I was asked by Rocky Mountain Innosphere and NoCoBio to speak about the globalization of drug development. In thinking about the challenges we most often encounter providing drug development consulting for our clients, the one overarching theme is globalization. Globalization is a term that has a lot of baggage. To some, it conjures up images of losing US jobs as MFG is increasingly being done overseas, the influx of inexpensive (and sometimes cheap) goods imported from countries with emerging MFG capabilities.
However, in terms of drug development, the term now means much more. Globalization for us means that we have not only face challenges of a global supply chain, but also challenges of a variety of regional-based regulations, the benefits and challenges of various attempts at harmonization, the desire to explore truly global marketing strategies for a given drug or device and the complexities of running clinical trials with sites around the world.
I spoke briefly at the Innosphere event about 4 areas I think shed light on globalization and its impact on drug and device development: Supply Chain, Submissions, Design Controls, and the value of a multi-faceted drug development team with representatives from each discipline (Reg Affairs, Tox, CMC, etc..), as well as team members experienced in running development programs on a global basis.
While China and India continue to be low cost providers of many APIs, stricter enforcement of regulatory standards and increasing wage pressures are narrowing the cost gap. Recent news of serious compliance problems with Indian manufacturers and resulting import refusals and supply chain disruptions has to be included in a company’s risk evaluation and cost assumptions. Additionally, movement of API and drug product around the globe during drug development continues to get more difficult. For drugs not yet approved or described in an effective IND, getting them through the FDA Import process can be quite challenging. If you are expecting to make an API in China and import it into the US to be made into drug product in advance of submitting your IND…think again. You essentially cannot import API (that could be used at any later point in humans) without an effective IND – although, you can’t get an effective IND without a representative Certificate of Analysis for your clinical batch. This can be a catch-22 for some products, and it is critical to take into consideration when selecting CMOs and your overall CMC strategy.
Submissions are an area where we see significant attempts at harmonization. The advent of the common technical document (CTD) format was to allow reviewers in nearly every region of the world know where to look to find specific information within a given submission. Harmonization was the goal, but as is so often the case, regional differences creep in and need to be understood and planned for. Within the next couple of years we will also see fewer health authorities accept paper submissions. The EU has already mandated certain submissions be electronic and the US is close behind.
Increasing global device sales revenue is now outpacing drugs. Countries around the world are enacting their own legislation covering drug and device pathways to market, making it particularly challenging to decide where to do clinical trials or how best to seek market approvals outside of the US and EU. One area that many device developers fail to understand early enough is Design Controls. It is essential that a systematic means of device development be employed. Did you design the device correctly? Did you design the correct device? These simple questions require considerable planning and adherence to formal processes. And maintaining the documentation that these controls are indeed in place is required by US regulation and ISO standards for the EU and much of the rest of the world.
Multi-Faceted Drug Development Team
These are just a few of the considerations that should be a part of any development team’s discussions to help ensure you have thought of the implications of your initial decisions (e.g., which indication will you target). Your development team should include, at a minimum: Clinical, Tox, CMC/QA, Regulatory Affairs – and also Legal (IP) and Reimbursement. Not every one of these disciplines needs to attend every meeting over the course of development, but the initial planning and decision-making should be done with the participation of all of the relevant stakeholders. Teams often feel pressured to make decisions even when they don’t have all the information needed. Assumptions get made that can have enormous impact to overall costs and timelines. E.g., If QA/CMC assumes that the trials will be done only in the US, then they may select a CMO perfectly acceptable for early phase manufacturing in the US, but lacks the facility, controls and procedures to meet EU GMP and the scrutiny of the Qualified Person that must release the investigational material even for clinical use in the EU. If you commit limited funds to MFG your drug only to find out that it will take $500,000 and 9 months to upgrade the facility (and re-make your clinical batch) to meet EU requirements, you might find that enough of a set-back to kill the entire program.
Nik Burlew is the vice president of quality systems at Clinipace.