Radiopharmaceutical therapy isn’t exactly new — using radionuclides to target cancer cells via an antibody or other conjugate has been in clinical trials for well over twenty years — but it continues to challenge how clinical trials are run across borders.
Due to the complexity of regulatory requirements within each country, clinical trials in radiopharmaceuticals run the risk of becoming delayed due to a myriad of possible complications. Because progress isn’t just about advancing new therapeutic agents but also navigating through the new regulations needed for these radioactive isotopes to travel about the world.
“Using radiopharmaceuticals as treatments is the biggest change over the last few decades,” says Rhonda Critchlow, Director of Operations, Oncology at PSI CRO. “Originally the only treatment was for thyroid conditions. Now we’re seeing it for prostate cancer, treating bone metastases, some neuroendocrine tumors, with more indications to come. We’re seeing a lot more of those products that are in clinical trials or moving out to approval.”
Nuclear medicine therapy uses radiopharmaceuticals to target specific tumors by delivering radiation to cure or control the disease. It can also be used either on selective targets or throughout the entire body or even combined with immunotherapy which uses the body’s own immune system to target the disease. When monoclonal antibodies are paired with a radioactive substance they can target cancer cells and deliver high levels of radiation directly to the tumor. Zevalin® (Ibritumomab tiuxetan) was the first pharmaceutical for radio-immunotherapy commercially available worldwide. In February 2002, the U.S. Food and Drug Administration (FDA) approved it for the therapy of recurrent and resistant forms of low-grade follicular B-cell non-Hodgkin’s lymphoma.
But we’re not talking traditional drugs: we’re talking about administering a product that has a very short half-life quickly starts to decay and become inert, hampering its usefulness to the patient. Cooperation and coordination is imperative every step along the way: from the facilities and procedures where the nuclear material is produced, to their handling and storage, all the way to the transportation of the drug and dispensation. In extreme cases, sites need to be chosen due to their proximity to the manufacturing site, with transport plans & timelines showing the maximum distance between the two locations. At every stage of its life, from its creation in the cylinder (called a cyclotron), or a reactor, to when it is given to a patient, and even beyond that, stringent regulations abound, especially on a global scale.
Many radiopharmaceuticals are now in clinical trials or moving out to approval. But timeliness defines each and every turn. Rhonda Critchlow points out, “In the US, the regulatory issues are as big as those outside of the US. But it’s true for just about any country that when it comes to these drugs; it’s all around the timing. There are always things that come up that you have to be ready for.” Anticipation is key.
When it comes to radiopharmaceuticals, regulatory is the name of the game. Stringent regulatory guidelines above and beyond the normal process have the possibility of hampering the process every step of the way. Having a CRO that understands these new regulations, not just in one country but many is imperative. Delays can occur, for example, in obtaining core submission documents. When there are queries from competent authorities those queries can take time to answer and resolve.
Having only limited experience with the regulatory process in multiple regions for clinical trials can lead to long delays. “In Europe, every country and almost every site has a different set of rules,” says John Round, Director of Business Development at PSI CRO. “That’s the added value we provide our clients simply because we’ve been involved in this area long enough, so we know what the rules are for 17 countries in Europe. There are a lot, and they’re all different.”
This is especially the case outside of the US. According to the National Center for Biotechnology Information, “in every single EU member state there is national legislation on medicinal products referring to EU directives, and in some instances, to regulations issued by the national competent authorities. Despite their shared references to the relevant EU directives, national regulations are not exactly equivalent to each other.”
Alan Morton, a Supply Chain Manager for PSI, explains that “transportation across borders needs to happen in accordance with the International Air Transport Regulations (IATA) Dangerous Goods Regulations (assuming it is being transported by air – other regulations cover surface transport). These govern how the supplies should be packaged and labeled for transport depending on the type and activity of the material being transported. US 49CFR Part 173 provides this direction for moving the material within the US.”
These directives are often based on jurisdictional politics and not usually on scientific evidence. This can hinder country cooperation which can lead to untimely delays and higher costs.
A good example is Germany. The Federal Office for Radiation Protection (BfS) must grant additional approval. This review can take time, almost seven months. Additionally, selected sites require specific training certificates. Plus, the manufacturing process is very different between a clinical trial vs routine practice, which means that a special manufacturing license is required for anything involving nuclear pharmacies.
The US requires approval from the Radioisotope Review committee, and that is needed before IRB submission for most sites. The sites that use Central IRBs are usually approved within 3-4 months. However, there are some that have to go through local radiation committee approval and local IRB waivers that will take 4-6 months to approve.
In Finland, an ethics committee and Regulatory Agency (Fimea) conducts reviews of studies with radiolabeled diagnostic ligands. Fimea recommends that a trial-specific calculation on radiation burden is included into submissions packages and that the radiation burden calculations are outlined in order to reduce delays.
Regulatory challenges just scratch the surface. There are even more obstacles standing in the way of running successful radiopharmaceutical clinical trials. Additional time, resources, and budget are required for applications for radiolabeling. CROs with little or no experience in radiopharmaceutical clinical trials often struggle to coordinate all these shifts in their typical mode of operation.
Only a few nuclear pharmacies can provide the needed expertise and support for such trials, including staff and facility adjustments. There are also restrictions to site locations. This is because of the instability of the radiolabeled product, if it is to be transported to a single-photon emission computerized tomography (SPECT) facility for example.
This also extends to the imaging devices used to track the isotype inside the patient. All cameras used in the radiopharmaceutical clinical trial have to be validated. There’s a whole process required to validate cameras across sites. And that needs to be done before you even start the study. Knowing that validation has to occur and making sure it occurs in a timely manner, gets documented and submitted and proofed is all part of running that trial.
Even the manufacturing of these supplies becomes a concern. “Normally supplies are packaged, released for a study, then have some time prior to being dispensed to a patient – in some cases, this can be months or years,” Alan Morton points out. “Due to the sometimes very short half-life when shipping ‘hot’ products, it is not uncommon for radiopharmaceuticals to have the manufacturing process to be turned backward and be scheduled to meet with a specific patient visit. This means that the production, release (QP Release, if within the EU) and transport to the site need to be coordinated with absolute precision in order to meet with the date & time of the patient visit.”
Currently, each country has their own set of rules and regulations for radiopharmaceuticals. There is no uniformity at present, so understanding the granularity and variety at the country level is imperative.
An article by the Journal of Nuclear Medicine states that “extensive documentation is required for investigational submissions. Although use of the common-technical-document format has been undertaken, a harmonized format between regulatory authorities and radiopharmaceutical-specific documentation has not yet been realized. This realization is vital, because reform and standardization will streamline submission preparation and review time and potentially decrease costs. An effort as simple as harmonizing submission document names between countries would be a significant step in more effective communication between jurisdictions.”
The Next Phase
Harmonization may take time to implement — if it can even be achieved. Granted, this is nothing new in terms of regulatory requirements; however, keeping abreast of new laws and requirements that crop up daily for radiopharmaceutical therapy is the key to successful clinical trials.
The ability to safely bring this new treatment from the clinical trial side to the bedside of the patient is paramount. Creating uniformity across global borders is still a long way off. Until then, clinical research organizations must be diligent and informed about the complexities of the regulatory process for radiopharmaceuticals. Only through knowledge and cooperation will clinical trials in this therapeutic area continue to move toward timely success.