Is it true that only 50% of stage 3 clinical drug trials succeed?

Most drug candidates these days do fail at a late stage of the drug development process.

In 2011, Pammolli et al examined a large global database of R&D projects on >28000 compounds investigated from 1990 to 2004 (1). They found a clear trend of increasing attrition rates across all stages of the drug development process including an increase to >50% at Phase III by 2004 (see below from 1).

In 2012, Mestre-Ferrandiz et al performed a meta-analysis of 11 studies from 1979 to 2011 that analyzed the A-to-Z process for new drugs (2). They estimated probability of Phase III success ranges from 50 to 71%, i.e., Phase III failures ranging from 29 to 50%.

In 2013, a group of Boston Consulting Group analysts examined the 2002 to 2011 record of 842 individual molecules with known full development outcomes. They found 205, i.e., 24.3%, gained regulatory approval while the remaining 637, i.e., 75.7%, failed in Phase II or later (3). Their analysis cuts right across the BioPharma landscape, covering small (<$200 million/year on R&D), medium ($200 million to 1 billion) and large (>$1 billion) companies, both private and public, and located not just in the US but also in the EU and the rest of the world. In their analysis, the factors that correlated most with drug development success were (see below from 3).

• Scientific judgment or 'acumen' in terms of shutting projects down early, rather than late.
• Solid track record of the company's R&D in terms of publications and patents per US dollar of R&D expenditure, and citation records (# of times papers were cited by others).

• A 2012 study by Pfizer also found scientific judgment / 'acumen' to be the most critical quality. Their analysis found that 2/3rd of the company's Phase I candidates, 'assets', were advanced down the pipeline for further development even when data was already available that they would likely fail (4).
• A 2014 AstraZeneca analysis of the decision-making about their drug pipeline concluded that the 'right culture' was crucial for effective decision-making, i.e., which candidates to advance and which to terminate early (5).

Thus, several studies have now not only pointed out increasing late stage failures for new drugs but also suggest part of the problem is too many poor drug candidates are advancing to later stages, i.e., failing late rather than early. It also takes ever longer for a drug candidate to advance down the pipeline, typically ~48 months and ~US $42 million to get from selection to Phase II (2, 6). Yet barring a rare report here and there like Eli Lilly and Company's Chorus (7), which claims to have shaved this time down to ~26 to 28 months, nothing much seems to change about the drug development process. Why? Obviously, can't be a simple case of one or two or even three simple factors. Rather, this status quo is the sum of entrenched cultural, technical and commercial imperatives.

Across the board, regardless of company size or therapeutic area, failing late rather than early suggests drug development decision-making appears mired in its version of the Concorde effect, i.e., Sunk costs. Why? As with just about everything in life, outcomes depend on the kinds of behaviors that are rewarded. Here, perverse incentives are one likely explanation. Currently, success for biopharma R&D scientific teams tracks with advancement of their drug candidate, i.e., 'progression-seeking', and not scientific 'truth-seeking' (3). Team members' personal success, promotion, bonuses, organizational influence, these and more depend on their advancing their 'asset' through the drug development pipeline, not on even-handedly examining both the positive and negative scientific data about it. When such a culture prevails, no surprise a drug candidate, aka the 'asset', is more akin to the proverbial hot potato, shunted down the development pipeline to become someone else's responsibility. This is one possibility.

Another major reason could be the pervasive culture of relentless focus on short-term profits. After all, markets react exuberantly every time a drug candidate moves forward in the development pipeline. In turn, company management and shareholders become extremely attuned, even habituated to such reactions. After all these reflect very well on their immediate bottom-lines.

Having the 'right culture' then means something much more consequential than merely rewarding scientific 'truth-seeking'. It means having management with sufficiently strong backbone to eschew short-term profit in favor of long-term success predicated on scientifically extremely thoroughly vetted drug candidates. That entails more investment (money, personnel, resources and time) on the earlier stages of drug development to sort through a bunch of candidates more thoroughly and failing them expeditiously so that a higher proportion of sure bets progress to the next stage.

However, reality shows though that short-term profits remain the major focus for all involved, the scientific teams, the management, the shareholders, the market, usually all the way until the inevitable chickens, i.e., putting off difficult decisions until years down the road, come home to roost in the form of Phase III failures.

Other reasons that feed into lengthy development times and increasing late-stage failures are

a) The notion that treatments for simpler diseases have already been achieved in the past and remaining challenges are much more scientifically difficult. Such challenges include lack of appropriate model systems, of in vitro approaches, of biomarkers, etc., and not knowing or understanding well enough the right patient/tissue/target.

b) Regulatory landscape is increasingly more risk-averse and there's a much higher, perhaps even implausible, bar for safety.

c) Comprehensive health economics weren't part of a given drug candidate's vetting early in the process. Years down the road, when they're finally prioritized, the data suggest insufficient market or vexing reimbursement and/or pricing issues or cost versus benefit analysis renders product inferior to standard of care.

Bibliography

1. Pammolli, Fabio, Laura Magazzini, and Massimo Riccaboni. "The productivity crisis in pharmaceutical R&D." Nature reviews Drug discovery 10.6 (2011): 428-438. http://moglen.law.columbia.edu/t...

2. Mestre-Ferrandiz, Jorge, Jon Sussex, and Adrian Towse. "The R&D cost of a new medicine." London: Office of Health Economics (2012). https://www.google.com/url?sa=t&...

3. Ringel, Michael, et al. "Does size matter in R&D productivity? If not, what does?." Nature Reviews Drug Discovery 12.12 (2013): 901-902. http://media-publications.bcg.co...

4. Morgan, Paul, et al. "Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival." Drug discovery today 17.9 (2012): 419-424.

5. Cook, David, et al. "Lessons learned from the fate of AstraZeneca’s drug pipeline: a five-dimensional framework." Nat Rev Drug Discov 13.6 (2014): 419-431. http://admin.indiaenvironmentpor...

6. Adams, Christopher Paul, and Van Vu Brantner. "Spending on new drug development1." Health economics 19.2 (2010): 130-141. https://www.researchgate.net/pro...

7. Owens, Paul K., et al. "A decade of innovation in pharmaceutical R&D: the Chorus model." Nature Reviews Drug Discovery 14.1 (2015): 17-28.

https://www.quora.com/Is-it-true-that-only-50-of-stage-3-clinical-drug-trials-succeed/answer/Tirumalai-Kamala

How can clinical trial enrollment be increased?

In this technocracy dominated era, there's no dearth of technological approaches to improve clinical trial (CT) participation. Ranging from alert systems linked to electronic health records (1) to online registries (2, 3, 4), the usual technology-based suspects have made their appearance on the scene to no avail. For e.g., available free to anyone online, ResearchMatch allows any US resident to register as a potential CT participant (volunteer). Hosted at Vanderbilt University and funded by the NIH, this registry launched in December 2008. Yet >7 years on, its name recognition is limited and <100000 volunteers have signed up (2).

Obviously, core of the problem requires a human, not technological, touch. Meantime, the general population gains the bulk of its knowledge about CTs from entertainment fare online or on TV and from news (5, 6, 7, 8). Obviously such sources are more likely to fuel and sustain misconceptions rather than anything remotely close to the truth about CTs. Essentially, the current CT ecosystem woefully under-utilizes two of its foundational pillars,

1) Referring physicians and other healthcare providers who lead patients to CTs (9, 10).

2) Current and previous CT participants, i.e., potential Patient Advocates.

Even more inexplicably, pertinent questions relating to the CT process remain unanswered

• What's the difference between healthcare providers who either do or don't participate in CTs, and between those who either do or don't refer patients to CTs?
• What are the recruiting strategies used by successful CTs (11, 12, 13)?
• Why don't organizers of successful CTs routinely record and report their recruiting strategies? Clearly trial funders should mandate their doing so.
• What level of engagement remains with CT participants after a trial's over? Do trial organizers and their staff stay in touch with them? While volunteers are enrolled in a trial, which can be for several months to even years, do trial organizers develop a rapport with at least their most enthusiastic participants, and teach and encourage them to advocate and recruit newer volunteers on their behalf within their families and communities (14, 15)? Given the current state of affairs, clearly not and yet wouldn't doing so set up a virtuous positively reinforcing cycle leading to cumulatively increasing CT participants? Instead, why is the system set up to recruit and forget once the trial's over? Isn't this an egregious example of re-inventing the wheel every time?

~70 years since the 1st double-blind, placebo-controlled randomized CT and with >210,000 ongoing registered CTs across the US and 193 other countries (see figure below from 16), it's scarcely believable but sadly true that such basic issues aren't well-studied nor their lessons freely available for others' benefit (17, 18).

Upon reflection, it's only to be expected that an inherently top-down and paternalistic enterprise like human biomedical research would under-utilize Patient Advocates. After all so insular is it that its very basics such as research ethics and regulatory oversight have been developed without seeking and incorporating the input of research volunteers (19), who are more frequently described condescendingly as subjects. Even peer-reviewed literature about woefully lacking CT participation rates is dominated by the voices of biomedical research aficionados. Where are the voices of CT participants? Why don't medical and scientific journals report their perspective, about their experiences and suggestions in their own words? Imbalance couldn't get starker than this (20). When was the last time the US FDA or the NIH convened meetings or town halls specifically inviting volunteer input into the CT process? Never. The current CT world is strikingly insular (21, 22).

'Findings concur with previous research suggesting that CT investigators rarely communicate about clinical research outside of specific, study-based recruitment messages, which are often only provided to current patients already familiar with the medical institution...Findings from the current study, however, show that CT teams rarely promote CT research outside of the medical setting or reach out to community organizations to serve as an important conduit between the medical institution ß and hard-to-reach populations...Although investigators rely heavily on local physicians to recruit patients into their studies, there may be limited communication between the investigators and local physicians [37] and between these local doctors and their patients [28].'

(8).

The funders and fund recipients, i.e., clinical researchers and their support staff working largely in academic medical centers, currently control the process. They hold endless rounds of meetings and write exhaustive white papers and reports filled with earnest recommendations. These current CT stakeholders haven't yet thought to expand their fold and bring into it the ones whose voices perhaps matter the most in CT participation and logistics, patients and volunteers who've participated in CTs, i.e., Patient Advocates. We all know new drugs and therapies can't get approved unless robustly tested on large pools of volunteers, and yet those same volunteers, the very heart of human biomedical research, have no say in how the process could be structured so their ranks stay filled, not depleted.

What Factors Deter CT Participation And How They Could Be Mitigated

Obvious ones are fears about unapproved medications and procedures, i.e., that one could be used as a 'guinea pig', as well as fears of side-effects, and that one could get a placebo instead of Rx due to randomization. Given such fears are likely pervasive among the population at large (23, 24, 25, 26), who could be more persuasive in convincing others to participate in CTs than those who've done so themselves? If previous trial participants aren't doing so, maybe there's something inherently discouraging about the process that urgently needs to be overhauled? While the medical and scientific aspects of CTs are rightfully the purview of clinical researchers and scientists, and should remain so, these patient-centric aspects are areas where Patient Advocates could help reshape the process to encourage others.

Studies also suggest local community-based sources of CT information are seen as more trustworthy. These include local doctors, TV and community health centers (7). As well, informal family and community networks, i.e., family and friends, and local church and faith-based organizations (26).

Cancer Clinical Trial (CT) Participation Rates Are High In Children Regardless of Race/Ethnicity But Very Low Among Adults. What Accounts For Such A Difference?

Poorly envisaged top-down policies often lack mechanisms to enforce their recommendations. In US biomedical research, one of the most prominent examples is the 1993 NIH Revitalization Act that mandates inclusion of racial and ethnic minorities in federally funded biomedical research (27). 23 years on, African Americans and Hispanics represent 12% and 16%, respectively, of the US population and yet constitute only 5% and 1% of CT participants (28) while whites are over-represented (29). Why is this so? Among US CT volunteers, blacks are supposed to mistrust medical research, and language and culture are supposed to be barriers to Hispanic participation while implicit bias among clinical researchers is supposed to disfavor minority participation in CTs. However, a crucial piece of data unerringly rebuts these oft-repeated myths because there's more than adequate participation among children regardless of race/ethnicity compared to dismal rates among adults.

In the US, only 3 to 5% of ~10 million adults with cancer participate in CTs (30). However, CT enrollment among <15 years old is anything but dismal. In the US, 60% of cancer patients aged <15 years are enrolled in CTs (31). That's not all. Proportion of minority pediatric cancer patients enrolled in cancer CTs (~10% blacks, ~12% Hispanic) ~matches their proportion in the population (32). This means neither do pediatric minorities systematically lack access to health research nor face systemic bias against CT enrollment. How to explain this huge difference between children and adult CT enrollment rates? What's different about the pediatric CT recruitment process? Undoubtedly, applying what works in recruiting children to CTs would hugely improve adult enrollment rates.

Crux Of The Problem: Huge Gap Between Eligible And Actual Adult Clinical Trial (CT) Participants

Real gap in adult CT enrollment is ~10X. For e.g., in the US, ~20% of cancer patients are typically eligible to participate (33, 34) but only 3 to 5% of them do so (30). This huge gap between eligible and actual participants is the critical problem needing to be solved. Weakest link in the chain? Extremely poor inclusion of referring physicians and Patient Advocates into the CT recruitment process, i.e., we're back to square one, the need to expand the fold of current CT stakeholders to include patients and volunteers, and their physicians, and seek their input in improving CT participation and logistics. One approach could be to have CT participants access trial-related procedures and services closer to their home rather than exclusively at academic CT sites, which are often far from their homes.

Clinical Trial (CT) Location Matters Hugely To CT Participants

Travel distance to and lack of transportation to and from the trial site are major barriers in CT participation (35, 36, 37). Even in the US, arguably the wealthiest country in the world and unquestionable global CT leader, many if not most CT volunteers need to drive >1 hour each way to reach a CT site (see figure below from 38).

Bibliography

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3. Denicoff, Andrea M., et al. "The National Cancer Institute–American Society of Clinical Oncology Cancer Trial Accrual Symposium: Summary and Recommendations." Journal of Oncology Practice 9.6 (2013): 267-276. Summary and Recommendations

4. Tan, Meng H., Matthew Thomas, and Mark P. MacEachern. "Using registries to recruit subjects for clinical trials." Contemporary clinical trials 41 (2015): 31-38.

5. Kelch, Robert P. "Maintaining the public trust in clinical research." The New England journal of medicine 346.4 (2002): 285.

6. Len-Rios, Maria E., and Qi Qiu. "Negative articles predict clinical trial reluctance." Newspaper Research Journal 28.1 (2007): 24.

7. Tanner, Andrea, et al. "Communicating Effectively About Clinical Trials With African American Communities A Comparison of African American and White Information Sources and Needs." Health Promotion Practice (2015): 1524839915621545.

8. Tanner, Andrea, et al. "Promoting clinical research to medically underserved communities: Current practices and perceptions about clinical trial recruiting strategies." Contemporary clinical trials 41 (2015): 39-44.

9. Baer, Allison R., et al. "Engaging referring physicians in the clinical trial process." Journal of Oncology Practice 8.1 (2012): e8-e10. Engaging Referring Physicians in the Clinical Trial Process

10. Robinson, M. Koa, JoAnn U. Tsark, and Kathryn L. Braun. "Increasing primary care physician support for and promotion of cancer clinical trials." Hawai'i Journal of Medicine & Public Health 73.3 (2014): 84. http://www.hjmph.org/HJMPH_Mar14...

11. Lai, Gabriel Y., et al. "Effectiveness of strategies to recruit underrepresented populations into cancer clinical trials." Clinical Trials 3.2 (2006): 133-141. Effectiveness of strategies to recruit underrepresented populations into cancer clinical trials

12. Friedman, Daniela B., et al. "How are we communicating about clinical trials?: an assessment of the content and readability of recruitment resources." Contemporary clinical trials 38.2 (2014): 275-283.

13. Friedman, Daniela B., et al. "A qualitative study of recruitment barriers, motivators, and community-based strategies for increasing clinical trials participation among rural and urban populations." American Journal of Health Promotion 29.5 (2015): 332-338. https://www.researchgate.net/pro...

14. Friedman, Daniela B., et al. "Improving our messages about research participation: a community-engaged approach to increasing clinical trial literacy." Clinical Investigation 4.10 (2014): 869-872. http://www.future-science.com/do...

15. Tanner, Andrea, et al. "Barriers to medical research participation as perceived by clinical trial investigators: communicating with rural and African American communities." Journal of health communication 20.1 (2015): 88-96.

16. Trends, Charts, and Maps

17. Michaels, Margo, et al. "Impact of Primary Care Provider Knowledge, Attitudes, and Beliefs about Cancer Clinical Trials: Implications for Referral, Education and Advocacy." Journal of Cancer Education 30.1 (2015): 152-157.

18. Sriphanlop, Pathu, et al. "New York state health care provider participation in clinical trials: a brief report." (2016). http://www.vipoa.org/journals/pd...

19. Dresser, Rebecca. "What Subjects Teach: The Everyday Ethics of Human Research." Wake Forest Law Review 50 (2015): 301. What Subjects Teach: The Everyday Ethics of Human Research

20. Holzer, Jessica K., Lauren Ellis, and Maria W. Merritt. "Why We Need Community Engagement in Medical Research." Journal of Investigative Medicine 62.6 (2014): 851-855.

21. Comis, R. L., et al. "Baseline study of patient accrual onto publicly sponsored US Cancer Clinical Trials: an analysis conducted for the global access project of the National Patient Advocate Foundation." Philadelphia, PA, Coalition of Cancer Cooperative Groups (2006): 1-52.

22. Friedman, Daniela B., et al. "What do people really know and think about clinical trials? A comparison of rural and urban communities in the South." Journal of community health 38.4 (2013): 642-651.

23. Meropol, Neal J., et al. "Barriers to clinical trial participation as perceived by oncologists and patients." Journal of the National Comprehensive Cancer Network 5.8 (2007): 753-762. Barriers to Clinical Trial Participation as Perceived by Oncologists and Patients

24. Weckstein, Douglas J., et al. "Assessment of perceived cost to the patient and other barriers to clinical trial participation." Journal of Oncology Practice 7.5 (2011): 330-333. http://nnecos.org/Resources/Docu...

25. Fleisher, Linda, et al. "Application of best practice approaches for designing decision support tools: the preparatory education about clinical trials (PRE-ACT) study." Patient education and counseling 96.1 (2014): 63-71. http://www.ncbi.nlm.nih.gov/pmc/...

26. Bell, Jennifer AH, and Lynda G. Balneaves. "Cancer patient decision making related to clinical trial participation: an integrative review with implications for patients’ relational autonomy." Supportive Care in Cancer 23.4 (2015): 1169-1196.

27. Chen, Moon S., et al. "Twenty years post‐NIH Revitalization Act: Enhancing minority participation in clinical trials (EMPaCT): Laying the groundwork for improving minority clinical trial accrual." Cancer 120.S7 (2014): 1091-1096. Twenty years post-NIH Revitalization Act: Enhancing minority participation in clinical trials (EMPaCT): Laying the groundwork for improving minority clinical trial accrual - Chen - 2014 - Cancer - Wiley Online Library

28. Clinical Trials Shed Light on Minority Health. FDA, April 2013. http://www.fda.gov/downloads/For...

29. ThinkProgress, Tara Culp-Ressler, April 4, 2014. There Are Too Many White People In Clinical Trials, And It’s A Bigger Problem Than You Think

30. Murthy, Vivek H., Harlan M. Krumholz, and Cary P. Gross. "Participation in cancer clinical trials: race-, sex-, and age-based disparities." Jama 291.22 (2004): 2720-2726. https://www.researchgate.net/pro...

31. Fern, Lorna A., and Jeremy S. Whelan. "Recruitment of adolescents and young adults to cancer clinical trials—international comparisons, barriers, and implications." Seminars in oncology. Vol. 37. No. 2. WB Saunders, 2010.

32. Bleyer, W. Archie, et al. "Equal participation of minority patients in US national pediatric cancer clinical trials." Journal of pediatric hematology/oncology 19.5 (1997): 423-427.

33. Sateren, Warren B., et al. "How sociodemographics, presence of oncology specialists, and hospital cancer programs affect accrual to cancer treatment trials." Journal of Clinical Oncology 20.8 (2002): 2109-2117.

34. Brawley, Otis W. "The study of accrual to clinical trials: Can we learn from studying who enters our studies?." Journal of Clinical Oncology 22.11 (2004): 2039-2040. Can We Learn From Studying Who Enters Our Studies?

35. Kanarek, Norma F., et al. "Geographic proximity and racial disparities in cancer clinical trial participation." Journal of the National Comprehensive Cancer Network 8.12 (2010): 1343-1351. Geographic Proximity and Racial Disparities in Cancer Clinical Trial Participation

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37. Itty, Tracy Line, Felicia Schanche Hodge, and Fernando Martinez. "Shared and unshared barriers to cancer symptom management among urban and rural American Indians." The Journal of Rural Health 30.2 (2014): 206-213. https://www.researchgate.net/pro...

38. Galsky, Matthew D., et al. "Geographic Accessibility to Clinical Trials for Advanced Cancer in the United States." JAMA internal medicine 175.2 (2015): 293-295. Accessibility to US Clinical Trials for Cancer

https://www.quora.com/How-can-clinical-trial-enrollment-be-increased/answer/Tirumalai-Kamala