Over the last couple of weeks, we have focused on some key challenges that, based on our interviews at various biotech congresses, appear to be at the forefront of Biotech executives’ thinking:

1. Finding patients

2. Challenges with clinical trial design and recruitment

3. Regulatory requirements

4. Long term revenue stream

5. Reimagining commercialisation.

In the first post we explored the challenges that Biotech companies face in finding patients and the low levels of awareness with rare and orphan diseases and advanced, novel therapies; and last week we highlighted the magnitude of the challenge that Biotechs face in clinical trial design and recruitment.

This week, which happens to coincide with rare disease day we focus on the specific regulatory challenges arising in rare and orphan diseases, especially in advanced, novel therapies.

At present the FDA is making more approvals than ever; and arguably with relaxed standards. The FDA set an all-time record for new drug approvals in 2018 with 59 novel drugs and biologics approved by the agency's Center for Drug Evaluation and Research (CDER) 34 (58%) were orphan drugs and 19 (32%) were first-in-class therapies.[1] Some oncology products are now being approved without a single randomized trial. In 2006 when doctors started testing a melanoma treatment made by Roche Holding AG on patients, they were used to facing slim odds - about one in eight - that the tumors would shrink on chemotherapy. With Zelboraf, eight out of 10 patients in an early-stage trial experienced significant tumor shrinkage. Zelboraf led some doctors to question whether to go ahead with the trials they had planned, trials that would pit Zelboraf against the standard treatment, a chemotherapy developed in 1975 called dacarbazine. Some doctors believed that would risk patients’ lives unnecessarily. Ultimately, the trial proceeded and the drug won U.S. approval in 2011. But the controversy over Zelboraf paved the way for approvals without randomized trials. For example GlaxoSmithKline Plc won approval from the U.S. Food and Drug Administration for Tafinlar, a drug targeting the same mutant genes as Zelboraf, based on a single clinical trial of just 250 patients.[2]

Taking these factors in to account it was perhaps a little surprising that we found there was a growing opinion from our discussions that regulatory authorities are not moving fast enough. With novel treatments becoming ever more complex and expensive to develop, there is some concern that regulatory authorities are not doing enough, quickly enough, to accommodate technological convergence and new innovations in drug development. There appears to be a clear consensus that technology is moving faster than regulations and this is likely to have a direct effect on patients who could otherwise benefit from these new technologies.

From first in human trials it is important for any company developing a product to talk closely with regulatory agencies and specialists to optimise their chances of future commercialisation success. The challenges around small and targeted population trials have even more hurdles. Not only are regulatory authorities still catching up with the pace of novel innovations in the field there are naturally a limited number of regulatory specialists who have deep expertise in analysing the area. As we discussed last week trials in a rare disease or a targeted patient population trial are likely to have very different end points than those in large patient populations. Biotech firms will need to adapt the way they design trials to demonstrate whether a specifically targeted drug is effective in a very small patient population.

As this is still an evolving process, regulatory bodies will likely demand follow-up studies to address questions such as drug dosing and duration. In areas such as immuno-oncology this will likely require collaborations among industry, academia, and regulatory bodies where sharing and pooling of information will be crucial in order to develop an effective programme[3].

Although there are currently many regulatory barriers for drugs targeted at smaller defined populations it is important to note that there are accelerated approval processes in place around the world as well as programmes to raise the level of cooperation between industry and regulators. An example of this is the Cancer Drug Development Forum that aims to accelerate drug development, reduce costs, increase efficacy and bring new and effective agents to patients as rapidly as possible. [4]

The accelerated approval process is not simple. Does a regulatory agency grant approval to promising treatment or let them go through the traditional process of Phase I, II and III? The FDA provides an accelerated approval process for new therapies with promising efficacy results treating life-threatening diseases, and surrogate end points are allowed in such a process[5] This type of approval process has to be followed up by confirmatory trials to monitor the post-approval activities. However, in regards to commercialisation decisions the product owner must also consider the aspect that it might be difficult to enrol patients after the treatment has been put on market, because the new treatment has already become available to all patients. The table below highlights some of the key accelerated approval programs globally.

Even though regulator bodies have put various regulations in place to fast track approval; if a drug becomes approved it does not guarantee it then makes it to the patients that need it. Especially in regards to drugs for rare diseases that are often very expensive, payers are often reluctant to reimburse these products based on limited data and outcomes. Given the typically high price of a rare disease drug, companies often struggle to win rapid market access, particularly in Europe. Take for example Shire’s product Obizur that is indicated for the treatment of Acquired Haemophilia A that effects approximately 1.5 people per million. The cost to control the bleed depends on the severity of the bleeding however can typically often cost more than $200,000. Payers frequently wish to see evidence of a drug’s value beyond the data packages developed to achieve market authorization, often because of the low number of patients available for Phase III studies. Biotech companies are often more successful when launching rare disease treatments when they invest in generating Real World Evidence (RWE) to strengthen the case they put to payers’.[6]

We are also working in an environment where new science and new technology advances are requiring new regulatory requirements in what has traditionally been a biopharmaceutical industry. Technological advances for example with new apps and devices and new interventions exploring complex areas like the microbiome now mean trials and regulations (often with different regulatory bodies) have added levels of complexity as more and more often they must consider this type of technology in combination or in competition with novel pharmaceutical compounds.

While the regulatory barriers appear to be ever increasing and whilst clinical trial designs are becoming ever more innovative it must be recognised that these regulatory hurdles are in place for a reason and although it is important to get novel therapies to the patients that need them in a timely manner it is of paramount importance that safety is ensured.

From our survey we recognised that the lack of regulatory harmony across global agencies was viewed as specifically daunting for Biotechs. In fact, many European Biotechs stated that they felt they would be able or comfortable to commercialise their product in their local country but they did not feel they would be able to achieve this without collaborations, strategic partnerships and/or a partner agency across the wider European or global markets. They believe that this is one key component dissuading them from commercialising their own product. US-centred Biotechs appear more likely to commercialise their own product as they can target a much larger patient pool under one single regulatory authority. It is the case that many agencies such as the EMA and country specific regulatory bodies such as MRHA in the UK give guidance on the regulatory approval of novel IO and Orphan designated products, however there is limited guidance on how ‘real’ access is achieved. Often this is done on a national and even local hospital by hospital level. Even if the multiple regulatory hurdles are overcome it does not guarantee successful commercialisation.


Dealing directly with regulatory agencies, alongside the other challenges we have started to explore, can be particularly daunting, complicated and time consuming. As a Biotech looking to commercialise your own asset it can be tempting to try to build capability and go alone. It is rare that any emerging Biotech will have all the capabilities, regulatory or otherwise, to successfully launch or commercialise their assets in multiple geographies alone. Therefore strategic partnerships and collaborations are critically important to success. One of the first questions to explore is where your strengths and capabilities, and connections reside? Which geographies, including the regulatory environment do you have specific experience, expertise and relationships in, and therefore where will you invest and build presence and capability vs. partner, collaborate and utilise partner agencies?

Coming back to the topic of this post, it is important to consider the current and future regulatory requirements from an early stage of development. This is paramount in orphan drugs and novel therapy development where  regulations are often changing. There are multiple agencies across the world that focus on providing drug regulatory and quality assurance services. Some we are aware of include; Innovative Science Services in the US,  Diamond pharma services in the UK, MARAS in Switzerland, Vera Rosas in Brazil and Sixmurs in Asia. Often these service companies have experts that have previously been in national or international regulatory agencies. They are able to provide guidance from an early stage of development in regards to national and international scientific and regulatory advice, Orphan drug applications and a number of critical regulatory hurdles that are likely to enhance the likelihood of future commercial triumph.

In conclusion, in Biotech there are a magnitude of commercial challenges. It is important to recognise your own capabilities, embrace partnership where it makes sense in the early stages of commercialisation. Although spending money on third parties is a difficult decision it will often result in increasing the chances of future success.