Current drug-development pipeline
For a long time, the first step of the process has been to test the candidate molecule in at least two animal species: a rodent (mouse or rat) and a non-rodent, such as canines and primates.
A lab-bred animal species reared in controlled conditions may not fully capture the human response to a drug.
Humans are more complex creatures, and biological processes and their responses often vary from person to person as well, based on factors such as age, sex, pre-existing diseases, genetics, diet, etc.
This ‘mismatch’ between the two species is reflected in the famously high failure-rate of the drug development process.
Despite increasing investment in the pharmaceutical sector, most drugs that cleared the animal-testing stage fail at the stage of human clinical trials.
Alternative testing modes
In the last few decades, several technologies have been developed using human cells or stem cells.
These include millimetre-sized three-dimensional cellular structures that mimic specific organs of the body, called “organoids” or “mini-organs”.
Another popular technology is the “organ-on-a-chip”: they are AA-battery-sized chips lined with human cells connected to microchannels, to mimic blood flow inside the body.
These systems capture several aspects of human physiology, including tissue-tissue interactions and physical and chemical signals inside the body.
Researchers have also used additive manufacturing techniques for more than two decades.
In 2003, researchers developed the first inkjet bioprinter by modifying a standard inkjet printer.
Several innovations in the last decade now allow a 3D bioprinter to ‘print’ biological tissues using human cells and fluids as ‘bio-ink’.
These systems promise to reshape drug-design and -development.
Since they can be built using patient-specific cells, they can also be used to personalise drug-tests.
Status of regulations worldwide
How global regulatory frameworks are designed will play an important role in determining whether researchers will adopt non-animal methods to test the effect and potential side-effects of new drug candidates.
In 2021, the European Union passed a resolution on an action plan to facilitate transition towards technologies that don’t use animals in research, regulatory testing, and education.
The U.S. passed the FDA Modernization Act 2.0 in December 2022, allowing researchers to use new technology systems to test the safety and efficacy of new drugs.
In the same month, South Korea introduced a Bill called ‘Vitalization of Development, Dissemination, and Use of Alternatives to Animal Testing Methods’.
In June 2023, Canada amended its Environmental Protection Act to replace, reduce or refine the use of vertebrate animals in toxicity testing.
In March 2023, the Indian government embraced these systems in the drug-development pipeline by amending the New Drugs and Clinical Trials Rules 2019.
It did so after inviting comments from the people and in consultation with the Drug Technical Advisory Board, the statutory body that advises Central and State governments on drug-related technical matters.
Challenges
Developing an organ-on-a-chip system typically requires multidisciplinary knowledge. Expertise in
Cell biology to recreate the cellular behaviour in the lab;
Materials science to find the right material to ensure that the chip does not interfere with biological processes;
Fluid dynamics to mimic blood flow inside the microchannels;
Electronics to integrate biosensors that can measure pH, oxygen etc.in the chip;
Engineering to design the chip;
Pharmacology and toxicology to interpret action of the drugs in the chips.
It’s a truly interdisciplinary endeavour and needs focused training and human-resource building, which is lacking in the country at present.
Another important problem concerns the resources needed for research.
Most of the reagents, cell-culture related materials and instruments for these technologies are currently imported from the U.S., Europe, and Japan.
There exists a huge gap and hence opportunity in several diverse areas related to cell culture, material science and electronics, to develop an end-to-end ecosystem in India.
To manage the complexity of recreating human tissues and organs in the petri dish, researchers often minimise the number of components required to simulate the disease being investigated.
This means, for example, there can be no ‘standard’ or ‘universal’ liver-on-a-chip to study all liver diseases.
So regulators sometimes express concerns about variability in the data arising from differences in lab-to-lab protocols and expertise.
Way forward
We need to create one or more institutes like the Wyss Institute in Boston, which is a dedicated centre that focuses on innovations that emulate human biology.
To enable the crosstalk between different disciplines, technology developers in academia and industry have proposed creating a ‘Centre for Excellence’ in India, akin to the Wyss Institute, to bring together scientists and others with a wide range of expertise to build preclinical human models.
It is important to bring out guidelines on the minimal quality criterion and standards for these systems.
The current guidelines on animal testing requirements must be re-evaluated and revised, considering newer developments in cell-based and gene-editing based therapeutics.
COMMENTS