Regulatory Strategy for the Submission of CMC Information to Support the Use of Radiolabeled Drugs in Clinical Trials

Introduction

This paper addresses the use of radiolabeled compounds in clinical research, in particular the considerations involved in regulatory submissions where radiolabeled compounds are used. Specifically, this paper covers the following topics:

• the importance of microdosing (sub-pharmacological amounts)
• an overview of what Chemistry, Manufacturing, and Control (CMC) documentation is needed to support the use of radiolabeled compounds in various scenarios, including specification setting, regulatory submission, and QA release
• a point-by-point examination of current regulatory expectations for the investigative use of radiolabeled compounds in the United State, European Union, Canada, and Japan

Why use radiolabeled drugs in the development process?

The key advantage of a radiolabeled drug is that radioactive materials can be detected in very small amounts. Materials labeled with beta emitters such as ¹⁴C or ³H (tritium) can be detected by counting the beta particles emitted in the course of the decay of the radioactive isotope. Materials labeled with either gamma emitters such as ¹²³I or ⁹⁹Tc or positron emitters like ¹⁸F can be imaged in vivo. One example of radiolabeled drug use is in Absorption, Distribution, Metabolism, and Excretion (ADME) studies. In the development of a drug it is necessary to find out how much of the material gets into the body by the chosen route of administration, how the drug is distributed once in the body, how it metabolized, and, finally, how it and its metabolites are excreted. Since the drug is diluted by being distributed throughout the body, it may be challenging to develop sufficiently sensitive analytical techniques to detect it. This is where the use of ¹⁴C or ³H can be valuable. It is important to remember, however, that what is being detected is the radioactive atom, not necessarily the whole drug molecule.

Not all drug development studies with radiolabeled material place the label on the drug itself. It is possible to use other labeled molecules with known affinity for certain receptors in vivo to evaluate the effect of the study drug on that binding. If the known molecule is labeled with a positron emitter such as ¹⁸F, it may be possible to measure displacement of the labeled drug from receptors by the study drug in living subjects. Such studies can provide a proof of concept that a potential drug molecule will interact strongly with a particular receptor. A third type of use for radiolabeled materials in drug development employs standard Nuclear Medicine tests to evaluate the impact of a potential drug on a particular body function such as cardiac ejection fraction, urinary excretion, or biliary excretion. In this case, since standard tests are used, there is no need to specifically address the radiation exposure received by subjects in clinical trial application, as there would be for the first two examples, as these are well known for the type of tests employed.

Pharmacological Dose vs. Microdose

In general, radiolabeled drugs are given at extremely low doses, in terms of the number of molecules. That is, a dose that provides sufficient radioactive material for imaging, or evaluating ADME, represents only a small amount of the drug when compared to a pharmacological dose of the non-radioactive drug.

Consider 2-fluorodeoxyglucose (FDG), a glucose analog that is widely used, labeled with positron emitting ¹⁸F to provide in vivo images of glucose metabolism. The amount of ¹⁸F fluorodeoxyglucose would be about 10 nanograms [1]. In fact, this amount would be somewhat more due to the fact that non-radioactive fluorine is deliberately added to ensure ease of transfer and improve reaction completion.

Nevertheless, the amount given of a radiolabeled drug is generally orders of magnitude below what would be expected to produce any pharmacological response. In practice, the potency of the drug is evaluated based on toxicological studies and early dose-finding studies in humans. The term ‘microdose’ has been defined as less than 1/100 of the amount calculated to yield a pharmacological effect based on primary pharmacodynamic data obtained in vitro and in vivo (typically doses in or below the low microgram range) and at a maximum dose of 100 μg [2].

There is an inherent risk in the use of radiolabeled drugs due to the radiation dose that they provide to the individuals receiving the material. This radiation dose is known for standard radiolabeled drugs, such as ¹⁸F fluorodeoxyglucose and can be reliably estimated for other drugs based on animal drug distribution data and the known decay properties of the radionuclide. The Medical Internal Radiation Dosimetry (MIRD) Committee of the Society of Nuclear Medicine has developed a procedure for this purpose. For perspective, the estimated radiation dose received by a person undergoing an ¹⁸F FDG study is about 11 milliSievert (mSv), while the same person receiving an abdominal CT would receive a dose of approximately 10 mSv. This is the approximate dose that a person normally receives from background radiation over three years [3]. Radiation doses from ¹⁴C studies are much lower.

The difference in radiation dose between typical ¹⁴C ADME studies and studies using other radioactive labels (e.g., PET) can be significant. The former administer doses of µCi of radioactive material, while the latter, typically imaging studies, use doses in the range of mCi, a difference of a thousand-fold. While there is no simple equation to convert the dose of radioactivity administered (i.e., µCi or mCi) into radiation exposure (mSv), as noted above, it is possible to reliably estimate the exposure received using the tissue distribution and excretion patterns observed in animal studies and the MIRD method [3]. Clearly, the radiation exposure from the imaging studies contemplated in this guide cannot be viewed as negligible, as can the exposure from ¹⁴C ADME studies.

It should be noted that in oral ADME studies, while the dose of radioactive drug is sub-pharmacological, it is combined with nonradioactive “cold” drug so that dose given mimics a normal dose (i.e., produces a pharmacologic response). Such studies are typically performed with a ¹⁴C label or, less commonly ³H.

In summary then, a radiolabeled drug may be used in a clinical trial for a number of reasons, but the key advantage obtained is the ability to detect sub-pharmacological amounts of the drug. Examples of instances in which radiolabeled drugs might be used include ADME studies, receptor binding studies, and evaluation of the impact of treatment on a disease state or excretion function. The radiation dose from these types of trials can be estimated and is in line with standard diagnostic radiologic tests.

CMC Regulatory Approach for Typical Radiolabel Studies

In submitting CMC documentation to support the use of radiolabeled compounds, certain items must be considered, such as specifications for the radiolabeled drug, its method of manufacture, shelf life, etc. How these items are dealt with will depend on answers to the following questions:

• Is the radiolabeled drug approved in the country where the trial is to be conducted? Examples of these types of drugs would include standard radiopharmaceuticals such as ⁹⁹Tc cardiac agents or ¹⁸F deoxyglucose.
• If not approved, has the radiolabeled drug been the subject of peer-reviewed publications detailing its preparation? Examples would include a number of receptor-binding molecules.
• Is the molecular structure the same as the compound under investigation or is this a novel chemical entity?

By answering these questions it should be possible to determine what CMC information, if any, needs to be submitted to regulators. The following scenarios grow out of the questions listed above and provide simple summaries of the regulatory expectations that each entails. In all cases, the manufacturing or preparation site for the radiolabeled compound should be approved by the applicable Quality organization, and a quality agreement should be in place. A more detailed exploration of global regulatory expectations may be found in the Detailed Assessment of Current Regulatory Expectations.

Approved Radiolabeled Compound for Clinical Study

A number of radiopharmaceuticals are approved for diagnostic or therapeutic use in the US, EU, Canada, and Japan. Any one of these may be used as part of a clinical trial without submitting any CMC information for the radiopharmaceutical provided that the intended use is on label. Good radiopharmaceutical and clinical practices need to be employed in all cases.

An approved radiopharmaceutical may also be used off-label in a clinical trial based on a medical decision weighing the risks (radiation dose, etc.) vs. benefits. In such cases, the CMC section of the Clinical Trial Application (CTA)[4] would provide a reference to the approved marketing authorization number, manufacturer, packaging sites, etc. This would typically involve completion of sections P.1.1 and P.3, referencing the approved information as applicable while providing details of the offlabel preparation or administration.

For compounds that are used on label, there is no additional Quality Assurance or Quality Professional (QA/QP) approval. However, if the compound is modified prior to use, additional QA or QP release would be required per the commitments within the CMC submission.

PET Studies: Unapproved Radiolabeled Compounds for Clinical Study

This section involves the use of an unapproved PET radiolabeled compound under one or more of the following situations:

• previously used by a Clinical Research Unit (CRU)
• documented in a peer-reviewed journal
• previously used in a specific country
• use of a novel investigational compound as part of a PET study

In most countries, it is necessary to provide CMC information in the CTA to use an unapproved radiolabeled compound in a clinical trial; however, where the compound has been the subject of publications in the peer-reviewed scientific literature, it is possible to use that information as the basis for the CMC submission. In terms of regulatory strategy, the more extensive the publication history of the unapproved radiolabeled compound, the less likely CMC information would be needed for the CTA submission. Consultation with the health agency would be advised to determine if a simple reference can be made.

It may also be possible and preferable to reference an existing CTA held by the clinical site where acceptable CMC information has been previously submitted. Part of the site selection process should include a discussion with the investigator, as well as the site representatives, to obtain permission to reference the previously approved CMC information. Again, it is a valuable practice to confirm the acceptability of this approach with the regulatory body with whom this would be submitted.

Specifications for these PET radiopharmaceuticals are created through collaboration with the manufacturing site and the appropriate internal scientists. Given the fact that these specifications are already established through previously approved studies, further specification setting or review is generally not necessary.

The QA release process for the PET precursor may be handled similarly to that of non-labeled compounds. This final release of the PET product is conducted by the designated QA representative or QP if conducted in Europe.

Where CMC information cannot be referenced as part of the submission, the following guide may be used when compiling the applicable information:

Suggested Content for Imaging Studies

ADME and Absolute Bioavailability Studies: Unapproved Radiolabeled Compound for Clinical Study

In addition to the scenarios mentioned above, it is possible to conduct clinical studies to further advance the understanding of the human absorption, distribution, metabolism and excretion (ADME). These studies usually involve compounds in which one atom is substituted isotopically (¹⁴C for ¹²C or ³H for ¹H). In such cases, submission of full CMC information is required to the health agency Specific guidance for the items that should be included within the submission can be found at the end of this section.

Typical ADME ¹⁴C Study

ADME studies utilizing a ¹⁴C (or sometimes ³H) radiolabeled modification of the investigational new chemical entity are usually conducted early in clinical development. Radiolabeled drug substance is manufactured and may be combined with “cold” drug substance to obtain the desired level of radioactivity for dosing while usually at the predicted efficacious dose. The route of administration is typically the same as that intended for the non-radiolabeled compound. ADME studies involve the collection of urine, feces, and plasma samples from the subjects for mass balance evaluation and pharmacokinetic assessment. Additionally, major metabolites can be identified and compared to those from non-clinical studies to assist in the linkage of animal safety data to man.

ADME studies of this type require a complete phase-appropriate CMC package containing information on both radiolabeled and nonradiolabeled drug substance for submission to regulatory authorities. Certain sections of the radiolabeled drug substance (e.g., Confirmation of Structure) may reference the corresponding sections of the nonradiolabeled drug substance.

The QA/QP release process for these ¹⁴C compounds is handled similarly to that of non-labeled compounds and the final release of the drug is against the approved regulatory documents.

Where CMC information cannot be included by reference to a previous submission, see the guidance table at the end of this section for recommendations on the type and amount of information to provide.

Absolute Bioavailability Studies Using Intravenous Administration of ¹⁴C Compounds

Traditional absolute bioavailability studies involve a two-part, crossover study where a subject is given an oral (or intravenous) administration of drug followed by washout period before second administration of drug is delivered in the alternate method (intravenous or oral). Measurements of plasma concentration to determine the absolute bioavailability are conducted using LC/MS.

By using intravenous administration of ¹⁴C labeled material at the same time as the oral administration, a significant reduction in variation can be achieved (elimination of day-to- day, patient-to-patient variability). Additionally, improved data accuracy can be obtained from using the sensitive analytical technique of Accelerator Mass Spectrometry (AMS). There have been several recently published articles [5,6] demonstrating the successful application of this technique. When considering this approach, it is important to note that the radiochemical doses are quite low (~nano Ci) as is the total quantity of ¹⁴C labeled material (~microgram). However, this approach still requires phase-appropriate CMC information to be supplied. Where CMC information cannot be referenced as part of the submission, see the guidance table at the end of this section.

The QA/QP release process for these ¹⁴C compounds is handled similarly to that of non-labeled compounds and the final release of the drug is against the approved regulatory documents.

Where CMC information cannot be referenced as part of the submission, the following guide may be used when compiling the applicable information:

Suggested Content for ADME Studies

Detailed Assessment of Current Regulatory Expectations

Regulations applicable to CMC requirements for the use of radiolabeled compounds in clinical studies vary depending on the region in which the study is intended. A common theme underlying all regulations is the need to provide assurance of patient safety regarding the quality of the radiolabeled drug. Specific references are provided in this section from several major regulatory agencies regarding human studies using radiolabeled drugs. The following table highlights the regulations/ guidelines that contain information that is most relevant to the types of radiolabeled studies conducted.

Primary Sources of Regulatory Guidance

United States

All human radioactive drug research in the U.S. is subject to Investigational New Drug (IND) or Radioactive Drug Research Committee (RDRC) regulations. Regulations in 21 CFR 312 applies to all investigational drugs intended to be used in human subjects. Although this is the conventional regulatory route to begin human safety/efficacy studies for new non-radioactive experimental drugs, it may also serve as the regulatory path for radioactive drugs.

U.S. regulations allow for flexibility in the amount of data necessary to support human studies depending on the intended goals of the clinical study and the expected risks. Studies using radioactive drugs may utilize an RDRC in lieu of the FDA for regulatory oversight by employing a regulatory mechanism set forth in 21 CFR 361 for planning and conducting research in human subjects.

21 CFR 312 Investigational New Drug Application (IND) [7]

• This regulation outlines the traditional pathway for clinical studies for determination of safety and efficacy.
• It allows sponsors to conduct clinical investigations of drugs (including radioactive drugs) in human subjects.
• CMC information is required as part of the IND submission.

Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products [8]

• This guidance emphasizes the flexibility of U.S. regulations in the amount of information that is expected to be submitted in an IND depending on the phase of investigation.
• It clarifies data requirements in 21 CFR 312.22 and 312.23 related to Phase 1 clinical studies.
• It outlines reduced CMC information that is necessary to allow the FDA to conduct a meaningful review and appropriately assess the safety of a drug intended for a Phase 1 study.

21 CFR 361 Prescription Drugs for Human Use Generally Recognized as Safe and Effective and Not Misbranded: Drugs Used in Research [9]

• 21 CFR 361.1 is entitled, “Radioactive drugs for certain research uses.” There are no other subsections within part 361.
• This regulation provides a regulatory mechanism for conducting human research without an IND.
• The clinical research must be approved by an RDRC; the RDRC is approved by the FDA.
• The drug dose to be administered must be known not to cause clinically detectable pharmacological effect in humans.
• The total amount of radiation to be administered must be the smallest radiation dose practical to perform the study without jeopardizing the benefits of the study.

FDA August 2010 Guidance: The Radioactive Drug Research Committee: Human Research Without an Investigational New Drug Application [10]

• This 2010 guidance provides additional guidance on the employment of an RDRC. The guideline expands on the requirements outlined in 21 CFR 361, thus helping sponsors determine whether clinical research studies using a radioactive drug can be conducted under an RDRC.
• It clarifies the definition of basic research applicable to this regulation and provides examples.
  • intended to obtain basic information on metabolism of radioactive drug or human physiology
  • not intended for immediate therapeutic or diagnostic purposes
  • not intended to study safety/effectiveness
• It provides criteria for research conducted under an RDRC.
  • qualification of investigators, licensure, AE reporting, protocol design, etc.
  • information to be provided to RDRC
• It outlines limitations on pharmacological and radiation dose limits.
• It provides an extensive appendix for frequently asked questions concerning the appropriate application of specific situations to the use of RDRC versus IND for conducting research studies.

Although the prospect of circumventing the IND process by utilizing an RDRC may initially seem appealing, the requirements and restrictions of using the RDRC process may in reality be more onerous than the traditional IND route. The FDA takes the position that any study with radiolabeled material intended to support the development of a specific drug needs to be done under an IND.

Further, in most cases it is simpler to amend an existing IND to allow for isotopic radionuclide substitution in the compound if studies using the non-radiolabeled compound have previously been conducted in humans. Even if the study meets the requirements for using an RDRC, much of the same information would need to be submitted to the RDRC as would be submitted in an IND. Since no clear guidance exists on the requirements for the contents of an RDRC submission, each RDRC may have unique expectations, thus imparting additional risk to gaining a timely approval to conduct the study. Of course, compounds that are substituted with a non-isotopic radionuclide (e.g., ¹²³I for Br) cannot be certain to produce no pharmacological effect, so studies using such compounds must be conducted under an IND. Some firms have elected to forego the RDRC process because of the inherent content and review uncertainties. Moreover, their extensive experience with INDs provides considerable assurance of an efficient and successful submission review.

FDA 2006 Guidance: Exploratory IND Studies [11]

For certain early clinical studies including those that utilize the concept of microdosing, the FDA has provided guidance on IND submissions that may utilize the flexibility of abbreviated content. The primary advantage of the Exploratory IND lies in a reduced amount of pre-clinical safety information required; CMC content expectations are comparable to those of standard INDs.

• Studies utilizing this guidance involve limited human exposure with no therapeutic or diagnostic intent.
• Drug doses may produce limited pharmacologic effect, but no toxic effect.
• Studies under this guidance involve a limited number of subjects.
• Applicable clinical studies impart less risk to human subjects than traditional Phase 1 studies that investigate dose-limiting toxicities.
• This guidance may be used for imaging studies (microdose/single dose) to explore PK characteristics in humans, to select a lead compound from a portfolio, or to characterize new therapeutic targets.
• This guidance requires less extensive pre-clinical safety data requirements than traditional IND studies.
• Exploratory INDs must be withdrawn upon completion of the clinical studies.

USP <823> Radiopharmaceuticals for Positron Emission Tomography – Compounding [12]

CGMPs that apply to the manufacture of PET radiopharmaceuticals are the subject of distinct regulations because of their unique method of production, application and limited half-life. Section 121(c)(1)(A) of the Food and Drug Administration Modernization Act (the Modernization Act) affirms that all PET drugs must be produced in compliance with compounding standards in USP <823> and must meet applicable USP monographs.

• USP <823> recognizes that radiopharmaceuticals for PET procedures typically contain radionuclides with short half-lives, and are produced by particle accelerators usually close to the site where the PET study is to be conducted.
• It establishes GMP standards for the compounding of PET radiopharmaceuticals for human use.
• It applies to all producers of PET drugs for investigational use (e.g., PET drugs produced under an IND) or basic research.
• Manufacturers of PET drugs marketed under an NDA or ANDA must meet these minimum GMP standards until 21 CFR 212 becomes effective on December 11, 2011.

21 CFR 212 CGMP Requirements for PET Drugs (Final Rule December 10, 2009; effective December 11, 2011) [13]

Section 121 of the Modernization Act further asserts that CGMP regulations are to be established specifically for PET drugs, as the need for less restrictive regulations applicable to PET drug production is generally recognized. These regulations are delineated in 21 CFR 212; they will become mandatory for PET drug production on December 11, 2011.

• This regulation applies to PET drugs marketed under an NDA or ANDA, or routinely manufactured PET drugs including those with a monograph.
• Research and investigational PET drug manufacturers have the option of complying with this regulation or following the requirements of USP <823>.

FDA 2009 Guidance: PET Drugs – Current Good Manufacturing Practice (CGMP) [14]

• This guidance provides additional detail surrounding 21 CFR 212 CGMP requirements for PET drugs.
• The FDA maintains authority to inspect investigational PET drug production facilities, which is generally done on a for-cause basis.

USP <797> Pharmaceutical Compounding – Sterile Preparations [15]

• This chapter addresses the fundamentals for understanding and preparing compounded sterile preparations (CSPs).
• A subsection of this chapter, “Radiopharmaceuticals as CSPs,” focuses on the additional handling and manipulation of a PET radiopharmaceutical that has previously been released as a finished drug product from a production facility.

European Union

In the European Union, all human trials are conducted under a Clinical Trial Application. For the purposes of investigating and/ or supporting studies involving medicinal products for human use, the 2001/20/EC and 2003/94/EC directives specifically apply. In addition, there are several other associated regulations and guidance documents that support and expound upon these directives.

The following sections outline the specific regulations from the applicable Directives and Guidance Documents which apply to radiopharmaceutical compounds.

2001/20/EC – the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use [16]

• There are several key items within this directive, most importantly the fact that there is no differentiation made between radiolabeled and non-radiolabeled investigational medicinal products. They are treated the same. Further, this directive provides for several key definitions which are outlined in the bullet points below.
• This directive defines a clinical trial as, “any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the object of ascertaining its (their) safety and/or efficacy.”
• This directive defines an investigational medicinal product as, “a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorization but used or assembled (formulated or packaged) in a way different from the authorized form, or when used for an unauthorized indication, or when used to gain further information about the authorized form.”
• Within Article 13, the Directive outlines the key components for the manufacture and import of the investigational medicinal product. Most important is the required adherence to Annex 13 (Manufacture of Investigational Medicinal Products) of the European Guidelines (European Commission, EudraLex, Volume 4, Good Manufacturing Practice (GMP) Guidelines).

2003/94/EC – laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use [17]

• There are several key items within this directive, and like the 2001 Directive there is no differentiation made between radiolabeled and non-radiolabeled investigational medicinal products. They are treated the same.
• This directive requires conformity with good manufacturing practices and requires that production of such drugs be carried out with the manufacturing authorization. It also requires good ‘pharmaceutical quality assurance’ and ‘good manufacturing practices’ to ensure, “that the products are consistently produced and controlled in accordance with the quality standards appropriate to their intended use.”

2003/63/EC – amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use [18]

• Within Part III (Particular Medicinal Products), subsection 2 specifically discusses radiopharmaceuticals and precursors. However, this subsection refers to Article 6 of 2001/83/EC which refers to placing medicinal products on the market. Therefore, this particular Directive does not usually apply if a firm only utilizes radiopharmaceuticals for the purposes of supporting the approval of non-radiolabeled medicinal products.

European Guidelines (European Commission, EudraLex, Volume 3, Scientific Guidelines for Medicinal Products for Human Use)

Quality Guidelines – Guideline on Radiopharmaceuticals [19]

• This guideline describes specific CMC information that is recommended for inclusion in a marketing authorization or variation. Within the Scope section of the guideline, it specifically states the following: “Concerning radiopharmaceuticals intended in the conduct of clinical trials (investigational medicinal products), the principles of this guideline expressed in Eudralex Volume 10 have to be applied.” This document does give a good outline for the requirements needed for the S and P sections of the application which can be used as guidance for clinical trial applications.

European Guidelines (European Commission, EudraLex, Volume 4, Good Manufacturing Practice (GMP) Guidelines)

Annex 3 – Manufacture of Radiopharmaceuticals [20]

• This annex discusses the requirements for manufacturing and handling of radiopharmaceuticals. Most notably, within note iii, it states that, “this annex is applicable to radiopharmaceuticals used in clinical trials.” It also discusses PET radiopharmaceuticals, radioactive precursors, as well as radiopharmaceuticals.
• This annex also specifically notes (line item 8) that radiopharmaceuticals used in clinical trials should be produced in adherence to the principals found in EudraLex Volume 4, Annex 13 (Good Manufacturing Practices, Manufacture of Investigational Medicinal Products).

European Guidelines (European Commission, EudraLex, Volume 10, Clinical Trial Guidelines)

Chapter I – Application and Application Form (Detailed Guidance for the Request for Authorisation of a Clinical Trial on a Medicinal Product for Human Use to the Competent Authorities, Notification of Substantial Amendments and Declaration of the End of the Trial [21])

• This guidance document discusses the fact that radiopharmaceuticals fall under the 2001/20/EC directive along with many other investigational medicinal products.
• This document also introduces the concept of a “noninvestigational medicinal product” or NIMP. An NIMP is defined as product which can be used as rescue medication, background treatments, for diagnostic purposes, or to induce a physiological response. It is recommended that NIMPs be used that have a marketing application in place; however, if this is not possible, a dossier may be requested by the competent authority. The Guidance on Investigational Medicinal Products and other Medicinal Products use in Clinical Trials further explains this type of medicinal product.

Chapter III – Quality of the Investigational Medicinal Product (Guidance on Investigational Medicinal Products (IMPs) and Other Medicinal Products Used in Clinical Trials [22])

• This guidance explicitly states that products that are not defined as IMPs per the 2001/20/EC directive may be supplied to a subject per the protocol. These products would be defined as NIMPs. However, this guidance does indicate that NIMPs without a marketing application would still need to ensure that appropriate GMP requirements are met to ensure patient safety. Specifically, it states that the “requirement will be fulfilled by applying for these NIMPs, the same requirements as provided for the IMPs, in particular, the standards as provided for in Title IV of Directive 2001/83/EC and the requirements established under Articles 13(3) and 15 of the Directive should be applied.”
• Within the appendix section of this guidance document, there are several examples of NIMPs listed including rescue medications, challenge agents, medicinal products used to assess clinical endpoints (e.g., PET compounds), and concomitant medicinal products. Specific examples of an NIMP would include a pain medication given to a cancer patient as part of the standard protocol along with the investigational drug. Another example would be a rescue medication given to a patient in case the IMP is ineffective at low doses. In both cases, these NIMPs would likely be market approved drugs specifically approved for that indication.
• In all cases, an NIMP that does not have a marketing authorization should be treated as an IMP with respect to CMC information provided in the clinical trial application. Moreover, the same level of GMP compliance must also be applied for these type of products.

Chapter III – Quality of the Investigational Medicinal Product (Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation Concerning Investigational Medicinal Products in Clinical Trials) [23]

• Within the scope of this guidance document, it states that, “This guideline addresses the documentation on the chemical and pharmaceutical quality of IMPs containing chemically defined drug substances…and chemically defined radio-active/radiolabeled substances to be submitted to the competent authority for approval prior to beginning a clinical trial in humans.”
• Throughout the document, there is reference to the specific quality requirements for the drug substance and drug product as part of the IMP. Many of those sections contain the words “radiolabeled” and/or “radiopharmaceutical.” There is no apparent regulatory relief or difference between a non-radiolabeled IMP used for clinical study and a radiolabeled compound.
• This guidance does not specifically mention PET compounds.

European Pharmacopoeia 6.0 (Volume 1) – Radiopharmaceutical Preparations [24]

• In this general chapter, there is a discussion regarding the definitions that are commonly associated with radiopharmaceuticals. There are several pages of review on the analytical tests which are conducted on these products. Those include identification, radioactivity, radionuclidic purity, radiochemical purity, specific radioactivity, and several others including sterility and endotoxin tests for parenteral products. There are also two very short sections included which cover storage and labeling.
• This chapter does not distinguish between clinical trial and marketed materials; however, it is applicable to all monographs found within the European Pharmacopoeia.

United Kingdom MHRA Website: Special Interest Groups Section on PET Trials [25]

• The MHRA provides guidance on general, as well as specific, considerations necessary for conducting a clinical PET study. Several example scenarios for using PET compounds are presented, along with their analyses to illustrate the expected focus of the corresponding CTA. An example CMC section of an IMPD is provided to clearly show how the CMC information necessary for a PET compound might differ from that needed for a standard compound. For example, several CMC sections are unnecessary for a PET compound because of the unique nature of the study and preparation of PET compounds (e.g., S.4, S.6, S.7).

Canada

All human radioactive drug research in Canada is subject to compliance with the Food and Drugs Act and the associated Regulations. Specifically, radiopharmaceuticals (including positron emitting radiopharmaceuticals (PERs)) are a specific class of drugs as defined by Schedule C of the Act. Since PERs can be used for diagnostic, therapeutic, or basic research applications, there are a number of very specific policies and guidelines which are also summarized below.

In any case, such studies would require a submission to Health Canada per the Regulations (Part C, Division 5).

The following sections outline the specific regulations, policies, and guidance documents which apply to radiopharmaceutical compounds in Canada.

Food and Drug Act [26] and the Food and Drug Regulations [27]

• All marketed drugs in Canada are subject to the Food and Drug Act and associated Regulations. Radiopharmaceuticals are often noted as being part of “Schedule C” which is simply defined within the Act as “Drugs, other than radionuclides, sold or represented for use in the preparation of radiopharmaceuticals; Radiopharmaceuticals.”
• The Food and Drug Act is the enabling statute for the Food and Drug Regulations which contains many sections (known as Parts). Within each Part, there can be multiple Divisions. Part C, Division 3, specifically refers to Schedule C Drugs (i.e., radiopharmaceuticals) for which is the basis for the subsequent policies and guidance documents. Within these regulations (C.03.201), a radiopharmaceutical is defined as a, “drug that exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons.” This Division also contains many other definitions associated with radiopharmaceuticals.
• Finally, it should also be noted that Part C, Division 5, sets forth the regulations associated for clinical trials. Specifically, a clinical trial is defined as, “an investigation in respect of a drug for use in humans that involves human subjects and that is intended to discover or verify the clinical, pharmacological or pharmacodynamic effects of the drug, identify any adverse events in respect of the drug, study the absorption, distribution, metabolism and excretion of the drug, or ascertain the safety or efficacy of the drug.” This definition is often referenced in the documents below.

Annex to the GMP Guidelines: Good Manufacturing Practices for Schedule C Drugs [28]

• This document was issued in 1999 and is intended to be used for all radiopharmaceuticals manufactured in Canada. It does state that, “interpretations are written in general terms to allow establishments to adopt and justify procedures appropriate for their products and operations.” The intent of the guidance is to highlight the important elements of the GMPs which apply to this class of drugs.
• The annex document also states that, “all sections of the main GMP Guidelines are applicable unless otherwise stated in this Annex.” Additionally, it points out that safety requirements for PERs are not covered by the annex but by the Atomic Energy Control Board (AECB) who provides the guidance and regulations for these activities.

NOTE: All subsequent Canadian documents pertaining to Radiopharmaceuticals are specific to PER compounds.

Regulatory Requirements Governing Investigations with Schedule C Drugs (Radiopharmaceuticals, Kits, and Generators) [29]

• This March 2003 document is found within Health Canada website under the Biologics, Radiopharmaceuticals & Genetic Therapies / Legislation & Guidelines / Policies. It is actually a communication regarding PERs which reasserts Health Canada’s position that 1) PER manufacturing activities are not considered compounding, and 2) In most cases the use of PERs requires the submission of a clinical trial application.

Policy: Regulatory Requirements for Positron- Emitting Radiopharmaceuticals (PERs) [30]

• Effective in August, 2003, this was the first Policy document written for radiopharmaceuticals in Canada. It is specific to PERs which are simply one subset of radiopharmaceuticals.
• This policy also reiterates the March 2003 position that the production of PERs for human use is considered a manufacturing activity and not compounding (note: with the exception of the final dose manipulations). Further, it emphasizes the importance of process validation since many tests (sterility, pyrogenicity, etc.) are not conducted before the product is given to the patient due to the very short half lives.
• It specifically points out that a clinical trial utilizing a PER must be authorized by Health Canada under an approved CTA. Several examples are also given to support this mandate.
• As part of the submission process, the CTA must include quality data (chemistry and manufacturing) as well as non-clinical data. The policy does elude to the option of utilizing published data as reference or supporting information, but does indicate that data from the PET center source be supplied if different. Prudence is advised when using ‘published data’ to support approval of a submission; it should be used as supportive or ancillary information in the submission.
• This policy acknowledges that GMP guidelines related to Schedule C PER compounds needs to be created. This new document was actually published in March, 2006 (see below).

Guidance Policy: Use of Positron Emitting Radiopharmaceuticals (PERs) in Basic Research – Policy – 0053 [31]

• This guidance policy became effective in February of 2006. There were two primary reasons for issuing this short, two-page policy. First, there is an extensive definition and several examples given for “basic research” involving PERs. The policy again reiterates the fact that this type of “basic research” still requires the submission of a CTA. Second, the policy acknowledges that Health Canada is in the process of developing the appropriate regulatory strategies for the use of PERs in basic research which would minimize the regulatory burdens while still ensuring patient safety is maintained. These proposed regulations are discussed further below.

Guidance Document: Factors Considered in the Assessment of Risks Involved in the Use of Positron Emitting Radiopharmaceuticals in Basic Research Involving Humans [32]

• This guidance document essentially provides additional detail with respect to the February 2006 guidance policy, “Use of Positron Emitting Radiopharmaceuticals (PERs) in Basic Research.”
• The minimum criteria for “basic research” involving PERs are a subpharmacologic dose, and a radiation dose of not more than 20 mSv (single dose) and 20 mSv (annual and total dose). There are other criteria mentioned as well (qualified investigators, quality of the PER, etc.), but the aforementioned two requirements are most important.
• Supporting scientific data for these studies include clinical (valid human studies or published literature) demonstrating no pharmacologic effect at the given dose, and valid human, animal, or published data on the safety of the proposed radioactive dose.
• The guidance document specifically states that “a research study in which the concurrent drug has not received a marketing authorization from Health Canada shall be submitted as a CTA.”
• Finally, this document outlines the list of CMC requirements needed for the submission. These include a list of ingredients, information on the manufacturing, specifications, batch analysis data from three production runs including stability, sterility, etc., as well as other Quality requirements.

Annex to the Good Manufacturing Practices Guidelines: Good Manufacturing Practices (GMP) for Positron Emitting Radiopharmaceuticals (PERs) – Guide-0071 [33]

• This document became effective in March 2006 and is intended to be used for all PERs used in PET studies. It highlights all of the important elements of the GMPs which apply to this class of radiopharmaceuticals.
• The annex document also states that, “all sections of the main GMP Guidelines are applicable unless otherwise stated in this Annex.” Additionally, it points out that safety requirements for PERs are not covered by the annex but the Canadian Nuclear Safety Commission (CNSC) (formerly the Atomic Energy Control Board (AECB)) provides the guidance and regulations for these activities.
• This annex details the requirements for adhering to GMPs in many different areas (e.g., premises, equipment, personnel, sanitation, raw material testing, manufacturing control, quality control department, packaging, finished product testing, records, samples, stability, and sterile products).

Draft Guidance for Industry – Preparation of the Quality Information for Radiopharmaceuticals (Schedule C Drugs) Using the Quality Information Summary – Radiopharmaceuticals (QIS-R) and Certified Product Information Document – Radiopharmaceuticals (CPID-R) Template [34]

• This draft guidance was issued in August 2001, however, there has been no final version issued at the time this paper was published. This draft guidance does provide a sound baseline for the Quality requirements needed for a radiopharmaceutical submission, including CTAs. However, it is recommended that the currently approved guidance document be used for Canadian CTA submissions (Quality (Chemistry and Manufacturing) Guidance: Clinical Trial Applications (CTAs) for Pharmaceuticals) [35].

Canada Gazette; Part I: Notices and Proposed Regulations: Regulations Amending the Food and Drug Regulations (Positron Emitting Radiopharmaceuticals) [36]

• This draft regulation was published in the Canada Gazette in March, 2009. The proposed amendment would loosen the regulatory requirements for clinical studies involving PERs in many, but not all cases. Most significantly, basic research, “involving the concurrent use of a drug that is not a PER and that has not received marketing authorization from Health Canada must be submitted as a CTA.”
• The proposed change in regulation would allow for basic research to be conducted on mechanisms of action, further understanding of pharmacokinetics of the PER, drug action, etc., without having to file a CTA to Health Canada if all the definitions and requirements outlined are achieved.
• The proposed application process would involve approval by the Research Ethics Board (defined in the proposed regulations) first, followed by a simple application for authorization to Health Canada. Once Health Canada determines that the study meets the requirements set forth in the new regulations, the study can be approved.

Other

• Many of the Canadian guidance documents and policies were obtained from the Health Canada website under the Biologics, Radiopharmaceuticals & Genetic Therapies / Applications & Submissions / Guidance Documents / Radiopharmaceuticals [37]. However, there were two guidance documents (Stability and Stereochemistry) which specifically noted that they did NOT apply to radiopharmaceuticals. The only other guidance document within this site was in draft form and originally published in 2001. It had little relevance and will not be commented on.

Japan

All human clinical studies using investigational drugs in Japan are governed by the Pharmaceutical Affairs Law (“PAL”) and the GCP Ordinance. These regulations apply to radioactive as well as non-radioactive drug research. CMC documentation for human studies is typically provided in the investigator’s brochure and/or the clinical protocol. For the specific case of studies involving radiolabeled compounds, the safety of the radiation dose, including the assessment method and the internal radiation dose, should be documented for the planned study and included in the protocol or investigator’s brochure.

Historically, regulators in Japan have exhibited a more protracted acceptance of such studies; thus, one might expect greater hesitance and more lengthy reviews of this type of submission.

Pharmaceutical Affairs Law [38]

• This contains regulations for the conduct of all human clinical studies for determination of safety and efficacy.
• The Ministry of Health Labor and Welfare (MHLW) must be notified prior to beginning a clinical study.

GCP Ordinance [39]

• This ordinance provides standards of Good Clinical Practices for the implementation of clinical studies of medicinal products. It also contains information beyond that found in ICH E6 Guideline for Good Clinical Practice.
• Further, contains additional detail beyond that found in the PAL regarding expectations of sponsors and medical institutions.

Human studies in Japan using radiolabeled drugs have been less common than similar studies in the U.S. and Europe. However, as the value of such studies has become more widely accepted, general guidance has been developed for conducting studies using microdose levels of radiolabeled drugs. Notification of such studies to the MHLW is performed in the same way as for standard clinical studies. This guidance describes the type of information a sponsor might be expected to collect in order to ensure subject safety.

Guidance for Conducting Microdose Clinical Studies [40]

• Microdose is defined as a dose level that is not exceeding onehundredth of the dose at which the pharmacological effect is estimated to develop in humans or 100 µg, whichever is lower.
• Studies expected to comply with this guidance include pharmacokinetic ¹⁴C studies in which blood levels are measured by Accelerator Mass Spectrometry (AMS); PET studies using a drug labeled with a positron-emitting nuclide such as ¹¹C, ¹³N, ¹⁵O, and ¹⁸F; and studies using a drug labeled with ¹²³I, ⁹⁹Tc, etc., measured by Single-Photon Emission Computed Tomography.
• Radiation safety information including the assessment method (e.g., AMS) and the assessment of internal radiation should be clearly described in the investigator’s brochure or related documents.
• This guidance also provides GMP considerations for the manufacture of PET compounds.

GMPs for Investigational Products [41]

• Provides general GMP standards for investigative drugs. The manufacture of radiopharmaceuticals is subject to these standards.

Conclusion

Radiolabeled molecules can provide important information in clinical trials. Whether using sub-pharmacological or pharmacologic doses of a labeled molecule, the CMC information needed for a clinical trial application may be provided in a number of ways. For an already approved radiopharmaceutical, no CMC information is needed unless the preparation or the route of administration differs from what is approved. Many radiolabeled compounds have extensive scientific literature which can be the source of necessary information, combined with validation data from the clinical site. It may also be possible to reference an existing CTA for such radiolabeled compounds.

For clinical studies using novel or less well-documented radiolabeled molecules, CMC information for a CTA submission may need to be assembled jointly between the manufacturer and the sponsor. It may not be necessary to submit the same level of CMC documentation typical for studies involving a non-radiolabeled compound; however, it must be noted that CMC information is required for most clinical studies involving radiolabeled compounds. This paper has provided recommendations on the extent and possible sources of the CMC information that must be submitted.

References

1. FDG has a molecular weight of 182.15 with stable fluorine and 181.15 when labeled with ¹⁸F. The typical dose is 10 mCi or 370 MBq of FDG (1 Curie (Ci) = 3.7 x 10¹⁰ decays/second; 1 Bequerel (Bq) = 1 decay/second). How many molecules of FDG does this dose represent? Activity (A) = (Number of F atoms N)(Decay constant λ for ¹⁸F) A= N λ. This can be put in more familiar terms by substituting ln(2)/t_½ = λ A=Nln(2)/ t_½. Since t_½¹⁸F = 6600 sec and ln(2) = 0.693 and the activity = 3.7 x 10⁷ decay/sec, N = 10 nanograms.
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38. Japan Pharmaceutical Affairs Law: Act No. 145 of 1960
    
39. Japan GCP Ordinance: MHW Ordinance No. 28, March 27, 1997
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41. Japan GMPs for Investigational Products: PMSB Notification No. 480, March 31, 1997.