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Feb 28, 2021
Transforming Rare Disease Treatment
An individual disease or disorder is defined as "rare" when, at any point in time, it affects less than one person in 2,000 in the population in Europe or about one in 1,500 in the United States. There are more than 6,000 recognized rare disorders; about 80% are of genetic origin. Prominent examples of these include cystic fibrosis, Duchenne muscular dystrophy (DMD), Phenylketonuria (PKU), Amyotrophic lateral sclerosis (ALS), and various retinal dystrophies. Many cancers are recognized as rare as well. As paradoxical as it may seem, it can be claimed that “rare diseases are really common” because there are so many of them. Rare diseases currently affect 3.5-6% of the worldwide population, an estimated 30 million people in Europe and 300 million worldwide. This means that almost everyone knows somebody with a rare disease. Rare Diseases and Orphan Drugs Much of the focus on rare diseases has arisen because, until recent decades, they tended to be neglected by developers of new medicines. In fact, that is why drugs developed for rare diseases have been termed "orphan drugs." In most countries, incentives are implemented by regulatory authorities to encourage the development of orphan drugs. There are real challenges in developing orphan drugs. Prominent among these is that it is difficult to recruit sufficient participants with rare diseases to clinical trials. Thus, several approaches to trial design have been advanced to overcome this issue. Regulators have also evolved ways of applying risk-benefit assessment to orphan drug trials through approval of new drugs on a "conditional" basis, for instance by requiring ongoing detailed safety reporting where trials have clearly shown efficacy but have not generated much safety experience. A major disincentive to developing orphan drugs is the restricted size of the potential market: "rare" implies few users. Legislation exists to provide financial incentives to overcome this to an extent, but ultimately the drug developer often has to attempt to recover their investment by charging high prices for their drug. This inevitably leads to protracted negotiation between the drug developer and the authorities that will have to reimburse the costs of prescription. The highest barrier to overcome in getting a new treatment to patients with a rare disease may be to convince whoever pays for the treatment that it is economically worthwhile. Part of the solution should be to move away from expensive, traditional, slow and labor-intensive ways of conducting trials, to embracing systems that maximize digitally facilitated acquisition of source data. A Transformative Era for Treating Rare Diseases In developing a new treatment for a rare disease, the role of patient advocacy organizations is crucial. They can participate positively by funding basic research in the disease and by focusing researchers to concentrate on getting promising treatment approaches from "bench to bedside" without delay. When treatments enter clinical trials, these organizations can identify likely trial sites and they can promote trial participation among their members. Ideally, they can contribute to trial design, especially by identifying meaningful endpoints. Patients' organizations, such as Eurordis in Europe and NORD in the US, fulfill outstanding roles in promoting and encouraging the development of orphan drugs, among many other advocacy activities. When legislation was formulated decades ago to define "rare," the era of personalized medicine had not yet dawned. Since then, we have become aware that many common diseases are comprised of numerous distinct subtypes, often defined by molecular biomarkers. For example, breast cancer, ostensibly a common disease, is now seen to comprise five main molecular subtypes with differing clinical characteristics, prognoses and treatment approaches. Therefore, some distinctive subtypes of overall common diseases may be rare. These have benefited from the evolution of ideas about drug development in more classical rare diseases. Although gene therapies have been attempted for some rare diseases since the mid-1990s, we are now at the start of a transformative era for treating rare diseases, particularly those of genetic origin. For example in 2012, Glybera, a gene replacement treatment for lipoprotein lipase deficiency, became the first such treatment to be approved for clinical use in Europe. And there has been a steady, if slow, stream of other new somatic cell gene replacement therapies. CAR-T cell therapies, using gene-replaced autologous T-cells, have been approved in the last couple of years to treat some rare cancers. Potentially most widely applicable, there is considerable hope for CRISPR/Cas9 gene-editing in the medium term to correct somatic genetic mutations that lead to disease. A couple of decades ago, people with a rare disorder had to put up with a gloomy diagnosis and the knowledge that little could be done to treat them. The Orphan Drug Act of 1983 in the US, passed to facilitate and encourage drug development for rare diseases, transformed their outlook and introduced hope. It also kick-started the global biotech industry. Unfortunately, drug development is a slow process, and many people are still waiting for cures. However, rare diseases are at the forefront of drug developers’ minds. Major advances in molecular and cellular biology have brought us to a place where we can see routes to treat and cure many of these debilitating and life-threatening conditions. Still, there are issues to be resolved, in particular one of economics. A hallmark of a truly civilized society is that it regards the right to treatment as equal among citizens. Those with a rare disease should not be left behind.
Jul 29, 2020
Why Are We Still Throwing Protocols over the Wall to Site Staff?
Findings in the Tufts CSDD-Teckro study are important for the industry to discuss There was a time when telephone companies distributed fat paper directories each year. White pages for personal numbers, yellow pages for business listings. Typically, they were delivered during the day to our homes, when most of us were at work. This meant they were left in mailboxes, on doorsteps and in hallways. Generally, mine was thrown over my garden wall and then sat for hours withstanding the weather of the day. I imagine that the phone company presumed that I used the directory, but they had no way of knowing for sure. And they probably also expected that I used the most current directory, but they couldn’t know that actually I often used an older one. Consider the millions of trees used to publish a new directory each year, when in reality the producer didn’t know when, or even if, it was used. With smartphones, printed phone directories are all but extinct. Clinical trial sites are still stuck in that past It is disappointing – but not surprising – to see the results of the industry research we conducted in collaboration with Tufts Center for the Study of Drug Development (CSDD). Paper is still heavily used at sites, along with static PDFs accessed from desktop computers. You could say that essential study documents like protocols are still “thrown over the wall” to sites, just like my telephone directory would have been decades ago. Who, when and why they are accessed is largely unknown, except through a survey like this. Yet each year, the most frequent inspection of observations from the FDA are related to investigations that were not conducted according to the protocol. What can we expect if retrieval of information from current documents is not so easy for sites? Archaic means of information retrieval just don’t cut it in our everyday lives, certainly not when we can reach for a world of knowledge 24/7 with the phone in our pocket. So, how can we justify not applying this same approach to the information in clinical trials? Simplifying jobs to be done for research staff To be effective, technology must focus on helping clinical trial sites to be more productive through simplifying, reducing friction and making things easier. I know this sounds obvious – design clinical trial software from the perspective of research sites. But I would venture to say that a lot of the technology out there has been designed by people who have never visited a research site and don’t really understand in practical reality what sites really need. We’ve seen it with most software over the years. Technology handed down from on high that doesn’t suit the jobs done by site staff typically has low adoption rates, it often adds complexity and increases workloads. Sites will only truly embrace technology because they love it. They will only love it if it makes their job easier and helps them do their job better. You might argue that many study portals can be accessed on smartphones. Sure, but in reality, small screens and PDFs are enemies. It’s against our very digital nature to scroll through a document when we are so conditioned to ask a question and get an answer. Besides, when was the last time – if ever – you ran a search in a PDF on your smartphone? I’m not even sure how to do it. The reality is that sponsors and CROs continue to operate in an apparent “safe zone” – one biased towards risk mitigation rather than task optimization. Paper and online portals appear superficially “safe” from an audit perspective. And we’ve always done it this way. But at what cost? If the paper protocol is not stored where participants are seen, as reported in the Tufts CSDD study results, then what is the cost of not having the right answer right there, to answer a question on eligibility? As an investigator, how good is it to have a paper protocol in my office or an online portal when a patient phones me at 8pm while I’m at a ball game to ask me how to handle a possible toxicity? Giving a voice to research staff Sites need to be seen more as crucial stakeholders rather than servants of trials. It’s time that we shine a light on those technology solutions that work well for sponsors and CROs but complicate life in the field. Online portals are fine in theory; a secure repository for documents. Perfect – if you don’t actually need to access the documents in a hurry. And when it comes to communicating changes, then email is the obvious safe choice. We see from the study results that only a few respondents find out about protocol amendments from updates pushed out in the sponsor/CRO portal. This compares with the majority who say they receive updates via email. But we know all about the tsunami of emails we get daily, and in spite of best intentions how many emails are put in the “get to you later” category. A lot of time and effort is spent in protocol design and amendment. Protocols are getting steadily more complicated. Why then is access to the protocol so outdated and inconvenient? It really makes no sense. We need to stop thinking that throwing protocols over the wall to sites is good enough. It is not. We hope the results of this Tufts CSDD-Teckro research ignite a conversation about the information needs of site staff – many of whom are trying to conduct clinical research in addition to standard clinical care. And sadly, because it is so difficult, half will never do another trial after their first one. You can access the full Tufts report here and the companion Teckro analysis here.    
Nov 19, 2019
The Trouble with Clinical Trials: Getting Rid of Zombies
New medicines are becoming increasingly complex to develop. As a result, clinical development is taking 25% longer and the chance of a new medicinal product getting market approval is half of what it was a decade ago. Much of this is reflected in the way clinical trials are performed, with a 10% annual increase in the number and variety of procedures required. Thus, the burden on investigators and trial sites is steadily becoming heavier. In most aspects of our lives, the internet has enabled us to rapidly access information. In particular, smartphones allow us to search and retrieve almost any information that we need “on the fly.” We book our flights and hotels, make restaurant reservations and communicate with our families on our phones. Who uses, or even possesses, a telephone directory anymore? However, a zombie-like relic of the telephone directory still lives on in clinical trials. It’s called the protocol, which: Is almost always a weighty document of perhaps 150 densely printed pages. Must only be used in its currently approved version, so it may need to be changed half a dozen times during the life of a trial. Each amendment must be approved for every individual site. Usually lives on a shelf in an office, often remote from where it is most needed in the clinical area in which its trial is being conducted. Is slow to search for information, especially if not immediately to hand. If it does have an electronic existence, it is usually as a PDF document which is hard to search in a hurry. The protocol hasn’t changed in any significant way for 40 years. It is no surprise that about 35% of adverse findings of FDA inspections are related to non-compliance with the protocol. This is not a harmless zombie! There are many examples to illustrate why printed protocols have outlived their utility. For example, typical oncology sites outside of the major centers may run about a dozen different trials at one time. It is a big ask to expect an investigator to remember the detailed inclusion and exclusion criteria for each one when they sit in-clinic seeing their patients. Their time constraints mean that they have only a few minutes to consider whether any patient in particular might qualify for one of these trials. They are unlikely to rummage through a dozen protocols to check. They may refer to a “cheat sheet” with the criteria listed. Are they sure it’s from the current protocol version? It’s easier to procrastinate and move along to the next patient waiting in line outside their office. Another possible trial participant misses out. Another example illustrates how adverse effects don’t respect office hours. Consider the following scenario. Its 8 p.m. on a Friday. A study coordinator in an Immuno-oncology study is about to sit down to dinner in a restaurant. A study participant phones urgently to report sudden onset bloody diarrhea and is desperate to know what to do. The protocol copy is two miles away. How will the coordinator instruct the participant exactly according to protocol? Do we expect them to recall precisely what the protocol says, or will they set off to consult it? Or will they just try to remember and hope that they are correct? It is vital that the right advice is given if the safety of the participant and the integrity of the trial are to be preserved. To effectively deal with the many weaknesses of relying on printed protocols that live on office shelves, we need to bring the whole process into the 21st century. Just as we have with almost all ways that we seek and find information in every other aspect of our lives. Do you have any other examples of how today’s paper protocol hinders clinical trial success? I’d like to hear them – you can email me at