Flawed evidence underpins approval of new cancer drugsBMJ 2019; 366 doi: https://doi.org/10.1136/bmj.l5399 (Published 18 September 2019) Cite this as: BMJ 2019;366:l5399
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EMA and FDA decisions based on flawed evidence to approve new cancer drugs negatively affects Latin American patients.
On September 18th, Barbara Mintzes and Agnes Vitry, published an Editorial on BMJ  raising awareness of flawed clinical trials as the basis of approvals of new cancer drugs in Europe  and in the United States . We would like to call the attention of your readers about the impact of weak science over the regulatory decisions outside of European and US borders.
Several Latin American (LA) countries including Mexico, Dominican Republic, Argentina, Ecuador, Peru, Paraguay, Uruguay and El Salvador, have adopted regulations abbreviating the approval process of new drugs in case of earlier approval by EMA, FDA and few others. These regulations state that once a manufacturer was able to fill in the requirements requested by the so-called strong regulators, the local regulatory authority will take that authorization as the ultimate proof to authorize the drug under a fast track procedure.
Let us give some examples to further explain our concerns. In 2012, the Mexican regulatory authority (COFEPRIS) launched a national strategy called Agreement for Promotion of Innovation. The plan allowed COFEPRIS to register under an accelerated procedure new drugs already registered by FDA, EMA, Australia, Canada and Switzerland. Between 2012 and 2017, 310 new drugs obtained the marketing authorization in Mexico under this mechanism .
Although the rationale was different, in 2011, the Ecuadorian government launched an accelerated registration process via standardization of marketing authorization certificates. The current regulation establishes direct standardization with US FDA, EMA, Canada, South Korea, Australia and some other regulatory authorities in the LA region. This short-cut mechanism has been widely used to register new oncologic drugs in the country. Finally in 2016, the Argentinian regulator (ANMAT) authorized 15 new cancer drugs through a similar standardization process; only 4 of these drugs have shown some added therapeutic value .
Furthermore, EMA and FDA have implemented procedures to shorten the marketing authorization processes of certain drugs. Under these programs, drugs could be authorized on the basis of phase-II trials, single-arm trials and surrogate endpoints . Davis and cols. (2017)  & Gyawali and cols. (2019)  have already proven that most of the cancer drugs that initially showed positive results on surrogate outcomes later had disappointing results on stronger end-points, i.e. overall survival. Thus the picture is complete, a new cancer drug that was authorized by EMA or FDA under an accelerated process can be quickly registered in several Latin American countries. This is the starting point of several other problems: high prices and financial risks to the healthcare systems, increased pressure to reimburse the drug or include it into the public procurement list, law suits, etc. Moreover, the regulatory authorities are seldom able to react, say revoking the authorization, when new contrasting evidence emerges; it is too late, the drug is already in the market.
Wrong endpoints behind clinical trials to approve new drugs have a negative impact over the regulatory decisions far away from the headquarters of the strong regulators. Of course, we would like to encourage Latin American regulators to take the lead and therefore strengthen the registration requirements for new drugs. However, under the harmonization horizon of national regulatory authorities, it will be difficult to go further in that direction.
We join the call to raise the bar for approving new cancer medicines [1,8]. Regulators must ensure real benefit for patients, which also includes protect them from unnecessary and serious adverse events, false hope and household impoverishing expenses. As long as the model stands as it is now, the EMA, the FDA and the others that became the international regulatory authorities of reference, must think globally to protect patients worldwide.
1. Mintzes B, Vitry A. Flawed evidence underpins approval of new cancer. Bmj 2019;5399:10-11. doi:10.1136/bmj.l5399.
2. Naci H, Davis C, Savović J, et al. Design characteristics, risk of bias, and reporting of randomised controlled trials supporting European Medicines Agency approvals of cancer drugs, 2014-2016: cross-sectional analysis. Bmj 2019;366:I5221. doi:10.1136/bmj.l5221.
3. Gyawali B, Hey SP, Kesselheim AS. Assessment of the Clinical Benefit of Cancer Drugs Receiving Accelerated Approval. JAMA Intern Med 2019;179(7):906-913. doi:10.1001/jamainternmed.2019.0462.
4. Comisión Federal para la Protección contra Riesgos Sanitarios. Impulsa COFEPRIS la innovación farmacéutica. Comunicado de Prensa del Gobierno de México. https://www.gob.mx/cofepris/prensa/impulsa-cofepris-la-innovacion-farmac.... Published 2018. Accessed September 25, 2019.
5. Cañás M, Buschiazzo HO, Urtasun MA. Therapeutic value and price of the new pharmaceuticals commercialized in Argentina: Are they worth what they cost? Salud Colect 2019;15(1). doi:10.18294/sc.2019.1962.
6. Chen EY, Raghunathan V, Prasad V. An Overview of Cancer Drugs Approved by the US Food and Drug Administration Based on the Surrogate End Point of Response Rate. JAMA Intern Med 2019;179(7):915-921. doi:10.1001/jamainternmed.2019.0583.
7. Davis C, Naci H, Gurpinar E, Poplasvska E, Pinto A, Aggarwal A. Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: Retrospective cohort study of drug approvals 2009–2013. Bmj 2017;359(j4530). doi:http://dx.doi.org/10.1136/bmj.j4530.
8. Lehman R, Gross C. An International Perspective on Drugs for Cancer. JAMA Intern Med 2019;179(7):913-914.
Competing interests: No competing interests
There is yet another major flaw in the determination of the effectiveness of drug treatment for cancers, which we must consider - specifically the lack of quantitative data measuring the true clinical response of the cancer to the treatment provided. The lack of prior quantifiable outcomes data has resulted in the use of qualitative imaging and the term 5-year survival.
Survival does not equal being cancer free, hence, survival does not equate to treatment success. Treatment success should be defined as nothing less than the ability to demonstrate that the treatment eradicated the cancer.
We need look no further than Jeopardy host, Alex Trebek, to see the results of supposed treatment success based upon qualitative imaging – only to be disappointed with the ominous return of the cancer.
Each cancer is the result of the cellular genetics of the particular individual interacting with the cellular environment, where a series of toxins and events have culminated in an attempt to harm or transform the cell. The interaction of this specific genome-cellular environment, elicits a series of reactions beginning within the cell. The consequence of those chemical reactions, results in the release of a variety of compounds - some of which elicit a response from the immune system, while others enhance regional blood flow to increase the delivery of nutrients to the cell and its environment.
Should the immunologic response be successful, everything returns to normal. Should the result be failure, tissue changes progress to what we have conventionally called cancer. An intermediate response, results in a change, which is neither cancer nor normal. Qualitative imaging has not allowed us to measure the true outcome – normal, transitional, cancer and hence, we cannot truly determine treatment success immediately following treatment – the time when it is most critical to know, if we are to save time, money and lives.
The greatest challenge facing treatment decisions is whether we have successfully eliminated the cancer. The current qualitative approaches do not allow us to make that clinical decision – leaving us with little credible information on treatment success. Failure to die in the face of residual cancer is not what we should consider treatment success – yet we cannot know true treatment success using qualitative testing.
True determination of treatment success requires the ability to measure the changes, which occur as a result of the cellular-environmental-treatment interaction. Like coronary artery disease (CAD), the changes resulting from the chemical processes set into place, are altered metabolism and regional blood flow differences. Quantification of these changes has recently been made possible through a utility patent (FMTVDM), which not only measures the subtle changes occurring prior to the actual development of cancer, but the subtle changes which demonstrate whether treatment is working, or should be changed.
If we are to raise the bar to ensure real benefits for patients, that bar must require the use of the ability to measure the actual benefit, or lack thereof, so clinicians can focus treatment based upon actual treatment response and not some hypothetic expectation of hope – for all the Alex Trebeks of the world.
Competing interests: FMTVDM was issued to author.