There are many hurdles still to be overcome
Mainstream print media and online portals are recently buzzing with the news of Covid-19 vaccines and their development. Does Bangladesh have the capability to develop a vaccine now?
To answer this, it is necessary to shed light on the competency of our pharmaceutical industries. But before that, we would like to share our educational and professional experiences on this subject.
More than 20 years back, we graduated from the Department of Microbiology, University of Dhaka. Dr Hossain has more than 10 years of top-notch training in the biomedical research field (PhD, National University of Singapore, Postdocs — DUKE-NUS Graduate Medical School and Singapore Cancer Centre), affiliation with academia (associate professor), and working experience in a renowned pharmaceutical industry in Bangladesh.
On the other hand, Dr Karim is currently working as a project manager at WHO-Utrecht Centre of Excellence for Affordable Biotherapeutics, Netherlands, to develop biotech drugs, where one work of his teams is currently in a Phase-I clinical trial (antibody drug).
Here, he works with the former executive director of the Netherlands Medicines Evaluation Board (MEB). Dr Karim was trained in immunology under the supervision of three world-renowned scientists in the field of immunology (MS, PhD, and Postdocs). He also worked as a pre-clinical scientist in a NASDAQ-listed biotech drug development company in the Netherlands, where his team developed two innovative bispecific antibodies which are now in Phase 1/2 of clinical trials.
In light of our experiences of working in academia, research, and industry for almost 20 years at home and abroad, we wish to share opinions about the current context of vaccine and biotech drug development capabilities in Bangladesh.
The rise of pharmaceutical industries in Bangladesh
In the last 30 years, the pharmaceutical industries in the country have made remarkable progress in manufacturing generic drugs (ie, copies of medicines made by the original drug manufacturers). After meeting 98% of the local demand, generic drugs produced in Bangladesh are being exported to more than 130 countries of the world, earning about $130 million every year.
At the heart of this achievement are the challenging initiatives of the owners of pharmaceutical industries, with the help of necessary support from the Directorate General of Drug Administration (DGDA).
Medicines are not like usual consumer goods, so to speak. It is very important to ensure the quality of medicine since sick people take drugs to recover from illness.
To ensure the quality of medicines, the regulatory department of drug administration investigates the production plant, quality control (QC), and quality assurance (QA) departments in the pharmaceutical industries, ensuring that pharma companies strictly follow proper and specific rules and regulations.
DGDA provides marketing authorization of drugs only to those pharma companies that pass the quality evaluations of DGDA. In regards to exporting generic drugs abroad, particularly in the US and Europe, it is often challenging to overcome the hurdles of the regulatory authorities of those countries.
The silver lining is that Bangladesh has gained tremendous expertise in the field of generic drugs (establishment of industry, skilled manpower, regulatory issues) in the last three decades.
Is Bangladesh capable of making raw materials of conventional generic drugs?
Despite considerable progress in the country’s pharmaceutical industry, Bangladesh has yet to achieve the capability to manufacture raw material API (active pharmaceutical ingredient) for developing drugs and these are imported from other countries. Only the formulations and packaging of medicines are done in Bangladesh.
If the capacity to produce raw materials is not achieved by 2033, the country’s whole pharma sector may be threatened. Being a developing country, Bangladesh has so far been exempted from the patent issue of the major pharmaceutical companies.
Making raw materials for generic drugs requires a lot of skills, investment, and experience which pharmaceutical industries in Bangladesh have yet to achieve. Only a handful of companies are trying to build API capabilities. It is hoped that by 2033 some companies will be able to attain those capabilities.
The comparative technical complexity of generic and biotech drugs
Generic drugs (small molecules, such as paracetamol, antibiotics) are made by the API chemical process. On the other hand, biotech drugs (large molecules) or biologics (such as insulin) are made through biological processes.
Chemical drug synthesis is relatively easy to control and batch variations are often low. On the other hand, controlling the biological system is a very difficult and daunting task where a small variation in process usually has detrimental impacts.
Therefore, strong scientific and technical skills in the biomedical field are required with huge investments to ensure the quality of biologics. That is why the manufacturers of biotech drugs are mainly from developed countries in America and Europe.
At least 15,000 thorough documents are required to discover any new chemical drug. A biologic drug, on the other hand, typically requires 60,000 documents.
A handful of pharma companies in Bangladesh are trying to acquire the skills to make biotech drugs (biosimilars). They have not yet achieved huge success. The biotech products of the domestic companies that are available in Bangladesh are mainly formulation-based, and the raw materials are imported from abroad. Obtaining approval for the marketing authorization of those biotech drugs in Europe and USA is currently not possible.
Some biotech drugs in neighbouring India have been approved by the FDA and the European Medicines Agency (EMA); that is why those companies can sell their biotech drugs (biosimilars) in America and Europe.
The demands for Indian drugs are increasing day by day as the drugs produced in India are generally cheaper but the quality of the drugs is similar to drugs produced in the Western world.
Soon, India’s biotech drugs are likely to find success in Western countries, potentially earning billions of dollars. Bangladesh can also take advantage of this if a research-friendly environment is ensured, which has been the key to India’s success.
Why is the quality of vaccines so important?
It takes a tremendous amount of scientific skills, resources, infrastructure, and time to develop an innovative vaccine. Unfortunately, most of the candidate vaccines fail to meet the regulatory approval and thus cannot be marketed.
The successful ones usually take about 10 years to bring into the market. Among many reasons why such a long time is required for the development of a vaccine, the vaccine candidate needs to be thoroughly examined to prove that it has the acceptable safety in humans.
Vaccines activate our body’s immune system to fight against invading pathogens like viruses. However, a vaccine may activate the immune responses wrongly, which can be very severe, ultimately leading to the death of healthy humans. Incidentally, the development of safe vaccines against some viruses (such as dengue, SARS coronavirus-1, respiratory syncytial virus, RSV) has not been as successful since 1960.
Candidate vaccines that activate the immune systems wrongly are responsible for immune backfire. The world-renowned Sanofi Pharmaceuticals released the dengue vaccine (Dengvaxia) after many years of effort. After receiving dengue vaccine shots in 2016, several people died in the Philippines due to antibody-dependent enhancement (ADE) immune backfire.
The criminal charge against Sanofi is still ongoing. The so-called Th1 mediated-immunopathology can cause the immune system to work against our own body, leading to multi-organ failure and death of subjects who received the vaccine.
For that exact reason, the development of a new RSV candidate vaccine was stopped for almost two decades. The candidate vaccine against feline coronavirus (feline infectious peritonitis virus) failed also due to the issue of immune backfire.
We want to stress our full attention to the issue that many of the vaccine candidates that were responsible for immune backfire and other severe adverse effects in humans were developed to protect against viruses that cause lung infection (lower-respiratory tract infections) as Covid-19 does.
So, it’s needless to say that unparalleled cautions need to be exercised to make the Covid-19 vaccine safe for humans.
Adults suffering from Covid-19 infection also develop an immune backfire called a cytokine storm. The Covid-19 patients die due to excessive immune activation. The million-dollar question which is still unanswered in the scientific community is whether the candidate Covid-19 would cause immune backfire (Antibody-dependent Enhancement and Th1-mediated immunopathology) or not.
That is why the think-tank researchers and clinicians in the field of vaccines are advising not to rush in releasing vaccines without proper vaccine safety analyses, and many scientific manuscripts have been published in top-ranked journals like Nature, Science, PNAS, etc.
Notable vaccine companies which have a lot of experience in working with vaccines/biologics seem to be moving away from the timelines announced initially. The famous American scientist Dr Fauci has been making the American people aware of this issue.
Chemistry, Manufacturing and Control (CMC), preclinical, and clinical characterization of vaccines are crucial to ensure the safety and efficacy of a vaccine. During the preclinical stage, side effects of the vaccine are tested in animal models.
Later, the main goal of the first phase (Phase I) of the clinical trial in the human is to thoroughly evaluate whether these candidate vaccines show acceptable safety profiles. Many types of biological assay development and validation under strictly regulated (good clinical practices) conditions are needed to evaluate the safety of a new vaccine. Since Covid-19 is a new virus, a substantial amount of time is necessary to validate all those bioanalyses.
The regulatory authority carefully evaluates the dossier of several thousand pages before approving the vaccine. This may take a long time.
For example, the European Medicines Agency requires an average of 210 days for evaluation of a dossier. A considerable number of experts from many disciplines, including renowned scientists and clinical researchers, evaluate the CMC, preclinical, and clinical development. We hope to write in detail about the different stages of vaccine development (CMC, preclinical and clinical development, dossier development) soon.
Ensuring the health and safety of the people is the crucial responsibility of the government of any country. The regulatory authority of Bangladesh must make sure that a vaccine is of high quality, safe, and effective to safeguard the people of our country before issuing commercial approval.
Mohammad Sorowar Hossain, PhD is Executive Director, Biomedical Research Foundation, Bangladesh, and associate professor, Independent University, Bangladesh (IUB). Rezaul Karim, PhD is Project Manager, WHO-Utrecht Center of Excellence for Affordable Biotherapeutics, Netherlands.