory processes have made it more feasible, and often quicker, to initiate trials in this region. As sponsor companies gain experience in these countries, realizing the benefits of a large, diverse population and becoming comfortable with the quality of investigational sites and clinical data, it is likely that more global trials will include this region.