Delays in Restructuring Medicines Control Council & registering medicines such as CAPRISA 008

Meeting report

Prof Peter Eagles, Chairperson of the Medicines Control Council, said that the 24 Members of the Medicines Control Council (MCC) served on a part-time basis and met roughly every six to eight weeks. Clinical knowledge, public health knowledge and scientific subject knowledge guided MCC and the Medicines Act defined the expertise requirements for the Council. The Registrar, Ms Mandisa Hela, who was also a cluster manager on pharmaceutical matters, managed the Secretariat.

MCC had been researching characterization and use of African Traditional Plants for Medicines for 20 to 30 years. Though an Expert Committee on African Traditional Medicine existed in the MCC and was of particularly interest to the MCC, conclusion as to how it should be registered, had not yet been drawn. It was of the MCC’s view that a Council for Traditional Health Practitioners would facilitate progress in this regard.

Ms Mandisa Hela, Registrar of Medicines: Medicines Control Council, said that the MCC had an obligation to protect the public through ensuring efficacy, safety and quality of medicines and had oversight on medicines throughout their lifecycle. It could take years before a registered medicine became a safety concern. Public interest and accountability was a mainstay of any regulatory authority and MCC safeguarded regulation against potential conflict of interest to prevent bias of any sort.

MCC was responsible for licensing of manufacturers, wholesalers and distributors. This enabled control of registered medicines throughout the value chain. The information provided by MCC was tailor-made for the providers, manufacturers, those who prescribed the drugs and the public at large.

An Expert Legal Committee had been included in the MCC structure and a Bio-Therapeutic Committee was in the process of being established - in anticipation of the global move toward Bio-Therapeutic Medicine. The African Traditional Committee had been located outside of the Complementary Medicines Committee to look specifically at African Traditional Indigenous Medicine and to fast-track innovation and development in that particular area of medicine.

Clinical trials involved three phases for registration - sample size, risk and factors, data focus, design and the target population. Phase III involved obtaining additional information about the effectiveness of clinical outcomes and overall risk-benefit ratio evaluation in a demographically diverse sample over a duration of several years. Phase IV of the clinical trial (post-registration) involved monitoring ongoing safety of the drug in the general population, monitoring of marketing/advertising ethics, quality control tests, Good Clinical Practice compliance, as well as data collection on the efficacy, pharmaco-economics, epidemiology and adverse events. MCC also had oversight on new scientific methods of synthesis of the active pharmaceutical ingredient of a registered drug and was responsible for approval of laboratory release thereof, as well as any variations such as new packaging, manufacturing site, and address.

All clinical trials had to have approval by the MCC and local Ethics Committee before commencement. The MCC had the authority to terminate a clinical trial due to safety issues, or violation of Good Clinical Practice. Trials were not granted approval if they were not of benefit to South Africans.

Through pharmaco-vigilance, MCC may enforce that a manufacturer respond to concerns on a product and conduct a focus study in a particular area, in a particular environment, with particular epidemiological patterns. Any time that the public reported a drug anomaly, MCC investigated the matter and recalled drugs when necessary.

For generic drug evaluation, MCC confirmed the chemical equivalence, stability and proportional similarity of different strengths of the generic drug and that the generic drug derived from appropriately designed bio-equivalence protocols.

In 2011, 254 new applications for clinical trials were received of which 154 had been approved, two had been withdrawn, three had been rejected; 93 were pending and two were in phase IV post-registration focus trial. Although there was progress on the backlog, which at the time of the Backlog Project totalled 2840 items, 1500 applications were still under evaluation. MCC aimed to clear the backlog as soon as possible.

Another challenge was that restructuring had not taken place and progress on in-house capacity was slow. MCC had an aging expert pool and young scientists left MCC for higher salaries elsewhere in the industry once they had gained experience. Although time-lines for priority conditions had improved (most of the ARVs had been registered within 12 to 13 months), registration processes continued to take too long. Newer complex technologies such as Bio-therapy and Complementary Medicine would demand additional skills and in-house capacity. During the week, the Minister would be tabling to Cabinet the proposal for MCC Restructuring. MCC would relay the outcome to the Committee.

Communication with the public about important medical information was lacking. The majority of South Africans did not have access to websites and newspapers and many did not understand the language of communication. Patient information leaflets for targeting of patients, provided by the manufacturer, were not widely distributed, nor in language that was understandable to the public, nor in all eleven South African languages. MCC was engaging with the consumer protection agency on how it could enforce that information leaflets were more effective.

Prof Eagles added that the presentation had outlined what Restructuring of the organization sought to obviate: issues of poor communication; lack of human resources; and lack of retention of staff and expertise. Salaries and cost of living affected the expert pool. The current situation was that without a long-term plan for advancement within the MCC, South Africa was not getting the full benefit of its investment in training of experts. Restructuring sought to improve efficiency, human resource and finance management. While reporting to the Minister as an authority, the organization aimed to advance to become a top class company which managed its own finances and which had the autonomy to hire and fire people as or when necessary.

Discussion
The Chairperson said that it would be helpful to call the Ethics Committee to explain the process of compensation to those affected by miscommunication or adverse effects associated with registered drugs on the market.

Mr P Smith (IFP) asked if MCC had internal processes such as Key Performance Indicators (KPIs), targets and timeframes to maximise efficiency and fast track backlogs. He also asked if mechanisms such as restraintive trade agreements or contractual agreements were in place to enhance retention of experts.

Ms E More (DA) asked about MCC’s communication policy.

Ms Hela replied that currently MCC did not have KPIs. Part-time experts who were pressured by MCC due to conflict of interest were likely to resign from MCC as they were also involved in other developments and industries. An attempt to introduce Service Level Agreements was also unsuccessful. MCC aimed to introduce clear timelines for phasing in KPIs with Restructuring to improve efficiency while maintaining the same level of transparency with the Department and when accounting to Parliament on operations and strategies to address challenges. With the new structure, communication within the unit would be easier.

Prof Eagles said that as an organ of state, MCC adhered to section 34 ‘Preservation of Secrecy’ of the Medicines and Related Substances Act, the Promotion of Access to Information Act, the Public Finance Management Act and the Promotion of Administrative Justice Act. The Minister was particularly interested in restructuring the MCC and creating an independent agency, which could make good use of its income, employ experts and operate more efficiently going forward. This process had been on the cards since 1994. The Legal Committee and Minister of Health scrutinized the proceedings of meetings on tape, consented to share minutes of meetings and were as transparent as possible. Under section 34, which dealt with peoples’ intellectual property, MCC could not divulge important information on new chemical entities, which may involve billions of rand. MOUs regarding protection of information and confidentiality were utilised in making decisions in South Africa.

Ms M Dube (ANC) asked if the DoH budget for Restructuring was sufficient.

Ms Hela said that at entry as an independent authority, there would still be a certain percentage that would come from the fiscus and R30 million per annum was generated from fees. MCC was engaging with National Treasury and industry to increase fees so that revenue could increase. Over time, the fiscal amount would reduce to about one third, which is what public entities normally received from government.

Mr M Waters (DA) asked what the staff component and vacancy rate was at MCC.

Ms Hela replied that currently there were 140 staff members in the Secretariat: 70 technical and 70 administrative staff. There were 23 vacancies for technical posts and three temporary employees against those vacant posts. In 2011, MCC appointed 12 technical people and requested an additional 26 technical posts. This capacity was still not adequate and was not close to that of the USA and EU.

Prof Eagles said that the MCC had 200 medical experts in the Expert Committees, compared to the USA and EU, each which had 3000 PhDs providing input on medicine registration in their country. The USA and EU also collaborated weekly through video conferencing. Through restructuring, MCC hoped to improve on relationships with other countries.

Mr M Hoosen (ID) commented that he had never received a patient leaflet regarding the medication he purchased. He added that the problem of communication to the rural people via the internet and newspapers was nothing new, yet MCC did not offer a plan on how the public would be educated effectively. If people were educated on the impact of illegal medications and self-medication, they would report illegal operations and many of the current problems would not exist.

Ms M Dunjwa (ANC) asked if MCC could offer product information in the languages of the people. People in the rural areas were taking prescribed medications without adequate instruction.

Ms T Kenye (ANC) asked if MCC, in its management of dissemination of information, was ethical towards patients who were illiterate.

Ms Hela agreed that the situation was unacceptable and that regulation and legislation did not enforce that patients received adequate product information. Legislation stipulated that patient leaflets should be available at the site of dispensation. MCC was engaging with industry to identify suitable methods of dissemination of information. It was clear that electronically generated information was not worthwhile.

Prof Eagles agreed that MCC communication with the public in the Government Gazette and through the Department of Health was not adequate. MCC had always believed that it should have its own communications office. However, when MCC had to convey urgent information to the public, it resorted to other measures such as official letters to the public. The MCC Legal Committee informed the board on decisions in accordance with the Act and was currently dealing with withdrawal of a painkiller manufactured by Adcock Ingram which caused Q-T prolongation of the heart muscle and which could cause cardiac arrest.

Mr Smith asked to what extent the requirements listed for clinical trials applied to Indigenous Medicines.

Ms Hela replied that once the African Traditional Medicine Practitioners Bill was passed, MCC would play a larger role in regulation of Indigenous Medicines. MCC regulated commercially produced medicines only. Currently, Indigenous Medicines were ingested at the person’s own risk.

Mr D Kganare (COPE) said that he believed that registration of African Traditional Medicine should be listed as a challenge for the MCC.

Ms Hela agreed that African Traditional Medicine should be listed under MCC challenges.

Prof Eagles said that in the past, people had faith in the MCC but more recently, thousands of Complementary Medicines had flooded the informal market and regulation of such medicine was lacking. MCC was interested in supporting the use of all classes of medicines and to ensure that they could continue to be used; that they were safe, efficacious, of good quality and for the good of the public.

Ms M Segale-Diswai (ANC) commented that the issue of registration of Traditional Medicines was critical as people were over-dosing and not educated on the risks and contra-indications. The high rate of public consumption of these medicines would continue, irrespective of whether they were approved by MCC or not.

Ms More asked what MCC’s strategy was to manage Traditional Medicine as it involved a vast amount of medicines and would require a great deal of skilled staff.

Ms Hela replied that the African Traditional Medicine Act had been given the go-ahead and MCC was very serious about regulating Traditional Medicine. African Traditional Medicine was a very complex and new area of medicine, which required capacity and competency. These medicines ranged from bones to blood. The Expert Committee on African Traditional Medicine had formulated guidelines and was peer-reviewing the concept of clinical trials on plant-based products.

Prof Eagles said that Traditional Medicine was close to the heart of the MCC. With the Minister’s permission, MCC had published regulations and guidelines for Complementary Medicine in South Africa, including Traditional Indian, Chinese and Middle Eastern medicine. The closing date for submissions was the 30 November 2011.

Mr Smith asked to what extent the requirements for clinical trials applied to Indigenous Medicines.

Ms Hela said that drugs registered by MCC could come from anywhere in the world. The requirements listed in the presentation were for clinical trials of orthodox medicines.

Ms Segale-Diswai asked how MCC controlled over-the-counter consumption, such as diet tablets, which were easy to access yet unsuitable for many people who were ignorant of side effects and contra-indications.

Ms Hela agreed that this was a problem to control. Although the package size of medications was optimal, people could buy many packages and over-the-counter drugs were easily accessible in many stores. Also, prescription drugs could be purchased from a variety of pharmacists. A solution would be to engage with the Pharmacy Council to control, through electronic records, multiple purchases of prescription drugs. The challenge however was that doing so would contravene patient confidentiality and privacy law.

Ms Dunjwa asked how confident MCC felt about controlling medicines in South Africa when there was sale of illegal medicines and advertisements for ‘safe’ abortion on street corners. She also asked how MCC communicated with law enforcement agencies on these issues.

Ms Hela replied that MCC had MOUs with law enforcement agencies to address matters of unlawful trade. This was an effective two-way process as law enforcement agencies also approached MCC for technical support on their findings. Introduction of a Registry would assist with uncovering trends, making inferences and implementing focus studies. 

Mr Waters asked how many inspectors for quality control site inspections were in the MCC.

Ms Hela replied that there were 24 inspectors and MCC had recently interviewed eight more potential inspectors.

Mr Waters asked how many site inspections took place per annum; what were the minimum criteria for licence withdrawal; and how many licences were revoked.

Mr Kganare asked if inspectors investigated institutions beyond the licensed institutions and how many illegal entities, such as the Chinese drug havens, had been prosecuted.

Ms Hela replied that MCC inspected manufacturer sites every three to five years and more frequently if necessary. MCC had issued notices that they intended to suspend/revoke two licences in 2011 and the matters were still in process.

Ms Segale-Diswai asked how MCC controlled television, radio and illegal advertisements on the streets, which manipulated people into buying unsafe products.

Ms Hela replied that MCC had published regulations on advertisements for public comment. Most of the advertisements on the street were for Complementary Medicine, which MCC did not control. She agreed that advertising restrictions were not adequately enforced and people were vulnerable to them. Spiking of slimming drugs was also a serious concern for MCC. Once Complementary Medicine was regulated, MCC would follow a risk-based approach to control them.

Mr Hoosen invited colleagues to walk the streets of Cape Town to witness all the remedies advertised, none of which had been registered by the MCC. Members would agree that in every city in South Africa, particularly Chinese medications, were all over the country.

Ms More said that she was very concerned about the Chinese connection. They sold virtually anything and had their own markets. She asked if the MCC had intervened.

Ms Hela replied that MCC had 10 law enforcement officers who co-operated with other law enforcement agencies on illegal substances sold on the street. Most of these substances were Complementary Medicines, not Orthodox Medicines. Once Complementary Medicine was regulated, MCC expected that the streets would be cleared of illegal trade. MCC had a MOU with Port Health Services that only sanctioned imports could enter South Africa. However, law enforcement on imports was not adequately covered and there were loopholes in the system. Until a Regulatory Framework for Complementary Medicine existed, challenges would continue.

Mr Hoosen commented that it appeared that there was no control on medicine scams. He asked how MCC controlled the purchase of medications on the internet from outside South Africa.

Ms Hela replied that the internet space was a monster. An MCC law enforcement officer was responsible for scanning advertisement sites that targeted vulnerable people but it was very difficult to control advertisements on the internet. This was a global problem.

Ms Segale-Diswai asked if the nurses in the clinics were sufficiently training for dispensing prescription drugs.

Ms Hela replied that the Nurses Council of South Africa had embarked on an initiative to categorize the competency of nurses and were committed to providing medical support, supervision and oversight of nurses.

Mr Hoosen said that the public perception was that MCC would always have a backlog of clinical trial applications. It was important that MCC had a plan for addressing the challenges and instilled confidence in the public that it could eradicate the backlog.

Mr Waters asked if the Backlog Project was continuing and if not, why not. Looking at the raw numbers, with 200 applications received per year and a current backlog of 1 500, would take an average of 7.5 years to eradicate the backlog. He also asked how far back the backlogs dated.

Ms Hela replied that currently there was a backlog of 1 500 applications at different stages of evaluation. Some dated back to around 2003. The challenge was that some applications had to be updated due to advancements in science and MCC was engaging with these applicants for updates and additional information. A spike in generic applications occurred shortly after MCC published a report on generic legislation.

MCC had identified the units that were lagging behind. The challenge was that regulatory science was not a subject offered at university and it took a year to get new employees up to speed to fast track the backlog. The Backlog Project discontinued in September 2010 and the backlog would be clear by June 2012.

Mr Waters asked why South Africa repeated a clinical trial that previously had been approved in a reputable country. The process delayed access to the drugs for South Africans.

Ms R Mmakosha (ANC) said that she was concerned about South Africa being a dumping ground for overseas medications and pharmaceutical companies making money at the expense of South African lives. She asked if MCC checked the ingredients of tablets that were imported.

Ms Hela replied that drugs that were imported had their dossiers registered by MCC. The extra step done by a licensed laboratory in South Africa was for verification that the drug adhered to the approved dossier.

Prof Eagles said that once mature international authorities such as Canada, EU, USA and Australia approved a drug, MCC expected the information, in its entirety, to be transferred to South Africa. However, with some countries, MOUs had not been established and there were many incidences where foreign countries tried to market their drug via South Africa into the African market. This was the main reason for the generic backlog.

Mr Smith asked what the status of the MCC was with regard to legislation that stated that Members could not serve for longer than 10 years. 

Ms Hela replied that since 2003, Members were eligible to be appointed for five years, which was subject to one renewal.

Ms Dunjwa asked why restructuring of MCC had been delayed until 2011. Part-time experts had been multi-tasking for a number of years and were responsible for delays and backlogs.

Mr G Lekgetho (ANC) asked when the restructuring process would be complete.

Mr Waters said that in 2008, amendments to the Act allowed for restructuring of MCC so that it could become more professional and efficient and staff could work full-time. He expected the MCC to report to the Committee on the progress made since 2008.

Ms Hela replied that restructuring was still the subject of Ministerial discussion. As an official, she found it difficult to talk about it before a report came from Cabinet.

Mr Waters asked if the MCC could brief the Committee on the progress on restructuring since the amendment to the Act in 2008.

Ms Hela replied that due to much changing of hands in the Department of Health since 2008, no progress had been made on restructuring. However, regulatory structures, job description, workload and staff requirement had been analysed.

The Chairperson summarized that the Members’ key concern was that in 2008 they had specifically made amendments to ensure that MCC could make necessary changes to the structure. Irrespective of the political reasons, MCC did not make changes and currently was tabling in Cabinet a new proposal for MCC restructuring. He asked how Members of Parliament could be confident that MCC would in fact make the changes.

Ms Hela said that she was sitting between a rock and a hard place. She would respond to the questions once she knew the outcome of the Cabinet process.

The Chairperson responded that while Members accepted that there was a Cabinet process, a law had been passed and officials did not implement it. Members wanted to know why implementation did not take place and if the same officials would be responsible for implementing a new law.

Ms Hela replied that a policy directive guided every piece of legislation. When there was a policy change, policy makers guided officials.

Mr Smith said that legislation required that in the event of conflict of interest, members should recuse themselves from meetings. The accusation was that the Chair, as non-executive director of Clicks, did not recuse himself when discussions were taking place.

Ms Hela replied that Prof Eagles declared to the MCC that he was a non-executive director of Clicks and indeed recused himself from meetings where there may have been conflict of interest. He resigned from Clicks in June 2009 and was currently a Member of a University team studying plant-based medicines. When MCC discussed issues pertaining to plant-based medicines, he recused himself from those discussions.

MCC had developed a new document to strengthen the management of conflict of interest. It would be accessible on the website for public comment.

Prof Eagles added that the document would be a declaration of interest for public comment on issues of conflict and would be a first for the country.

Mr Smith said that another accusation was that the wife of a Council Member ran a laboratory owned by the MCC. He asked if the accusations were true or false.

Ms Hela replied that the question would be answered outside of the meeting.

Ms M Shinn (DA) asked why MCC was delaying approval of the Centre for the AIDS Program of Research in South Africa (CAPRISA) 008 Tenofovir Anti-retroviral Gel trial. CAPRISA 008 wished to explore the effectiveness of using family planning clinics for distributing the gel where the trial took place. R30 million had been secured for CAPRISA 008 and the application was launched on the 18 November 2010. CAPRISA 004 had been approved by the Minister of Health and was applicable to CAPRISA 008, as the chemistry of the gel, the patient population and the protocol were the same. It took MCC nine weeks to respond to CAPRISA with questions, to which CAPRISA replied within five days. It then took five months for MCC to respond with more questions to CAPRISA and this form of communication was repeated several times. In the US, approval of such a trial would have taken 28 days and in South Africa it was taking one year. A reason for the delay was that qualification requirements for staff on the trial had changed, but there had been no indication for qualification requirements on the first trial (or that there should be new qualification requirements for subsequent trials), nor was there documentation of these new requirements available on the MCC website. With a world-renowned CAPRISA clinical research team and with international funding secure, it was not clear why MCC was stalling on approval of CAPRISA 008.

Ms Dunjwa commented that in their oversight role on the CAPRISA project, Members were taken-aback by the emerging challenges.

Mr Smith asked if 12 to 13 months for registering drugs was a good timeline compared to other countries.

Mr Waters asked if MCC set time-frames for approval of applications and if MCC, rather than the company, was penalised when approval was delayed. The gel approval for protecting women against the HIV virus, as mentioned by Ms Shinn, did not appear to be urgent.

Ms Hela replied that she would investigate why it took five months for MCC to respond to CAPRISA. Applications were submitted in eight-week cycles and the standard time for responding to applicants was 10 to 12 weeks. The Expert Committee did not have a legal mandate to make decisions but rather made recommendations to the MCC which, at Council meetings, had the mandate to sanction resolutions or request re-categorisation of a clinical trial. This may cause delay.

CAPRISA 004 was a Phase II proof of concept study, not a phase III trial. In phase III, MCC had to determine whether the product should be extended to the public. While there was provision within Section 21 of the Act that trial participants who gained access to benefits of a trial drug that was imported would continue to have access to the trial drug, in the CAPRISA trial, this provision had not been enforced. While the reason for the delay in approving CAPRISA 008 would be investigated, Ms Hela emphasized that the trial drug was a new indication and not one that had been registered previously. While Tenofovir was registered, Tenofovir use as a vaginal microbicide gel was a new indication trial drug. MCC was interrogating the evidence as speedily as possible and MCC would respond to the applicant. Recommendations to the last submission by the applicant would be forwarded to the applicant that day, which was within the 10 days after a Council meeting as required in the guidelines for response to an applicant.

Ms Shinn asked for clarification on whether the gel for the CAPRISA 004 trial was the same as the gel for the CAPRISA 008 trial.

Ms Hela replied that it was the same gel.

Ms Shinn then asked what the real reason was for MCC procrastinating on processing the CAPRISA 008 application. The trial involved the same gel; the same women; it would be at a family planning clinic in the same area; and had passed through all possible ethical and legal hurdles.

Ms Hela replied that she had already explained that CAPRISA 008 was an additional indication. CAPRISA 004 was a Proof of Concepts study. For a trial to move from Proof of Concepts study to a trial testing the general population, there were problems that needed addressing. There were fewer headaches when a Proof of Concepts study continued, with the same people who were part of the trial.

The Chairperson interrupted Ms Hela’s reply as the meeting had exceeded its time allowance. Discussion could continue outside the meeting room. He said that the Minister or Head of Department of Health should have been called to the meeting to answer some of the questions. The law would take a year to be passed and it was not clear how MCC would deal with the current challenges.

The meeting was adjourned.