Big Pharma: Taking a Drug from Theory to Research and Development
Did you know that it can take up to 15 years to develop one new medicine from the earliest stages of discovery to the time it is available for treating patients? And out of the multiple new medicines being created only 10 percent reach the clinical trials phase, with only one of five ever being approved for human use?
It’s a lengthy and challenging process, but a deeper understanding of the R&D (research and development) process can explain why so many compounds don’t make it.
Success requires immense resources, sophisticated technology and complex project management. It also takes persistence and, sometimes, even luck. Ultimately, though, the process of drug discovery brings more than just a new pill to the pharmacy shelves – it brings hope and relief to millions of patients around the world.
Understanding the Disease
Before any potential new medicine can be discovered, scientists work to understand the disease to be treated, as well as the underlying cause of the condition.
Numerous studies are conducted to understand how genes are altered, how that affects the proteins they encode, and how those proteins then interact with each other in living cells. They way said affected cells change the specific tissue they are in are then analyzed, finally giving scientists an understanding of how the disease affects the entire patient.
Researchers from government, academia and industry all contribute to these studies.
Once enough information is gathered, scientists select a “target” for a potential new medicine. A target could be a single gene or protein that is involved in a particular disease. After choosing a potential target, scientists must then show that it is actually involved in the disease and can be acted upon by a drug.
Magnetic resonance imaging, X-ray crystallography along with powerful computer modeling capabilities, chemists can visualize the target in three dimensions and design potential drugs to more powerfully bind to the parts of the target where they can be most effective.
On average, it costs $800 million to $1 billion to research and develop a successful drug, according to PhRMA, so target validation is crucial to help scientists avoid research paths that look promising but lead to dead ends.
Once scientists fully understand a disease and are ready to begin looking for a responsive drug, they search for a molecule or “lead compound” that may act on their chosen target. If successful over years of testing and numerous odds, the lead compound can become a new medicine.
New techniques have revolutionized the ability of researchers to optimize potential drug molecules.
There are four key ways scientists can follow to find a lead compound:
Nature: This was once the primary method for finding a lead compound, until recently. Bacteria found in soil and moldy plants both led to important new treatments, for example. Nature still offers many useful substances but there are now other ways to approach drug discovery.
De novo: Thanks to advances in chemistry, scientists can also create molecules from scratch. Using sophisticated computer modeling, scientists can predict what type of molecule will work.
High-throughput screening: As the most common way that leads are usually found, advances in robotics and computational power allow researchers to test hundreds of thousands of compounds against the target to identify any that might be promising.
Biotechnology: Through biotechnology, scientists can also genetically engineer living systems to produce disease-fighting biological molecules.
Entering Early Safety Tests
Once lead compounds are determined, they go through a series of tests to provide an early assessment of the safety of said lead compound. Scientists test absorption, distribution, metabolism, excretion and toxicological (ADME/Tox) properties of each lead.
These studies are performed in living cells, in animals and via computational models. Successful drugs must be absorbed into the bloodstream, distributed to the proper site of action in the body, metabolized efficiently and effectively, successfully excreted from the body and demonstrated to be non-toxic.
Lead compounds that make it successfully out of this round are then optimized to make them even more effective and safer. Hundreds of different variations of the initial leads are made and tested with biologists and chemists working together closely to test the effects of variations.
Once optimized compounds have been narrowed down to a handful, researchers turn their attention to testing them extensively to determine if they should move on to testing in humans.
In vitro and in vivo tests are conducted, where in vitro tests are experiments conducted in the lab and in vivo studies are those performed in living cell cultures and animal models.
During this stage, researchers also must determine how to make large enough quantities of the drug available for clinical trials. The drug will need to be scaled up, as drugs on a small scale do not translate easily to larger production, and may later on need to be scaled up once more if it is approved for use in the general patient population.
The Phases of Clinical Trials
Before any clinical trial can begin, researchers must file an Investigational New Drug (IND) application with the FDA. The application includes the results of the pre-clinical work, the candidate drug’s chemical structure and how it is thought to work in the body along with a listing of any side effects and manufacturing information. The IND also provides a detailed clinical trial plan that outlines how, where and by whom the studies will be performed.
In addition to the IND application, all clinical trials must be reviewed and approved by the Institutional Review Board (IRB) at the institutions where the trials will take place.
Phase 1: In Phase 1 trials the candidate drug is tested in people for the first time. These studies are usually conducted with about 20 to 100 healthy volunteers. The main goal is to discover if the drug is safe in humans.
Phase 2: In Phase 2, researchers evaluate the candidate drug’s effectiveness in about 100 to 500 patients with the disease or condition under study, and examine the possible short-term side effects and risks associated with the drug. Researchers also analyze optimal dose strength and schedules for using the drug.
Phase 3: Once entering Phase 3, researchers study the drug candidate in a much larger number of patients, typically 1,000 to 5,000. This phase is key in determining whether the drug is safe and effective and provides the basis for labeling instructions to help ensure proper use of the drug.
As the costliest and longest phase, hundreds of sites around the world participate in the study to get a large and diverse group of patients. During this phase, researchers are also conducting other studies to determine full-scale production and preparation of the complex application required for FDA approval.
New Drug Application and Approval
Once all three phases of the clinical trials are complete, the sponsoring company analyzes all of the data. If the findings demonstrate that the experimental medicine is both safe and effective, the company files a New Drug Application (NDA) with the FDA requesting approval to market the drug.
Following rigorous review, the FDA can do one of three things: 1) approve the medicine, 2) send the company and “approvable” letter requesting more information on studies before approval can be given, or 3) deny approval.
Once a new drug is approved, research continues. As a much larger number of patients begin to use the drug, companies must continue to monitor it carefully and submit periodic reports.
Medical device companies: how to prepare for Brexit
Over the last decade, medical device businesses have been no strangers to regulatory changes and new compliance requirements. Companies with devices in the EU market have been working hard to achieve conformity with the requirements of the EU Medical Device Regulation 2017/745 (MDR) and In Vitro Diagnostic Regulation 2017/746 (IVDR), but the UK’s exit from the EU, effective as of 1st January 2021, demands yet another change: to comply with the new UK regulatory regime.
The Medicines and Medical Devices Act passed into law on 11 February 2021 does just that; it enables the UK to build its own regulatory system, although when this new framework will be fully in place is not yet known.
The transition to the UK’s new regulatory regime officially began on the 1st of January 2021, and with it a series of deadlines and phases that medical device manufacturers exporting to GB and Northern Ireland would do well to take close notice of. During the transition period, the UK Medical Devices Regulations (UK MDR) 2002, not to be confused with the EU MDR, will continue to apply in England, Scotland and Wales, whilst CE marked medical devices will still be accepted up to 30th June 2023.
The conformity assessment processes defined in the UK MDR 2002 (as amended) will require that medical devices carry the UKCA mark for entry in the GB market or the UKNI mark for entry in Northern Ireland (where the devices are not CE marked for the EU). In Northern Ireland, where the rules for placing a device on the market differ, the EU MDR and IVDR will apply in 2021 and 2022 respectively, in line with the EU’s implementation timeline.
This easing-in period of transition is valuable time that should be used productively by manufacturers to ensure that they get up to speed, keep up with relevant updates and prepare strategies and product portfolio for the next phase. To do this, businesses should make sure they consider the following areas as they assess their strategy for UK market access:
Potential Overlap with EU MDR and IVDR
Medical device manufacturers have been working to implement measures to ensure they comply with EU MDR and IVDR for quite some time. The experience, processes and objective evidence that they have gathered in these efforts are certain to be of use when applying for UKCA marking.
Product portfolios and new product pipelines should be evaluated against both overall compliance risk and commercial and strategic value. By identifying the regulatory compliance status for each product for the UK market and the efforts required to maintain that compliance, manufacturers can plan to use the grace period up to June 2023 to complete their activities. These plans should also be evaluated in consideration of the commercial importance of the individual products to help prioritise the workload. This may well result in the decision to discontinue certain products in the UK or to introduce new products on the UK market ahead of other markets.
Engage with Approved Bodies
This activity cannot take place too soon; as of the 1st of January 2021, UK organisations that were acting as EU Notified Bodies have become Approved Bodies in the UK, while EU Notified Bodies are no longer able to provide conformity assessments under the UK regulations. As there are currently only three UK Approved Bodies offering this service, there is a very real risk that latecomers will struggle to find a UK Approved Body to carry out the conformity assessment required to attain their UKCA mark in time.
Just as EU Notified Bodies are no longer relevant to pursuing UK certifications, UK-based Authorised Representatives are no longer valid when CE marking against the MDR or IVDR. Manufacturers using UK-based EU Authorised Representatives must switch to an EU-based Authorised Representative.
For the UK market, the role of the EU Authorised Representative is also no longer applicable. Non-UK manufacturers must have a UK-based Responsible Person (UKRP), which is equivalent to the EU Authorised Representative in terms of roles and responsibilities. Only one UKRP may be appointed, unlike EU Authorised Representatives, and they must have a registered place of business in the UK in order to register with the MHRA. Approved Bodies may be able to provide details of organisations acting as UKRPs and once this role has been assigned it will be critical for manufacturers to determine exact procedures for managing documentation and that clear communication channels are established.
Labelling and Import/Export
New UK regulations require that medical devices bear a UKCA mark in addition to the name and address of the UKRP for non-UK based manufacturers. Manufacturers who use the same products/packs for the EU and UK markets will need to consider the impact of adding more content to their labels in terms of usability for the supply chain and end-users.
While CE marking and certificates will continue to be recognised by the UK until June 2023, import/export administration is likely to change and become more burdensome. Manufacturers using separate products for GB (UKCA) and the EU and Northern Ireland (CE marked) will need to plan for how to ensure that the CE marked product is not shipped to GB post June 2023. Ensuring that processes and resources are in place to deal with developing situations will help manufacturers hit the ground running.
Many businesses will find that clinical investigations are carried out across multiple sites, some of which are outside the UK. In these instances, manufacturers will do well to have a plan for implementation and management of investigations, in compliance with local requirements. It is likely that the MHRA will also continue to update their requirements for clinical trials in the UK.
Data Protection and Standards
New tensions are emerging between the EU and the UK concerning UK data protection rules and the EU’s General Data Protection Regulation (GDPR), suggesting that maintaining ‘equivalency’ may involve a number of different phases.
Compliance with applicable standards also requires close attention; the list of designated standards for medical devices issued by the UK’s Department for Health and Social Care is based on the list of harmonised standards published in the Official Journal of the EU, which in turn are harmonised to the MDD, AIMDD and IVDD. More recently published standards, however, have not been harmonised to the latter European directives and are thus not in the UK’s designated list, despite being considered state of the art. It would be prudent for manufacturers to monitor the state-of-the-art standards and apply where applicable, rather than rely on superseded and outdated standards.
As the UK moves into a new regulatory regime, medical device manufacturers who have already invested time and resources to comply with EU MDR and IVDR can use this to attain their UKCA mark. However, a dynamic compliance environment combined with the new onus relating to export policies means that close attention needs to be paid on numerous fronts. Keeping pace with this changing environment will ensure that manufacturers face the future with confidence and do not lose important space on their markets.