MRI CELL TRACKING: WHAT IS NEEDED FOR CLINICAL TRANSLATION AND IMPLEMENTATION ADRIAN D NUNN PHD.
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MRI cell tracking: What is needed for clinical translation and
implementation
Adrian D Nunn PhD.
Ernst Felder Laboratories, Bracco Research USA Ltd., 305 College Road East, Princeton,
NJ 08540, USA. Email: anunn@bru.bracco.com
Introduction
A new chemical entity (NCE) cannot (should not) be introduced into man without an
assessment of the risk/benefit ratio which requires knowledge of its safety profile in
animals. The first clinical studies are performed using doses that are low relative to the no
observable adverse event level (NOAEL) found in animal testing. This requires practical
knowledge of toxic effects and an understanding of the dose response relationship.
In order to predict the expected behaviour in man from the animal results the quality of
the material used in each case should be known and be similar. If the proposed testing is
of an existing compound that involves a (new) route of administration or dosage level or
use in a patient population or other factor that significantly increases the risks (or
decreases the acceptability of the risks) associated with the compound, then additional
relevant preclinical safety testing may still be necessary.
Recently the authorities have made efforts to develop a common set of requirements for
the registration (approval) of new drugs. This process is termed the International
Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use. (ICH) [1] The ICH website contains a list of useful,
readable publications covering the whole range of topics pertinent to first administration
to man and extending to ultimate approval and routine use.
The general requirements for filing an Investigational New Drug application (IND) in the
USA are laid down in 21 CFR 312 [2] and specific rules for radiopharmaceuticals (only)
are found in 21 CFR 315. [3] There are also a number of guidances addressing all imaging
agents. This presentation will focus mainly on the safety aspects of these requirements
with the understanding that the Chemical Manufacturing and Control (CMC) elements
are met.
General considerations
Medical imaging agents, including cell labeling agents, are governed by the same
regulations as other drug and biological products. The overall need is to acquire sufficient
non clinical biological data to allow the development of a safety profile for the NCE. This
is then used to:
1) Identify an initial safe dose and subsequent dose escalation schemes in humans;
2) Identify potential target organs or tissues for toxicity and for the study of
whether such toxicity is reversible; and3) Identify safety parameters for clinical monitoring.
Phase I trials are safety studies performed initially at low doses so no efficacy data are
expected and this is indeed the case for a therapeutic. If imaging is performed during an
imaging agent trial efficacy may be observable. This is a double edged sword as it tends
to obscure the true need of the phase I trial which is to collect the safety data. More
recently a Phase ‘0‘ study has been described that seeks to obtain data at doses that
should have no deleterious effects.
The ICH document M3 [4] lays out the following framework for studies, and the
information that should be obtained, prior to first human exposure of any drug.
Single dose (acute) toxicity. A repeated dose toxicity study in two species (one
non-rodent) for a minimum duration of 2 weeks.
Repeated dose toxicity in two mammalian species (one non-rodent) – the
duration should be equal to or exceed the duration of the human clinical trials up
to the maximum recommended duration of the repeated dose toxicity studies. In
the USA this may be replaced with a more extensive single dose study.
Toxicokinetic/pharmacokinetics (Absorption, distribution, metabolism,
excretion - ADME), and the generation of pharmacokinetic data in order to assess
systemic exposure.) Toxicokinetics is the pharmacokinetics under the conditions
of the toxicity studies which may exhibit different behaviour than the expected
clinical dosing conditions due to non-linear kinetics etc. [5]
Safety pharmacology - the assessment of effects on vital functions, such as
cardiovascular, central nervous and respiratory systems [6]
Local tolerance studies – the assessment of tolerance to the drug using routes
relevant to that intended for clinical use..
Genotoxicity studies – in vitro tests for the evaluation of mutations and
chromosomal damage.
These requirements and/or guidelines may be modified based on the type of NCE and
also on the intended clinical pathology.
Imaging agents
Imaging agents have their own Guidance document, divided into contrast agents and
radiopharmaceuticals, issued by the FDA. [7] The FDA have suggested that there may be
two general categories of imaging agents separated based on their potential for toxicity
and which may qualify for different levels of safety assessment during the early phases of
clinical trials. [8] Generally, a less extensive clinical safety evaluation is appropriate for
Group 1 agents. Biological agents, which includes labeled cells, are assumed to be Group
2 agents unless they can be demonstrated to lack immunogenicity.[9]
Recent first in man concepts
The desire to speed up the development of drugs lead to a new set of guidelines being
issued that covered not just imaging agents but all drugs. The idea was to allow limited
testing in man to determine proof of concept of compounds that had a sufficient set of
preclinical safety data to establish the risks of the initial testing but not necessarily of the
higher doses usually seen in the traditional phase I design. The goal of these microdosing
or Exploratory IND (E-IND) trials is fundamentally different to that of phase I which isone of safety. Risks must be managed but the low doses that these new trial designs
require, markedly reduce the risks. Anticipated pharmacologic effects may be acceptable
but, unlike phase I, the studies are not designed to establish maximally tolerated doses
(MTD). Instead, they are designed to assess feasibility for further development of the
drug or biological product. Both microdosing and the E-IND provide the option of
studying closely related drugs or therapeutic biological products, under a single
application.
Study Type ICH M3 FDA Imaging Guidance EMEA Microdosing E-IND (Imaging)
1997 2004 2004 2006
Safety Yes Yes Maybe No
pharmacology
Toxicokinetic Yes Yes Yes
pharmacokinetic
Single-dose toxicity Two Expanded acute single Expanded acute Expanded acute
or dose escalation species dose single dose 2 weeks single dose 2 weeks
one species one species
Short-term (2 to 4 Yes No No No
weeks) multiple
dose toxicity
Genotoxicity In vitro In vitro In vitro No
Reproductive and Yes Yes or waived No
developmental
toxicity *
Dose limits Group 1 agents 1/100 1/100
EITHERExploratory IND
The FDA elaborated further on the concept of a microdose, in the form of an E-IND. The
guidance[11] describes preclinical and clinical approaches, and the CMC information that
should be considered when planning E- IND studies in humans.
Examples of information that an E-IND trial may provide are to:
1) determine whether a mechanism of action defined in experimental systems can
also be observed in humans (e.g., a binding property or inhibition of an enzyme),
2) provide information on pharmacokinetics (PK),
3) select the most promising lead product from a group of candidates designed to
interact with a particular therapeutic target in humans, based on PK or
pharmacodynamic (PD) properties, and
4) explore a compound’s or group of compounds biodistribution characteristics
using various imaging technologies.
In agreement with the EMEA a ‘microdose’, as defined by the FDA, is less than 1/100th
of the dose calculated to yield a pharmacologic effect in man based on animal data and a
total dose of < 100 microgrammes per individual. The maximum dose for proteins is ≤30
nanomoles due to the high molecular weights. The total dose per individual of all test
compounds should not exceed 100 microgrammes so if multiple compounds are being
tested or if receptor blocking studies are being performed the total dose should not exceed
this.
It is important to understand that the microdosing or E-IND options are a means to
expedite entry of NCEs into early stage clinical trails. Encouraging results in these early
trials do not allow continued progression without meeting the requirements as laid out in
ICH M3, indeed, the stated intention of the FDA is that the E-IND should be withdrawn
on completion of the intended studies (and an IND opened if warranted).
Cell Labelling
The mass of 1-2microgrammes iron particles needed lies well within the mass limits of
microdosing and the E-IND. The studies can also be conducted using cancer patients
where life expectancy is short, obviating long term effects, and higher initial doses of
10% of the MTD are acceptable. However, although the safety profile of the iron
particles after iv administration is established the toxicity to any particular cell is not, so
what is the meaning of a (whole body) MTD in this case? Labeled cells possess another
layer of complexity in that the methods used to label the cells may have an unpredictable
affect on the cells. There are potential safety and regulatory issues of labeling cells using
unapproved iron particle preparations or gadolinium compounds, antibodies, transfection
techniques etc. The more conservative route is to use the normal phagocytic capacity of
cells with an approved, (if not for this indication) iron particle. One can perform
functional in vitro assays and observe the anticipated behaviour in vivo to surmise that
the cells have not been grossly altered by their high iron loading. When labeling cells of
the immune system it is not unreasonable to ask if this is sufficient.
Larger issues will have to be addressed regarding labeled stem cells where their ability to
differentiate into a multitude of cell and tissue types offers at least a theoretical capability
to repair, regenerate, or grow almost any type of tissue or organ. How does one establish
the long term toxic effects, if any, of labeling such cells? These are issues that are not
touched on in the published regulatory advice.References
1. ICH guidance documents. Available at: http://www.ich.org/cache/compo/276-
254-1.html Accessed March 28 2006
2. Investigational new drug application. 21 CFR 312 Available at:
http://ecfr.gpoaccess.gov/cgi/t/text/text-
idx?c=ecfr&tpl=/ecfrbrowse/Title21/21cfr312_main_02.tpl Accessed March
28 2006,
3. Regulations for In Vivo Radiopharmaceuticals Used for Diagnosis and
Monitoring. 21 CFR 315. Available at: http://ecfr.gpoaccess.gov/cgi/t/text/text-
idx?c=ecfr&tpl=/ecfrbrowse/Title21/21cfr315_main_02.tpl Accessed March
28 2006.
4. M3 Nonclinical safety Studies for the Conduct of Human Clinical Trials for
Pharmaceuticals. ICH 1st July1997 and amended on 9th November 2000.
Available at: http://www.ich.org/cache/compo/276-254-1.html Accessed
March 28, 2006.
5. S3A Note for guidance on toxicokinetics: The assessment of systemic exposure in
toxicity studies. ICH 27th October 1994
6. S7A Safety pharmacology studies for human pharmaceuticals. ICH 8th November
2000
7. Guidance for Industry Developing Medical Imaging Drug and Biological
Products Part 1: Conducting Safety Assessments. FDA June 2004 Available at:
http://www.fda.gov/cber/guidelines.htm. Accessed March 28 2006
8. Guidance for Industry Developing Medical Imaging Drug and Biological
Products Part 1: Conducting Safety Assessments. Part IV, Group 1 and 2 Medical
Imaging Agents. FDA June 2004 Available at:
http://www.fda.gov/cber/guidelines.htm. Accessed March 28 2006
9. Nunn AD., Translating promising experimental approaches to clinical trials. In
Eds Modo MMJ and Bulte JWM Molecular and cellular MR imaging. CRC Press,
Boca Raton, Florida, USA, 2007.p 395-403
10. Position paper on non-clinical safety studies to support clinical trials with a single
microdose. EMEA June 2004 Available at:
www.emea.eu.int/pdfs/human/swp/259902en.pdf Accessed March 28 2006
11. Guidance for Industry, Investigators, and Reviewers. Exploratory IND Studies. FDA
January 2006. Available at: http://www.fda.gov/cder/guidance/7086fnl.htm
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