Navigating The Regulatory Landscape For Therapeutic Radiopharmaceuticals

There’s a growing industry curiosity about radiopharmaceuticals, particularly regarding those that are therapeutic as  opposed to diagnostic. Many of us are familiar with nuclear imaging and how it has significantly impacted diagnostic medicine. The FDA defines a diagnostic radiopharmaceutical as (1) an article intended for use in the diagnosis or monitoring of a disease or a manifestation in humans and that exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons or (2) any nonradioactive reagent kit or nuclide generator that is intended to be used in the preparation of such an article. Diagnostic radiopharmaceuticals are generally radioactive drugs or biological products that contain a radionuclide that typically is linked to a ligand or carrier. Diagnostic procedures generally involve the use of relatively small amounts of radioactive materials to facilitate imaging of certain organs to help physicians locate and identify tumors, size anomalies, or other physiological or functional organ problems. Although traditionally referred to as nuclear medicine, no medical claims are made regarding patient treatment for these valuable nuclear diagnostic treatments. 

Therapeutic uses of radioactive materials are typically intended to kill cancerous tissue, reduce the size of a tumor, or reduce pain. Advances in theragnostics, the use of molecular diagnostic techniques, e.g. the identification of the enzymes one person makes that another does not, to guide treatment decisions such as the choice of drugs that will be optimally metabolized by a particular patient, are paving the way for new therapeutic applications of radiopharmaceuticals. Over the past decade or so, many of the key nuclear imaging and manufacturing companies have been moving toward making a larger impact when it comes to treating rather than diagnosing patients following the underlying principles of theragnostics.

There have long been numerous global and local regulations for how nuclear materials are transported, compounded, monitored, and dosed for the purpose of diagnostic evaluation. These continue to be applicable for both diagnostic and therapeutic nuclear medicines. However, establishing therapeutic medical claims for nuclear medicines increases the list of regulations that must be followed. The regulations and expectations of the FDA and other global regulatory authorities are the same whether a therapeutic medication includes nuclear elements or not. This added complexity is new territory for some in the nuclear medicine field. 

How Radiopharmaceuticals Are Regulated And By Whom

When we hear the term nuclear, we instantly think of power, weapons, and all the scary things that can happen without extremely tight controls. So how do national, state, and local governments ensure that medications, either diagnostic or therapeutic, containing nuclear elements can safety remain part of our medical repertoire? It’s complicated, and that complication is increased when radiopharmaceuticals are therapeutic vs. diagnostic. Radiopharmaceuticals are used worldwide; however, we’ll focus on how they are regulated within the U.S. 

The FDA, U.S. Nuclear Regulatory Commission, and State Boards of Pharmacy all play pivotal roles in regulating and monitoring how radiopharmaceuticals are developed, manufactured, marketed, distributed, and administered. It’s important that companies and staff involved in the radiopharmaceutical business understand how the various regulations apply and dovetail to ensure that all bases are covered, particularly as they move into the therapeutic market.

The U.S. Nuclear Regulatory Commission

The U.S. Nuclear Regulatory Commission (NRC) and its Agreement States license and regulate the possession and use of radioactive materials for nuclear medicine. The NRC has agreements with many states; in this scenario, the Agreement State either adopts NRC regulations or develops its own to monitor the use of radioactive material within the state. Their focus is on the mechanics involved.  NRC/Agreement State regulations are designed to ensure the proper use of radioactive materials in medical diagnosis, treatment, and research to ensure the safety of patients, medical workers, and the public, and to protect the environment.

The NRC/Agreement States regulate nuclear medicine with a focus on the nuclear aspects.  Like the FDA, they follow the U.S. Code of Federal Regulations (CFR). Their oversight is based upon two specific parts of the CFR: 10 CFR Part 20, Standards for Protection Against Radiation and 10 CFR Part 35, Medical Use of Byproduct Material. These regulations limit the amount of radiation that a worker, member of the public, or patient may receive, establish the controls that a licensee must exercise over radioactive materials, establish training and experience requirements for users of the materials, set quality management and reporting requirements, and provide a number of technical and administrative requirements for the possession and use of the materials.

State Boards Of Pharmacy

The practice of nuclear pharmacy is a state licensed professional activity in which radiopharmaceuticals are prepared pursuant to prescriptions and are dispensed to specific “authorized practitioners” because NRC regulation prohibits dispensing these drugs directly to the patient. The individual activities of the licensed nuclear pharmacy and the licensed nuclear pharmacist are regulated by the State Boards of Pharmacy. Since most nuclear medicine products are injectable, the primary regulatory focuses of the boards of pharmacy are pharmacy practice and sterility rather than radiation safety.  

The FDA

In 2004, the FDA published a three-part guidance, Developing Medical Imaging Drug and Biological Products, to clarify expectations on imaging agents, which includes diagnostic radiopharmaceuticals. The guidance states that “medical imaging agents generally are governed by the same regulations as other drug and biological products. However, because medical imaging agents are used solely to diagnose and monitor diseases or conditions as opposed to treat them, development programs for medical imaging agents can be tailored to reflect these particular uses.”

Once approved, the lion’s share of regulatory responsibility for diagnostic radiopharmaceuticals shifts to the NRC/Agreement States and State Boards of Pharmacy. The regulatory focus is on the nuclear elements of the diagnostic agent.

For the public safety elements on which the NRC/Agreement States focus, therapeutic nuclear medicine is generally accepted as having a comparable safety profile to that of diagnostic nuclear medicine. However, a new layer of FDA regulations comes into play for both investigational and marketed radiopharmaceutical therapeutic products. These products no longer fall under the 2004 FDA Guidance. Their development must follow 21 CFR 312 and all the others that apply to any other therapeutic investigational product. In addition, upon approval, they must also follow 21 CFR Part 314.  This means that pharmacovigilance regulations come into play as well.  And this is just in the U.S.  Global regulations may apply depending on the clinical development and commercialization goals.

FDA regulations for drug development and post marketed safety do not specifically address radiopharmaceuticals. In August of 2019, the FDA published a guidance, Oncology Therapeutic Radiopharmaceuticals: Nonclinical Studies and Labeling Recommendations, a signal to industry that the FDA has recognized the need for guidance for this evolving niche. It seems it is tackling the topic logically, given the drug development process and the primary area to which these products are initially being applied: oncology.

Key Regulatory Challenges For Therapeutic Radiopharmaceutical Development & Commercialization

Most companies and other industry players involved in radiopharmaceuticals have traditionally been active in the diagnostic space, rather than therapeutic, where satisfying the more stringent and defined NRC/Agreement States and State Boards of Pharmacy regulations has been the focus.  Adverse reactions to diagnostic radiopharmaceuticals are still not consistently reported worldwide as they have yet to be clearly defined. As they move into the therapeutic arena, it’s foreseeable that a knowledge and experience gap will develop. Radiopharmaceutical manufacturing companies will need to call upon those in the traditional pharma arena to help ensure that their drug development and commercialization strategies incorporate all applicable FDA and global regulatory requirements and that they are inspection ready. 

Once radiopharmaceutical companies move into the therapeutic arena, they not only have to continue to follow all of the FDA, NRC/Agreement States, and Boards of Pharmacy requirements that apply due to the nuclear aspect of their product, they must also satisfy every regulation that traditional pharma companies have been operating under for decades.  As with any pharma company these days, all this needs to be planned and executed in a way that makes practical sense, addresses key risks, and stays within established budgets and timelines. Strategies they have relied on for diagnostic products will no longer suffice.

About the Authors:

Penelope Przekop, MSQA, RQAP-GCP, partners with pharma and biotech companies of all sizes to develop risk-based strategic solutions for establishing (or enhancing) clinical and pharmacovigilance quality systems that support growth and ensure long-term compliance. She has 25-plus years of industry experience in strategy development, quality systems and assurance, inspection readiness, and organizational training. Przekop has held leadership positions in both Big Pharma and CROs, including Novartis, Covance, Wyeth, and Johnson & Johnson. She is the author of Six Sigma for Business Excellence (McGraw-Hill) . Her upcoming book, 5-Star Career: Why You Don’t Have Yours Yet and How to Get It (Productivity Press) launches in late 2020.

Mark Przekop, R.Ph., is a commercial and operational leader with more than 25 years of pharma industry experience. He has worked and consulted with numerous radiopharmaceutical companies, including both manufacturers and pharmacies. He is often sought out for his nuclear industry experience, both from an operational and commercial perspective. He is the former vice president of Pharmacy Services | East and vice president of operations at Jubilant DraxImage Radiopharmacies. He has also held leadership positions at GE Healthcare and Amersham Healthcare.