In 2010, with the support of the international drug purchasing agency UNITAID, the Medicines Patent Pool (MPP) was established in Geneva. MPP negotiates with the original pharmaceutical company on the voluntary license of the drug patent. The original drug company puts its drug patent into the patent pool, and the generic drug company applies to the MPP to obtain the patent implementation license in the patent pool, and produces it in low- and middle-income countries. Supply generic drugs.
The establishment of MPP has its background in the times. The Doha Declaration of the TRIPS Agreement and Public Health adopted by the WTO in 2002 reaffirmed the right of developing countries to use TRIPS flexibilities to obtain affordable medicines to solve their public health problems. Since then, governments including Thailand, Malaysia, Brazil, and South Africa have successively imposed compulsory license production or imported generic drugs on patent-protected expensive original drugs to address public health problems caused by infectious diseases such as AIDS. Under the compulsory licensing “wave”, on the one hand, many multinational pharmaceutical companies feel frustrated and need a mechanism to balance or reverse the situation in which patent drugs are frequently declared compulsory by the government. On the other hand, the decision-making process for compulsory licensing of drug patents in various countries Full of political games, the results are full of uncertainty.
MPP seeks a balance between the commercial appeals (or even monopoly interests) of the original pharmaceutical companies seeking investment returns and the government’s duty to protect citizens’ right to life and health in an innovative way, to some extent alleviating the resulting compulsory license for pharmaceutical patents. tension. At the beginning of the formation of the MPP concept, it was recognized and supported by international organizations, governments, civil society organizations, academics and social activists who advocated access to medicines. Ms. Ellen FM ‘t Hoen, the former head of the Law and Policy Department of MSF’s “Drug has its medicine” project, served as the first executive director of MPP.
MPP licensing model
MPP was originally established to promote and promote the accessibility of new high-priced anti-AIDS drugs in developing countries. MPP itself does not produce and sell generic drugs. It negotiates with the patentee to obtain a patent license, and then invites the generic drug company to apply for a license in the patent pool through the Expression of Interest (EOI). If the pharmaceutical company is willing to apply for an MPP license, it can fill out the EOI online, provide specific information on production capacity, quality-guaranteed drug production records, research and development capabilities, and regulatory compliance. MPP screens qualified generic drugs through information in EOI. The company authorizes the implementation of the license, and the licensed generic drug company produces and sells generic drugs to low- and middle-income countries as agreed in the license agreement.
MPP encourages competition for generic drugs, and prices have fallen sharply, allowing more people to get treatment. MPP’s license agreement usually stipulates whether to pay royalties and rates. From a practical point of view, due to the limited ability of governments and patients in low- and middle-income developing countries, and the small scale of the market, it is not very attractive to many European and American pharmaceutical companies. On the one hand, MPP’s licensing mechanism allows patients in some low- and middle-income countries to obtain cheap new drugs. On the other hand, it allows the original drug companies to exploit these non-profitable markets for new drugs, but they can also obtain license fees, or free of charge. Licensing but winning a good social reputation is a win-win situation.
Currently, MPP has reached licensing agreements with a number of multinational pharmaceutical companies and research and development institutions. The following table is a list of pharmaceutical companies and R&D institutions currently working with MPP.
MPP license features
Voluntary licenses are more common in patent enforcement, and MPP has features that are not common to ordinary voluntary licenses because of its public health-oriented business model:
- A wide geographical range. The existing MPP license covers a total of 131 countries, covering all low-income countries under the World Bank standards and 50%-80% of middle-income countries. In these countries, as many as 90% of AIDS patients and 65% of hepatitis C patients. Moreover, if all the pediatric drug licenses for anti-AIDS drugs in MPP are implemented, it will benefit 99% of AIDS children worldwide.
- The quality of the medicine is guaranteed. The patentee usually requires MPP to sub-license its patents to generic manufacturers that have the ability to pass WHO pre-certification or ICH-approved “strict regulatory agencies” (eg FDA, EMA) standards.
- Encourage generic drug competition. All MPP licenses are not exclusive exclusive licenses, and intended and qualified generic laboratories can apply for MPP licenses.
- Disclosure of patent information. The patentee who licenses the patent implementation license of a drug to the MPP shall disclose the patent information of the drug. In the license agreement signed between the original drug company and the MPP, the patent information of the drug in each country is usually listed.
- Give up data exclusive rights. The patentee authorizes the MPP patent license to waive its exclusive right to data. Moreover, when a generic drug company produces a drug under the MPP license and sells it in a contracted country, it usually has to give up its exclusive rights in these countries.
- Compatible with TRIPS flexibility. All of MPP’s terms of agreement are compatible with the flexibility of the TRIPS Agreement, and MPP’s license does not prohibit generic companies from producing and selling drugs outside the agreed geographic scope, as long as they do not infringe their patents. The MPP license also does not prohibit generic companies from challenging the patents owned by the original pharmaceutical companies or objecting to patent applications, or even prohibiting any government from compulsory licensing of drug patents in the patent pool.
- Transparency. All MPP license information is publicly available, and all license agreements for MPP are available on its website.
In addition to the above, MPP also encourages innovation to a certain extent, which is more prominent in the development of pediatric dosage forms and fixed-dose combination preparations (FDC). MPP will consider the applicant’s readiness for the dosage form required to produce the drug through the information submitted by the generic drug company in the EOI, including FDC and pediatric dosage forms, as the MPP license allows generic drugs to develop FDC and pediatric dosage forms. This is extremely important for AIDS treatment, and effective cocktail treatments usually require a fixed dose combination of 3-4 drugs. In many cases, a single patent for a single drug in a combined preparation is sufficient to prevent generic drugs from developing FDC.
Similar to many technology transfer, the MPP license agreement usually includes a technology transfer clause, and the patentee transfers the know-how related to the patent technology that is licensed to be implemented to the generic drug company. The technical knowledge includes but is not limited to clinical data.
Already eight years since the establishment of the MPP, MPP has contributed greatly to the promotion and promotion of affordable life-saving drugs in low- and middle-income countries and patients. MPP was originally only to promote the accessibility of new anti-AIDS drugs, but in recent years due to the severe situation of global anti-tuberculosis and many countries are facing the challenge of the high price of new hepatitis C drugs, MPP has extended the drug category to treat tuberculosis and hepatitis C. New drug. To date, MPP has signed licensing agreements with nine patentees (original pharmaceutical companies or R&D institutions) to obtain 13 new AIDS drugs, two direct antiviral drugs for hepatitis C, a TB treatment program, and a patent implementation for the AIDS technology platform. license. According to KPMG statistics, as of December 2017, for anti-AIDS drugs and hepatitis C drugs, the sales of generic drugs produced under the MPP license covered 128 countries, and the cumulative savings from 2012 to 2017 were 553 million US dollars. Seventy-seven million patients received these drugs. It is estimated that by 2028, the cost of drugs directly saved through MPP will reach $2.3 billion. The G8 and the UN High Level AIDS Conference rated the MPP as “a promising and innovative approach to promoting access to medicines”.
According to public information, there are four pharmaceutical companies in China that have obtained MPP licenses, mainly producing and selling anti-AIDS drugs. In contrast, Indian pharmaceutical companies have been more active in this regard, including Cipla, Mylan, Aurobindo and many other well-known Indian generic drugs companies have obtained MPP license.
Disputes facing MPP
Despite these achievements, is MPP the perfect model for addressing the accessibility of medicines? No, MPP has also attracted a lot of criticism.
First, the essence of the MPP license is still the voluntary license between the original drug company and the generic drug company. The MPP plays an intermediate role in promoting public health. To a certain extent, it has achieved a single or a few generic drugs. The effect that thin and the original research drug companies can’t achieve. Although MPP did its utmost to negotiate licensing with the patentee and to allow the license to cover as many of the beneficiary countries and patients as possible, the license, the scope of the license, and other additional conditions were ultimately determined by the patentee. Enterprise decision.
The original research firm imposes strict restrictions on the geographic scope in which generic drugs produced under the MPP license can be sold. Large markets such as Brazil and China are usually not included in the geographical scope of licensed sales. For example, information published from the MPP website indicates that three Chinese pharmaceutical companies have obtained MPP licenses for tenofovir disoproxil (TDF) fumarate, according to the licensing agreement, TDF generics produced by Chinese pharmaceutical companies (including Formulations containing TDF can be sold to 112 countries, but China is not included. In September 2017, Gilead and MPP revised the licensing agreement for tenofovir alafenamide (TAF), and the well-known Indian generics factories such as Cipla, Natco and Aurobindo obtained the MPP license from TAF. Compared with the original agreement, the country of license sales has expanded to 116 countries, adding Belarus, Malaysia, the Philippines and Ukraine. However, 36 middle-income countries were excluded from the geographic scope of the license agreement, meaning that it is difficult for some 3.7 million AIDS patients in these 36 middle-income countries to obtain affordable TAF generics. Three pharmaceutical companies in China have obtained the TAF license, but they are also unable to sell in the Chinese market.
Second, the MPP mechanism as a whole has weakened the enthusiasm and legitimacy of many developing countries in applying TRIPS flexibilities such as patent challenges, parallel imports, and compulsory licensing to solve their own public health problems. For example, beneficiary countries can purchase cheap generic drugs without resorting to compulsory licenses, and generic drug companies that receive MPP licenses may not actively challenge patents. However, as mentioned earlier, there are still some countries and a significant number of patients excluded from the benefits of MPP licenses. Moreover, the types of drugs and indications currently listed in MPP are limited, and the current main benefit is still AIDS patients, and the use of TRIPS flexibility is still very important for the accessibility of new drugs such as anti-cancer drugs and other non-communicable diseases. .
Moreover, the original research drug companies are also strategically using the MPP mechanism. In early 2015, Merck and the MPP reached an agreement to license the patent for the new anti-AIDS drug Raltegravir to MPP. The country covered by the license agreement can cover 98% of children, which is the license granted to MPP by Merck. The only product. However, some observers pointed out that this is a “wrong solution to a real problem” and that the license agreement looks more like a public relations because it does not make patients who need these drugs the most. Excluded from the agreement. “If the rights of developing countries to use the flexibility of the TRIPS Agreement can be respected, there is no need to obtain permission from the MPP… Voluntary licensing through mechanisms such as MPP has greatly weakened the negotiating power of these countries and the flexibility of applying TRIPS. Sexual ability.” Some original research companies use MPP to criticize the public from all walks of life in order to ease their patent monopoly.
Third, the operation of MPP also exposes certain problems of drug accessibility from one side, and MPP itself may not be able to solve it. For example, the accessibility of pediatric drugs. MPP currently has three anti-AIDS pediatric drugs licensed from the original drug companies, namely Avacavir from ViiV Healthcare, lopinavir/ritonavir from Abbott and Retegovir from Merck, although these The licensing conditions for pediatric drugs are relatively loose. For example, the original research drug company does not require a license fee, and the geographical scope is large. It can even benefit 99% of the world’s children, but apply for adult drugs from the generic drugs listed in the table below. The comparison of pediatric drugs can be seen that the enthusiasm of generic drugs for the development of pediatric drugs is far less than that for adults. Some insiders pointed out that the real problem facing the accessibility of anti-AIDS drugs is not patents, but a lack of investment returns, so that even if there are no patent barriers, generic drugs are too reluctant to produce.
The future of MPP
MPP creatively uses voluntary licensing and patent pool mechanisms to promote and promote the accessibility of life-saving drugs, benefiting low- and middle-income countries and patients with limited ability to pay. In 2016, the WHO and Lancet Essential Medicines Policy Committee recommended that all patent-protected essential drugs should be included in the scope of the MPP. This proposal is also made because many low- and middle-income countries are facing the problem of accessibility to new anticancer drugs and other new drugs. At the same time, the issue of antibiotic resistance has received increasing attention, and some research reports also suggest that MPP can play an important role in this regard. In May of this year, at the 71st World Health Assembly, MPP announced its strategic plan for the next five years, in addition to continuing to promote the accessibility of existing and new drugs in low- and middle-income countries in the areas of treating AIDS, hepatitis C and tuberculosis. The patented drugs in the WHO Essential Drugs Demonstration Catalogue will also be used as a future work direction to support the needs of patients with other diseases for basic treatment. To this end, the MPP has done a feasibility study for diseases and corresponding therapeutic drugs that burden many low- and middle-income countries.
For example, the WHO Essential Drugs Demonstration Committee recommended dasatinib and nilotinib as second-line treatments for Philadelphia chromosome-positive chronic myelogenous leukemia. The first line of the disease is mainly imatinib, which has expired in most countries. However, a significant number of patients will develop resistance to imatinib. For these patients, dasatinib and nilotinib are better second-line treatment options. In addition, dasatinib can also be used as a first-line treatment for acute lymphoblastic leukemia. Dashatinib and nilotinib have varying degrees of accessibility in low- and middle-income countries. The two drugs expired between 2020 and 2030. There are no generic drugs at present, and some countries have adopted the original drug companies. These two new drugs are only available at the drug-sponsored program or discounted price. MPP analysis believes that although the market for low- and middle-income countries is relatively small for dasatinib and nilotinib, it is not attractive to generic drugs, but with reference to the example of imatinib, some generic drugs Before entering the high-income country market, it was developed and sold in small-scale markets in low- and middle-income countries. The licensing model of MPP helps promote the competition of generic drugs and expand the accessibility of these drugs sustainably.
Take type 2 diabetes as an example. Type 2 diabetes affects approximately 300 million patients in low- and middle-income countries, and the resulting economic impact is quite profound. It is expected to cause about $11 billion in economic losses to low- and middle-income countries in 2030. The first-line treatment regimen has a lower cost of metformin and is acceptable in low- and middle-income countries, but most patients with type 2 diabetes require second-line drugs several years later. In 2017, the WHO Expert Committee reviewed six second-line treatment options. The second-line treatment of SGLT-2 inhibitors as patients with high risk of cardiovascular disease showed relevant clinical benefits and reduced overall mortality, but the committee believes that other trials are needed. confirm. According to the MPP study, if the MPP licensing model is applied to SFLT-2 inhibitors, 1.1 million to 3.3 million diabetic patients may be treated. According to the relevant clinical benefit data of patients with high risk of cardiovascular disease, 31,000 may be avoided. To 126,000 major cardiovascular adverse events occurred.
For the more popular anticancer drugs, WHO set up a special working group to comprehensively evaluate a series of new anticancer drugs to determine whether to include the drug list. Correspondingly, in the feasibility report, MPP analyzed four new lung cancer drugs, erlotinib, afatinib and clizozinib, two new prostate cancer drugs, abiraterone and anzazamine. Three new breast cancer drugs, such as tocilizumab, atropoxuzumab and lapatinib, and lenalidomide for the treatment of multiple myeloma. The accessibility of these drugs in low- and middle-income countries is relatively limited, and the MPP licensing mechanism can play a certain role.
In addition, low- and middle-income countries also have a large demand for biopharmaceuticals, but new drugs are less expensive. Many people think that perhaps MPP can explore how to promote biosimilar drugs (SBP) in these countries through its licensing model. However, the development and production of SBP is very different from that of small molecule generics. The biggest challenge is that similar drug manufacturers need to conduct more extensive studies to prove that similar drugs are quite effective and safe compared to reference preparations; In addition, countries have different requirements for the listing of SBP, and the development of biosimilar drugs requires a large amount of capital investment, which has greatly weakened the role of MPP in the accessibility of biosimilar drugs. However, the technology transfer link in the MPP license may be helpful in overcoming some of the difficulties in the development and production of biosimilar drugs.
The significance of MPP to Chinese pharmaceutical companies
At this stage, compared with Indian pharmaceutical companies, Chinese pharmaceutical companies are not active in applying for MPP licenses. The main reason may be that China’s domestic market is excluded, while other countries that sell licenses have small market size and high development costs. However, as an international mechanism, MPP is of great significance to the future development of Chinese pharmaceutical companies.
In the near term, MPP has set up a good platform for Chinese pharmaceutical companies to improve their R&D production capacity in the international market for testing the generic drug companies, and to provide technology for excellent multinational pharmaceutical companies. The opportunity for cooperation. In the near future, more innovative drugs may be included in the scope of MPP licenses. Biopharmaceuticals may draw on the MPP licensing model to meet the demand for biosimilar drugs in low- and middle-income countries. MPP can become a channel for more Chinese pharmaceutical companies to enter the international market. First, actively participate in international competition. In the longer term, with the continuous improvement of the technological innovation capability of Chinese enterprises, more and more global new drugs developed by Chinese pharmaceutical companies will appear. As a patentee, Chinese pharmaceutical companies can also fully utilize the mature platform of MPP. Seeking overseas cooperation and exploring the international market.