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International Clinical Trials

Joined-Up Thinking

We are witnessing a changing landscape in the healthcare sector in terms of increasing cost-consciousness among governments and payers and declining R&D productivity in the pharmaceutical industry. However, we have not seen any corresponding developments in the legislative and business framework in which these pharmaceutical companies operate in order to help address these issues. There is a clear need to accommodate these changing requirements and to help promote this industry so that it continues to flourish and play an important role in saving lives, in improving healthcare and in the economy on a global level. Instead, the framework in which pharmaceuticals operate is becoming more complex, lengthy and costly. Ten to 15 years ago it used to cost half of the amount the industry now spends to develop a new drug, and it was quicker to bring the product to the market. Therefore, now with lower patent protection periods at the time of approval of a medicine, it translates into high-priced medicines to accommodate the time and money spent on developing the drug, and to generate finances to support further R&D. On the other hand, governments and payers are becoming cost-conscious, and new drugs are being refused entry to the market as they are too expensive. This is ultimately affecting the patients who are being denied emerging and innovative therapies.

The framework in which the industry operates needs to be aligned with this changing paradigm to ensure that we are not stifling the industry and denying the patient access to innovative medicines in order to save money. We need a holistic approach that will look into this issue, and should design a framework that is acceptable to all stakeholders – industry regulators, government and payers, and patients. This article intends to initiate discussion of how we can meet the requirements of each stakeholder without excessive compromise and to address the requirements of 21st century healthcare provision.


The conventional drug development process consumes time and money – the average time is currently estimated at 10 to 12 years, and the cost is over $1 billion. So can we look at this whole process and design a framework in which we can bring the products to market within six to seven years. The cost will be reduced and will offer longer exclusivity to pharmaceutical companies, which in turn would be reflected in more costeffective medicines for payers and patients. In order to expedite the drug development process we would need intervention by policy makers and regulators to work in close collaboration with the industry.

Six Sigma Based R&D – Regulatory Framework
Drug development companies face one of the toughest operating environments. Clinical research costs continue to rise steadily at a rate of 12 to 14 per cent annually, average development and regulatory cycle times are worsening, and the volume and scope of clinical research activity is increasing, while the volume of approved new drug applications and drug development success rates remains low. It appears that the regulatory frameworks are too rigorous and have made the R&D processes a more costly exercise in terms of time and financial investment. For instance, the costs have risen as a result of increased insurance prices and fees to regulatory authorities or ethics committees, as well as the massive increase in staffing that has been necessary to deal with managing the complicated procedures contained within the governing regulatory frameworks.

There have been numerous articles and debates pressing the pharmaceutical industry to embrace Six Sigma based R&D models in order to evolve its processes to survive in this changing paradigm. However, pharmaceutical R&D works within a highly complex and regulated environment; therefore, the evolution and creativity from the industry will not bear fruit unless there is reciprocal receptiveness for innovation from the regulators. As a result, the onus also lies on the regulators to embrace innovation and to adapt the regulatory framework governing the R&D processes to ensure effectiveness in terms of cost and time.


The current regulatory framework of clinical trials can be improved. We should be working towards seamless transitions through the various development Phases with minimum administrative delays. Why stop and start; why can’t it be a continuous process with a continuous dialogue between industry and regulators? We can design an adaptive single continuous drug development process encompassing the traditional three Phases. In this model, at any given time, there would be patients on a trial at various Phases ranging from I to III. A trial would start off as conventional Phase I/II, and those subjects meeting the primary requirements can then be allowed to move into the final stage of development – Phase III. In order to ensure transparency and the safety of the subjects, a mechanism can be agreed whereby the sponsors update the regulators periodically (at pre-agreed regular intervals) on any issues relating to safety and efficacy, as assessed by the independent data monitoring committees. This will provide the regulators with a live and complete history of the compound and when it is filed as a new MAA, it might also help reduce the review time to grant approvals. This will reduce the cost and time associated with approval, initiation and maintenance of the trials.

The whole idea of randomised controlled trials seems obsolete, in that all cost-effective analyses are now performed by the payers. There should be clear guidelines as to how a trial should be designed in order to meet the criteria of ‘value’. A placebo controlled trial only seems suitable for a disease where there is no existing treatment available. For other diseases where there are available therapies, a list of minimum mandatory parameters (based on safety, efficacy and cost-effectiveness) should be made available to the industry to help design development plans for new candidates. This will ensure resource-effective and targeted drug development to ensure that it is fully aligned with the minimum expectations of the regulators and will help avoid failures when marketing authorisation applications are made.


The initiation and maintenance of clinical trials can be improved. A way forward could be to implement a framework for clinical trials, which is similar to marketing authorisation procedures (initial submission, variations, extension application and so on). A single EudraCT number can be assigned for a new investigational compound entering the clinical drug development process. Therefore, the first protocol would be classified as an initial application and, once approved, will serve as the basis of subsequent submissions relating to that given compound. Transfer from Phase I through to IV could be classified as extension applications, instead of new submissions every time. This will be beneficial for both regulators and industry. From a regulator’s perspective, this will allow capturing and assessing the entire safety and efficacy profile of the compound regardless of various indications, patient population and Phases. From an industry perspective this will be very useful for operational effectiveness. It will allow less documentation, effective data capturing and analysis methodologies, and it will help to generate comprehensive safety and efficacy data when requested by the regulators. It will also help the industry to effectively manage the entire development programme in terms of sites, contracts, protocol writing and so on. This will result in resource effectiveness for both industry and regulators.

Moreover, we should work towards streamlining the life cycle management of clinical trials in order to ensure resource and cost efficiency. A comprehensive list can be generated for changes that are anticipated during the drug development process (including new sites, various types of protocol amendments, safety and manufacturing updates), and these can then be classified into various types on the same principles as variations (for instance, Type IA, IB, Type II, notification and self-certification). For self-certification changes, the periodic intervals for reporting can be agreed (quarterly, halfyearly and annually). Only critical substantial amendments should be required for submission and approval in order to avoid potential delays. Moreover, if a substantial amendment was approved in the previous Phase, the same change could be made by notification only in subsequent Phases. For instance, if a substantial amendment was submitted and approved for addition of a site/investigator in a Phase II, and if in future the sponsor decides to add the same site/investigator in Phase III/IV, it should not cause any delays and could be submitted as a notification.


Additionally, the regulators can grant ‘limited licenses’ for use in selected patient populations on a limited scale once relative safety and efficacy has been established (post Phase II) to observe performance of new therapies in real clinical settings outside of conventional Phase III trials. The sponsors can then be allowed to gather relevant safety, efficacy and cost-effectiveness data from this types of ‘registries’ and this would then be submitted periodically (at pre-agreed intervals) to the regulators. In this way, upon demonstrating effectiveness – both clinical and economic – the ‘limited licenses’ can be extended into full licenses subject to MAA submission and approval process. There are named patient supply schemes available, but this process can be improved to generate critical safety and efficacy information in real clinical settings in order to support full approval. This approach could be particularly effective in new and emerging therapies where there is serious unmet medical need. This will also allow the healthcare professionals and support staff to gain first hand experience and get accustomed to the treatment regimes and observation/maintenance of any potential side effects of these new therapies. This will also ensure that once the product is granted full licence, the healthcare providers have already gained valuable experience in using this new product. These types of trials and development methodology can be started as pilot projects on limited scales, and later on can be developed as standard models.


The changing paradigm of 21st century healthcare provision underscores the importance of innovation, creativity and resource effectiveness. While the industry is starting to embrace these principles in their internal processes, a similar approach from regulators will greatly complement the desired outcome – cost-effective healthcare. We are starting to see collaboration between industry and regulators. However, existing collaboration is limited to a few pre-selected areas and high level policy issues. There are many areas of pharmaceutical R&D where we need innovation and creativity to ensure resource effectiveness. Smaller workstreams and forums can be established where industry and regulators can critically evaluate the operational aspects of drug development processes and work together to bring innovation and creativity in pharmaceutical R&D. This will greatly help to bridge the gap between advancements in sciences and R&D and meaningful benefits for the payers and ultimately the patients.

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Mian Atif Saeed holds an MSc in Microbiology with a postgraduate qualification in administration. He is a pharmaceutical professional and an independent healthcare writer with over 10 years of professional experience in life sciences sector spanning across R&D, intellectual property, drug development and global regulatory affairs. He has worked in both OTC and ethical side of the pharmaceutical business at county, regional and global level. He is currently working as Manager of Global Regulatory Sciences at Bristol-Myers Squibb in their UK office.
Mian Atif Saeed
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