A Three Institution Approach to Address the Drug Dose Gap

For the past several years, the generic recommended drug dosage as presented by pharmaceutical companies has undergone renewed scrutiny with highly publicized accounts of patient impairment and subsequent injury. While these concerns create hazards for both sexes, eighty percent of the drugs recalled from 1997 to 2000 produced greater side effects in women [1][2]. Even during this period, murmurs in the scientific community of possible linkage to gender arose; however, it was not until the media advertised the connection during the Zolpidem scandal that these suspicions were deemed legitimate with widespread public support.

Zolpidem, a sedative-hypnotic medicine more commonly known as Ambien, increases time spent in restorative stages of sleep for insomniacs [3], but also corresponds with decreased alertness in the morning leading to hindered cognitive function and reflex time [4]. In 2010, almost twenty years after the drug’s release, the FDA mandated a change in the recommended dosage with over 700 reported incidences of “impaired driving and/or traffic accident[s]” [5]. These concerns, which initially prompted a warning added to the label in 2007, were addressed only after numerous crashes. The subsequent investigation by the FDA discovered highly divergent sex-dependent elimination rates causing large concentrations to remain in women’s blood even eight hours after intake [4][6]. When lower doses were shown to be just as effective, the original 10 mg dose was reduced to 5 mg in immediate release tablets and 12.5 mg to 6.25 mg in extended release tablets [7].

Such an extreme disparity between prescribed and effective dosage for women highlights the greater risk for adverse drug reaction produced by male-dominated clinical trials. Accepting that women and men respond differently to drugs necessitates a change in drug development, testing, and publishing. This can be addressed most effectively by 1) the pharmaceutical industry creating drugs with sex-specific difference in mind, 2) the government enforcing stricter regulation of sex analysis of drugs, and 3) medical journals holding companies accountable to maintain these standards.

When treating and dosing patients, physicians formerly considered the human body to be a complex organization of tissues and organs that was repeated within men and women and varied very little, even in younger children. While the now archaic idea that children operate as miniature adults could be attributed to a nascent understanding of physiology, treatment of men and women as identical systems discounts the tremendous amount of available research which establishes differences in both pharmacokinetics and pharmacodynamics [8][9][10].

Pharmacokinetics describes the characteristic drug distribution, absorption, metabolism, and excretion. One of the more obvious factors, size, is related to drug distribution. As men are generally larger than women, the corresponding amount of mass and therefore weight is proportionally larger [11]. This corresponds to a smaller total blood and tissue volume in women through which the drug can circulate thereby generating a higher concentration when equal doses are prescribed [9]. Absorption is highly dependent on body composition with women possessing a larger percentage of body fat leading to an over-accumulation of lipid soluble medications, such as benzodiazepines [8]. A lower glomerular and renal filtration rate compounds this and reduces excretion in the blood, increasing the risk of toxicity [12][13]. The menstrual cycle, a clearly sex-specific trait, induces fluctuating hormones that dictate several factors including metabolism and maturation. Other considerations include the more basic environment of the female gut which can alter drug release, absorption, and kinetics depending on the pH of the medication [8].

Further experiments have determined the pharmacodynamics’ dissimilarities. These more nuanced aspects examine the sensitivity down to particular enzyme activity as in the liver [2][9] or precise voltage gated receptors like cerebral neurons [10]. Another important point of consideration stems from not just the incomparable biological processes, but also the fact the women tend to be prescribed more medications than men. The interaction and possible harmful side effects between the different chemicals must be considered when confounding drugs such as birth control are so common [2].

As the healthcare community continues to find evidence in support of sex-based differences, pharmaceutical companies must respond by utilizing sex specific pharmacokinetics and pharmacodynamics when identifying practical targets for treatment in disease pathogenesis and development. Such a shift requires transformation of not just the final drug label, but also the beginning concept of the medication. Disregarding the enumerated distinctions during the development of drugs cannot be viewed as anything but negligent given a doctor’s imperative duty to “do no harm” while providing care to the best of his/her abilities.

Because research relied on male biased data for so many decades, a new framework upon which to organize studies requires a radical shift for pharmaceutical companies. Representation of females in early clinical phases proves difficult when businesses are faced with the desire to garner federal approval as quickly as possible. With competing companies searching for patents and rights to newly formulated chemical combinations, time becomes a distinguishing factor for which company becomes profitable. In order to reduce variability and the time spend assessing toxicology for investigational new drug (IND) submission, males are generally employed in animal models. Use of only one sex inherently eliminates some variables. As this stage of trial uses concentrations far in excess of that to be used in humans, the efficiency of the practice can be permitted as direct translation to humans that will not be employed. When only a narrow therapeutic range is indicated before reaching toxicity, the use of both sexes becomes more important to ascertain possible dissimilarities.

Of greater concern, however, the FDA does not require reproductive toxicology studies before approving continuation of development which thereby disallows women from Phase I and II trials [15]. The information acquired during these initial phases is critical in drug modification and assessment though impossible for women to participate in without knowing the full extent of risk. This inconsistency similarly exposes males to potentially damaging compounds though the side effects tend to be less catastrophic [1]. Requiring both toxicology reports to be submitted at time of approval would indeed delay the progress of the study, though arguably at the benefit of creating a better end product and more comprehensive data.

Although determining the most apparent side effects would prevent unnecessary endangerment of all participants, pharmaceutical trials often raise additional objections. The irregularity of female hormones, for instance, often serves as an eliminating variable for recruitment despite its natural role in development. Ignoring details simply because it makes analysis more difficult is not a valid excuse when hormones control so much of the internal environment and preliminary findings have already suggested vital drug-hormone interactions. Several studies have already confirmed increased levels of progesterone in women directly modify GABA receptors triggering chronic pain and potentially lethal respiratory depression under anesthesia [19][20]. Even recent reevaluation of aspirin, well known to help lower the occurrence of stroke and heart attacks, found opposite reactions by sex due to different hormonal levels. Women had limited stroke prevention and no myocardial infarction decrease while men had limited MI prevention and no stroke decrease [8]. With renewed focus on how these factors affect pharmacology, more research continues to prove the necessity for companies to consider both sexes during initial conception and final clinical trials.

Serving as a self-proclaimed “watch dog” of the pharmaceutical system, the Center for Drug Evaluation and Research (CDER) of the FDA evaluated these novel medications for trends and serious risks [14]. As these differences between sexes have become more apparent, the FDA has reversed many old policies in addition to implementing new mandates to reflect current knowledge. Thalidomide, a drug prescribed for nausea during pregnancy, initiated the focus on potential harms to the fetus and subsequent generations. The daughters of the women who took the drug in the 1950s gave birth to children diagnosed with phocomelia, a condition characterized by stunted flipper-like limbs [15][16]. In response to the extensive subsequent birth defects, the FDA published General Consideration for Clinical Evaluation of Drugs in 1977, desiring to protect women from other drugs with unknown long term consequences [17]. While the document stated that “women of childbearing potential should be excluded from the earliest dose-ranging studies,” developers interpreted the guideline to exclude women almost entirely from all phases of clinical trials [16].

The FDA’s well-intentioned but hurried response to prevent further calamities inadvertently created conventions for unrepresentative research and clinical trials which are yet to be fully overturned. After nearly a decade of criticism that the directive harmed women by eliminating their response to novel medication, two new guidelines, Format and Content of the Clinical and Statistical Section of an Application (1988) and Study of Drugs Likely to Be Used in the Elderly (1989), advocated for analysis by sex as well as age and race [17]. With no consequences for failure to do so, the recommendations generated no impact to change the standard of male-focused treatment and response. Using women in later stages was viewed as yielding little benefit when compared to the additional costs to recruit more subjects and analyze each group separately. Only after a Government Accountability Office (GAO) found clinical trials to contain insufficient data to establish sex-specific effects was the former policy reversed in 1993 in an effort to promote inclusion of women in earlier phases of study [15].

In more recent years, government agencies have continued to seek equitable representation with varied degrees of success. These achievements, however, occurred at an extraordinarily slow pace when compared to the rate of research demonstrating sexual difference in drug response. When presenting data for a new drug application (NDA) to the FDA as of 1998, the results must include documentation of differences in age, race and sex whereas the preliminary investigational new drug (IND) must have this information tabulated [15]. As of 2001, women represented 52 percent of all participants in FDA-reviewed drug studies [16], yet still comprised less than the proportion of women diagnosed in trials concerning medical devices, heart disease, cancer, and several other prevalent illnesses [6][16]. In an effort to ameliorate this discrepancy, the Institute of Medicine (IOM) Committee on Women’s Health Research convened in 2010 to establish areas of immediate attention and improvement. Corroborated by the FDA’s new amendment in 2011, both organizations affirmed the need for research to be designed around sex-specific differences as well as for medical journals to encourage this transition by requiring sex-specific analysis [16].

Pursuing a more knowledgeable design of treatment for both sexes first requires stricter enforcement of federal policy. Stemming from the Enlightenment’s ideology which shaped much of the United States’ political framework, the social contract charges the government with the duty to protect the citizens who have relinquished some personal freedoms in return for mutual order and welfare. The Universal Declaration of Human Rights of 1948, as decided by the joint resolution of the UN, reconfirmed the government’s responsibility to protect the individual’s “right to a standard of living adequate for the health and well-being of himself and his family, including…medical care” [21]. This obligation extends to the FDA who must determine the safety of drugs manufactured for all people of the population. Despite the FDA releasing numerous policies, mandates, and recommendations, only 26 of the total submitted NDAs from 1977 and 1995 showed data specified according to sex [10]. Even when these manufacturers legally complied with the rules set forth, the reports present little usable knowledge if they cannot be proven to hold an association let alone applied to the general population.

In order to promote the increased welfare of women when similar numbers continue to be seen with the relative dearth of a novel drug research focused on sex-specific differences, the CDRH must implement its Evaluation of Sex Differences in Medical Device Clinical Studies (2011). These guidelines not only encourage greater female participation in medical device trials, but also advocate considering body weight and known sex-dependent differences when interpreting data [16]. Rather than a sweeping mandate to enroll women and men in equal numbers for each study [15], a more suitable approach would be to have at least the percentage that represents the true proportion in society. This compromise would prevent wasting valuable resources on illnesses where other factors such as age or race are of more consequence while also allowing for sex differences to be assessed with significance. The enforcement of this legislation would fall to the FDA to ensure an unbiased review of the data [14]. The last few decades spent in deliberate effort to change governmental policy, however, emphasize the slow pace of shifting standard procedures regularly stymied by legislation and lobbyists.

Much of the conflict between the pharmaceutical industry and the FDA originates from their disparate roles and objectives in society. As part of a capitalist structure, the pharmaceutical companies function as a business with the intention of earning a profit according to the supply and demand of the market economy. With time and money of utmost concern, methods to reduce cost and increase efficiency, such as recruiting one sex to allow fewer participants for significance, become standard practice.

While many would hope that companies would independently move beyond just a transaction in order to establish the best product, such an assumption rarely happens even with evidence of toxicity for the consumer. For example, corporations have long claimed current procedures operate under the provisions proposed by the government, but women are 50-75% more likely to experience not only adverse reactions but also severe complications including death [22]. When the hazards are so much greater for such a large portion of the population and may result in the loss of life, the current risk assessments cannot be deemed tolerable let alone acceptable.

Changing standards to include sex differences even hold some potential for profitability in addition to operating with better practices. Formation of a product targeting more precise biological pathways and molecules inherently reduces danger, benefitting the consumer, and establishes consumer trust with fewer recalls and side effects. As a provider of goods that directly affect health and general well-being, pharmaceutical companies hold a greater responsibility to explore all possible effects and utilize the growing data of sex-specific differences.

Because one cannot solely rely on all companies to universally act with integrity, the FDA’s at times opposing aim—to that of industry—serves to ensure the “clinical benefits of a drug outweigh its potential health risks” for the consuming population who relies on the government to determine the acceptable level of risk [1]. Without money as a possible conflict of interest, the branch can uphold the social contract to maintain the welfare of the population. Despite efforts to tighten regulation, the enforcement of policy only occurs slowly with extended legal processes needed to review every new drug proposal. The current inadequacy of the government to amend the disparity indicates the need for another outside body that can more directly control the industry’s profit margin.

Because pharmaceuticals rely heavily on journals in order to gain acceptance in the medical community and establish the validity of their results, this relationship uniquely places review boards in a position to most effectively address the gender dose gap. As authorities in their own right in the field of medicine, journals maintain an impartial dissemination of information that doctors utilize to treat patients, a role arguably of greater importance than either the government or the industry. Trusting the journal review boards’ critical viewpoint to publish convincing research, physicians can then evaluate the product to determine what would be most effective for their patient while minimizing potential adverse reactions. The statisticians, scientists, doctors, and field authorities on staff provide a final tier to analyze the legitimacy of the data as well as to identify potential areas for revision or further investigation. By accepting a lower standard of research that neglects a vital focus concerning sex-specific traits, they ultimately disallow clinicians from providing the best care possible.

Transforming journal standards to include data analyzed according to sex, or to clearly state why the assessment would not pertain to the area of research, would force companies to modify how studies are conducted. With sex-specific data no longer a recommendation but a norm in order to be published, companies would be more likely to pursue research with the distinct interaction of sex-specific pharmacology considered from the beginning [16]. Current designs that present sex-dependent results often search for dissimilarities after the completion of the trials, causing symptoms to be overlooked that could have some relevance if seen throughout the set trial population [11]. If not including this information leads to the inability to publish and consequently decreased publicity, companies would have a financial incentive to move beyond the old frameworks.

While tradition focuses on male biology and effects, journals must assume the responsibility to improve upon “do no harm” to yield benefit to men and women alike. The fundamental goal of journals may be neither to protect the citizens of a region, nor to earn a profit, but the pursuit of knowledge requires some responsibility to humankind. Researching humans particularly requires the results to have some assistive value for future generations in addition to minimizing potential risks. Simply tampering with other people’s bodies with no structure to achieve usable knowledge leads to the horrific events that caused the Nuremburg Code to be created. In order to push the limits of science, it makes sense logically and ethically to include all factors of variations when developing drugs and dosage, especially when women represent approximately half the entire population. As the OWH conference in 2011 summarized, “[t]he ultimate goal would be a culture change in scientific research that embraces sex as a key variable for analysis” rather than elimination [16]. With a duty to expand the field of knowledge in medicine, journals must lead the industry to finally close the sex dose gap.

By Mary Beth Amrine, Viterbi School of Engineering, University of Southern California

Works Cited

[1] J. Heinrich, “Drug Safety: Most Drugs Withdrawn in Recent Years Had Greater Health Risks for Women,” United States General Accounting Office, Washington, DC, 2001.

[2] R. Jacobson, “Psychotropic Drugs Affect Men and Women Differently,” Scientific American, 1 July 2014.

[3] J. MacFarlane, C.M. Morin and J. Montplaisir, “Hypnotics in Insomnia: The Experience of Zolpidem,” Clinical Therapeutics, vol. 36, no. 11, pp. 1676-1701, 2014.

[4] FDA, “FDA Drug Safety Communication: Risk of next-morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem (Ambien, Ambien CR, Edluar, and Zopimist),” 16 Jan 2016. [Online]. [Accessed Jan 2016].

[5] FDA, “Questions and Answers: Risk of next-morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem (Ambien, Ambien CR, Edluar, and Zopimist),” 23 December 2014. [Online]. [Accessed Jan 2016].

[6] M.F. RADM (Ret.) Sandra L. Kweder, “FDA Is Committed to Determining Sex Differences in How Drugs Work,” 14 February 2014. [Online]. [Accessed Jan 2016].

[7] FDA, “FDA Drug Safety Communication: FDA approves new label changes and dosing for zolpidem products and a recommendation to avoid driving the day after using Ambien CR,” 14 May 2013. [Online]. [Accessed Jan 2016].

[8] H.P. Whitley and W. Lindsey, “Sex-based differences in drug activity,” American Family Physician, vol. 80, no.11, pp. 1254-8, 2009.

[9] D. Marazziti, S. Baroni, M. Picchetti, A. Piccinni, M. Carlini, E. Vatteroni, V. Falaschi, A. Lombardi and L. Dell’Osso, “Pharmacokinetics And Pharmacodinamics Of Psychotropic Drugs: Effect Of Sex,” CNS Spectrums, vol. 18, no. 3, 2013.

[10] O.P Soldin, S.H. Chung and D.R. Mattison, “Sex Differences in Drug Disposition,” Journal of Biomedicine and Biotechnology, vol. 2011, 2011.

[11] O.P Soldin, S.H. Chung and D.R. Mattison, “Sex Differences in Pharmacokinetics and Pharmacodynamics,” Clinical Pharmacokinetics, vol. 48, no. 3, pp. 143-157, 2009.

[12] S.E. Gaundry, D. S. Sitar, D. D. Smyth, J.K. McKenzie and F. Y. Aoki, “Gender and age as factors in the inhibition of renal clearance of amantadine by quinine and quinidine,” Clinical Pharmacology and Therapeutics, vol. 54, no. 1, pp. 23-27, 1993.

[13] U. B. Berg, “Differences in decline in GFR with age between males and females. Ference data on clearances of inulin and PAH in potential kidney donors.,” Nephrology Dialysis Transplantation, vol. 21, no.9, pp. 2577-2582, 2006.

[14] FDA, “Development & Approval Process (Drugs),” 29 Jan 2016. [Online]. [Accessed 10 Feb 2016].

[15] “Sex Differences and Implications for Translational Neuroscience Research: Workshop Summary.,” in National Academies Press (US), Washington (DC), 2011.

[16] R. W. Diaz and K. B. Steuer, “Reforming Women’s Health Research: A Renewed Focus on Sex Differences in Clinical Trials,” ABA Health, vol. 8, no. 7, 2012.

[17] FDA, “Understanding Sex Differences,” 14 October 2014. [Online]. [Accessed Jan 2016].

[18] FDA, “How Drugs are Developed and Approved,” 18 August 2015. [Online]. [Accessed January 2016].

[19] K. Ueno, “Gender differences in pharmacokinetics of anesthetics,” Japanese Journal of Anesthesiology, vol. 58, no. 1, pp. 51-58, 2009.

[20] C. A. Frye and J. E. Duncan, “Progesterone metabolites, effective at the GABA(A) receptor complex, attenuate pain sensitivity in rats,” Brain Research, vol. 643, no. 1-2, pp. 194-203, 1994.

[21] The United Nations, Universal Declaration of Human Rights, 1948.

[22] R.M., “Do women have more adverse drug reactions?”, American Journal of Clinical Dermatology, vol.2, no.6, pp. 349-51, 2001.