Silvio Garattini and Rita Banzi
The diseases common to both sexes are not the same in males and females and differ in various factors, including prevalence, symptoms and outcomes. There are also other important differences regarding the ways in which the bodies of men and women react to the presence of drugs in the human body. We also know that the toxicity of drugs is different and that women usually suffer more from the toxic effects of drugs. A new approach is needed in pharmaceutical research paths to remedy this injustice towards women.
The approval of new drugs is currently carried out at the EMA level (European Medicines Agency) on the basis of the rules dictated by European legislation. In practice, to be authorized, new drugs must guarantee three important characteristics: “quality, effectiveness and safety”. These elements are adequate for drugs that act on symptoms or diseases for which other treatments are not authorized, but are not sufficient when other drugs are already available for the same therapeutic indication. In fact, we often don’t know whether the new drug is better or worse than existing ones, because there are no comparison studies or because a placebo is used as a control instead of the best treatment in use in clinical practice. This is an unacceptable situation from an ethical point of view, especially when it comes to serious and chronic diseases, and which clearly benefits the industries that market the drugs and not public health. The scenario would change completely if legislation established the approval of new drugs on the basis of “quality, efficacy, safety and added therapeutic value”. In this case it would be necessary to carry out comparative studies and demonstrate that the new drug improves important efficacy and/or safety outcomes compared to available alternatives. Consequently, if the new drug were equal to or inferior to what we already have, it would not be approved; if it proved to be superior, other drugs would no longer have any reason to be used.
As is known, the research process necessary to obtain the authorization of a new drug is very long and complex. Generally speaking, it begins with preclinical in vitro and then in vivo studies on various animal species. These models are overwhelmingly male, unless it is a disease that only affects women, and young people. Once the preclinical part has been completed, there are three clinical phases: the phase 1, which is used to study pharmacokinetics, toxicities and establish the maximum tolerated dose, generally involves healthy volunteer subjects almost exclusively males. There level 2, which serves to extend the study of pharmacokinetics in the target population and to study the response, is often conducted in men. Finally, also in the phase 3, which serves to establish the effectiveness of the new drug, the majority of subjects participating in the studies are adult men mainly between the ages of 20 and 65. For phase 3 two clinical studies are normally necessary, and both are carried out by the industry interested in marketing the drug. Greater objectivity would be achieved if one of the two studies were carried out by an independent body.
One of the main problems of the current approach to the drug development and approval process concerns the representativeness of the populations studied in clinical trials. More than 50 percent of drug spending is used for the elderly who are frequently not included in experimental studies. Frailties, comorbidities and different pharmacokinetics in elderly people can significantly alter the efficacy and tolerability of drugs, so extending the results obtained to an adult population is often not correct. A similar argument can be made for children, in which drugs are often used by adjusting the adult’s doses based on body weight, forgetting that the child is not a small adult, but a growing organism on which the drug could have different effects.
The situation of women is even worse because they are included in controlled clinical trials only when most of the drug’s characteristics have already been acquired in humans (1). Not only that, but they are included in an insufficient percentage and this happens for various reasons including the risk of a possible pregnancy. It is estimated that for approximately 75 percent of phase 3 studies it is not possible to establish the level of efficacy for men and women and therefore the data relating to females are also merged with those of males. However, it is known that men and women differ in many ways genetically, epigenetically and hormonally and this causes notable differences in physiology and in the development and manifestation of diseases. Women have a different chromosome from men, they have a completely different hormonal situation, a more effective immune system than that of men.
If we measure 130 parameters in the blood of women and men, 102 are different. From a metabolic point of view, women are more sensitive to insulin than men, women accumulate fats, while men use them more for energy purposes. We could continue to describe the differences related to sex, to which we should add gender differences, still little known in medicine, i.e. those linked to the social characteristics in which identity, relationships and the characteristic behaviors of men and women at the various ages of childhood and maturity are built and old age.
Given these important differences, it is normal to expect that diseases common to both sexes are not the same in males and females and differ in various factors, including prevalence, symptoms and outcomes.
For example, Parkinson’s disease it occurs in 30 percent of women and at a higher age than men. In males it is characterized by rigidity, eye movements and drowsiness, while in females tremors, nervousness and depression prevail. There atrial fibrillation it is a risk factor for cerebrovascular stroke, but the risk is different between the two sexes, being 5 percent in men and 7.4 percent in women. Not only that, but the same number of stroke It occurs half the time in women compared to men. This creates a difficulty in calculating the number of patients to be studied in phase 3 clinical trials evaluating new drugs to reduce the risk of stroke; these differences in risk must be carefully considered in order to avoid undersizing the sample for one of the sexes, which is not ethically correct. Other examples of differences concern the lung cancer. Adenocarcinomas are more frequent in women than in men, the mutations causing these tumors are often different and women respond better to chemotherapy and have longer survival. In the type 2 diabetes coronary events are more frequent in women than in men. There metabolic syndrome in subjects under 65 years of age it is 65 percent in women and 35 percent in men. Always in people with diabetes senile dementia they are more frequent in women than in men. Also for the Alzheimer’s disease the prevalence in women over 65 represents two thirds of the total. The depressive syndromes, anxiety disorders, post-traumatic stress they have a double prevalence in women compared to men. The description of the differences could continue.
There are also other important differences regarding pharmacokinetics, that is, the way in which the organism of men and women reacts to the presence of drugs in the human body. Weight, body surface area and muscle mass are greater in males, while females have greater fat mass which determines a different distribution of the drug. The absorption is different because the gastric pH is higher in women and the intestinal motility is lower. Hepatic metabolism is different, due to a different expression and action of the enzymes that interact with drugs. In the end, renal elimination it is generally greater in men than in women. Unfortunately, pharmacokinetic studies are not systematically conducted in both sexes, so we do not fully know the effect of these differences. However, some available examples highlight that these differences can have important clinical consequences. The same dose as diazepam induces a double blood concentration in women compared to men. The verapamil it is eliminated renally in a given period of time by 65 percent in men and 35 percent in women when the same dose is administered orally. In women it would then be important to study the pharmacokinetics in the reproductive age compared to menopause or in the various phases of the menstrual cycle; for example, prednisolone elimination is 16.6 percent premenstrually compared to 11.6 ml/min/kg postmenstrually.
We also know that the toxicity of drugs is different and that women usually suffer more from the toxic effects of drugs. Eight of the 10 drugs withdrawn from the market due to side effects showed toxicity in women. Furthermore, the fact that we do not know the real effectiveness of the drug in women does not allow us to precisely calculate the so-called NNT (Number Need to Treat), that is, how many people we have to treat for one to have an advantage. On the basis of indirect data we know, for example, that a statin administered for four years as primary prevention has a NNT of 43 for men and 148 for women, which means that we have to treat 42 men but 147 women unnecessarily so that one does not have a heart attack, but the 147 women will be subjected to the numerous toxic effects of the statin. Low-dose aspirin in primary prevention is not active in women. The idea therefore that the solution is to have 50 percent of women in phase 3 studies is, on the basis of the arguments presented, insufficient because we include women when doses, times, side effects have already been highlighted on the basis of data obtained mainly in the male. It is therefore necessary that the development of a drug is carried out starting from in vitro and in vivo studies in animals on two different protocols for males and females. It is unethical to continue with the current methods, that is, to use drugs studied mainly in men and women. It’s probably even illegal. A great effort and a change of perspective in which common sense prevails is therefore needed to make the two protocols mandatory for drugs awaiting future approval. However, we must not forget that we should also study in depth the effectiveness and toxicity of the drugs currently used for women.
Europe and its countries must urgently respond and remedy this injustice towards women.
Silvio Garattini and Rita Banzi. Mario Negri Institute of Pharmacological Research IRCCS
Bibliography
Garattini S , Banzi R . A medicine that penalizes womenneither. Ed. San Paolo, 2022, Cinisello Balsamo (MI).