Financial Disclosure: Much more than meets the eye

I have always wondered what the disclosures mean. Financial disclosure, to my understanding, means that no sums of money are involved in the publishing of the manuscript.

If a funding organisation has offered grants to a researcher that leads to publication, is the researcher acting as an “agent” of that organisation by researching what the agency wants?

There’s always an agenda.

Conflicts of interest sound more fanciful. It is a philosophical argument that seems like more of an afterthought and a subtle print as a footnote. I believe that most readers have turned a blind eye to this relative obscurity. I am also surprised that people in conferences often highlight this, but I digress. It is a matter of personal preference.

I think that the time has now come to be more comprehensive about the research agendas as well as identify motivation behind publications. This post was triggered by an innocuous write up in one “prestigious journal” where the lead author had pushed for a particular technological breakthrough in the healthcare system (Disclosure: I don’t want to highlight it for fear of reprisals!). One of the names that caught my eye was a company I had previously aliased. I was keen to bring in the same technology in India and report it’s suitability for Indian conditions. The executives decided not to implement it (and that’s another story!)

But how many people aware that the company in disclosure has precisely the same division working to popularise the health care intervention listed in the article? I have my genuine doubts because it is very niche.

Hint: Most users are unaware of who manufactures the innards of mobile devices.

I think it is time to explain these disclosures comprehensively in the context of the article.

Glioma research: Asking right questions

There is an arms race to find the next molecular target. The potential spin-offs are enormous. Royalty payments. Insurance payouts.

Despite insane profits, big pharma has lost its drive to push forward for drug discovery. The easy way is to buy out the biotechnology companies (startups) or chase the clinical conditions which have healthy fat margins (like hypertension). Rare diseases like brain tumours haven’t seen any incremental investments over the past few years because of poor outcomes. Tumour treating field is the only “breakthrough” in recent times for recurrent tumours.

Therefore, the onus lies on informal networks of universities and individual researchers for pushing this narrative forward. Despite the wasted research dollars, there is a lot of promise for translational research.

My proposal has the following (very broad/generic) outline here.

The problem, at the outset, is the cost of sequencing. But it is a necessary evil. Unless we know what type of a tumour we are dealing with or its genetic signature, we cannot hope for proper characterisation. This information needs to be mated to clinical follow up with standard protocols.

Is there any scope for in-vivo monitoring? If yes, what is going to be its timeline? How frequently are we going to see for the mutations? What is the rate of mutations? What is its timescale? When should we intervene?

Another favourite pet theory is the class distinction for stem cells. Do they exist? If yes, why can’t they be reliably identified? What are their niches and what is the best way to target them?

Each sequencing would reveal a wealth of clinical data (both genomics as well as radio-genomics) and spur on more deep dive into the molecular ontology. Yes, that might fulfil the wet dream for molecular targets as well. However, as a radiation oncologist, I am only keen to know whether I can reduce my tumour volumes, how we can reduce the dose to normal structures (brain) and combine efforts with patient-related outcomes.

Bring it on! Let us do it! (Have some laughs!!)

Research and biotech: Asking right questions

The Ken is a wonderful resource for myriad issues.The staff at The Ken is constantly churning out some of the highest quality journalistic write ups in India. Their focus is mostly on start ups, biotech and increasingly now on security of digital assets. The reason why I recommend it is to broad-base your reading sources and think laterally beyond our narrow confines. Financial crunching may not be everyone’s cup of tea but it has spurred me on to understand more about it’s complexity. In the end, it is a deep dive learning experience to write effectively. In the sea of otherwise hopeless mediocrity that Indian journalism has seeped itself, The Ken (and to some extent, Business Standard) redeem themselves.

Today’s post was motivated by an excellent coverage of biotech sector and this prodded me on to think about what the research goals ought to be. Biotech companies are chasing the end of the rainbow for the pot of gold. The reason why US remains the “gold standard” for these companies is because of a perverse incentive that pharmaceutical companies and hospital corporations have to milk the consumer. That’s where the big money is. And these companies are pushing themselves to crack the market in order to get the first mover advantage.

I will not name a few companies that I have worked with (due to non-disclosure agreements with them and that included not calling them names publicly). There were some great individuals, that I had the good fortune to learn from, as well. This aside, they are mostly floundering pushing their luck. In proverbial terms, trying to see what sticks to the wall.

In one presentation, they presented a “case scenario” which showed how the medical oncologist based his decision on genomic details for lung cancer. In another, they were keen to show for cool-rectal cancer. All laudable but with one significant omission. They did not have any follow up for outcomes! Not only this, none for any clinical trial, suitability for a vast majority or how the specific gene sets were chosen to be marketed.

Its stupidity compounded by idiocy. Over and over again.

Sadly, the translational science hasn’t made specific progress and now we have the buzz words like “precision medicine”. Pray, what is precision medicine?

Hype fuels another set of hype cycles. It is a good thing that all of this looks great on dossiers or fanning our collective egos in fancy conferences but they remain a collective effort for intellectual masturbation. We need hard core data sets and equally hard nosed questions before we thrust all of this in front of hapless patients.

The company mentioned in The Ken write up hasn’t specifically mentioned as to how they will find out the difference in the genetic mutations (from primary index lesion) to the current state. I had earlier explored this concept in an editorial arguing for liquid core biopsies as means to monitor the course of treatment in lung cancers because of the range of molecular mutations.

Rest assured, I have a healthy disdain for pharma company sponsored trials with results that appear too good to be true. When it is translated into actual clinical practise, it doesn’t live up to it’s hype. Remember the Cetuximab “landmark trial”? Or even for that matter, Bevacizumab?

Lets pause. Think.

There ought to be healthy skepticism. A side note to fellow radoncs- there is a lot that can be achieved in Radiation Therapy. We need to explore different fractionation schedules or even radiation sensitisers. Combination therapies do-not always work out. That is the subject for another blog post.

Quality of life in brain tumours

This issue is very thorny one in the neuro-oncology community. How do you measure the quality of life objectively?

A RANO working group has defined that outline and is aware of it. We, as radiation oncologists, aren’t oblivious to the fact that radiation therapy offers one single shot to give the maximum chance of cure. I am not discussing the issue of re-irradiation here, but the idea is to minimise the impact of existing delivery mechanisms.

Beyond the tumour volumes (2-3 cm for high-grade gliomas), this is both empirical and observational. They observed that bulk of failures happened in the high dose region. It brings us to two important questions here.

1) If we know that it is going to happen in the 95% isodose, why don’t we focus on intentional dose heterogeneity, at the expense of conformity? We could explore mathematical formulations for it- how best to predict which dose fractionation would be best suitable for the likely outcomes, where the failure is expected to take place and escalate the dose to that region.

2) Some tumours usually fail elsewhere, outside the treatment area. If this is the case, why not “lower” the dose to the treatment area (so-called “de-escalation”)?

Do you see the immediate impact?

Lower the total dose to the normal brain!

Now, that leads us to two more questions.

1) Why don’t we lower the dose to 55+Gy for Grade III tumours, because they have a better outcome?

2) Does Temozolomide also act as a radiation sensitiser?

The problems with these very broad-based assumptions are that we do not have a robust criterion for pre-operative or even intra-operative validation of tumour subsets by use of MR spectroscopy or perfusion (or use of any other metabolites, for that matter). Likewise, after intense scrutiny and numerous workshops, we have just been able to define the glioblastomas/grade III astrocytomas along with the molecular data (or even other variants) objectively. Previously, palisading necrosis was all that we had from my pathology colleagues. Now, we are wading in molecular soup, and no one has the complete picture of how things can be nailed!

However, use of these molecular methods isn’t widespread.

One way out is to sequence the tumours completely, follow up patients standard course fractionation and prospectively identify patterns of failure.

It would be akin to a very preliminary “precision medicine” and not the hype cycle that seeks to identify the “molecular targets”.

No, we don’t need more “research” on something that is being duplicated across the labs. But we need to be able to channelise something that we have learned.

Who is going to bell the cat?

I think, currently, we are just trying to identify who the cat is.

Can we have a Spotify like model for academic publishing?

I have always disliked the idea of paywalls. If I have to borrow the cliche from silicon valley rags, it amounts to having “friction” in accessing the resources. It is a huge pain, especially, if you don’t have the resources.

Much has been written about the advent of scientific publishing in the internet era. And despite the monopolistic tendencies of publishers in erecting huge barriers, likes of Sci-Hub are winning. A few “pirate” websites have extended its support and currently houses the bulk of published scientific literature. Interestingly, the majority of access happens from university campuses where they have already paid for the access! It is a natural human tendency to look for the most comfortable way out!

This post is not about accessing Sci-Hub, but it reminds me of a bitter battle between pirates and Hollywood executives who had similar issues in 90’s with torrents. They are losing profits, as per their claims (despite mansions/big cars/lavish lifestyles) and are locked in pitched battles with telecom service providers to identify those who “pirate”. Paywalls and digital rights management system did not deter those who were determined to access content. Telegram, for example, has emerged as one of the largest piracy hubs for movie distribution on mobile because of its generous file limits.

This post is not to discuss these nuances, but it set me thinking. Why can’t we have a Spotify/Netflix like model for academic papers? At a monthly cost of around 10 USD with all publishers pooling in their resources, it can be a formidable challenge to a tendency to pirate. Technology has made DRM easier. Do we see pirated Netflix original content? Yes, true. But Netflix/Spotify offers a superior UI. The ratio of people paying up versus those who pirate is larger; hence these companies are profitable.

Publishing houses should accept the writing on the wall. I would be all for a Spotify like model for papers. Every stakeholder stands to gain.

Brain tumour advocacy:What is the role?

The Role of Brain Tumor Advocacy Groups

This is an excellent paper which I came across, and I find it is very pertinent. I have highlighted the most important aspects here. The full article is behind the paywall (another blog post coming up soon for this!). However, nevertheless, despite the repetitiveness, these are the essential highlights.

Brain tumor patients, caregivers, and loved ones realized that research is underfunded, which catalyzed the creation of nonprofit patient advocacy groups to bridge the gaps that the for-profit sector and the government have not addressed.

I agree here. Rare tumours are “rarely” the focus of researchers. Sadly, I have a strong feeling that bulk of current research in these tumours is dressed up to impress the charities. Because when the push comes to the shove, we hardly have moved the needle.

The challenges that brain tumor advocacy groups and organizations face and the role that they must play are reflective of the nature of their patient population. Individual efforts to combat the deadly disease are driven by a shared sense of urgency.

It is precisely my motivation to set up exclusive Telegram group and a public broadcast channel. It helps to gather all the information in one place with vetted links so that patients or their caregivers do not have to wade through the toxic Google searches.

As recently as fall of 2013, patient advocacy organizations were defined as providing “patient- and caregiver-oriented education,advocacy, and support services”

It is difficult to “define” them (advocacy groups), Definition, by its very nature, limits its scope. I would prefer to call them formal or informal support groups but more on that later.

This role may be sufficient in disease areas where there are effective treatments, but for brain tumors, where treatment options are limited and often ineffective, the community requires proactive research programs, as well as a host of advocacy and patient support services

Exactly. The issues are stark in developed economies while in most of other health care systems where research is either fledgeling or non-existent, brain tumours are likely to be axed. Breast cancer or even head and neck cancer are public health issues, and the bulk of biological research has been directed towards it. The idea is to define “targets” and spin it off to pharmaceutical companies. It does de-risk it but with it comes the high price of failure for other disease sites. Not every research leads to a breakthrough; like for example, in the case of Temozolomide. What next? Electric fields?

The goals of public policy advocacy include improving treatment options and access for brain tumor patients, supporting research funding and innovation, and optimizing conditions for drug development and approval.

As above. It is essential to raise the voice and create awareness. When this was published, using Twitter by patient advocates was not mainstream. However, in light of recent developments, it is essential that physicians also join in patient advocacy. Here’s the shocker. Very few oncologists pursue brain tumours as a career pathway. It is either because of limited treatment options (which is a fact) or restricted interest in putting efforts for what is a uniformly fatal disease. More importantly, it is likely to lead to high burnout rates. However, most of them do agree- it is intensely academically and emotionally challenging.

Owing to the nature of the disease and its treatment(s), the burden on caregivers is often very high, both emotionally and financially. Patients and their caregivers benefit from a variety of support services.

It is true.

Brain tumor treatment is expensive. Brain surgery, radiation therapy, chemotherapy, and targeted drugs all add up to a steep medical bill

Moreover, this leads to financial toxicity. It is true for most of the healthcare systems across the world.

Beyond its steep financial cost, brain tumor treatment is incredibly complicated. Coordinating care requires managing appointments, connecting with the right physicians, and finding the appropriate care services. This burden often falls on the caregiver because of the impact that the disease and treatment have on the brain tumor patient

This is what I dread the most. It is because advocacy groups are far and few in-between. Most general practitioners have a low threshold for diagnosis (which is also okay because these are rare tumours with a low index for suspicion). By the time it is understood in its context, it is usually too late. This issue is more pronounced for childhood cancers (and that breaks me entirely).

By funding research and changing the research system, advocacy groups today strive to identify a cure and transform a deadly disease into a manageable, treatable condition.

More importantly, funding the caregiver system because that is the urgent need. Basic biological research in gliomagenesis will take a long time to mature. I propose that advocacy groups should work with policymakers to push for public funding (because of a high risk of failure/difficulty in reproducing ideal lab conditions to in-vitro conditions) and at the same time, invest in support infrastructure to provide succour to affected families.

Today, the median survival for patients with GBM is approximately 15 months, with a 5-year-survival rate of less than 5% In spite of the money poured into research and although some targets and pathways have been identified, brain tumors such as these are still poorly understood in terms of causal and maintenance mechanisms. If this is a war against brain tumors, few (if any) would say that we are winning.

This is the most realistic statement. (emphasis mine)

Is this paucity of treatment options a question of a broken brain tumor drug discovery and development pipeline?
Is this a question of the research environment generally being inadequate?
What are the real barriers to advance research to treatments?
And which stakeholders are responsible for addressing these barriers? The true role of the advocacy group is to address the issues that the government and for-profit sectors cannot, or will not.

I agree, and these are the set of questions that advocacy groups should ask. (emphasis mine)

Instead, as patient groups have become more sophisticated, there has been a shift from funding research that increases scientific knowledge of the disease to targeting funding to specific points along the drug discovery and development pipeline that will provide incentives for others (such as pharmaceutical and biotechnology companies) to invest in the field.

This is one aspect. I still hold that advocacy groups should push for basic public funded research and invest in support groups on the other. It is a collaborative effort. Individual patients don’t have a voice. However, groups can collectively raise their voice- in mainstream media, social network and align with research charities.

Finally, it gets me to define the patient advocacy groups as a bridge between the policymakers to push for funding and caregivers to provide resources or access to them.

This area has not yet been fully explored by brain tumor advocacy groups, but advances in citizen science and computational platforms have opened the door to leveraging new communities of researchers. Interdisciplinary efforts in systems and computational biology have the potential to translate “big data” into meaningful analyses that further translate into clinical impact

The big data (machine learning/artificial intelligence) is still a way far off, and despite being the catchword of press releases, it is still very much in its infancy. Indeed, I get riled up because of the hype factor built in “tailored research” (which is dressing up done to squeeze in more funding). (Personalised medicine remains an elusive goal).