Dr. Mel Spigelman , President and Chief Executive Officer of the Global Alliance for TB Drug Development (TB Alliance) is regarded as one of the world’s leading experts in tuberculosis and TB drug development. He was instrumental in forging key organisational partnerships and building the pipeline of TB drug candidates when he was the Director of Research & Development at TB Alliance. In an email to R. Prasad, Dr. Spigelman explained the various facets of paediatric TB drug development.
Is there a greater involvement by drug companies in producing paediatric TB formulations after UNITAID provided a grant of $16.7 million and USAID also contributed funds?
The goal of the grant is to develop first-line TB treatments designed for children, in the proper doses and formulations, but also to help catalyse paediatric TB drug development among pharmaceutical companies through a variety of incentives. More accurately defining the market, clarifying the regulatory pathways for new products, and addressing barriers to entry for manufacturers are all within the scope of our work, and will help bring new partners into the field.
We’ve already engaged and entered into collaborations with interested generic manufacturers, including Svizera, which will help improve access to treatments. It’s also important to note that TB Alliance’s work under this grant will aim to reduce the lag time between adult and paediatric formulations of new drugs, accelerating the availability of new TB drugs in paediatric form. For example, we are working with Janssen to speed up the availability of the paediatric formulation of bedaquiline, which was approved for the treatment of MDR-TB in adults last year.
Is this a big amount to attract pharmaceutical companies to get into paediatric drug development?
The funding provided in the grant is designated for a discreet set of projects; it is not a pot of money to be given to pharmaceutical companies to work on paediatric TB drug development in a broader sense.
The impact of the work from this grant, in addition to bringing new products to the market, is to create an environment conducive to sustained and productive efforts in the field of paediatric TB drug development. This will require the involvement of pharmaceutical companies, as well as numerous other sectors including regulators, clinical researchers, Ministries of Health and Finance, drug sellers and even patients and their families. By prepairing the market for these products, we intend to lower the barriers for the necessary parties to work toward improved TB treatment for children over the long term, beyond the life of this grant.
Has any Indian pharmaceutical company shown interest in developing fixed-dose combination drugs for children?
The current paediatric TB fixed-dosed products sold through the WHO’s Global Drug Facility are produced by Indian pharma companies (Lupin and Macleods). TB Alliance has already entered into an agreement with Svizera to produce new first-line treatments in the doses now recommended by WHO and we are in discussion with other Indian pharmaceutical companies.
Because of their experience, Indian manufacturers are among those for whom we see a likely role in producing new TB drug products for children.
How long would it take to come up with fixed-dose combination drugs for first-line TB drugs? How long would a clinical trial take and how many subjects are needed to test bioavailability?
One of the significant challenges to the development of new paediatric TB treatments is the need for additional clarity on what is needed for such a product to receive approval by the various regulatory authorities around the world. These studies can take 6 to 18 months to complete. The quantity and scope of these studies required for regulatory approval can vary by country. We are working to collect that information and disseminate it widely, so that those with the capacity to work in this space have a clear understanding of what needs to be done, how to do it, and what regulators need to see to make approval decisions.
That said, we expect that the first wave of new, simpler, fixed-dose combinations for children will be available in 2016, fulfilling a significant need.
Since we need several dosages to cater to different weight bands, will the cost of drug development become expensive?
Fixed-dose combinations of current first-line TB treatments are weight-banded for both adults and children. The improved first-line TB treatments for children that will be made available as a result of this grant will be weight-banded as well. Dose-ranging studies are underway for the small group of newborns for whom this information is not already available. Dispersible tablets allow the same tablet to be dissolved in water or other liquid; different amounts are then given for each of the different weight groups, which is a cost-effective means of delivery.
When do you think the first-line, fixed-dose combination drugs would become available?
Our goal is to have optimised formulations of existing first-line treatment for children available to be sold through a global procurement agency by 2016, with a phased market rollout to follow.
Are there any attempts to come up with child-friendly second-line drugs? Cancombination drugs be produced for second-line drugs, as the choice of drugs depends on the drug sensitivity test results?
There are a number of obstacles to developing fixed-dose combinations of the current second-line drugs for children, including the fact that not all the second-line TB drugs are administered the same way. Kanamycin and capreomycin are delivered via injection, for example. While many groups advocate for drug developers to develop child-friendly formulations of the current second-line drugs, in the long run, we need new drugs to treat MDR-TB. Only then can we shorten the long treatment time (up to two years) and avoid the many toxicities that are associated with today’s MDR-TB treatments. Compared with adults, children respond better to second-line treatment — but no person should have to endure such a difficult regimen. With the development of new regimens for the treatment of drug-resistant TB with hopefully new drugs to which there is no pre-existent resistance, combination products will become readily available for treatment of what is now considered drug-resistant TB.
How long would it take and how many children are needed to undertake bioavailability of fixed-dose combinations drug trials?
The number of children to be enrolled and the timeline for either a bioavailability or bioequivalence study are agreed upon between the manufacturer and the regulatory authority reviewing the product for market authorisation/approval.
Will such trials have a control group that receives regular dispersible drugs/syrups?
Efficacy trials that require control groups are not needed to obtain regulatory approval for improved first-line paediatric drug formulations already in the market. Mostly bioequivalence and bioavailability studies on fixed-dose combinations are needed, which compare the combination tablet with the single drug and make sure they deliver the same dose.
Don’t these dispersible drugs have their own problems — requiring refrigeration and having a shorter shelf life?
The manufacturer has to demonstrate the stability of the drugs they make. Today’s FDCs do not require refrigeration, but must be kept at below 30 or 40 degrees C. They have a shelf life of 2 to 3 years.
But current treatments do have substantial problems. The most significant problem, as it relates to children specifically, is that current treatments are not manufactured in doses that match the WHO guidelines for paediatric TB treatment, which were issued in 2010. Therefore, in practice, providers and caregivers must crush or cut adults pills to reach the proper dose.
In addition, the length of treatment and side effects are a burden to [both] children and the adults caring for them. Parents must transport their child to receive treatment, ensure the child completes treatment, and often administer the treatment over six months or longer.
As part of the effort to develop new first-line TB drugs specifically designed for children, one of the options we are exploring is the more preferred formulations for such drugs — dispersibles, sprinkles, syrups, etc. Different formulations may have different profiles in terms of storage requirements and other characteristics with logistical implications for storage, manufacture, and distribution.
When the shelf life is shorter, can countries be able to procure drugs in large quantities and stock them for a long time? Will drug stock-out not become a regular feature?
Stock-outs of drugs can be caused by many factors, but a critical component is ensuring that the forecasted need for the drugs is close to the actual need. When planning, National TB Programmes include a buffer stock in any order to ensure that if the forecast is a little off, there are sufficient products. However, if the projected need is miscalculated, then stock-outs can occur. A longer shelf life can help prevent a stock-out even when forecasts are inaccurate.
Ensuring access to the treatments we develop is a critical priority for TB Alliance. Among the attributes we consider when determining the viability of a product are its stability and shelf life. We do not develop products or formulations of products which we believe would impose new or significant challenges on storage and administration of treatment.
The child-friendly combination drugs are for those younger than five years. Do we know the disease burden in this age group?
For clarification, child-friendly TB products are limited to children under 30 kg which limits the use of the drugs by weight and not by age. Depending on the region of the world, median weights for different age groups can vary. Children five years and under are a critical group, since they are most susceptible to becoming sick and dying from TB; however, all children need improved TB treatment.
Determining the actual number of paediatric patients, including those who are younger than five years old is a challenge, given the overall challenges in diagnosing paediatric TB. However, as part of this grant and in conjunction with other groups such as WHO, we are working to develop a better estimate of this cohort than has previously been available.
How can formulations be developed when pharmacokinetics of the first-line TB drugs are not known for children under two years of age?
There are only a few studies in this younger population that provide evidence for the 2010 WHO recommendations, and WHO recommended additional studies in the smallest children to be sure of the correct dose. We do know that this group absorbs, metabolizes and excretes certain drugs differently. These differences may or may not require separate recommendations for first-line treatment. Rather than have caregivers guess the correct dose for these children, the project will obtain pharmacokinetic data of the first-line TB drugs for children less than 12 months old where there are no data, and publish recommendations for this group to ensure that all children are treated optimally and are cured. There is a fairly good understanding of dose for children above 5 kg.
Since we don’t know the true disease burden in those younger than five years, are we not underestimating the disease burden and hence the market size for paediatric drugs?
The current market size is based on the number of treated patients, whereas the potential market size involves disease burden, which includes both treated and untreated patients. One of the efforts of this grant is to determine a more accurate and complete estimate of the global paediatric TB market, current and potential. We are working with partners to develop a better model for estimating these numbers, and have many studies, both underway and planned, that will yield additional information that will enable the further refinement of that model.
We realise there is much that will improve our estimates, including identifying where children are treated and where they are lost in the diagnosis and treatment process. Importantly, systems to improve reporting of cases to the National TB Programmes need to be expanded and improved to ensure that all children with TB are counted. Some may be seeking treatment in the private sector and therefore not be counted. Also, it is thought that a significant amount of childhood TB is actually misdiagnosed, or mis-categorized and that a substantial amount of childhood TB “hides” in other morbidity categories, such as pneumonia.
What delayed the development of drugs for children — the unknown disease burden and hence unknown market size, unprofitable business, lack of interest as children do not spread disease, difficulty in doing trials, resources to conduct trials, unknown pharmacokinetics in young children (<5 years)…?
I think there are a number of factors that have contributed to the stagnation of activity in this field.
Lack of financial incentive: This dynamic is seen across all neglected disease areas, and is a major obstacle to engagement in TB in general.
Lack of understanding of regulatory approval requirements and mechanisms: A lack of clarity about how best to obtain regulatory approval in various regions for new TB drugs for children serves/served as a powerful disincentive to engagement.
Incorrect information regarding burden/market size: Most experts believe the global paediatric TB burden to be larger than official estimates state. This underestimation undersells both the urgency and level of return in addressing the problem.
Insufficient information regarding the treatment recommendations: Manufacturers were told of a new dose form shortly after they had developed the current form. As a result, they were not confident that the dose recommendations would not change again and they were unwilling to commit to development of a new product.
Traditional research strategy: When it comes to new drugs in development, new drugs are traditionally developed for adults first and then tested in children, of decreasing age, for ethical reasons. Having only been rekindled roughly a decade ago, it took several years for the pipeline of new TB drug candidates to reach the point where traditional drug development processes dictated that it was time to turn attention to paediatric patients.
Complacency: Greater advocacy around such issues, and TB in general, is needed to pressure all stakeholders to engage in this activity.
As a result of all this, a comprehensive approach, with a multitude of partners, is needed. TB Alliance appreciates UNITAID’s grant in this area, which allows the organisation to kick-start this work. Clearly, more support is needed to see all of it through and end the neglect of children with TB.
What is the knowledge-sharing initiative that TB Alliance has undertaken? How will it improve the development of drugs?
TB Alliance intends to share all the lessons and insights learned throughout this endeavour widely available to those in high TB burden countries managing the TB epidemic, to the manufacturers, to new drug developers as well as to the general public. These efforts will take many forms, including a web portal that will be launched early next year where these groups can seek a range of information and gain answers to their questions. In reshaping the information landscape, we hope to lower the barriers for many to participate in advancing new treatments for children.
Will the regulatory requirements be the same for paediatric formulations as for adult formulations?
Some of the requirements are expected to be the same, whereas others will be different. Clarifying the regulatory pathway for new paediatric TB treatments is a key part of this initiative. We are in conversations with leading regulatory bodies and experts around the world and will communicate what we learn though both discussion and practice. It is envisioned that many of the lessons learned through the development of improved first-line TB treatments for children will translate to a clear and accelerated path for the development and approval for children of the new TB drug candidates just approved for adults or anticipated to reach market in the next few years.
The UNITAID grant includes defining the disease burden. But considering that 85-90 per cent of young children (<5 years) are smear-negative, how can you get to know the disease burden, even an approximation?
Children, smear-positive and smear-negative, are being clinically diagnosed; we just cannot confirm those diagnoses with sputum in smear-negative patients. Now, children are lost in the diagnostic/treatment process so there are significant complexities...and we intend to use various data and analyse that data in many different ways to reach better estimates. The model developed to estimate the global TB burden will be a living tool, and many studies of different types are scheduled and already underway to feed information into that model to continually refine and improve its accuracy. Examples of the types of data that can reveal insight into this question are: inventory studies of treatment programmes, investigation into practices of private treatment providers, sales figures of TB drugs, and many others.
What is the incentive for drug companies to keep producing child-friendly drugs for the ‘poor’ people who can’t be charged a premium price?
When any organisation collaborates with TB Alliance on product development work, we insist they agree to make any products developed affordable to those who need them. However, we recognize that to maintain steady supply of a product, companies need to avoid losing money on the product; however, the price of these treatments will still be affordable. All around the world TB medicines are made available free of charge to patients via the National TB Programmes. This arrangement is often possible with the commitment of donors and governments who recognise the need to invest in life-saving drugs for children with TB.
TB Alliance’s involvement lowers the technical barriers, as we are working in partnership to help organisations tackle the challenges they face in this area. Additional incentives include the moral impetus of such work, potential innovative financing mechanisms, a likely larger than previously expected market for such products, and a simple procurement model — large quantities will be bought from certain core suppliers, such as the WHO’s Global Drug Facility (GDF).
