Lead Author: James Freeman
Additional Author: Dr. Andrew Hill
Organization: GP2U Telehealth, the FixHepC project, and St Stephens AIDS Trust, Chelsea and Westminster Hospital
Country: Australia; UK
Abstract
Worldwide, public health could be rapidly advanced if a robust system existed to rapidly deploy generic versions of patented medications where the existing legal framework allows it. The experience with HIV has proven the power of generic medication to deliver impressive results, but sadly this experience is not being efficiently duplicated to other globally significant infectious diseases such as Hepatitis B and Hepatitis C.
If we look at the Who Model List of Essential Medicines we can observe the listing of Entecavir (for Hepatitis B) and Sofosbuvir and Daclatasvir (for Hepatitis C). Sadly, if we then look at the WHO List of Prequalified Active Pharmaceutical Ingredients, or the WHO List of Prequalified Medicinal Products, we do not find them available.
While patents present obvious challenges many countries either do not, or are not required under TRIPs to, recognize them, so generics are possible right now. With Entecavir the patents have either been rejected, expired or will expire by Mid 2016 presenting the opportunity to tackle Hepatitis B globally. Sadly the key preparations, such as prequalified APIs and Medications, have not yet been attended to.
The current prequalification process places considerations such as GMP and bioequivalence front and centre. In clinical medicine both doctor and patient are less concerned with provenance, and far more concerned with two pragmatic questions:
If I give this medication, from this manufacturer, to a patient:
• What are the chances of cure? and
• What are the chances of adverse effects?
We assert these two questions can be efficiently answered using the power of the crowd and the cloud through inexpensive distributed patient monitoring – in effect Phase 4 post marketing surveillance of generics already in use.
Proof is the ultimate yardstick.
We have built a prototype of this system and encouraging interim results are to hand.
Submission
Facilitating Proof of Concept Trials for low cost Generic medicines
Background
Worldwide, public health could be rapidly advanced if a robust system existed to rapidly deploy generic versions of patented medications where the existing legal framework allows it. Public health could be further enhanced if innovative new medications could reach the market faster.
“Big Pharma” is a heavily subsidised industry, and as always, subsidies distort markets. In routine business a company develops a product and sells it at a price consumers can afford. If the product is good enough, consumers buy it and not only are the R&D costs recovered, but a handsome profit is returned. Looking to big screen televisions we have not seen any of Sony, Teac or Samsung go out of business because of a competitive market. We have seen high initial prices rapidly fall, with increasing volumes compensating for reduced margins. Both workers and consumers have benefited from this increase in scale.
The key consumers of medications are government and insurers who provide the patient subsidies required to support prices that end users simply cannot afford. While this market distortion should be changed, doing so is complex and will take a great deal of time, so it will not be addressed directly here. Rather we will look at practical ways to deliver results in the short and medium term.
What we need from our pharmaceutical juggernauts is more innovation, and less duplication and ever-greening of existing ideas. Ever-greening refers to the process of extending an existing drugs patent life by submitting a minor change [1]. Unfortunately the current incentives have seen the truly innovative medications like the cholesterol lowering medication Simvastatin followed by no less than 8 “me too” sequels from different Pharma companies – Atorvastatin, Crivastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin [2,3].
Not only is such duplication a substantial waste of time, energy, and capital resources it also carries real risks – Crivastatin, a medication for which there was no real need, was withdrawn from the market following a number of deaths [4].
On this topic of risk we know that our Pharmaceutical manufacturers are less than 100% transparent with the data they deliver when seeking new drug approvals [5]. Entities like the US FDA simply check what is submitted but do not provide independent validation. The withdrawal of block buster drugs like Vioxx [6] and Avandia [7] after what is estimated at over 100,000 deaths [8] speaks loudly to the need for independent oversight, and this is precisely what we propose, however it is not oversight simply for the sake of it, it is oversight that delivers tangible benefits on a very low cost base by leveraging the power of crowd sourced data and cloud computing.
Recommendation
We propose that WHO set up a body that is independently administered and funded by WHO to provide open access medication monitoring, initially targeted at assessing the clinical efficacy of generic medications, and in the longer term expanding to provide resources useful for investigational Phase 1, 2 and 3 drug trials.
The impact of voluntary submission of generic medications to such a process is not limited to simply proving that that a generic medication works in clinical practice. It also provides a valuable mechanism to independently validate the claims relating to the original medication and might reasonably be expected to reveal issues that have previously not been reported. The knowledge that independent validation of results is likely is a powerful mechanism to ensure transparency.
We have built a prototype of this system and encouraging interim results are to hand in relation to generic versions of the Hepatitis C Direct Acting Antiviral (DAA) medications Sofosbuvir, Ledipasvir and Daclatasvir. If our late breaker abstract [ILC2016-LB-4611] is accepted these results will be presented at the European Association for the Study of the Liver (EASL) conference in April.
The experience with HIV has proven the power of generic medication to deliver impressive results, but sadly this experience is not being efficiently duplicated to other globally significant infectious diseases such as Hepatitis B (HBV) and Hepatitis C (HCV).
If we look to history we can see that the publication in the Lancet in 2004 of a study funded by Médecins Sans Frontières (MSF) and conducted in Cameroon was pivotal in provisioning confidence in HIV generics [9].
We have performed a similar study in Australia targeting HCV, but have leveraged cloud based Internet technology to allow reporting of results remotely from around the country. This study is called REDEMPTION (Reviewing DAA Efficacy Managing Patient Treatment In Online Neighbourhoods) [10] and we are hopeful it will have the same impact as the MSF trial in provisioning confidence in generics.
If we look at the Who Model List of Essential Medicines [11] we can observe the listing of Entecavir (for Hepatitis B) and Sofosbuvir, Ledipasvir and Daclatasvir (for Hepatitis C). Sadly, if we then look at the WHO List of Prequalified Active Pharmaceutical Ingredients [12], or the WHO List of Prequalified Medicinal Products [13], we do not find them available.
While patents present obvious challenges many countries either do not [14], or are not required under TRIPs to [15] recognize them, so in many locations generics could be delivering results right now. With Entecavir the patents have either been rejected, expired or will expire by Mid 2016 presenting the opportunity to tackle Hepatitis B globally. It is a matter of concern that key preparations, such as prequalified APIs and Medications, have not yet been attended to.
The current prequalification process places considerations such as GMP and bioequivalence front and centre. In clinical medicine both doctor and patient are less concerned with provenance, and far more concerned with two pragmatic questions:
If I give this medication, from this manufacturer, to a patient:
• What are the chances of cure? and
• What are the chances of adverse effects?
We assert these two questions can be efficiently answered using the power of the crowd and the cloud through inexpensive distributed patient monitoring – in effect Phase 4 post marketing surveillance of generics already in use.
Proof is the ultimate yardstick, and in our view a better way to judge the quality of a restaurant is to taste the food, rather than simply assess the quality of the fit out of the kitchen and assume everything will be all right.
In essence the system we have developed presents users with a single intuitive form to which data can be added. There are structured and unstructured data fields to fill in and a secure file repository where copies of results can be uploaded to validate the accuracy to any additions. Baseline demographics are gathered as part of the registration process, and reporting is real time and completely automated.
For example the overview looks like this:
Summary for EASL
n: 420
SOF+RIBA: 0.7% (3/420)
SOF+LED: 44.8% (188/420)
SOF+LED+RIBA: 4.8% (20/420)
SOF+DAC: 43.6% (183/420)
SOF+DAC+RIBA: 6.2% (26/420)
Naive: 48.3% (203/420)
Cirrhosis: 29.9% (121/420)
Mean Age: 54.3 years
Mean HCV RNA: 6.46 log IU/ml (2897317 IU/ml)
GT1: 63.6% (267/420)
GT2: 5.0% (21/420)
GT3: 28.1% (118/420)
GT4: 2.4% (10/420)
GT5: 0.2% (1/420)
GT6: 0.5% (2/420)
These numbers make this trial of generic medications larger than the majority of those sponsored by industry. It would in fact be the largest trial ever, however we are only tracking about 20% of the patients we know of on generics due to financial resource limitations. The trial has not excluded patients using criteria designed to improve the results so the sample represents something far closer to that which exists in the real world making the results far more relevant to clinicians.
On the subject of the financial requirements for such a system they are remarkably small. We built a rapid prototype leveraging an existing Telehealth platform and have found the unit cost per patient being monitored is approximately $140 to provision 1 labour day chasing down and validating results. This cost would be further reduced if the labour was provisioned in a country where cost are lower than our circa $20 per hour rate.
The beauty of cloud computing is that once the initial development costs have been covered the delivery cost per patient/drug unit is negligible and almost completely limited to labour, most of which is provided free by doctors and patients simply going about the business of treatment.
We estimate that turning our existing single disease focussed prototype into something completely generic could be achieved for under $2 million dollars and it could be done within 6 months. This low cost is because the vast majority of the work has already been done – it is only a small step from Telehealth, which in effect is a system to deliver care remotely, and what is proposed.
The entire project was bootstrapped from an initial seed of $200,000 so these numbers are not fanciful.
Short Term Goals
Worldwide the 5 big ticket causes of infectious disease death are Malaria, TB, HIV, Hepatitis B and Hepatitis C. Millions die annually from these.
Relatively recently effective treatments for Hepatitis B, and outright cure for Hepatitis C, have been invented and put to market. Sadly these treatments are not being deployed on a mass scale due to extremely high prices, so the fact of their invention is having a negligible impact on global health.
Taking the invention of the drug Sofosbuvir as an example we can observe that, although 150,000,000 people worldwide are infected with Hepatitis C, in the 3 years since this drug was approved a mere 613,000 [16] people have been treated with it.
In a tragedy of breathtaking proportions, during this same time period, 1,500,000 people have died due to lack of affordable access to Sofosbuvir. On current trends by the time the patent expires around 20,000,000 people who could have been saved will have perished unnecessarily.
Also looking at Sofosbuvir we can observe that the entire development cost was $325 million through to the end of Phase 2. We know this because the balance sheet of the company that was set up to develop it is public knowledge. The initial investors received a 30 x return for their risk which seems not entirely unreasonable. The 3 x return over the last 2 years on Gilead Sciences $11 billion investment buying the patent seems less reasonable [17], particularly when we look at the impact of the pricing structure on global health.
Hepatitis B is similar in scale, however the patent expiry presents the opportunity to treat everyone, everywhere, and do it now.
Generic medications offer the solution and our goal is to see them clinically validated to provision the confidence to deploy them on mass scale. This can be achieved without the need for legislative changes.
Longer Term Goals
The time taken to bring a new drug to the market has risen from approximately 3 years in 1960 to 12 years at the start of the new millennium [18] The barriers to entry in the realm of new medications are currently so substantial that innovators struggle to find sufficient capital to take a product all the way from concept and invention through to final marketing approval.
There is a staggering untapped capacity for countries such as China and India to drive not only generic drug production, but also new innovation. A major barrier is the path to market and the current cost of clinical trials to validate the utility of a new medication.
It is relatively easy to envision how a system initially used to monitor generic drugs in post marketing surveillance could also be utilised for the pre-marketing trials. This would vastly reduce the barriers to entry for new and innovative manufacturers to the benefit of the entire world.
A major global trend is that medication prices have been increasing far faster than GDP growth [19]. While there is little doubt regulatory changes can address competition will remain an effective tool in the battle to control rising medication prices.
Provisioning generic tools to assist the deployment of generic medications is a simple and actionable step forward and could help restore balance to a distorted market that is currently failing to deliver treatment to the world, even where such treatment exists.
The WHO Constitution enshrines:
“…the highest attainable standard of health as a fundamental right of every human being.”
When Jonas Salk invented polio vaccine he did not patent it. When asked why he said "You can't patent the sun". Humanity as a whole continues to reap the benefits.
While it would be unreasonable to expect such generosity in our modern self centric times, it is entirely possible to regain a middle ground that more equitably balances patent rights, with patient rights.
Bibliography and References
References:
1) New drugs for old http://www.australianprescriber.com/magazine/29/6/148/9
2) List of Statin Medications https://en.wikipedia.org/wiki/Statin
3) Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors http://www.nature.com/nrd/journal/v2/n7/full/nrd1112.html
4) Withdrawal of cerivastatin from the world market http://www.ncbi.nlm.nih.gov/pmc/articles/PMC59524/
5) Clinical trial registration, reporting, publication and FDAAA compliance: a cross-sectional analysis and ranking of new drugs approved by the FDA in 2012 http://bmjopen.bmj.com/content/5/11/e009758.full.pdf
6) FDA Public Health Advisory: Safety of Vioxx http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm106274.htm
7) FDA Drug Safety Communication: Updated Risk Evaluation and Mitigation Strategy (REMS) to Restrict Access to Rosiglitazone-containing Medicines including Avandia, Avandamet, and Avandaryl http://www.fda.gov/Drugs/DrugSafety/ucm255005.htm
8) First do no harm. Improving drug safety through legislation and independent research http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2267386/
9) An advance for HIV/AIDS treatment access in the developing countries http://www.msfaccess.org/resources/press-releases/632
10) Reviewing DAA Efficacy Managing Patient Treatment In Online Neighbourhoods (REDEMPTION) https://clinicaltrials.gov/ct2/show/NCT02657694
11) WHO List of Essential Medicines - http://www.who.int/selection_medicines/committees/expert/20/EML_2015_FINAL_amended_AUG2015.pdf
12) WHO List of Prequalified Active Pharmaceutical Ingredients (APIs) - (Updated 19 February 2016) http://apps.who.int/prequal/lists/API/2016/API_PQ-List_V3_19February2016.xlsx
13) WHO List of Prequalified Medicinal Products http://apps.who.int/prequal/ (use a blank search to bring up the entire list)
14) WHO updates patent information on sofosbuvir and ledipasvir for the treatment of Hepatitic C Virus http://www.who.int/phi/implementation/ip_trade/ip_patent_landscapes/en/
15) Agreement on Trade-Related Aspects of Intellectual Property Rights https://www.wto.org/english/tratop_e/trips_e/t_agm0_e.htm
16) Gilead's Sovaldi Tied to Slow Heartbeat in Hepatitis C Patients http://www.bloomberg.com/news/articles/2015-11-04/gilead-s-sovaldi-tied-to-slow-heartbeat-in-hepatitis-c-patients
17) The Real Development Cost of Sofosbuvir http://fixhepc.com/blog/item/25-the-real-development-cost-of-sofosbuvir.html
18) Decline in new drug launches: myth or reality? Retrospective observational study using 30 years of data from the UK http://bmjopen.bmj.com/content/3/2/e002088.full.pdf+html
19) Can the U.S. Afford New Prescription Drugs Headed to the Market? http://www.usnews.com/news/articles/2015/07/28/expensive-prescription-drugs-contribute-to-growth-in-health-care-spending