As a step towards this goal, Ichor has recently gained the support of long-standing industry veteran Cornelis (Cees) Wortel, who is aiding the company in the role of Chief Medical Officer. He has advised on and guided near two hundred clinical trials in his career, and is now focused on helping Ichor's therapies to achieve success in the regulatory pipeline. Here, he writes on some of the subtleties inherent in the complex regulatory systems of the FDA in the US and EMA in Europe, and the priorities that companies must develop in order to be successful - particularly those that newcomers to the regulatory environment might find surprising or unexpected. I think you'll find it a most interesting and informative read, regardless of your position on the current regulatory system for medical research and development. You might look at some of my recent comments on nuanced opposition to the FDA as a companion piece to the article here.
Most products provided to people, which may impact their safety one way or another, undergo some form of regulatory review and approval before they are allowed on the market. Medications and devices undergo a very extensive development, review and approval process, as they can have a significant short term and very long term impact on a patient's safety and quality of life. The regulatory bodies, including the FDA and analogous regulatory authorities in other parts of the world, are not perfect. The premise of regulation in medical development however is good and very necessary: to ensure that people are safe and that therapies work. These regulatory agencies focus on consumer protection and aim to prevent serious harm such as that which came to patients when medical research was not done properly, such as the thalidomide disaster which caused countless women to give birth to babies with extremely deformed limbs and other birth defects. Treatments also have to have the effect they promise, as patients pay for them and tolerate the side effects that often come with the treatments. The overall risk-benefit balance needs to be known and acceptable.
The execution of the regulatory development path can be flawed in all the usual ways present in any structure built by fallible human beings, however. I would imagine everyone who has spent significant time working with regulators has a list of items they'd like to change or improve upon. That said, the regulatory systems available are the only viable way to put safe, new treatments into the clinic, and make them ultimately available to large numbers of people. Once we realize and embrace this, we can engage with the regulatory agencies in an informed and purposeful manner and work towards the best common path forward across different parts of the globe.
I have just recently engaged with the rejuvenation research community and it seems that it has been firmly focused, and rightly so, on the early stage research portion of progress, but it may have had comparatively little experience with later stage clinical development of agents for this new frontier. This is the natural progression of a new and exciting frontier in clinical development. I understand the existence of a certain amount of regulatory phobia, as the first view of the enormous cost and complexity of the path of clinical trials for a new therapy is very intimidating. Having been engaged in many clinical trials developing potential treatments for life-threatening diseases such as pediatric brain tumors, I also understand the enormous frustration and the need for access to new potential solutions. But as long as drug candidates are under clinical study, there is still a real inherent risk that one does more harm than good (which is exactly what the trials are intended to find out) and thus the regulations are designed to protect the trial participants first and foremost. In too many cases potential treatments have turned out ultimately harmful or have a much more modest effect impacting the risk-benefit balance negatively. Thus engaging the current regulatory systems is the road we have to travel in order to get treatment options in the hands of medical professionals and patients.
Not all study drugs in development make it; in fact most drugs turn out to be toxic or do not have an acceptable risk-benefit balance. I have been lucky enough to be part of a few innovative drug development projects which dramatically improved the medical outlook for some serious diseases (Remicade, the very first anti-TNF monoclonal antibody was the first successful drug development project I became deeply involved in). It is very gratifying to know that so many patients with Rheumatoid Arthritis, Crohn's Disease and other serious ailments are benefitting from treatment with biologicals, far beyond the reach of any single doctor's direct patient focused capabilities.
For drug development, there are ways to de-risk the complex development path. The development pathway is broken up in separate pieces, which makes the phases more manageable and the development risks (and safety risk for the trial participants) are decreased along the way. Doing this translational step from science to the clinic poorly however, often results in very promising technologies 'dying on the vine' and therefore deprives us all of potential worthwhile solutions. One of the reasons I joined Ichor Therapeutics is to help build this development bridge for the team across its varied projects, to build on and validate the scientific focus by constructing a robust infrastructure for the clinical development of innovative new options to treat aging and its conditions.
A Pharmaceutical Developer's Initial Considerations
As a company founder and pharmaceutical developer, with a specific implementation of new technology in mind, what should one be thinking about? An important initial step is to build a living model of the path ahead, and the first and most important consideration is which indication or indications to pursue. An indication is the reason to use the treatment under development, meaning the specific medical condition and class of patients that will be treated to produce the intended benefits. For example, a therapy that enhances muscle growth might be applied, depending on the technical details, to muscular dystrophy, frailty syndrome, sarcopenia, cancer cachexia, and so forth. Selecting the best initial indication can be based on different departing points: the indication with the best regulatory approval pathway versus an indication which reaches the most patients in a common disease, for instance. Choosing an indication also depends on the initial funding available and timeline constraints. There are almost always far more choices than can reasonably be tackled in the near future by any one company, and understanding the development ramifications of each top contender is key.
Interactions with regulators over the initial development years of any drug candidate will be focused on preparing for, building, and conducting a series of experiments - clinical trials - to rigorously prove that the therapy is safe and effective for the selected indication. This will involve a sizable amount of time and effort; the following costs are middle of the road estimates for indications with a high medical need and a modest sample size studying a chemical drug and might be halved or doubled for any specific company and therapy. Much will depend on the cost of manufacturing the therapeutic, implementing the pre-clinical programs, the regulatory filings, the type of disease and therapy, the medical assessments needed to prove safety and efficacy, the required length of follow up for patients, the geographical location of the trials and so forth.
a) Getting ready for the pre-trial engagement with regulators: design the overall development plan, rigorously develop the manufacturing process and implement the animal studies for initial safety assessment and other scientific building blocks such as mechanism of action and drug exposure. The doses in the animal models are much higher and exposure much larger than will be given to people and thus provide a safety margin. Costs depend on many factors, including whether the drug in development is a chemical or biological drug, the duration of intended treatment and number of patients dosed for instance. This initial work can easily cost $4-6 million, of which about half goes to the manufacturing.
b) Phase I trials: the purpose is to establish safety in a limited number of people (first in man and thus limited exposure of number of individuals) and obtain a baseline set of mainly safety data across escalating doses. Expect at least $2.5-4 million for the trial alone, and then an additional $2.5-3 million for ongoing support and all of the other work necessary to run the development team and activities in a company.
c) Phase II trials: the purpose of phase II is to 1) expand the safety database on recipients of the study drug and to start understanding how the trial endpoints are changed due to exposure to the study drug, meaning the specific measurements of the disease needed to prove safety and effectiveness, and 2) obtain information on the optimal dosage. It takes often at least 300 patients to obtain a rigorous set of data for these items. Much depends on the magnitude of the difference in an endpoint between treated and control participants. This builds the necessary data to design a Phase III. Often multiple Phase II studies are needed. This will cost $10-15 million for a single Phase II trial, and expect the average pharmaceutical company to spend another $10-15 million on ongoing operations and related costs.
d) Phase III trials: the purpose of Phase III is to determine the treatment benefit to a specific population. It also provides most of the safety data. Two such trials are typically needed, and these are the big, expensive, high-publicity projects. The cost will often run $25-50 million for the trial alone.
e) Often other specialized Phase II trials are needed to study the effects on the heart, metabolic breakdown of the study drug, and interactions with other drugs already on the market, for instance, adding to the cost. Also not included are the ongoing manufacturing costs for the study drug needed for the trials, which for each Phase grows in size of number of patients included in the trial, as well as all the regulatory costs (for instance safety reporting). Later stage trials also often require expanded pre-clinical safety work.
The overall development costs vary per study drug and indication and often run in the hundreds of millions of dollars or more. Once a drug is approved for one indication, one can build on the existing file to develop follow-on indications, saving significantly on additional development costs.
A full Gantt chart for the end to end process of all the development tasks might take 3 months to assemble and be 3 meters long when printed out. Given that, and the escalating costs during the development timeline, the more that can be done early on to consider and design the best path ahead, the better off one is. No-one wants to have to raise the funding to repeat a later stage trial which came up short, but this happens! In many cases, better planning and choices made far earlier could have avoided such costly outcomes.
An Initial Model of Indications
Many therapies will have multiple possible indications, which can be developed in interactions with regulators. Some will be better than others from the perspective of establishing a foothold in the clinic, and some will be better than others from the point of view of helping more patients (suffering from a disease which affects more people). It is usually the case that these two concerns are opposed as far as size of the required dataset for approval: the intent of the regulator is to protect the public, and applications for approval that lead to the most widespread use will generally require more evidence, time, and funding to reach a sufficient standard of proof of safety and efficacy.
Thus the preferred strategy (if possible) for clinical development professionals is to put forward an initial application for a narrow, critical usage that solves a focused, high medical need problem, one that can be evaluated and proven more easily. Then, once this is well underway, the company can expand their work with regulators to cover other, larger uses of the therapy. This sort of incremental approach to development also allows for applying what one has learned along the way, letting it be more readily incorporated into the ongoing development of the product. A second regulatory application will usually be able to build on the manufacturing and pre-clinical dataset developed for the first indication.
When looking over possible indications, one should consider the following:
a) The medical need - the greater the better. Are patients suffering severe disease effects? Is there no existing therapy? This goes a long way towards determining the degree to which all involved (patients, professionals, doctors, and regulators) will work with you and proactively support your application through the process.
b) The patient population size. This is important in several ways. Firstly, a small population size can lead to an orphan designation, which can offer a number of advantages to development, though maybe now less so than used to be the case. On the other hand, a population that is too small will require more time to enroll the number of patients needed and will render the company unable to produce data that is rigorous enough to pass muster in a reasonable timeframe. A very large population is good as enrollment may be much easier and it supports the ultimate goal of a company to help more people, but as noted above it will lead to greater demands for stringent proof of safety from the regulators - it is often not the optimal first step, but better attempted as an expansion of an indication with a smaller patient population, once the study drug manufacturing is accepted and the drug is proven to be safe in at least one indication. Larger disease indications also may have more competing treatments under development and thus also compete for patient enrollment in these studies.
c) The disease severity. A more severe disease makes it easier to obtain strong data, because the size and speed of onset of the intended benefit resulting from a successful therapy is proportionally larger. It is much easier and less costly to prove effectiveness given large and relatively rapid changes in patient health than it is for more subtle effects which appear over time. Large and rapid beneficial changes are generally only possible to achieve in severe disease conditions.
d) Plausible endpoints that can be measured, and the cost of measuring them. Mortality is a definitive and good endpoint because it is less expensive to assess, but a hard to reach endpoint because patients will have to be followed for many years, unless the disease is rapidly fatal and amenable to intervention. Endpoints based on simple biomedical assays or measurements that can run soon after a therapy is administered, such as presence of a persistent virus, or blood pressure, or blood lipid levels, are much more cost effective where they have been well established in the field and are already accepted by regulators for an indication. Where they have not been established, be aware that the process of introducing a new surrogate endpoint is a long and expensive struggle. Further, some endpoints, such as imaging endpoints, can increase the cost of a trial significantly.
e) The duration of a trial. The cost of a trial is as much determined by its duration as by the number of patients enrolled. Diseases for which there is much competition to enroll patients can be also hard, as all companies and academic groups are looking for the same patients. Some indications will be ruled out for a company at earlier stages simply because there is no practical way to raise sufficient funding given a very long timeline for trials to lead to concrete results.
In most cases, the best approach will either stand out, or be the one left standing after others are eliminated. Here, eliminated can mean "put off for later" as all companies will try to expand their indications as they move forward with more successful data and proven confidence in their approach.
Orphan designation can be obtained for an indication that has a has a small population size and great medical need. The intent on the part of regulators is to incentivize companies to work on therapies for what would otherwise be financially impossible diseases. This is achieved through a combination of fast-tracking, vouchers to speed later development, and a greater willingness on the part of regulators to work with companies to smooth the passage of a therapy for an orphan indication. Success in an initial orphan indication has in the past been a more reliable road to initial approval for many companies, even though on the whole it doesn't make the process significantly less expensive. As a consequence, a complex structure and industry has sprung up around the orphan designation, which has arguably veered into attempts to game the system.
On this topic, it is important to realize that the system is not just the rules as written. It is the intent of the regulators, the interpretation of the regulations, and the relationship built with regulators. I have sat in numerous meetings over the years listening to people engage with the regulators to try to design short cuts, where in the end they would have been far better off trying to work within the regulations while building the relationship with regulators in different jurisdictions around the world. Regulators are people just like the rest of us, and being open, earnest, and intent on producing a good outcome for patients receiving the treatment goes a lot further than aggressively trying to cut corners and rules-lawyering. The degree to which the regulatory teams you interact with are engaged with you can be an important determinant of the pace of the regulatory progress. For instance, once I have been happily surprised to receive a phone call from an FDA doctor overseeing the complex important trial I was running, asking how the agency could help us to increase the difficult enrollment and help getting the trial finished.
On starting with an orphan indication, consider, for example, that most gene therapies will be applicable to some form of genetic disorder. If a gene or protein is being manipulated, then there is probably a population of patients who have loss of function mutations in that gene resulting in an inherited disorder. But what if there are only ten such patients ever recorded, all of whom die young, and none presently known? It simply isn't practical to try to address this super rare condition at the outset of development as an orphan indication. Even if a patient is found in the next few years, the results from one intervention are not rigorous enough to proceed with. I'm aware of a trial for a rare condition that lasted for more than 25 years in order to find 90 or so patients, for example, and that is far beyond any timeline a startup company should be considering.
Further, is a proposed orphan designation biologically defensible? For example, one could look at the very large HIV patient population and try to designate a small orphan population of individuals who show adverse reactions to the common antiretroviral drugs, and thus cannot find effective treatment without bothersome side effects. But is that designation of a biological population, and the measures or metrics used, widely accepted by the research community and by regulators, or does it look more like an entirely novel slicing and dicing of the patient population to enable the aforementioned gaming of the system to try to gain advantage? If the end goal is to treat all HIV patients, then the regulators will see that and treat the application accordingly.
At the end of the day, the final safety database resulting from the clinical trial work available for submission should provide sufficient protection to the population of patients who will receive the treatment in the real world. And if that population would be much larger than the one studied, side effects that are less common (and thus not likely observed in the smaller population) will impact the larger population and only be found after exposure of many more individuals. It is because of this that regulators are stringently doing their reviews. Consider work on an orphan indication, but don't take it as a mandatory step and plan to build a safety database commensurate with the intended patient exposure.
Off-label usage interacts with orphan indications and other incremental approaches to providing a therapy to an ever-large patient population over time, and can be viewed through a similar set of lenses. In principal, any approved medical technology can be prescribed for off-label use - for use with another, different medical condition, unrelated to the approved indication. The manufacturer cannot advertise that use, but physicians and patients can follow their own judgment. In practice, consider that the intent of the regulator is firstly to minimize possible harm to patients, and secondly for all use to be tested and proven to accepted and sufficiently high standards. Small amounts of off-label use will typically fly under the radar, as regulators have limited resources. If off-label use expands greatly for any particular therapy, then regulators are bound to intervene and with good reason.
Thus it isn't wise to adopt a restricted or orphan indication and expect off-label use to take the therapy to the broader patient population. Ethically one should be going through the formal and full regulatory process to bring a therapy to that larger population in order to do no harm (primum non nocere, as the first principle). Doing things the right way in the end also works far more effectively than trying to find loopholes and does justice to the risk taken by the study participants and the recipients of the drug when on the market.
There is another factor to consider, as well. A common joke in the development community is that "it is easy to obtain approval, but hard to obtain reimbursement." It is of course not at all easy to obtain approval, which is where the humor lies. In recent years, the payer institutions, such as insurance companies and government medical entitlement programs, have become a gatekeeper and very important factor in the drug development planning of pharma/biotechnology companies. It used to be the case that one could largely put this off as a concern in the earlier stages of company development, but now it has become the case that one can have a therapy approved, but find that no insurance company or other payer will pay for it. Thus in addition to proving worthiness to regulators, when planning trials one must also take into account the evidence that payers will require in order to accept the treatment in their plans. This also serves to suppress any significant off-label use.
Aiming to be a Worldwide Company
It is a good strategy, and well established in practice, to work on application for approval of an indication with multiple regulatory bodies. The goal is to make a successful therapy available to patients globally and a larger eventual market also provides a more realistic scenario to recoup the significant developmental costs and eventually may provide profits for corporate growth, return of investment for early (high risk) investors and further development of additional drug and indications. For example, the US FDA and the European EMA and others, have a solid set of guidelines for harmonized submissions under the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). In the course of talking to both the US and EU, one can craft a plan for trials that will satisfy both agencies, at a similar cost to just one filing. The trials are designed to have the standard components and answer all specific questions for each party, are run once, and provide data for multiple applications, in order to gain approval to access two or more large markets.
My experience is largely with the FDA and EMA. I prefer Europe, as in my experience the Netherlands and Belgium are the best and the fastest locations for the initiation of the initial Phase I study. In general, studies can be conducted at a lower cost and the regulations are more accommodating in Europe. Currency exchange rates can influence these cost differences dramatically, of course.
If Europe is cheaper and faster, then why submit to the FDA early on? A counterpoint is that the US has deep clinical research experience for many diseases in its academic centers and hospitals, and a very sophisticated disease tracking system. This helps in designing clinical trial protocols and predicting enrollment. It also has an extremely large patient population. Compared to Europe, one does not have to deal with quite so many language barriers in the execution of clinical trials. So each continent has its own advantages and certainly the indication should be driven by the geography: certain diseases are not found in the highly developed countries for instance and others are predominantly found there due to lifestyle issues. Certain diseases can only be found in certain geographies or populations.
In summary, the regulators will accept clinical trial data that is developed under ICH guidelines from many parts of the world as long as the clinical trials are implemented appropriately and it is worthwhile to engage with multiple regulatory agencies once one enters later stage trials. As the regulations and local issues constantly change, it is important to keep up to speed or receive the latest information from professionals in the field.
Developing for Quality is Vital
As I mentioned, one of the important parts of the early work in a company that leads up to engagement with regulators is to develop a highly robust development plan and manufacturing and toxicity assessment process. This is the item that surprises many founders, both in terms of the stringency required by regulators, and in terms of the cost of achieving this goal.
It is comparatively easy to produce research grade products on an ad hoc basis, with a moderately wide variation in quality of the output. The core demonstration in cells or mice in any gene therapy paper can be recreated in a laboratory for $100,000 or less, and much of that cost lies in setting up the protocols, not actually running them or assessing the mice. That is far from good enough for a study drug entering the clinic, however. It does in fact cost a few million dollars to assemble a suitable infrastructure to narrow down the product quality to a level suitable for medicine. Appropriately manufactured drug product needs to be used in the definitive pre-clinical toxicity tests as well (non-GLP experiments can provide early stage guidance to select drug candidates and inform the toxicity models).
The focus on developing the overall development plan and required infrastructure and embracing its necessity from the start is one of the distinguishing marks between successful and likely-to-fail startup companies. Smaller startups are able to make enormous advances with relatively little initial funding nowadays, often stimulated with local seed investments. The next phase during the "valley of death" selects the ones which will continue to grow, as they are able to obtain follow-on funding for the more financially challenging phases of the development path. In order to obtain such follow-on funding, a solid and living development plan and meticulous execution of the steps (and if needed, adjustments to the plan!) are key. It pays to be data driven. So is making sure one always has a little extra financial buffer before the next round of funding is thought to be needed, as milestones are always harder to meet and may take a little bit longer. Having to go back for more money before a value inflection milestone is a hit will cost dearly.
Regulation is Complex, and Guidance is Necessary
I would not advocate start up founders attempting to navigate the drug development pathway and regulatory system by themselves. While founders as a category are obviously capable of rapid self-education, in the case in which they are not yet trained and have access to expertise, this isn't in the same category of difficulty as, say, raising the first round with a lead investor (and we all know how difficult that is). It is a much more complex, living, constantly dynamic system that changes in its nuances year to year, and is as much about actual practice (interpretation of regulations), good people, and knowledgeable resources, as it is about the regulations as written.
Find a guide who understands drug development and the regulatory systems you intend to work with very early in the life of the company, soon after founding, and preferably before even starting on the development work - as that work will be strongly shaped by the nature of the indications you choose. Talk to several such people to obtain different views of the development path and regulatory field, and engage one as a consultant and truly integral part of your team. Use smart outsourcing for those activities, which are much better done in specialized (large scale) vendors, and use their highly specialized expertise in a true team like fashion. Never lose oversight though, and manage for success with your associated expert partners as extended team members.
In summary, drug development is a challenging road - don't let anyone tell you differently. The reward at the end is building an extended team with highly specialized complex expertise, now successfully applied, and resulting in the ability to meaningfully improve the lives of patients. Once the core engine is built and running, many projects can be taken through the pipeline and new medical frontiers can be forever changed.