Why every step in drug development is critical

By Abiaz Rwamwiri

By the time a drug gets onto the market or is accessible to the public, it will have gone through rigorous steps from its discovery to the sale and use. Each step is critical as it ensures the safety, quality and efficacy.

Most of us only get to know about a drug when it has been prescribed to us by a health worker. Of course, the Internet and specifically social media has enhanced drug information, testimonials and self-medication. Medicines have not received greater attention like they have during the global COVID-19 pandemic.

Scientists, herbalists, medicine manufacturers, funding organisations and interested parties are all looking for the best intervention to manage, control and deal with the coronavirus and its symptoms. The pandemic has increased the wave of social media “doctors” who prescribe to their audience what intervention works better, faster or cheaply. It is a global challenge.

The National Drug Policy and Authority Act Cap 206, mandates National Drug Authority (NDA) to regulate the importation, manufacture and sale of drugs in Uganda.

The profile of Ugandan scientists, especially those involved in herbal medicine research has been raised in this pandemic. Several products are coming up; others being looked at as magic bullets to COVID-19 that has become a health monster. Some of these products have been leaked on the market, when they are still undergoing laboratory studies or before their safety and efficacy in humans have been established.

Locally manufactured herbal medicines are given a notification by NDA after meeting the minimum regulatory requirements based on evaluation of preliminary scientific data and audit of the factory for good manufacturing practices to confirm the safety, efficacy and quality of the drug. A notified product is only used as supportive treatment in management of a particular condition and cannot carry any cure claims. That is why NDA goes ahead to advise the clients to conduct clinical trials to confirm or validate the safety and efficacy of the proposed medicine.

Clinical trials are scientific investigations that examine and evaluate the safety and efficacy of drugs, devices, diagnostic tests or lifestyle interventions in humans. The World Health Organisation (WHO) defines clinical trials as any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes.

It involves human volunteers to test new methods of screening, prevention, diagnosis or treatment of a disease, reactions caused by the medicine and how to manage them. During the clinical research, the dosage targets an organism or the microorganism and helps to determine the usefulness of the drug and side effects.

The results that these clinical trials generate are considered to be the most robust data in the era of evidence-based medicine and they support the registration or market authorisation decision.

There has been an argument about why NDA requires clinical studies to be done on herbal medicinal products which historically have been used by our forefathers to cure different diseases. In therapeutic doses, the mass productions take large quantities of the herb composition and in this concentration of dosage, the drug content could be higher and it becomes toxic or too low for the product to be effective. Mandated by section 40 of National Drug Policy and Authority Act Cap 206, NDA is empowered to approve clinical trials to be undertaken in Uganda. By this mandate, NDA assesses the clinical trial application, including the clinical research protocol which has been vetted by an accredited Research Ethics Committee and cleared by the Uganda National Council for Science and Technology before submission to NDA. In public health emergencies, if there is a need to fast-track the process, a joint review mechanism by all relevant regulatory bodies has been put in place and is co-ordinated by the Uganda National Council for Science and Technology.

NDA has guidelines for conducting clinical trials as well as good clinical practice (GCP). All clinical trials have to be conducted in accordance with ethical principles of research in human participants, sound scientific evidence and clear detailed protocols. Clinical trials are heavily regulated and must be conducted in accordance with standard ethical guidelines, codes of conduct and national laws. This is to ensure participant safety, protection of human rights and privacy, responsible research conduct, and data integrity. The primary goal is to ensure that the benefit of the drug outweighs its risks. Monitoring this balance is a continuous process that is regarded as pharmacovigilance. When the application meets the set standards, NDA gives the applicant a certificate to conduct the clinical trials.

NDA inspects and approves the site where clinical trials are to be conducted from to ensure compliance with the conditions under which the certificate was granted. When there is a need to make any amendments during the study, an amendment application has to be submitted to the research ethics committee and then to NDA for approval.

The trial team needs to have mechanisms for monitoring the conduct of the trial, for instance through independent data and safety and monitoring boards or committees and monitoring visits by the trial sponsor representative. NDA also monitors ongoing trials through regulatory inspections that may be announced or unannounced, review of annual progress reports from the trial sites as well as review of safety reports and other mandatory notifications arising from the clinical trial.

NDA has the mandate to suspend or terminate the study, if the conditions of approval have been violated, if there are serious safety concerns or if the preliminary results from the study show that there is more risk of harm than benefit associated with the treatment. On the other hand, a trial may be terminated in the event of overwhelming benefit; if the interim results indicate a substantial benefit associated with the treatment, in which case market authorisation or licensure may be fast-tracked.

Following its approval on the market, the drug continues to be monitored primarily by the applicant as well as the NDA to ensure its benefits still outweigh the risks. This is important because clinical trials are conducted in controlled conditions and also some rare side effects may not show up during the trial. In real-world use, new side effects often emerge or known side effects may affect more people and these need to be continually assessed in light of the benefits of the drug. Should the benefit-risk balance change, NDA may request the applicant to conduct post-approval studies to verify the continued use of the drug.

There are also risk managements that require the manufacturer to predict risks that might arise while the drug is on the market, NDA monitors their implementation.

The National Drug Policy and Authority Act Cap 206 also empowers NDA to authorise the importation of any drug into Uganda. NDA has guidelines that help to verify that the drug to be imported has undergone clinical trials. An application for market authorisation is submitted to NDA in an acceptable format for submission of medicines documentation.

The documentation contains information on safety, efficacy and quality of medicines, including how clinical trials were conducted.

For the generic product, the manufacturer who utilises the exact drug molecules (original drug formulation) of the innovators, they inherit the safety, quality and efficacy of the original product. The generic manufacturers are further required by NDA to have undertaken bioequivalence trials; these are mini clinical trials to ascertain comparability or non-inferiority of their product with that of the innovator.

The results of the bioequivalence trial are submitted with details of the clinical trials conducted by the original innovator as part of the dossier of the generic product to be reviewed and assessed by NDA before the product can be registered.

Some generic products qualify for biowaivers basing on safety and efficacy information generated by the innovator of the original molecules and the comparative dissolution studies conducted between the generic product and the innovator product. This biowaiver is subject to the permeability and dissolution properties of the product.

NDA conducts audits of the manufacturing premises to ascertain that products manufactured at these premises comply with current good manufacturing practices in addition to assessing the information submitted in the applications.

Once products pass the safety, quality and efficacy assessments, they are registered by NDA and authorization for importation of products is granted to only products from approved sources. We also conduct post-marketing surveillance which involves monitoring the quality of medical products on the market through ensuring the integrity of the drug supply chain, conducting investigations on drug-related complaints and in extreme cases of side effects, some products are recalled from the market.

The totality of all these steps in drug development are for quality assurance so that we have a product on the market that can be trusted. Our regulatory principles and guidelines are to minimize risks related to medicine as we deliver our mandate of ensuring availability, at all times of essential, safe and efficacious drugs for both human and animal to the entire population of Uganda as a means of providing satisfactory health care and safeguarding the appropriate use of drugs.

The writer is the public relations manager National Drug Authority