Caffeine, the same stimulant that helps millions of people start their day, also saves lives in hospitals. If a premature baby is unable to breathe at birth, called primary apnea, caffeine citrate gets its immature lungs going. It is an old drug, well known and cheap to produce. But it has an important uncertainty: only two companies manufacture it and some presentations have only one alternative on the market. If there were to be a problem in the drug’s long supply chain, many newborns’ chances of surviving would be compromised.

The vials of 20 milligrams of caffeine citrate are one of the 508 medicines —made with 264 active ingredients— that the Spanish Agency for Medicines and Health Products (AEMPS), dependent on the Ministry of Health, has included in a new list of strategic medicines for the health system, a category that seeks to shield the supply of drugs so that they are never lacking in hospitals and pharmacies. “They are essential drugs, but they have also been on the market for many years and whose price has been falling over time. This makes them less attractive for the pharmaceutical sector. In many cases there are only one or two manufacturers in the market, which makes them vulnerable”, explains the director of the agency, María Jesús Llamas.

Drug supply problems, more frequent in those cheaper presentations, have become entrenched in recent years throughout the world. A recent report from the AEMPS highlights that in the last year they have grown by 38% in Spain and affect one in every 30 presentations on the market. In the vast majority of cases, these difficulties have little impact on the patient, since there are several identical alternatives for the drugs involved. “But this does not always happen and sometimes the problem affects a drug with no alternatives on the market and we have serious difficulties administering it to the patient who needs it,” explains Olga Delgado, president of the Spanish Society of Hospital Pharmacy (SEFH) and head of this area in the Son Espases Hospital (Palma de Mallorca).

An example is mitomycin, a key drug in the fight against bladder cancer. Others are cytarabine (against some types of leukemia and lymphoma) and methotexate (an immunosuppressant also used against cancer and rheumatoid arthritis). “Several of the drugs to be protected are oncological, but there are almost all specialties, such as some presentations of hydrocortisone [anti-inflammatory and immunosuppressant] and amiodarone, used against serious arrhythmias,” adds Olga Delgado.

Managing deficiencies in some specialties is not always easy. “It takes a lot of work and a lot of planning to buy the affected medicines abroad, where it is still available. It also forces us to restrict its use only to those patients for whom there is no other alternative and to look for others for those who do have it…”, illustrates this specialist.

If a drug is only produced by one company, the risk of a problem occurring in the production plant or during transport skyrockets, with serious consequences for the health of the patients who need it. But it can also give rise to bad practices, if a pharmaceutical company decides to take advantage of the de facto monopoly that it enjoys. This was what happened with Aspen Pharma in 2018, when the company maneuvered to multiply the price of five anticancer drugs, four of which have now been included in the AEMPS list.

As the Ministry of Health did not agree to pay up to 30 times more for any of them, Aspen Pharma left the Spanish market without supplies, forcing hospitals to buy drugs that were much more expensive. The conflict was not resolved until 2021, when the European Commission became involved in the case and its Competition authorities threatened the company with a multi-million dollar fine for abusing its dominant position. Finally, Aspen Pharma relented and agreed to lower the price of its drugs by 73%.

“A medicine that is not attractive to produce for the pharmaceutical sector is a problem for the health system,” summarizes Emili Esteve, the director of the technical department of the Farmaindustria employers’ association. “We must find a way to resolve this situation and the creation by the AEMPS of the list of strategic medicines is a step in the right direction. The objective is for more manufacturers to be interested and, to achieve this, protecting them from the erosion caused by the current reference price system (which limits price increases or drives them down to save on pharmaceutical bills) is essential”, he adds.

The AEMPS initiative is the culmination of years of effort, also in the international arena, to identify the most important medicines for health systems and find the formula to guarantee their supply. The World Health Organization (WHO) has been publishing a list of essential medicines for years and the European Commission has also developed its own strategy with member states “to make supply chains more resilient and stronger,” according to the agency. .

These policies also have a scientific and industrial component, with the aim of contributing to the consolidation of a strong and innovative European pharmaceutical sector. The Profarma Plan is the translation at the Spanish level promoted by the Ministry of Industry and in which those of Health and Science also participate.

“Spain has a very good manufacturing capacity, both for the synthesis of active ingredients and for finished medicines, and we hope that this will be a stimulus. The general objective of the plan, which provides for aid, is to collaborate so that it is more innovative and competitive and, in this case, it also includes incentives for more companies to commit to the production of strategic medicines”, explains María Jesús Lamas.

Diversion to other countries
A recurring complaint from the sector in recent years has been that Spain is one of the European countries with the lowest drug prices, which would be behind some cases of shortages, since distributors – pharmaceutical companies usually have production quotas fixed for each country—in some cases obtain higher profits by diverting them to countries where prices are higher.

The AEMPS, which admits the need to guarantee the economic viability of strategic drugs, describes these cases as anecdotal and cites its latest shortage report as an example, in which only 2.4% of the 1,105 presentations with problems explained the reason. alleged by the owner of the drug was the lack of “commercial interest”. 25.3% of incidents were due to “non-quality manufacturing issues”, 24.6% due to lack of “plant capacity”, 22% due to “increased demand” that was not able to be met. cover, 8% to problems in “the supply of active ingredients” and 7.5% were related to “quality” problems, among other reasons.

“The problem of the supply chain is global and as such we are facing it with our European and international partners. There are active ingredients that are only produced in one or two places in the world. A problem in that factory or in the means of transport that distributes them to the whole world affects all countries. That is why it is so important to review each of the links in the chain, to identify at which points there may be a vulnerability and to have specific measures for each of them: have contingency stocks, increase the number of suppliers, plan the maintenance of production plants and planning any shutdown, among many others”, concludes the director of the agency.

(Taken from Therapeutic Arsenal)

This reality is described in an article on the sector’s contributions to the COVID-19 battle, published in the Cuban Academy of Sciences’ journal, Anales, authored by five

of our country’s most accomplished scientists: Eduardo Martínez Díaz, BioCubaFarma CEO; Rolando Pérez Rodríguez, director for Science and Innovation for BioCubaFarma; BioCubaFarma CEO advisors, Luis Herrera Martínez and Agustín Lage Dávila; and academic Lila Castellanos Serra.

The text begins by recalling that Cuba’s bio-pharmaceutical sector has accumulated extensive experience in confronting complex epidemiological situations on a national level.

In case of COVID-19, the authors outline factors that were decisive in ensuring that Cuban health services were never overwhelmed and that both incidence and mortality rates have not reached even one sixth of their international levels. These critical factors include early preventative action; the integration of different institutions and sectors of society in all efforts; the direct link between the scientific community and the government; and the participation of the vast majority of the people.

When the new coronavirus, labeled sars-cov-2 and cause of the disease COVID-19, first appeared in the Chinese city of Wuhan, in December of 2019, Cuba began to carefully monitor the situation.

Before the first three cases were reported on the island, this past March, a strategy to confront the pandemic was already being implemented by the Party, state institutions, and the government.

The article notes, “The Ministry of Public Health created a COVID-19 national technical group which approved the National Prevention and Control Plan in January of 2020,” continuing, “BioCubaFarma, through its representatives in China, obtained information early regarding the outbreak in Wuhan, and measures adopted in this country. Based on this valuable information, along with reports and recommendations from the World Health Organization (WHO), an intense process of scientific debate was launched and the elaboration of proposals for research and development projects by its enterprises and expert groups within its scientific-technical council.”

The fact that Cuba has a national industry in state hands, with tested production and research capacity, has been a key strength, allowing results to be achieved and an effective response to the demands of the national health system provided, within a short period of time.

“The first task was guaranteeing the production of medications included in the approved National COVID-19 Research Protocol,” the authors recount, citing among these

recombinant Interferon Alfa-2b and other drugs for hospital use, to treat the disease and its complications.

Likewise, the production of facemasks and sanitization products was initiated, while the repair of intensive care equipment was stepped up, along with production of personal protective wear for health workers including facemasks with filters, face shields, googles, and airtight scrubs.

The scientific capacity of BioCubaFarma enterprises was mobilized to introduce a series of novel products used on a number of fronts in the battle to contain the disease.

The joint research program undertaken by Minsap and BioCubaFarma currently includes dozens of projects addressing a number of issues, such as the prevention of infections in at-risk and vulnerable groups; treatment of confirmed cases, and patients in serious and critical condition specifically; as well as recovery from the disease, with a view toward reducing the risk of long term consequences of the infection.

This strategy has undoubtedly served as an important tool that does not reflect the distorted interests of private property and the market economy, but rather serves as a great strength in the entire people’s struggle for life.

THE CUBAN PAHARAMCEUTICAL INDUSTRY

-The founding steps to establish the industry were taken 35 years ago by Comandante en Jefe Fidel Castro, who consistently encouraged and guided its growth and development

-Cuba has been active in the sector since the very beginnings of modern biotechnology and established its own model of scientific work and innovation, with internationally

recognized results.

-The National Center for Scientific Research (cnic) emerged in 1965 and became the training ground for scientists who went on to establish other institutions.

-The first great success f nascent Cuban biotechnology was a vaccine against type B meningitis, that served to contain an epidemic of this illness in the 1980s.

-This decade marked the take-off of Cuban biotechnology with the creation of the Biological Front and the inauguration of the Center for Biological Research in 1982, the

Genetic engineering and Biotechnology Center (cigb) in 1986, the Inmunoensayo Center (cie) in 1987, and other institutes that in 1992 came together in the Havana Scientific Pole.

-In 2012, these institutions merged with pharmaceutical industry companies, to become part of the BioCubaFarma state enterprise group.

IN FIGURES

BIOCUBAFARMA TODAY

32 enterprises

+ 800 products delivered to the national health care system including 349 medications included in the Basic Supply

182 patents

+ 100 clinical trials being simultaneously conducted with its products at 200 sites

+ 50 countries importing its products

INMUNOENSAYO CENTER (cie):

1 562 laboratories in Cuba

546 laboratories abroad

CUBAN EXPERIENCES IN CONFRONTING EPIDEMICS:

Dengue

Bacterial Meningitis

AIDS

The participation of biotechnology and the pharmaceutical industry in national health emergencies, under the leadership of our Comandante en Jefe, constitutes an example of integration with other social actors, in the mobilization of science and productive capacities with a sense of urgency and strategic focus, which this year has served as the foundation of efforts to contain COVID-19.

ACHIEVEMENTS IN THE COVID-19 BATTLE

BioCubaFarma has worked on 16 projects to produce new treatments and medical technologies to prevent and combat the disease. Eleven of these products involve clinical studies or trial interventions with patients and at-risk groups. Five products with preventative properties have been evaluated to stimulate the immune system, both the innate and adaptive, for different vulnerable groups, including medical personnel.

PRODUCTS

Biomodulina-t, immunomodulator of natural origin

Hebertrans (Transference factor)

Nasalferón (for nasal administration of recombinant human interferon alfa-2b)

Heberon® (recombinant human interferon alfa-2b)

Heberferon® (ifn alfa-2b + ifn gamma)

Jusvinza, peptide immunomodulator

Itolizumab, monoclonal antibody anti-cd6

MEDICATIONS BEING EVALUATED

Peptidecigb300, inhibitor of enzyme caseína quinasa.

Anti-meningococcus vaccine vamengo-bc, & cigb2020 vaccine.

Specific vaccines against sarscov-2: The Cuban immunization regimen includes 13 vaccines, 8 of which are produced in Cuba.

SOURCE: ARTICLE: “LA INDUSTRIA BIOFARMACÉUTICA CUBANA EN EL COMBATE CONTRA LA PANDEMIA DE COVID-19,” PUBLISHED IN THE CUBAN ACADEMY OF SCIENCES JOURNAL “ANALES”

The medicine, created at Cuba’s Genetic Engineering and Biotechnology Center (CIGB), contains as its active ingredient recombinant human epidermal growth factor, a peptide of 53 amino acids that couples with a receptor to activate anabolic metabolism, promoting the synthesis of amino acids and proteins, thus leading to cell division.

The product, considered unique and the first of its kind, is administered directly to the diabetic patient’s ulcerated tissue, generating accelerated healing of the wound. The basic principles of its functioning were based on the research of U.S. scientist Stanley Cohen, in the 1960s, who observed the behavior of many animals which lick their wounds, applying large quantities of saliva, a pattern common among humans, as well, especially when it comes to cuts or burns on our fingers.

Dr. Manuel Raíces Pérez-Castañeda, a member of the CIGB promotion and communications team, related that professor Cohen was able to isolate epidermal growth factor, in 1962, thinking that in the future this molecule could be used in healing therapies, but at the time the technology to purify large quantities did not yet exist.

Dr. Manuel Raíces Pérez-Castañeda is well versed in the history of Heberprot-P. Photo: Dunia Álvarez
“Beginning in the 1980s, with the development of genetic engineering, it became possible for scientists to move genes from an initial host cell to another which was easier to manipulate, principally in microbial fermenters like bacteria and yeasts, developing rapid, effective, sophisticated biotechnological procedures. These bacteria and yeasts can fabricate complex molecules of great therapeutic value at an attractive cost, and within a very brief time period,” the Cuban researcher explained.

Cuba became involved in the cloning of genes in the 1980s, as one of the world’s pioneer countries in the field of biotechnology. Epidermal growth factor (EGF) was among the first molecules cloned in our country through genetic engineering, achieving the addition of silver sulfadiazine, used in treating burns. Produced in this way was the medication Hebermin, currently in use in burn units across Cuba’s public health system, allowing for the recovery of patients with first degree burns over much of their bodies.

By 1994, Cuban researcher Jorge Berlanga, a member of the biomedical wound healing team at the CIGB, developed a model in rats to study the use of epidermal growth factor in the management of neuropathy, one of the complications of diabetes.

This investigation consisted of cutting thesciatic nerve in rats’ extremities and injecting epidermal growth factor to stimulate the regeneration of nerve cells at the site of the cut. If regeneration occurred, it could be expected that measurements could be taken of variations or improvement in the transmission of nervous impulses from one end of the nerve to another, through the cut segment. “The fundamental purpose was to see if, with the introduction of the medication, regeneration of the sciatic nerve could be achieved, and with that, address the neuropathy. This was the genesis of Heberprot P,” Dr. Raíces explained.

“Berlanga began to observe that the animals receiving the injection of epidermal growth factor did not develop ulcers or lose toes. While the negative or placebo controls, given injections of water, developed scabs and lost extremities,” he continued.

The door was opened to research on the treatment of diabetic foot ulcers, with severe effects on nerve endings in extremities. Until that moment (1994), researchers and clinicians who treated diabetic foot ulcers has used topical medications with different ingredients active on the surface of wounds, thus the injection of EGF was a notable change and a pioneering move in the management of this pathology.

Research through 2001 focused on demonstrating the effectiveness and safety of the new treatment in animals, comparing the advantages noted with the injection of epidermal growth factor, as opposed to topical applications. A second line of investigation showed that at deeper levels within the tissue, there were more receptors for the growth factor than present at the surface. Thus injection of EGF was recognized, backed by scientific data published in distinguished international journals.

By 2001, a request for permission to move to clinical trials was submitted to Cuban regulatory authorities, and the first Phase 1 trials were conducted with 29 patients who had severe ulcers on their extremities, and faced the likely prospect of amputation.

“These experiments were conducted at the National Institute for Angiology and Vascular Surgery, by expert doctors familiar with the treatment of such ulcers.

They validated the new therapy, since in this first trial, around 59% of all patients evaluated experienced healing of their open wounds,” Dr. Raíces said.

Between 2001 and 2005, the Phase 2 and 3 trials were initiated and concluded at several different public health care system centers. At these sites, showing improvement were 86% of patients with complicated diabetic foot ulcers, which with treatment developed high levels of effective granulation and healing.

The next year, the treatment was registered in Cuba, and another challenge emerged for Cuban medicine – training doctors, vascular surgeons, angiologists, podiatrists, intensive care nurses, etcetera, in the use of Heberprot-P.

This national program began in 2007, and ten years later, the medication is used in 458 health care centers in the country’s 15 provinces and the Isle of Youth Special Municipality. Thanks to the results achieved, patients themselves, their families, and the health professionals involved have become the best promoters of Heberprot-P.

Dr. Raíces noted, “The main outcome of this study consisted in taking a statistically rigorous count of the cases treated to measure results, detect errors, rectify them, and move forward.”

During 2010 and 2011, research was conducted in seven Cuban hospitals to determine the results among doctors using Heberprot-P and those of doctors not yet including the medication in their procedures. The compilation of this data on three occasions has shown that, among patients admitted to hospitals with complicated ulcers, who did not receive treatment with the medication, 29.6% required an amputation. However, those patients admitted with this condition who were initially treated with Heberprot-P, had an amputation rate of only 5.6% – more than four times lower.

In 2012 and 2013, a Phase 4 post-commercialization study was done of some 2,000 Cuban patients who had received the treatment. This led to two very important international publications, showing the benefits of Heberprot-P in the treatment of diabetic foot ulcers.

The advantages were so obvious that the drug was included in the country’s list of basic medications in 2013, and soon became standard treatment in such cases here, the doctor reported.

Currently some 458 Cuban health care centers at the primary, secondary, and tertiary levels, offer patients therapy with Heberprot-P. They have disseminated the pharmaceutical properties of the medication which promotes the growth of granulation tissue, productive in patients with ulcers that do not heal, even promoting the development of new blood vessels at the site of the open wound.

Among Cuban centers that today use Heberprot-P is the Diabetic Treatment Clinic in Havana. At this institution, it has been observed that the medication stimulates the secretory phase of the granulation process, particularly in neuropathic patients, producing the narrowing of the wound and its restoration, according to endocrinologist Dr. Ana Ibis Conesa González.

She reported that patients recruited for treatment have open ulcers, fungal lesions, infections, and arterial insufficiency. Before applying the medication, patients’ metabolic parameters are tested, to ensure that they are at a normal level. They are also given antibiotics to prevent sepsis, before an angiologist, nurse, or licensed podiatrist administers the treatment.

RN Ivón Gómez Jiménez reported that she was trained to administer Heberprot-P in a course on diabetic foot disease. She learned that the medication is injected in and around the wound.

Diluted in 5ml of distilled water, the drug is injected with an appropriate hypodermic needle at a depth 0.1cm. The treatment is offered as an ambulatory service, although the patient must be bandaged and walk as little as possible. When granulation is adequate, the patient receives follow-up care from an endocrinologist during office visits with topical treatment, until the wound is fully closed.

According to all those interviewed, Heberprot-P offers many therapeutic benefits that accelerate healing, and could serve to reduce the number of lower extremity amputations in all national health care systems.

(Granma)