Products Used in Clinical Studies
Should Remaining Inventory Regulations Be
Changed?
The
enactment of Federal Law 14.874/2024, that sets forth the basic norms
regulating Clinical Research with Human Beings in Brazil, has generated a lot
of optimism on the part of almost all stakeholders in that area. While some
apprehension remains, mostly in relation to the two presidential vetoes,
that researchers hope are overturned by
Congress, and to the regulations that must be enacted so that the law can be
dully implemented, the bringing of this subject to the limelight has, also,
brought back, at least to our mind, a point that, while already referenced in
international regulations (presently under discussion for updating), we believe
would be worth some attention.
The issue
at hand is the destination of eventual surplus of inventory of approved and
commercially available medicine, used, either as a New Investigational Product,
as a Comparator Medicinal Product, as object of clinical trials for a New
Therapeutic Indication or, in Phase IV studies.
It is
noteworthy that, while not object of this article, in many cases, equipment and
devices used during clinical trials that, although perfectly fit for reuse, are
frequently discarded.
Even
considering that the existence of surplus of approved and commercially
available products used in clinical studies is not frequent, it does happen
more often than one would imagine, for example, in cases where the study ends
earlier than planned, either because the efficacy of the investigational
medicine was demonstrated earlier than at the planned life of the study period
or, conversely, when the lack of its efficacy is the case. The same is the case
of commercially approved medicines object of new therapeutic indication studies
or phase IV studies.
Considering the regulations contained in the present
version of the “International Council for Harmonization of Technical
Requirements for Pharmaceuticals for Human Use (ICH)” of the “Harmonized
Guideline – Good Clinical Practices (GCP)” (together ICH/GCP), the primary
source for Clinical Study Regulations throughout the world, it is not be
possible, as a rule, to donate remaining inventory of a Comparator Medicinal
Product used in a clinical study, even if registered and commercially
available, and/or other commercially approved products.
As in
clinical studies Comparator Medicinal Products that are commercially available
medicines, may be relabeled and/or repacked to indicate that the use is
restricted to one specific clinical trial, the changes in the packaging (or
labeling) make them, in principle and under strict interpretation, different
from that object of their respective marketing authorization. Nevertheless, it
is important to keep in mind that these comparator products should be packed,
handled, and stored observing the due specifications for the maintenance of
their integrity and efficacy for their entire approved validity term.
In the
case of Brazil (and of the Pan American Health Organization - PAHO), the
destination of remaining inventory of clinical trial medicinal products is expressly
mentioned in few of the past regulatory/legislative norms regulating clinical
trials and it is not mentioned in the new law either. References existing today
are:
Resolution RDC 38/2013 (as amended)
... at the end of the
program, count the medication imported and not used, giving its proper
destination, whether its destruction in Brazil or its return abroad, keeping
the due record of the adopted procedures.
PAHO
Guideline: Good Clinical Practices: Document of the Americas, 2008
The
sponsor should:
…….
(b) Maintain records that document
shipment, receipt, disposition, return, and destruction of the investigational
product(s).
It is
clear that ANVISA adopts the Guidelines issued and published by the
“International Council for Harmonization of Technical Requirements for
Pharmaceuticals for Human Use (ICH)”; the “Harmonized Guideline – Good Clinical
Practices (GCP)” and of the PAHO Guideline: Good Clinical Practices: Document
of the Americas, 2008 so, as a rule, it would not be possible today, in Brazil,
to donate, or make any use of any surplus clinical study product, even if the
product is already approved by regulatory authorities and commercially
available.
The
version of the GCP/ICH presently in force is the “ICH E6 (R2) and, as per its
clause 5.14.3, sponsors of clinical trials must ensure that unused
investigational products must either be returned to the sponsor or disposed.
ICH E6 (R2)
5.14 Supplying and Handling Investigational Product(s)
5.14.3 The sponsor should ensure
that written procedures include instructions that the investigator/institution
should follow for the handling and storage of investigational product(s) for
the trial and documentation thereof. The procedures should address adequate and
safe receipt, handling, storage, dispensing, retrieval of unused product from
subjects, and the return of unused investigational product(s) to the sponsor
[or alternative disposition if authorized by the sponsor and in compliance
with the applicable regulatory requirement(s).
For a
better understanding of the matter and of the regulations, it should be noted
that the ICH/GCP(R2) defines “Investigational Product” as:
“A pharmaceutical form of an active
ingredient or placebo being tested or used as a reference in a clinical trial,
including a product with a marketing authorization when used or assembled
(formulated or packaged) in a way different from the approved form, or when
used for an unapproved indication, or when used to gain further information
about an approved use.”
And
defines “Comparator (Product)” as:
“An investigational or
marketed product (i.e., active control), or placebo, used as a reference in a
clinical trial.”
It is
clear then, by the wording of the definitions that even products that are
already authorized for marketing by competent authorities are considered
investigational products even if carrying only labeling changes.
The
ICH/GCP(2) does not define any other medicinal product or device used in
clinical trials.
It is
common knowledge that drugs are costly, if not extremely expensive, and should,
whenever possible, be used for any patients that may need them. It does not
seem to us that the destruction of products that would enable a better quality
of life (if not a lifesaving possibility) for many people, can be seen as a
reasonable/rational decision. The possibility to donate or put to further use
such products should be more than welcome, provided, of course, it is
thoroughly regulated and controlled.
As there is a new
version of the ICH E6 presently under public consultation, we believe its terms
could be the starting point for the possibility to give more rational
destinations to clinical trial drug surpluses.
This new
version, the ICH E6 (R3), has already been endorsed by the Expert
Working Group – EWG on May 19, 2023, but remains under consultation and, as
such, still a work in progress. Under this new version, when it is formally
adopted, and if adopted as per present draft, it could open the possibility to
give different destinations to surplus Clinical Trial products (see below). It
is important to keep in mind, however, that eventual alternative
approaches/destinations should, for obvious reasons, only apply for products
that are duly authorized by the respective regulatory authorities.
2.10 Investigational Product Management
2.10.3 The
investigator/institution and/or a pharmacist or other appropriate individual
should maintain records of the product’s delivery, the inventory, the use by
each participant (including documenting that the participants were provided the
doses specified by the protocol) and the return to the sponsor and destruction
or alternative disposition of unused product(s). These records should include
dates, quantities, batch/serial numbers, expiration dates (if applicable) and
the unique code numbers assigned to the investigational product(s) and trial
participants. For authorized medicinal products, alternative approaches to
the aforementioned may be considered, in accordance with local regulatory
requirements.
We
believe that the proposed changes to the ICH, could help set in motion the
discussion of new local regulations that could allow, always considering the
quality risk, alternate use for surplus of approved and commercially available
products used in clinical studies.
It is
important to note that, while Brazil does follow the ICH Guidelines, during the
COVID-19 (SARS-CoV-2) pandemic ANVISA issued a Resolution RDC 568/2021 (that
remained in force until May of 2023), formally revoked by Resolution RDC
805/2023, that allowed, under very strict conditions, the use of medicines and
biological products for the treatment of COVID, from remaining inventory of
clinical trials carried out, or still in course, in Brazil. https://antigo.anvisa.gov.br/legislacao#/visualizar/462282
We hope this article contributes to the discussions on
the changes in the ICH and to local regulations that will certainly follow it.
Marcos Lobo F. Levy Silvia
V. Fridman
Advogado Farmacêutica
