Drug company shenanigans: this one remarkably unethical

 A recent study documented a significant ethical violation by drug companies, finding that for low income countries that were involved in drug testing studies, the successful drugs were not subsequently available to the participants (see clinical trials countries involved not get meds later JAMAIntMed2025 in dropbox, or doi:10.1001/jamainternmed.2025.6060)

 

Details:

-- they identified all novel drugs and biologics approved by the FDA from 2015 through 2018, along with their approved indication, as well as all phase 2 and 3 clinical trials supporting their FDA approval from 2015 to 2018, with data from the Drugs@FDA database, ClinicalTrials.gov website, and drug regulatory agency websites, in this retrospective analysis

-- countries were categorized into 4 income groups (high, upper middle, lower middle, and low) using the World Bank's historical classification of economies, and by the geographic regions using the United Nations regional groupings of member states

 

-- 172 medications were approved by the FDA from 2015-2018

    -- 86 were sponsored by large companies and 86 sponsored by non-large companies

-- year of FDA approval: 2015 in 26%, 2016 in 13%, 2017 in 27%, and 2018 in 34%

-- medication indications: oncology and hematology 39%, infectious diseases 14%, autoimmune/musculoskeletal/dermatology 13%, neurology and psychiatry 10%

-- priority review in 80 and orphan drug status in 81

-- total number of trials 885; trials per medicine 4; total number of trial sites 2563

 

-- mean outcomes and measures: proportion of medicines receiving market authorization (ie, became physically accessible) where tested for FDA approval, median time to market authorization, and proportion of countries with physical access to all medications that they tested within 1 to 5 years of FDA approval by country, income group, and geographic region

 

Results:

-- across 780 trials (88%), 158 medicines (92%) had publicly available trial site location information

-- prior to FDA approval for a US population, the 158 medicines were tested in 89 countries around the world:

    -- high income countries: 48 (55%) of meds tested

    -- low or middle income: 40 (45%) of meds tested

        -- upper-middle  income: 23 (26%) of meds tested

        -- lower-middle income: 12 (13%) of meds tested

        -- low income: 5 (6%) of meds tested

-- each medicine was tested in a median of 16 countries:

    -- 13 in high income

    -- 2 low or middle income

-- each trial occurred in a median of 6 countries

-- 144 of the 158 medicines (91%) were tested outside of the US as well as in the US

    -- 3 were tested in a low-income country: a 4-drug combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide for HIV was tested in Uganda and Zimbabwe; tafenoquine for malaria was tested in Ethiopia; and moxidectin was tested for onchocerciasis in Liberia.

    -- most products were tested in Western Europe (127 [80%]), Eastern Europe (106 [67%]), Oceania (94 [59%]), Asia (90 [57%]), Middle East (66 [42%]), Latin America and the Caribbean (64 [41%]), Africa (40 [25%])

    -- the top 5 countries hosting trials for FDA approvals, beyond the US, were Germany, Spain, the UK, Canada, and France, with approximately 66% of products tested in each of these countries

 

--Physical Access to Medicines

    -- of the 144 medicines tested outside of the US, 10 (7%) were physically accessible in all of the countries where they were tested within 1 year of FDA approval

        --this increased to 34 (24%) at the 5-year time point

    --at 5-years:

        -- 45 of 142 medicines (32%) were physically accessible in all of the high income countries where they were tested

        -- 19 of 87 medicines (22%) were physically accessible in all upper-middle income countries

        -- 7 of 55 medicines (13%) were physically accessible in all of the lower middle income countries

            -- overall, high-income countries had statistically significant better physical access than upper-middle–income or lower-middle–income countries, with p <0.001

    -- of the 3 medicines tested in low-income countries, only one was available in all tested countries at the 5-year time

        -- the HIV combination medicine was tested and physically accessible in Uganda but not in Zimbabwe at 5-years.

        -- the malaria medicine was tested and physically accessible in Ethiopia at 5 years

        -- the onchocerciasis medicine was tested but not physically accessible in Liberia

   -- Of the 89 countries hosting trials for FDA approvals, 77 had publicly available medicine authorization information

        -- Among those 77 countries, 3 (4%) gained physical access to the medicines they tested within 1 year and 11 (14%) within 5 years of FDA approval.

    -- 104 of 127 medicines (82%) tested in a country in Western Europe were physically accessible in those countries

    -- but 11 of 40 medicines (28%) tested in a country in Africa were physically accessible there within 5 years of FDA approval (not at the 1-year check)

        -- this difference in physical accessibility was statistically significant (82% vs 28%; P < .001).

    -- physical access varied within geographic regions:

        -- Middle East: physical access to medicines ranged from 0% (0 of 1 for Qatar) to 100% (2 of 2 for Saudi Arabia) at the 5-year time point [but very few meds involved]

        -- Africa:. ranged from 0% (0 of 1 for Ghana, Liberia, and Zimbabwe) to 100% (1 of 1 for Ethiopia and Uganda) at the 5-year time point [again very few meds involved]

            -- and, medications in Africa, even if ultimately available, had a median 40 months wait after FDA approval, 10 times longer than in Western Europe

        -- all of the high-income countries: 45 of 142 medicines (32%) were physically accessible in where they were tested

    -- so, overall:

        -- all upper-middle–income countries: 19 of 87 medicines (22%) were physically accessible in where they were tested

        -- all of the lower-middle–income countries: 7 of 55 medicines (13%) were physically accessible in where they were tested

            -- high-income countries had statistically significant better physical access than upper-middle–income or lower-middle–income countries at the 5-year time point (P < .001)

 

Commentary:

-- there have been clear international guidelines on ethical issues regarding studies done internationally, specifically declaring that individuals involved in research studies need to be provided post-trial access to beneficial interventions

    -- the World Medical Association Declaration of Helsinki for Ethical Principles for Medical Research Involving Human Subjects in their initial 2013 Declaration of Helsinki stated in point 8 "while the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over the rights and interests of individual research subjects." https://jamanetwork.com/journals/jama/fullarticle/1760318?utm_campaign=articlePDF&utm_medium=articlePDFlink&utm_source=articlePDF&utm_content=jamainternmed.2025.6060 .

    --this principle was readopted in the 75th World Medical Association General Assembly in October 2024; there was a similar recommendation by the Council for International Organizations of Medical Sciences (CIOMS) and the World Health Organization (the United States used to be the dominant and largest financial contributor to the WHO until Trump took office) in their 2016 guidelines. these ethical guidelines affirm that there is an obligation to provide post-trial access to proven interventions tested

-- a prior study by this same group as in the current paper found that of the 34 medications sponsored by large pharmaceutical companies and approved by the FDA in 2012 and 2014, only 15% received market authorization and were accessible to the participant nations within 5 years of FDA approval; there were significant wealth-based disparities, finding that Canada and Western and Eastern Europe gained physical access to almost all medications but no countries in Africa had access to any.

    -- of note this study only involved the 20 largest pharmaceutical companies and did not include biologics such as vaccines.

    -- however, 60% of medicines approved by the FDA are sponsored by non-large pharmaceutical companies and 35% are biologics (hence the broader current study)

    -- this study analyzed these meds from 2012-2014, still a valid ethical breach, but before the Helsinki guidelines

 

-- the goal of the current study was to assess whether patients residing in countries that were involved in successful clinical trials had subsequent physical access to such medicines between 2015 and 2018, subsequent to the above mentioned international ethical guidelines

-- findings in this study:

    -- 88% of trials were done with 92% of medications having available trial site location information. It seems to me that anything less than 100% is a violation of what clearly should be reported by the drug companies

    -- there is a gradient of access to the meds after the studies was over

    -- access to the meds was reasonably good in the highest income, ranging to miserable as one steps down to progressively lower income countries

    -- and, at least for many of the drugs tested in lower income countries, the prevalence of the targeted disease is often much higher than in the wealthier countries (which is likely one of the reasons that the poorer country was chosen: higher disease prevalence translates to fewer people needing to be recruited into the study, less money spent on monitoring the study, quicker results, and overall lower costs). But, of course, these countries need the med post-trial more than anywhere else to continue to decrease morbidity/mortality from the med, and they may well have no other alternatives

    -- though the higher income countries have had improvement in access to the medications in comparing the 1- and 5-year time-periods and they still had access to only 32% of them..., this was much lower in the poorer countries..

 

Limitations:

-- these researchers had access to databases, and there may well be missing or inaccurate information there

-- their focus on marketing authorization does not necessarily translate to actual patient access: there are issues of affordability, adequate supply, effective distribution systems (especially with some meds/vaccines that need refrigeration), trained clinicians working in the countries, diagnosed capabilities to identify the medical problem etc

-- they did not identify what/where the roadblocks were leading to the authorization delays. And, the drug companies should be responsible to identify and determine how to fix these roadblocks

 

So, a pretty upsetting revelation, which was not only contrary to the international ethics standards, but also by the World Health Organization, which at the time had the US being the largest contributor and dominant force:

    -- this malfeasance is fundamentally unethical, especially for the poorest countries with the fewest resources and least access to other medications, and is really exploitative: using people there as the substitute for guinea pigs, then abandoning them when the drug company is done, is highly exploitative of the participants and countries

    -- and, in Africa, the 3 medications were all new meds to fight highly prevalent infectious diseases

        -- withholding access to these types of medications not only stops the beneficial effect found for these medications but also puts the individuals at risk for future drug resistance to them and perhaps to other new ones coming around that are similar enough to lead to cross-resistance

        -- which means that these individuals may well face subsequent increased morbidity/mortality as a result of study participation

    -- it is ethically imperative that these medications be available right after the end of the study. Waiting 1 year vs 5 years (the latter having somewhat higher availability rates) as in this study may really not be any different: being off the meds even for 1 year might lead to rebound exacerbation of the underlying medical condition as well as to future (perhaps even current) medication resistance. So finding that even the 3 studies in Africa that rose from 0% at one year to 100% (with very few studies done) may well be meaningless

    -- it should be highlighted that the array of diseases in low to medium income countries has changed pretty dramatically. Mortality used to be primarily from infectious diseases. Now noncommunicable diseases (oncologic, cardiovascular, obesity-related including diabetes) are responsible for 60% of deaths worldwide and 80% of them are in the poorer countries (and increasing). though there are some studies now done on these noncommunicable diseases in low income countries, it is clinically and ethically important to do more studies on noncommunicable diseases in lower income areas where globalization has led to these disease changes but these countries are least able to treat them (https://pmc.ncbi.nlm.nih.gov/articles/PMC7705176/)

-- this drug company malfeasance is certainly not limited to international exploitation of the lower income countries as well-documented above, but shenanigans have been going on for oh-so-many years in oh-so-many ways, eg:

    -- https://gmodestmedblogs.blogspot.com/2015/12/the-drug-co-shenanigans-reach-new.html documents drug company greed in dramatically inflating even generic drug costs, with attendant legal threats against other drug companies manufacturing the drugs

    -- https://gmodestmedblogs.blogspot.com/2023/05/drug-company-shenanigans-narcolepsy-drug.html where the drug company used a drug that had been a date rape drug but found that it seemed to work for narcolepsy. they used a small and inexpensive study, with FDA approval, to dramatically increase the cost of this inexpensive drug

        -- this last blog has reference to many others on drug company shenanigans…..

-- despite our current anti-regulation government, this study does highlight that we really need governmental requirement for post-study availability of the drugs, stronger accountability mechanisms, regionally-tailored policy solutions, and extended study of countries that have successfully secured post-trial access to medicines for their populations, in order to assess better the intervention's long-term benefits and risks. Addressing these issues is essential not only to uphold ethical standards in research, but also for improving global health

geoff

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