Sunday, April 3, 2016

Do western drug companies test more dangerous drugs on the poor in India, and should they be held accountable?


Doubtless, regardless of their location, badly run clinical trials are anathema, delaying development of much-needed treatments and cures, shaking public confidence in biomedical research, and eroding public trust in the biopharmaceutical enterprise.

Who's accountable for clinical trial mishaps in India?
Let's not forget that a clinical trial in India typically has multiple partners, only one or few of whom may be a foreign entity funding the trial, be it a pharma company or a non-profit. When a clinical trial goes wrong, who's responsible? Only the foreign entity? If someone answers yes, they also have to explain why, something impossible to do. OTOH, vilifying only the foreign partner(s), one of the many entities involved in a clinical trial, certainly makes for some easy poutrage. For example, in the case in question, the Phase V HPV (Human Papilloma Virus) vaccine trials consisted not of dangerous drugs, as the question sensationally asserts, but rather of two HPV vaccines, Gardasil and Cervarix, approved for use in many countries years ago, with the former approved in 121 countries as of 2011 (1). As well, it wasn't sponsored by a western drug company but by PATH (global health organization), a non-profit that over the years has become the largest beneficiary of public health funding from the Bill & Melinda Gates Foundation. So with the predictable misinformation out of the way, let's examine global clinical trial responsibility through this trial's lens.

Typically, foreign drug companies can't conduct clinical trials directly. They need local partners, for legal, logistical, operational and cultural reasons, partners such as ICMR (Indian Council of Medical Research), DCGI (Drug Controller General of India), state and central governments, different ministries, public health departments, etc., who know the local laws, rules, regulations and language, and most importantly know and/or oversee the local infrastructure. Thus emerges a daisy chain of partners with different expertise and priorities. Issue is whether each of these partners is equally well-versed in conducting clinical trials.

With decades of experience under its belt, the foreign pharma or non-profit entity knows or should know how to conduct clinical trials. OTOH, the local partners may typically not be as well-versed, especially in crucial details such as importance of informed consent, and need for careful monitoring and reporting of adverse events. These weren't learned by clinical trial professionals in one smooth, fell swoop either. Countries well-versed in conducting clinical trials today went through their share of the learning curve, unfortunately often at the expense of hapless trial participants. *, **, ***, ****.

What about the responsibilities of the local partners? Each trial partner has a stake in ensuring that clinical trials uphold the highest standards of ethics and medical care, all of which which begs the question why they would be or ever become badly run in the first place. As clinical trials increasingly globalize, hiccups are inevitable because the core issue is culture clash. From all accounts, this was the situation with this Indian clinical trial. How well trial partners communicate across their daisy chain, particularly in plugging crucial knowledge gaps with respect to risks and risk assessments, is key. Not sufficient to explain what to do when and how but also why. If the local partner on the ground pays lip service to informed consent or adverse outcome monitoring, it's not just a question of who's responsible but also why it turned out that way. This is where cultural differences weigh in. Maybe the foreign trial partner explained what adequately but not why. So, who's responsible? Everyone involved, not just the foreign entity. Investigations revealed the trial in question had a two-fold problem (2, 3).

1. Informed consent, a cornerstone of clinical trials. Medicine already walks a tightrope between patient autonomy and welfare. Life itself doesn't come with a risk-free guarantee so it's unrealistic to expect medicine, let alone experimental medicine, to do so. This is only accentuated in a clinical trial, where the risks of a possible drug/intervention remain largely unknown. After all, one of the purposes of clinical trials is to reveal such risks. Clinical trial participants need to understand these risks as fully as they can, understand that their participation comes with inherent risks. Sometimes those risks may be minor such as local, temporary injection site reactions yet they range all the way to life-threatening. Comprehensively explaining these risks is the purpose of informed consent. Since this trial involved minors, parents/guardians were required to give informed consent. Instead in thousands of cases, teachers and school principals were found to have signed them, even when the children concerned had parents/guardians.

2. Adverse effect, another cornerstone of clinical trials. One of the purposes of clinical trials is to carefully monitor and assess harmful effects of any drugs/interventions. Perhaps nowhere else is the phrase, 'safety in numbers' more appropriate than in medicine. More people assessed for a drug/vaccine's safety during its journey to approval through the clinical trial process, more robust the data that underpin its safety profile. Investigations revealed this particular trial had paid lip-service to monitoring and recording adverse events.

As an entity well-versed in clinical trials, PATH, the foreign non-profit that conducted this trial had no excuse whatsoever for the lapses in informed consent and adverse effect monitoring. What about the local partners though, ICMR, DCGI, the state governments of Gujarat and Andhra Pradesh where these trials were held, the schools the girl participants were recruited from? After all, as we proceed lower down the daisy chain, don't we also come closer to increasing personal responsibility for the welfare of minors? Thus, in this case, ICMR and DCGI also bear responsibility at the national level while the local governments, and local departments of education, public health and child health bear responsibility at the local level. Public scrutiny of clinical trial mishaps is a public good only when it's accurate and impartial.
Other open questions which remain unanswered:
  • Did PATH adequately train and monitor the ground staff, especially on the issues of informed consent and adverse event monitoring?
  • Did ICMR and DCGI monitor and ensure that PATH adequately trained the ground staff?
  • Who monitored the ground staff during the course of the trial? Was it PATH, ICMR, DCGI, local public health department? Was the monitoring responsibility clearly delineated and did it have checks and balances?
  • What kind of recording and monitoring systems were in place to ensure participant safety?
More entities involved, more difficult to identify and assign blame. Be it an individual or group, taking responsibility when things go wrong is often akin to the proverbial flying pig. Yet mishaps like this trial offer an opportunity to examine and improve the global clinical trial blueprint, especially the weak links in the chain the open questions reveal. Finally, when it comes to accountability, it's not just a question of who but also how. With respect to how, monetary fines could be imposed on the foreign entity. What about the local partners? Reprimand or fire local and/or senior officials? Obviously, when it comes to global clinical trials, more productive to develop processes for accountability ahead of time, not impose them ad-hoc in a haphazard and reactionary manner. In particular, potential legal redressals need to be developed proactively.

Potential benefits of clinical trials to countries like India
Self-righteous indignation can easily create a fog that obscures sound thinking. Clinical trials are hugely expensive. A more pragmatic approach shows that basing them in countries like India could be a common good from multiple standpoints,
1. Drug companies save costs substantially. Less it costs to bring a drug to market, lower the drug company needs to price it to recuperate R&D costs. In other words, drug companies lose the fig leaf of high R&D costs in pricing new drugs outrageously.
2. Historically, drugs approved post-WW II were largely tested on white men. That's hardly representative of the global human population. By basing clinical trials in countries like India, the diversity of population tested increases, theoretically improving drug efficacy and safety profile data.
3. Conducting clinical trials in countries like India can be an opportunity for meaningful technology transfer. As life expectancy increases globally, healthcare consumes increasing proportions of countries' wealth and infrastructure. Need for more novel drugs and therapies is becoming more, not less, inevitable. In turn, conducting more clinical trials to develop them becomes more, not less, inevitable. Makes it all the more worthwhile for a country like India to thoroughly learn how to conduct them properly, rigorously and ethically.
4. Conducting clinical trials is and should be considered an opportunity for a country to use as leverage to bargain to gain better access and price to drugs and therapies, both old and novel, for its population. 


Bibliography
1. Haupt, Richard M., and Heather L. Sings. "The efficacy and safety of the quadrivalent human papillomavirus 6/11/16/18 vaccine Gardasil." Journal of Adolescent Health 49.5 (2011): 467-475.
2. Final Report of the Committee appointed by the Govt. of India, (vide notification No. V.25011/160/2010 - HR dated 15th April, 2010,) to enquire into“Alleged irregularities in the conduct of studies  using Human Papilloma Virus (HPV) vaccine” by PATH in India, Feb 15, 2011. http://icmr.nic.in/final/HPV%20P...
3. PARLIAMENT OF  INDIA RAJYASABHA  DEPARTMENT-RELATED PARLIAMENTARY STANDING COMMITTEE SEVENTY-SECOND REPORT On ALLEGED IRREGULARITIES IN THE CONDUCT OF STUDIES USING HUMAN PAPILLOMA VIRUS (HPV) VACCINE BY PATH IN INDIA (DEPARTMENT OF HEALTH RESEARCH, MINISTRY OF HEALTH AND FAMILY WELFARE) (Presented to the Rajya Sabha on 30th August, 2013) (Laid on the Table of Lok Sabha on 30th August, 2013). http://www.preventdisease.com/ne...


https://www.quora.com/Do-western-drug-companies-test-more-dangerous-drugs-on-the-poor-in-India-and-should-they-be-held-accountable/answer/Tirumalai-Kamala


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