Small biopharmaceutical companies are becoming increasingly important as drivers of innovation in drug development. It has recently been estimated that the majority of drugs currently in development are in the hands of small biopharmaceutical companies.1 Such companies range in size from virtual companies with no commercial products and no revenue to those with only a few commercial programs.
Small biopharmaceutical companies often encounter important challenges in designing and implementing clinical development programs. In a context in which only approximately 10% of clinical programs result in drugs that achieve regulatory approval, small-company clinical programs may have an even lower rate of success than that of large companies2 owing to limited internal experience in clinical development and limited infrastructure, which may also affect manufacturing and clinical supply. However, these challenges are largely overshadowed by limited resources and funding, which in turn fuel demand for short timelines owing to the need to demonstrate progress to investors. As such, these companies must focus their resources on small, less-costly development programs for very specific targets and often must spearhead new approaches to testing new products in order to survive.
Small companies use a variety of approaches to address these challenges, including the use of new technical platforms, the use of new formulations or technologies that enhance the actions of known drugs, or the use of trial designs that take advantage of the specific market they hope to enter. Other companies develop products that are spun off from or licensed from large companies. In fact, many small companies may choose to partner with larger companies to add resources and experience.
Many small companies also repurpose drugs or pursue narrow niche markets — such as rare inherited diseases, uncommon cancers, or specific infectious diseases — to remain viable. Furthermore, many companies turn to rare diseases for an opportunity to successfully negotiate many of the aforementioned issues, though such diseases present their own challenges — in particular, the small number of patients available for clinical trials. Table 1 illustrates some examples of approaches used by small companies that achieved Food and Drug Administration (FDA) approval for their drugs in 2014 and 2015.
It is beyond the scope of this article to provide a comprehensive review of all the challenges and strategies used by small biopharmaceutical companies. Herein we provide an in-depth discussion of several examples, with an emphasis on drugs developed for rare diseases.
Use of a Historical Control Group When the Use of Placebo Is Problematic
Although randomized, double-blind, placebo-controlled clinical trials are the standard in clinical development and usually present the quickest way to discern a treatment effect, severe and uniformly rapidly progressive, life-threatening diseases may present a challenge to the acceptability of placebo controls when preliminary data suggest a lifesaving potential. Pompe disease results from a deficiency of the enzyme acid α-glucosidase (GAA). GAA degrades lysosomal glycogen, and if there is insufficient GAA activity, glycogen accumulates in cardiac and skeletal muscle, causing progressive cardiomyopathy and generalized muscle weakness and hypotonia, which result in severely delayed motor development and cardiorespiratory failure.3 Patients may begin to exhibit signs and symptoms in the first few days of life or as late as the sixth decade. The most severe and rapidly progressive form is infantile-onset Pompe disease, in which clinically significant manifestations generally develop within the first months of life. If the condition is left untreated, 70 to 80% of children with infantile-onset Pompe disease die from cardiac or respiratory failure before 1 year of age.3
Enzyme-replacement therapy with recombinant human GAA (rhGAA, Myozyme) was approved for the treatment of Pompe disease in 2006. This approval was based on a study that evaluated the effects of rhGAA in 18 infants with severe infantile-onset Pompe disease; these patients exhibited cardiomyopathy and profound deficiency of GAA activity at an age of 7 months or younger. It was considered unethical to include a placebo group as part of the study design, because infantile-onset Pompe disease is a rapidly fatal disorder and early clinical trials had shown that treatment with various forms of rhGAA can improve survival, cardiac and respiratory function, and growth and motor development in severely affected infants.4 Instead, this study used a historical control group as a comparator. The authors identified a historical control group of 61 severely affected infants 6 months of age or younger by applying the study inclusion and exclusion criteria to a group of 168 patients with infantile-onset Pompe disease who were identified through a retrospective chart view. The cohort included 168 patients from nine countries and 33 different sites who were born during a time period in which contemporaneous care was available that was similar to the care available for the 18 infants in the study group. Overall survival and survival free from invasive ventilation were compared between treated patients and this historical cohort; the sample size of 18 treated patients provided more than 95% power to detect an absolute difference of 60 percentage points in overall survival between treated and control groups. Patients who received rhGAA treatment for 52 weeks had a markedly higher survival rate than the historical control group, and they had better respiratory function and less evidence of cardiomyopathy; a subgroup of patients also had better motor function (Figure 1).5
The use of a historical control group was acceptable for regulatory purposes owing to the objective and well-defined end point and the large treatment effect observed. Enzyme-replacement therapies for lysosomal storage disorders may result in such large effects on disease, which justifies the use of such an approach. Admittedly, many drugs in development do not produce such dramatic treatment effects.
Use of a New Biomarker End Point That Is Likely to Predict Clinical Benefit
A frequent challenge for small companies pursuing orphan niche products is that many of these disorders lack previously recognized end points and have poorly characterized, heterogeneous rates of disease progression. Without such knowledge, it is difficult to determine the sample size and duration of a clinical trial.
Fabry’s disease is another lysosomal storage disorder, but it is caused by an X-linked mutation in the gene encoding α-galactosidase. In male patients, the disease has a pronounced vascular phenotype with effects most commonly in the kidney, heart, and brain, owing primarily to storage of globotriaosylceramide (GL-3) within the endothelium; the disease results in renal failure, cardiomyopathy, cardiac events, and strokes. Prolonged and heterogeneous rates of disease progression among patients with Fabry’s disease complicate the design of clinical trials and typically necessitate large cohorts that are followed for very long time periods to discern between-group differences in clinical outcome end points. A new surrogate end point could allow greater homogeneity among patients in baseline assessments and response to therapy, with a smaller sample and shorter duration of study.6
GL-3 storage in the endothelium is directly related to the cause of eventual renal failure that affects most patients with Fabry’s disease. In animal models and a phase 1 study, analysis of GL-3 granules that were present in glomerular endothelial cells in renal biopsies showed that a recombinant enzyme could clear GL-3 storage and return the endothelial cells to near-normal, if not normal, status in a dose-dependent manner within a few months.6
The challenge of using GL-3 clearance in glomerular endothelium as a surrogate end point was that biopsy data can be quite variable when samples are obtained from different areas of the kidney and the scoring can be subjective. Extensive work on multiple biopsies and scoring systems, adjudication of results, and meetings with FDA reviewers were needed to gain agreement on the reliability of biopsy and on the extent of GL-3 clearance that could be considered to be clinically meaningful to support this pathological assessment as a surrogate end point.
It was reasoned that a reduction to normal or near-normal amounts (scored as 0 on a 4-point scale) would be likely to predict clinical benefit.7 The investigators chose this end point and used a panel of three renal pathologists to score the biopsy material. The pathologists independently assessed slides of renal biopsies that were presented in a blinded and randomized fashion. All the pathologists participated in preliminary sessions to establish the criteria for the grading scale that was used to evaluate clearance from affected tissues.8The results of this trial showed a significant treatment effect: 20 of the 29 treated patients had renal biopsies with a score of 0, whereas none of the 29 patients who received placebo did (P<0.001). Similar results were observed in the endothelium in heart and skin biopsy samples.
The FDA accepted the argument that the reduction to normal or near normal in GL-3 accumulation in renal glomerular endothelial cells is reasonably likely to predict clinical benefit, and the product received accelerated approval after the results of this randomized, placebo-controlled study using biopsy results as an end point were disclosed.7
Predictive Enrichment with the Use of a Genetic Marker
Today “targeted therapies” offer more precise ways to identify patients who are likely to benefit from treatment. In the past, therapies with promise were studied in a large population with the hope that enough participants would have a response to make the trial successful, and a broad indication for use would be granted. However, if a therapy benefited only a small number of patients, such trials might fail.
Cystic fibrosis is a progressive lung disease that provides a context to illustrate clinical-trial design that takes advantage of a targeted patient population. The disease is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial ion channel that is involved in salt and fluid transport in multiple organs, including the lung.9 Some mutations permit the CFTR protein to reach the epithelial-cell surface, but the protein is defective in chloride transport. The most prevalent mutation of this type in patients with cystic fibrosis causes a substitution of glycine for aspartic acid at amino acid 551 (G551D-CFTR mutation); this mutation occurs in only 4 to 5% of persons with cystic fibrosis.10
Pharmaceutical agents that increase the ion-channel function of activated cell-surface CFTR are referred to as “potentiators.” Ivacaftor is an approved oral CFTR potentiator and was tested in a randomized, double-blind, placebo-controlled trial. In this trial, 167 patients who tested positive for the targeted mutation were randomly assigned to either 150 mg of ivacaftor or placebo every 12 hours. The change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001), and a significant treatment effect was maintained through week 48 (Figure 2).10,11 Ivacaftor was also associated with significant benefits with respect to average weight gain, concentration of sweat chloride (a measure of CFTR activity), and freedom from pulmonary exacerbations. This study suggests that a drug targeting CFTR dysfunction can affect lung function and symptoms and thus confirms that CFTR is a valid therapeutic target. This is a great example of predictive enrichment — that is, the study used genetics to identify a population of patients with cystic fibrosis who were likely to have a response to this treatment.
As suggested above, identifying the patients who are likely to have a response to treatment, and then studying them, greatly enhances the power of a study and has clear implications for how a drug will be used. The use of such patient-selection tools can greatly reduce the number of patients needed to show efficacy. It can be especially critical when those who are likely to have a response are only a small fraction of all patients with a disease (e.g., 4 to 5%). In such a case, finding an effect in an unselected patient population may be practically impossible.
A High Placebo Response Rate and the Importance of Controlled Trials
Up to this point, we have focused on successful strategies and orphan diseases. A common error of many small companies is an overemphasis on the results of early, uncontrolled trials for planning and business decisions. To illustrate this error, we turn to an example from Parkinson’s disease.
Transplanted human fetal mesencephalic tissue survives and has antiparkinsonian effects in some patients with advanced Parkinson’s disease.12 However, practical and ethical issues preclude widespread use of fetal tissue as a therapeutic option for Parkinson’s disease. So, before initiating a large-scale confirmatory trial, a small biotechnology company (Diacrin, Charlestown, MA) conducted an uncontrolled trial involving 12 patients with Parkinson’s disease.13 These patients received unilateral implants of embryonic porcine mesencephalic tissue into the caudate and putamen. Half received cyclosporine treatment for immunosuppression, and half received fetal tissue treated with a monoclonal antibody directed against major histocompatibility class I.
At 1 year, there was significant decrease in the total score on the Unified Parkinson’s Disease Rating Scale (UPDRS; scores range from 0 to 199, with higher scores indicating greater disease severity) in the “off” state (i.e., while medication effect is at its least), with an adjusted mean decrease of 19% from baseline (mean score, 83.7 at baseline vs. 66.8 at 1 year). The “off” score on the UPDRS subscale for activities of daily living (range, 0 to 52, with higher scores indicating greater disease severity) also decreased, from a mean of 27.1 before surgery to a mean of 20.4 at 1 year after surgery. Only two patients, both in the cyclosporine group, individually showed large decreases, but 18F-fluorodopa positron-emission tomography failed to show changes on the implanted side of these two patients. In two patients who died, small numbers of implanted cells that included dopaminergic neurons and other porcine neural and glial cells were detected at postmortem analysis.
Although changes in UPDRS motor scores were considered to be “objective” results, the study was very small, and the sponsor was urged to conduct a multicenter, prospective, randomized, double-blind, placebo-controlled study to evaluate this therapy further. The FDA suggested that the use of sham-surgery controls — in which burr holes are created without further experimental intervention — is the preferred method to test new neurosurgical inventions for Parkinson’s disease. The primary end point of the confirmatory trial was the difference between the treatment group and the control group in the change in the total UPDRS score in the “off” state, 18 months after surgery. The 10 treated patients showed a mean decrease of 24.6±25.0%, but the 8 control patients surprisingly showed a mean decrease of 21.6±14.0% (P=0.60). No significant between-group differences were observed on four secondary end points.14
One of the possible reasons for the disappointing results of this trial might be the high placebo response rate (overall rate, 16%; range, 0 to 55) that has been documented in several surgical trials in Parkinson’s disease.15 To account for a placebo effect, a sufficient number of patients and a defined patient population are needed. Because of the limited resources that were available to a small biotechnology company such as Diacrin, it had to take major risks to achieve its stated goal (i.e., expecting a large treatment effect with a small number of patients). The goal can be met only if there is a large treatment effect with little or no placebo effect. Soon after the announcement of the trial results, Diacrin could not remain a viable company and closed the further development of this therapy in patients with Parkinson’s disease. Unfortunately, this is a not uncommon outcome for many small companies.
The unique challenges of clinical development by small companies are often addressed with the use of smaller clinical development programs than those used by large companies. Development of drugs for rare diseases may be used as a strategy, but the small size of the populations with such diseases and the small samples available for trials require approaches that can maximize the power to detect efficacy, which can include the use of historical controls, new surrogate end points, or enrichment for participants who are likely to have a response. Temptations to use uncontrolled, early, small studies to support further development of products may prove problematic. Small companies with limited resources require both innovative approaches and rigor for success.
ABLE, a biotech industry lobby group formed in 2003, in its report noted that the Indian bioeconomy has crossed $42 billion in 2017 and biotechnology industry is valued at $19 billion. Contrary to this, India Brand Equity Foundation (IBEF), in its Biotechnology Sector Report – March 2017 referring to ABLE – Bio Spectrum Industry Survey noted that the total biotechnology industry stood at $11 billion by FY16 and is estimated to reach $11.6 billion by FY17. Can industry people shed light on this? What is the exact size of the biotechnology industry?
Association of Biotech Led Enterprises (ABLE), a not-for-profit pan-India forum and a thirteen-year-old organization founded in Bengaluru, representing the Indian Biotechnology Sector, along with CMR (CyberMedia Research) that specializes in primary market research, consulting and advisory services, has released a report titled ‘Primary Research Based Profiling of Biotech Sector in Karnataka’ released during the Bangalore Tech Summit 2017.
ABLE was identified by Karnataka Biotechnology and Information Technology Services (KBITS) that provides secretarial services to the State Level Single Window Agency and High Level Committee, for quick clearance of the Information Technology and Biotechnology Projects in Karnataka as the most suitable entity to carry out a real-time survey of the activities in the Biotechnology space in Karnataka.
According to the ABLE – CMR report- The Indian biotech industry commands 5% share of the global biotech industry, comprising of about 800 companies, and is valued at $ 19 billion growing at 25%. The Government of India has to invest $5 Billion with intent to develop human capital, research infrastructure and biotech research initiatives to realize the vision of a $ 100 billon industry by 2025. The biotech industry comprises of five major segments: BioPharma, BioAgriculture, BioServices, BioIndustrial, and BioInformatics. Biopharma is the largest sector contributing about 64% of the total revenue followed by Bioservices (18%), Bioagri (14%), Bioindustrial (3%), and Bioinformatics contributing (1 %).
However ABLE, in its special report – India Biotech Handbook 2017, prepared for Biotechnology Innovation Organization (BIO), the world’s largest biotech trade association, released on the inaugural day of the BIO International Conference at San Diego, (June 19-22, 2017) by the Minister of State for S&T, Mr Y S Chowdary who lead a 75-strong India delegation to the world’s largest biotech industry event, noted that India’s BioEconomy is fast-growing at $42 billion.
ABLE it its previous year’s report released at Moscone Convention Center in San Francisco on June 7, 2016 noted that India’s fast-growing BioEconomy has crossed the $35.1 billion in 2015.
While releasing the Special Report at the India Pavilion at the BIO Convention in presence of Ms Holly Vineyard, Assistant Secretary of US Department of Commerce, and Mr Nandamuri Ramakrishna, member of Andhra Pradesh Legislative Assembly and Mr Venkatesan Ashok, the Consul General of India-San Francisco, ABLE Chairperson and CMD of Biocon, Dr Kiran Mazumdar-Shaw, said “This is just an initial estimate and the actual size of the country’s BioEconomy could be actually much more.”
While inaugurating a two day Global Biotechnology Summit on “Destination India” in New Delhi on February 5, 2016 the Union Minister for Science & Technology & Earth Sciences Dr Harsh Vardhan pointed out that the young population of India should take forward ideas to achieve target of $100 billion for the biotechnology sector by 2020 instead of 2025 for which the target has been set now. The summit was held as a run up to the Department of Biotechnology (DBT) celebrating its 30th Foundation Day on, February 26, 2016.
However, referring to ABLE – Bio Spectrum Industry Survey, India Brand Equity Foundation (IBEF), a trust established by the Department of Commerce, Ministry of Commerce and Industry, Government of India, in its Biotechnology Sector Report – March 2017 noted that growing at a faster pace, in comparison with the previous years, the Indian biotech industry witnessed Year on Year growth of 57.14 per cent in FY16; the total industry size stood at $11 billion by FY16 and is estimated to reach $11.6 billion by FY17 driven by a range of factors such as growing demand, intensive R&D activities and strong government initiatives. IBEF noted that the biotechnology industry has increased from $4.3 billion in FY 13 to $ 5 billion in FY 14 and stood at $ 7 billion in FY15.
A report produced by Burrill Media with support from the Biotechnology Industry Organization (BIO) and the Association of Biotechnology Led Enterprises (ABLE) in 2014, pointed out that the Indian bioeconomy grew to $4.3 billion at the end of fiscal 2013, up from $530 million in fiscal 2003. This is endorsing the industry size noted by IBEF.
Referring to the IBEF data, Prahlad Joshi, chairman of the standing committee on petroleum and natural gas, Government of India while inaugurating a three day international conference on ‘environmental bio-technology’ on November 23 at Andhra University said, “Biotechnology sector in India is growing at a rate of 20 per cent a year. It is expected to grow up to $11.6 billion by the end of this current year. Currently, India’s biotech industry holds two per cent of the global market share and is the third largest in Asian Pacific region. The sector has immense potential to grow and provide plenty of opportunities to investors.”
According to IBEF, The Indian pharma industry, which is expected to grow over 15 per cent per annum between 2015 and 2020, will outperform the global pharma industry, which is set to grow at an annual rate of 5 per cent between the same period! The market is expected to grow to $ 55 billion by 2020, thereby emerging as the sixth largest pharmaceutical market globally by absolute size, as stated by Mr Arun Singh, Indian Ambassador to the US. Branded generics dominate the pharmaceuticals market, constituting nearly 80 per cent of the market share (in terms of revenues). The sector is expected to generate 58,000 additional job opportunities by the year 2025.
India’s pharmaceutical exports stood at $ 16.4 billion in 2016-17 and are expected to grow by 30 per cent over the next three years to reach $ 20 billion by 2020, according to the Pharmaceuticals Export Promotion Council of India (PHARMEXCIL).
Looking at the numbers for biotechnology industry and that of pharma industry can we say that has Indian Bioeconomy outgrown the Pharma industry?
The CDSCO looks to give show case notices along with cancelling their licenses for the offence. These companies were apparently selling combination drugs to treat diabetes and fungal infections without the required approval.
The Central Drug Standards Control Organisation (CDSCO) has put Wockhardt Limited, Mascot Health Series Pvt. Limited and Ambic Aayurchem Limited under the scanner for selling drugs without carrying out proper safety trials.
According to a Mint report, CDSCO is contemplating cancelling their licenses for the offence. These companies were apparently selling combination drugs to treat diabetes and fungal infections without the required approval.
An official who spoke to the paper said that the authorities had conducted raids on Mascot and found that it was manufacturing the product without the prior approval from the regulator.
Mascot Health and Wockhardt are being probed for launching and marketing an anti fungal Fixed Dose combination (FDC) -Itraconazole 100 mg and Terbinafine 250 mg tablets in the market without conducting any safety trials, two people aware of the matter said, requesting anonymity.
Narendra Kukreja, managing director of Mascot Health, denied any such wrong doing, calling it a ploy to tarnish the image of the company. However, another official stated they found over 50 unregulated products in Mascot’s plant in Haridwar.
Combination drugs are drugs that are sold with two drugs packaged in a single dose in a specific ratio. Similarly, another drug is the anti-diabetic diabetic FDC-Teneligptin Hydrobromide Hydrate 20 mg+Metformin Hcl 500 mg +Pioglitazone Hydrochloride 15 mg manufactured by Ambic Aayurchem. Such a combination is not allowed by global standards.
Global health is poised to meet a series of key turning points, and changes seen in 2018 will mark the key inflections that drive the outlook for the next five years and beyond. The types of medicines being developed, the way technology contributes to health, and how the value of healthcare is calculated are all markedly changing.
Innovation is a key theme, including the way regulators of medicine and applicants filing for approval will increasingly support clinical submissions with real world data. A wave of cell and gene therapies are bending the definition of what constitutes a drug, both clinically, and in terms of expectations of outcomes, duration of treatment and costs.
Technology itself can be a treatment, and mobile apps are newly appearing in treatment guidelines as a key feature of future care paradigms. Furthermore, mobile technology can be an enabler of telehealth communication that brings providers and patients together at substantially lower costs than traditional consultations.
In recent years, concerns about escalating medicine costs have captured significant attention. In 2018, some of the key drivers of medicine spending growth appear to be slowing spending rather than driving it upward. The causes of slowing growth are directly linked to payers concerns about budgets and to newly emerging mechanisms to adjudicate value and thus limit the potential for out-of-control spending growth.
Invoice spending in the developed markets will reach over $650 billion by 2022, while net spending will remain flat
- Over the past five years, branded drug net spending in developed markets has risen from $326 billion to $395 billion. In total, 87% of the $69 billion of net growth has come from the United States.
- In 2018, net brand spending will decline in developed markets by 1-3%. This has the effect of reducing net spending overall on brands in developed markets by approximately $5 billion to a total of $391 billion in 2018.
- While the absolute share of spending from new medicines may be small, control of pricing and access to new drugs is a key point at which payers can influence drug spending trends for the longer term.
Branded specialty drugs will drive all growth in 2018, while traditional growth declines
- The past decade has seen a sustained shift in the focus of new medicines towards specialty pharmaceuticals. These are defined as those medicines treating chronic, complex or rare conditions, among other criteria.
- Specialty share of global spending has risen from 19% in 2007 to 32% in 2017. For the tenth consecutive year, specialty medicine growth exceeded traditional medicines in developed markets. In the ten developed markets, specialty represented 39% of spending in 2017, totaling $297 billion.
- Specialty share in developed markets will continue to rise, albeit more slowly than the last few years, and surpass half of medicine spending in 2022 in the United States and in four out of the five key European countries: France, Germany, United Kingdom and Spain.
The number of Next Generation Biotherapeutics in the pipeline and market is set to rise
- Next Generation Biotherapeutics include the latest generation of cell-based therapies, gene therapies and regenerative medicines.
- In 2018, between five and eight Next Generation Biotherapeutics will be approved and launched and, over the next five years, these therapies will make up 20% of the 40-45 New Active Substances (NAS) projected to be launched each year.
- In most cases, Next Generation Biotherapeutics will have costs approaching or exceeding $100,000 per patient. The challenge both for manufacturers and payers will be to create a new payment and reimbursement paradigm that maximizes access to these new therapies.
Published evidence of digital health will increase over 500 percent through 2022
- In 2018, approximately 340 digital health efficacy studies will be completed and published, continuing the trend of building hard evidence to support digital tools and interventions.
- An acceleration of evidence building will bring an estimated 3,500 studies over the next five years and the incorporation of apps by major professional groups into practice guidelines.
- Alignment on the appropriate sets of features and safeguards for apps has emerged and technology innovators are advancing into the field in significant numbers. Integration with provider workflows that occur in the next five years will be critical to stakeholder adoption.
- The emergence of well-designed apps and mobile devices offers the potential to improve outcomes for patients, sometimes at near-zero incremental costs.
In 2001 there were 1,198 pharmaceutical organizations with a total of 5,995 drugs in the pipeline; as of January 2017, Pharmaprojects reports those numbers rose to 4,003 pharmaceutical companies with nearly 15,000 drugs in the pipeline.
Sponsors and trials are abundant, and as the FDA ushered in a new commissioner, the pace of drug approvals seemed to improve last year. Despite this significant growth in sponsors and trials, only 1 in 5 drugs actually make it to market. In the U.S. alone, it takes an average of 12 years and $2.6 billion dollars for an experimental drug to travel from the lab to a medicine cabinet. With millions of people waiting in the balance for life-changing therapies, the clinical research community is always looking for ways to speed the clinical development process, while maintaining safety and compliance.
Technology inherently aims to streamline processes, eliminate manual effort and create efficiencies, but is technology still doing this for clinical research?
The 1990s were a time of great technological advancements in the Life Sciences industry, but those advancements have also led to the current challenges we’re seeing in the eClinical space today.
We saw the emergence of Electronic Data Capture (EDC) software which captures and stores critically important data from patient information to case reports electronically, enabling data managers to eliminate time-consuming, manual entry of patient data from paper-based forms. Then in the mid-90s the first Randomization and Supplies Management (RTSM) systems emerged to help biostatisticians and clinical supplies managers replace binders, sealed envelopes and phone calls for trial randomization and supplies management. As promised, RTSM systems reduced the amount of paperwork and eliminated double data entry, thereby reducing study set-up times. During the same period, a worldwide standard for drug safety reporting was agreed upon and we saw the emergence of pharmacovigilance and drug safety reporting software to track adverse events and report to the FDA and other global regulatory bodies.
The technological innovations of the 90s through today have certainly introduced process efficiency to support advances in clinical research, but the way in which this innovation came about—as independent point solutions in piecemeal fashion—has created a Frankenstein of overlapping, siloed systems that has introduced a whole new set of problems. Each system requires many of the same pieces of information, effectively requiring study teams to re-enter the same information multiple times. Not only is this redundant and inefficient, it also introduces risk related to manual data entry, data accuracy and data consistency.
Clinical R&D in most pharmaceutical companies or contract research organizations (CROs) consists of data managers utilizing their EDC system to capture valuable patient data, while biostatisticians and supplies managers down the hall are utilizing their RTSM system to set up a new study and prepare for the management of supplies. Meanwhile, team members on another floor gather clinical trial adverse events data in another system for drug safety and pharmacovigilence (PV) reporting. Aren’t they on the same team? Don’t they work for the same organization? Isn’t this data for a single trial? Well yes, but inadvertently, the siloed systems have each of these functional roles collecting, re-entering and ploughing through the same information in several different places, creating duplicative work and redundant data that is not shared across teams. This Frankenstein effect has actually increased clinical study startup and execution times, so while the point solutions are saving time for individual parts of the process, the overall impact is slowing down the trial.
It’s time to dismantle the eClinical Frankenstein and reimagine clinical trial management with single, unified, cloud-based environment that supports the entire clinical development lifecycle from bench to bedside. Only by removing the blinders created by the current environment of independent point solutions can we see the possibilities. The eClinical platforms of the future must be built with the big picture in mind—considering all the requirements of the people and processes from start-up and conduct, to close-out and post-marketing—in order to make a significant positive impact on clinical trial efficiency. To do this, these platforms will need to offer common features and functions that support multiple processes, and allow for shared datasets, so that data only has to be entered once, not multiple times for every part of the process. Imagine a study in which patient data capture and management, study design, site management, screening, inclusion/exclusion criteria, protocol deviation, adverse event reporting management and more could be shared across all functional areas and teams involved in a study. Only when we start to think about eClinical technology in this way, can we truly see the potential for clinical trials tomorrow. If done right—with a blueprint for the big picture—new eClinical platforms will reduce the redundancy, streamline effort, reducing study start-up processes from weeks to days, or event to hours. This will restore the promise of technology to speed clinical trials—not slow them—which will help get new therapies to market faster for patients in need, which is ultimately, what we are all here to do.
Clinical research associates/monitors outside the United States don’t appear to be very happy in their jobs. According to a new “niche” survey from HR+Survey Solutions, international employee turnover in this job category leapt to nearly 23% in 2016. That’s up some 40% compared to 2015’s 16.4%.
It’s not a much prettier picture in the U.S., however. Turnover for clinical monitoring jobs with contract research organizations (CROs) remained just above 25%, which represented a slight uptick from the previous year.
It’s important to remember that the niche survey did not assess a wide swath of the industry; it included findings from 28 public and private CROs with fewer than 500 to more than 12,000 employees.
Digging a bit more deeply into the numbers, more than 70% of international companies, and 40% domestically, are enduring turnover well above the overall U.S. professional turnover of 17.8%.
Overall average turnover at CROs (all job types) in the U.S. inched up to 21% in 2016, compared to 20.1% in 2015. Outside the U.S., the overall average turnover rate increased to 18.7% in 2016, versus 17% the prior year.
Looking at paychecks, the survey reported that salaries for professional, non-managerial, clinical research positions increased by just over 8%.
Most clinical trial professionals remain in the catbird seat. One factor: The number of registered clinical trials has soared to 256,544 as of October 12 of this year, up about 11% from 2016, and well above the 24,941 in 2005. Those numbers come from ClinicalTrials.gov.
Rare diseases, which are often referred to as orphan diseases, are estimated to have impacted 72-96 million people in India. The Indian government has now put a National Rare Disease Policy in place and Rs 100 crore funds have been allocated towards genetic disorders.
Under the policy, the Central government will contribute 60 percent towards spending on treatment, while state governments will have to bear the remaining 40 percent of the cost. The government’s effort to improve diagnosis and bring better treatment and care to patients is already in progress, building on existing capabilities.
Disorders such as Thalassemia, Hemophilia, Spinal Muscular Atrophy, Duchenne Muscular Dystrophy, Fragile X, Inborn Errors of Metabolism, and Lysosomal Storage Disorders are just some frequently encountered genetic disorders, informed Dr. Ratna Dua Puri, Senior Consultant, Institute of Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi.
Approximately 7,000 rare diseases have been identified so far, with about 80 percent of these are genetic in origin and predominantly affect children. Even though these diseases are rare, collectively they contribute to a significant burden and affect 06-08 percent of the population. Rare diseases impose a significant societal, medical and economic burden on patients, communities and healthcare systems.
Commenting on World Rare Disease Day, Dr. Puri said, “The exact burden of rare disorders in India is not known due to the lack of epidemiological data. Currently, we do not have a standard definition for rare disorders but can extrapolate one from the current existing definitions to estimate that disorders that affect less than one in 2500 individuals are rare disorders”.
The symptoms of the rare disease vary based on the disorder. For example, in Thalassemia there is chronic anemia with Hepatosplenomegaly. Rare disorders also affect the central nervous system and some have multi-systemic involvement.
“If we really want to bring change for rare disease patients and make the National Rare Disease Policy effective, the country should explore the possibility of setting up a technical body within the Ministry of Health and Family Welfare in order to effectively monitor corpus fund spending at a central and regional level, as well as taking steps to ensure the states are implementing the policy so that patients start benefitting from this great government initiative”, commented Dr. Puri on the policy.
In addition, attention to generating awareness, early diagnosis and prevention are paramount for appropriate management of genetic disorders, she further noted.
Clinical trial sponsors often rave about the data they collect from mobile devices, and visionaries wax poetic about the ways these datasets—combined with artificial intelligence and machine learning—will change medicine.
But along the way clinical trial sites are drowning in devices and systems and the charging cords for all of them.
The Clinical Trials Transformation Initiative (CTTI) conducted a survey of potential research participants as part of its Mobile Clinical Trials program. The survey found that most potential clinical trial participants said they would be interested in a “mobile” clinical trial, here defined as one in which most of the study data are collected at home using a wrist-worn health monitor and a smart phone app. These survey respondents reported that they would be happier being part of a clinical trial with only three site visits a year rather than a “traditional” trial with more than 13 site visits a year.
But the looming caveat to these preferences is that a large majority of participants—79%—said they would want to contact the clinical trial staff if a device stopped working, and 57% said they preferred to be trained on a new mobile technology by site staff.
Patients want to talk to a real person, Beth Harper, Workforce Innovation Officer, Association of Clinical Research Professionals (ACRP), said in a panel at the end of the final day of SCOPE* last month. And a site, in turn, wants to talk to a real person for technical help as well. A survey of sites reported four hours of wait time for technical assistance, she said. Some sites simply quit enrolling patients because they are so frustrated with the technology.
David Vulcano, Assistant Vice President & Responsible Executive for Clinical Research, Hospital Corporation of America, minced no words. Patient-facing devices are a pain, he said. Sites are responsible for device set up, serve as the device help desk, and troubleshoot participant problems. All of that is uncompensated time for the site, Vulcano said, and it’s not in their area of expertise.
Sean Walsh, Chief Development Officer at Raleigh Neurology Associates, said the site has about 100 clinical trials going on right now. He estimates there are 2-3 devices needed for each trial. He’s hired an IT person to help with the technical aspects of all of the devices, a cost he said is not paid by the study sponsors.
Walsh has had to devote an entire room to charging space, he said. Volcano agreed, saying he has stacks of iPads sitting in a back room; it has become both a space and a security issue.
The reasonable solution, then would be device-agnostic, or BYOD (bring-your-own-device) trials, in which patients use a device they already own to collect data. But patients do prefer provisioned devices.
Slightly more than half of participants in CTTI’s survey expressed a preference for provisioned devices over their own devices; a third didn’t care. Only 13% preferred a BYOD trial. One major concern for patients using their own device: that their own personal data minutes not be used for the trial. Volcano, in reporting his own experiences, said patients would rather have a device supplied than use their own.
Systems, Software, and Step Counters
But sites’ technical challenges go beyond just finding charging space for hundreds of iPads and guarding against theft of hundreds of Fitbits.
Harper cited an ACRP and CenterWatch survey that showed 11 different systems per study (not all devices, but separate systems a site must use). She advocated for the creation of a technology navigator role to help sites manage the different systems and devices they are required to implement.
The panel, though, pled for interoperability between vendors. Your efficiency is our inefficiency, Vulcano said. He advocated for “putting your foot down on eConsent or eSource; they’re all basically the same.” You can actually service a system if you know it well and have been using it.
That’s an expensive and challenging proposition, he acknowledged. But for a freestanding site doing 100 studies—with a nod to Raleigh Neurology Associates—Vulcano believes system investments are worth it for efficiency.
HCA is a hybrid center, though, and Vulcano said that clinical trials will always compete with regular routine care. The reasoning can easily be: if it’s a hassle, rather than invest in eConsent, just stop doing clinical trials and see more patients.
Top-line trial data unveiled by Janssen at the 2018 American Academy of Dermatology (AAD) Annual Meeting over the weekend indicate that the benefit of Tremfya in patients with severe plaque psoriasis is maintained in the long-term.
The company said that the “vast majority” of patients with moderate to severe plaque psoriasis receiving Tremfya (guselkumab), who achieved at least a 90 percent improvement in the Psoriasis Area and Severity Index (PASI 90) at week 28, maintained a PASI 90 response with continuous treatment through week 72.
According to the data, 86 percent of patients taking the novel biologic who achieved PASI 90 continued to do so through week 72, while only 11.5 percent of patients who were withdrawn from treatment maintained a PASI 90 response.
Findings from the VOYAGE 2 study also showed that of the 173 patients who were withdrawn from receiving Tremfya, 87.6 percent achieved a PASI 90 response within six months of re-commencing retreatment.
“The longer-term data from VOYAGE 2 shows promising results for guselkumab as both a continuous, long-term treatment for moderate to severe plaque psoriasis, and as an option for patients who have been withdrawn from therapy and retreated,” said study investigator Prof. Kristian Reich, MD of Dermatologikum Berlin and SCIderm Research Institute in Hamburg, Germany.
“These data provide important information to dermatologists should they need to interrupt treatment with guselkumab for a period of time, as the findings demonstrate guselkumab quickly and robustly re-established a PASI 90 response within six months.”
Tremfya is the first biologic approved to treat psoriasis that selectively blocks interleukin (IL)-23, a cytokine that plays a key role in initiating a specific immune inflammatory response in patients with the condition.