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) and internalized in many countries, 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 with the constant modernization of management systems, it does happen more often than one would imagine, especially in places where study medicines need to be imported, 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.
It must be pointed out that the present regulations reflect, as it should, the concerns with the safety of the stakeholders (study subjects or individuals, sponsors, investigators, regulatory authorities), aimed at mitigating, as much as possible, risks related to medicines destination, logistics, and efficacy.
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, this being the case, 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 ANVISA 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.
